CN1882529A

CN1882529A - Histone deacetylase inhibitors

Info

Publication number: CN1882529A
Application number: CNA2004800345711A
Authority: CN
Inventors: O·莫拉代伊; I·帕奎因; S·莱特; S·弗雷谢特; A·法斯博格; J·M·贝斯特曼; P·泰西尔; T·C·马拉伊斯
Original assignee: Methylgene Inc
Current assignee: Methylgene Inc
Priority date: 2003-09-24
Filing date: 2004-09-24
Publication date: 2006-12-20
Also published as: CN101445469B; CN101445469A

Abstract

The present invention relates to the inhibition of histone deacetylase. The present invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

Description

Histone deacetylase inhibitors

The right of priority that No. the 60/561082nd, No. the 60/532973rd, U.S. Provisional Patent Application that the application requires to submit on September 24th, 2003 U.S. Provisional Patent Application was submitted on December 29th, No. 60/505884 1 and the U.S. Provisional Patent Application of submitting on April 9th, 2004.

Technical field

[0001]

The present invention relates to the inhibition of histone deacetylase.More particularly, the present invention relates to be used for the Compounds and methods for of inhibition of histone deacetylase enzymic activity.

Background technology

[0002]

In eukaryotic cell, nuclear DNA combines formation and is known as chromatinic close composite with histone.These histones constitute a class basic protein of highly being preserved usually in the eucaryon species.The core histones that is known as H2A, H2B, H3 and H4 is in conjunction with forming protein core.DNA is coiled in around this protein core, and wherein the electronegative phosphate groups of the basic aminoacids of histone and DNA interacts.About 146 pairs of DNA base pairs are wrapped in histone nuclear on every side to constitute nucleosome particle, promptly chromatinic repeating structure die body.

[0003]

Csordas, Biochem.J., 286:23-38 (1990) have described the α that histone is carried out the terminal lysine residue of N-, epsilon-amino translate the back acetylize, this is by the catalytic reaction of histone acetyl based transferase (HAT1).The acetylize positive charge of lysine side-chain that neutralized, and be considered to influence chromatin Structure.In fact, Taunton etc., Science, 272:408-411 (1996) described by the highly acetylated transcription factor that makes of histone easier of the chromatin template.People such as Taunton further propose, and have been found that the histone of transcribing enrichment ethanoyl deficiency (underacetylated) in the inactive zone genomic.

[0004]

The histone acetyl baseization is a kind of reversible modification, and the class of enzymes that is known as histone deacetylase (HDACs) can the reaction of catalysis deacetylate.Grozinger etc., Proc.Natl.Acad.Sci.USA, 96:4868-4873 (1999) propose HDACs is divided into two classes, and the first kind is representative with yeast Rpd3-proteinoid, and second class is representative with yeast Hda1-proteinoid.People such as Grozinger point out that also human HDAC1, HDAC2 and HDAC3 protein belong to the member of first kind HDACs, and disclose the novel protein of HDAC4 by name, HDAC5 and HDAC6, and they belong to the member of the second class HDACs.Kao etc., Genes ﹠amp; Dev., 14:55-66 (2000) discloses HDAC7, the newcomer of the second class HDACs.More nearest, Hu etc., J.Bio.Chem.275:15254-13264 (2000) and Van den Wyngaert, FEBS, 478:77-83 (2000) discloses HDAC8, the newcomer of first kind HDACs.

[0005]

Richon etc., Proc.Natl.Acad.Sci.USA, 95:3003-3007 (1998) discloses with trichostatin A (TSA, isolated natural product from streptomyces hygroscopicus) with synthetic compound Vorinostat (SAHA) and has suppressed the HDAC activity.Yoshida and Beppu, Exper.Ccell Res., 177:122-131 (1988) point out that TSA makes the G of rat fibroblast in the cell cycle ₁And G ₂Phase stagnates, thereby involves the HDAC in the Cycle Regulation.In fact, Finnin etc., Nature, 401:188-193 (1999) point out that TSA and SAHA have suppressed the cell growth, bring out terminal differentiation, and prevent to form in the mouse body tumour.Suzuki etc., United States Patent (USP) the 6th, 174, No. the 10138957th, No. 905, EP 0847992, JP 258863/96 and Japanese publication disclose the benzamide derivatives that brings out cytodifferentiation and suppress HDAC.Delorme etc., WO 01/38322 and PCT/IB01/00683 disclose other compound that plays the hdac inhibitor effect.

[0006]

Molecular cloning with the active gene order proteins encoded of HDAC has caused existing one group of discrete HDAC enzyme isoforms.Some isotypes have shown has specific function, for example, shows, HDAC-6 participates in the active adjusting of microtubule.Yet the effect of other each HDAC enzyme is still unclear.

[0007]

These discoveries show that a kind of new way of interfering Cycle Regulation has been represented in the active inhibition of HDAC, and hdac inhibitor has very big treatment potentiality in the treatment of cell proliferation disorders or symptom.Up to now, only know seldom histone deacetylase inhibitors in the prior art.

Summary of the invention

[0008]

Anthranilamide is known hdac inhibitor.The effectiveness that can damage inhibitor in the ortho position and the replacement on the position of amino; Yet, can allow some small-substituents to a certain extent, for example-CH ₃,-F or-OCH ₃We have been found that now, the anthranilamide hdac inhibitor that in the contraposition of amino part, contains much bigger but flat aromatics and heteroaromatic substituting group (for example phenyl, furyl, thienyl and similar group), be not only and allowed, can also obviously improve HDAC and suppress active.

[0009]

Therefore, the invention provides the novel cpd and the method for treatment cell proliferation disorders.The invention provides the new inhibitor of histone deacetylase enzymic activity.

[0010]

In first aspect, the invention provides the compound that can be used as histone deacetylase inhibitors.

[0011]

In second aspect, the invention provides the composition that comprises according to histone deacetylase inhibitors of the present invention or its pharmacologically acceptable salts and pharmaceutically acceptable carrier, vehicle or thinner.

[0012]

In the third aspect, the invention provides a kind of in cell the method for inhibition of histone deacetylase, comprise and will need the cell of inhibition of histone deacetylase to contact with histone deacetylase inhibitors of the present invention.

[0013]

Aforementioned content has only been summarized some aspect of the present invention, and in fact is not restrictive.Below these aspects and others and embodiment will be described more fully.All publications (patent or other) are all this complete quoting for your guidance; Under the situation that has any conflict between these materials and this specification sheets, should be as the criterion with this specification sheets.

Description of drawings

[0014]

Accompanying drawing shown according to histone deacetylase inhibitors of the present invention, in vivo to as chemical examination embodiment 2 hereinafter described in the antitumous effect of human tumour heterogeneity graft.

Fig. 1 has shown the antitumous effect that uses the histone deacetylase inhibitors of compound 6 in hct116 human colon rectum cancer cell.

Fig. 2 has shown the antitumous effect that uses the histone deacetylase inhibitors of compound 29 in the A549 Human Lung Cancer.

Fig. 3 has shown the antitumous effect that uses the histone deacetylase inhibitors of compound 29 in the SW48 human colon rectum cancer.

Fig. 4 has shown the antitumous effect that uses the histone deacetylase inhibitors of compound 67 in the W48 human colon rectum cancer.

Fig. 5 has shown the antitumous effect that uses the histone deacetylase inhibitors of compound 258aa in the A549 Human Lung Cancer.

Fig. 6 has shown the antitumous effect that uses the histone deacetylase inhibitors of compound 43 in the A549 Human Lung Cancer.

Fig. 7 has shown the antitumous effect that uses the histone deacetylase inhibitors of compound 43 in the A431 carcinoma vulvae.

Fig. 8 has shown the antitumous effect that uses the histone deacetylase inhibitors of compound 258aa in the A431 carcinoma vulvae.

Fig. 9 has shown the antitumous effect that uses the histone deacetylase inhibitors of compound 258aa in the hct116 human colon rectum cancer.

Figure 10 has shown the antitumous effect that uses the histone deacetylase inhibitors of compound 29 in the colo205 human colon rectum cancer.

Embodiment

[0015]

The invention provides the Compounds and methods for of inhibition of histone deacetylase enzymic activity.The present invention also provides the composition and the method for treatment cell proliferation disorders and symptom.Patent that this paper quotes and scientific literature have been established the knowledge that those skilled in the art can obtain.Disclosed patent, application and reference that this paper quotes all are incorporated herein on same degree for your guidance, just look like that each document all reaches specially and individually points out and through being hereby incorporated by reference.Under inconsistent situation, be as the criterion with the disclosure.

[0016]

For the purposes of the present invention, use following definition (unless otherwise noted) clearly:

[0017]

Term used herein " histone deacetylase " and " HDAC " are meant from the omega-amino-of the lysine residue of histone N-end and remove any the class of enzymes of ethanoyl.Unless otherwise noted in the context, term " histone " is meant any histone from any thing class, comprises H1, H2A, H2B, H3, H4 and H5.Preferred histone deacetylase comprises I class and II fermentoid.Preferably, histone deacetylase is human HDAC, includes but not limited to HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, HDAC-10 and HDAC-11.At some other preferred embodiment in, histone deacetylase is from protozoon or originated from fungus.

[0018]

Term " histone deacetylase inhibitors " and " inhibitor of histone deacetylase " are used in reference to the compound with structure defined herein, and it can interact with histone deacetylase and suppress its enzymic activity." enzymic activity of inhibition of histone deacetylase " is meant histone deacetylase is removed ethanoyl from histone the ability that reduces.Some preferred embodiment in, it is about 50% that the active reduction of this histone deacetylase is at least, more preferably about at least 75%, more preferably about at least 90%.Other preferred embodiment in, histone deacetylase is active to reduce at least 95%, more preferably at least 99%.

[0019]

Preferably, this inhibition is a specific, and just under the low concentration of the inhibitor concentration more required than the another kind of incoherent biological effect of generation, histone deacetylase inhibitors has reduced the ability of histone deacetylase from histone removal ethanoyl.Preferably, the required inhibitor concentration of histone deacetylation enzyme inhibition activity is hanged down at least 2 times than producing the required concentration of incoherent biological effect, and more preferably low at least 5 times, preferred lower at least 10 times, most preferably low at least 20 times.

[0020]

For simplicity, in entire article, chemical part mainly is defined as and relates to monovalence chemical part (for example alkyl, aryl, or the like).But under the suitable constructional aspect that those skilled in the art know that, these terms also are used to represent corresponding multivalence part.For example, although " alkyl " part typically refers to univalent perssad (CH for example ₃-CH ₂-), but in some cases, the divalence connection portion can be " alkyl ", in this case, those skilled in the art can recognize alkyl be divalent group (for example-CH ₂-CH ₂-), be equivalent to term " alkylidene group ".(similarly, needing divalent moiety and be known as under the situation of " aryl ", those skilled in the art can recognize that term " aryl " is meant corresponding divalent moiety, arylidene.) all atoms all are interpreted as to have and are used to form strong normal valence mumber (that is, carbon 4, nitrogen 3, oxygen 2,

sulphur

2,4 or 6 depends on the oxidation state of sulphur).Sometimes, a part can be defined as, for example, and (A) _a-B-, wherein a is 0 or 1.In this case, when a was 0, this part was B-, and when a was 1, this part was A-B-.

[0021]

For simplicity, " C _n-C _m" heterocyclic radical or " C _n-C _m" heteroaryl is meant heterocyclic radical or the heteroaryl that contains " n " to " m " individual annular atom, wherein " n " and " m " is integer.Therefore, for example, C ₅-C ₆-heterocyclic radical is to contain at least one heteroatomic 5-or 6-unit ring, and comprises pyrrolidyl (C ₅) and piperidyl (C ₆); C ₆-heteroaryl comprises, for example pyridyl and pyrimidyl.

[0022]

Term " alkyl " is meant straight chain, side chain or cyclic alkyl, alkenyl or alkynyl, and they separately as defined herein." C ₀" alkyl is used in reference to covalent linkage.Therefore, " C ₀-C ₃-alkyl " comprise covalent linkage, methyl, ethyl, vinyl, ethynyl, propyl group, propenyl, proyl and cyclopropyl.

[0023]

Term used herein " alkyl " is meant and contains 1 to 12 carbon atom, preferred 1-8 carbon atom, the more preferably straight chain of 1-6 carbon atom and the aliphatic group of side chain that it is chosen wantonly by one, two or three substituting groups replacements.Preferred alkyl includes but not limited to methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, sec-butyl, the tertiary butyl, amyl group and hexyl." C ₀" alkyl is (as at " C ₀-C ₃-alkyl " in like that) be covalent linkage (similar " C ₀" alkyl).

[0024]

Term used herein " alkenyl " is meant and contains one or more carbon-to-carbon double bonds, and contain 2 to 12 carbon atoms, preferred 2-8 carbon atom, the more preferably unsaturated straight or branched aliphatic group of 2-6 carbon atom, it is chosen wantonly by one, two or three substituting groups replacements.Preferred alkenyl includes but not limited to vinyl, propenyl, butenyl, pentenyl and hexenyl.

[0025]

Term used herein " alkynyl " is meant and contains one or more carbon-to-carbon triple bonds, and contain 2 to 12 carbon atoms, preferred 2-8 carbon atom, the more preferably unsaturated straight or branched aliphatic group of 2-6 carbon atom, it is chosen wantonly by one, two or three substituting groups replacements.Preferred alkynyl includes but not limited to ethynyl, proyl, butynyl, pentynyl and hexin base.

[0026]

" alkylidene group ", " alkenylene " or " alkynylene " are between two other chemical groups and are used to connect alkyl as defined above, alkenyl or the alkynyl of these two groups.Preferred alkylidene group includes but not limited to methylene radical, ethylidene, propylidene and butylidene.Preferred alkenylene includes but not limited to vinylidene, propenylidene and crotonylidene.Preferred alkynylene includes but not limited to ethynylene, inferior proyl and butynelene.

[0027]

Term used herein " cycloalkyl " comprises and contains 3 to 12 carbon, preferred 3 to 8 carbon, the more preferably undersaturated cyclic hydrocarbon group of saturated and part of 3 to 6 carbon that wherein cycloalkyl also can be chosen wantonly and be substituted.Preferred cycloalkyl includes but not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, suberyl and ring octyl group.

[0028]

Term " assorted alkyl " is meant that the one or more carbon atoms in the chain are selected from the alkyl as defined above of the heteroatoms replacement of O, S and N.

[0029]

" aryl " group is the C that contains one to three aromatic ring ₆-C ₁₄The aromatics part, its optional being substituted.This aryl is preferably C ₆-C ₁₀Aryl.Preferred aryl groups includes but not limited to phenyl, naphthyl, anthryl and fluorenyl." aralkyl " or " arylalkyl " group comprises covalently bound aryl to alkyl, and any all can be chosen wantonly independently and be substituted or be not substituted.This aralkyl is preferably (C ₁-C ₆) alkyl (C ₆-C ₁₀) aryl, include but not limited to benzyl, styroyl and menaphthyl.

[0030]

" heterocycle " group (or " heterocyclic radical ") for contain about 3 non-aromatics lists to the optional replacement of about 14 atoms-, two-or tricyclic structure, wherein one or more atoms are selected from N, O and S.Two rings of one of bicyclic heterocycle ring or tricyclic heterocyclic can be aromatics, as in indane and 9, in the 10-dihydroanthracene like that.Heterocyclic radical is chosen wantonly on carbon and is replaced by oxygen or by one of above-listed substituting group.Heterocyclic radical also can be replaced by alkyl, aryl, aralkyl, alkyl-carbonyl, alkyl sulphonyl, aryl carbonyl, aryl sulfonyl, alkoxy carbonyl, aromatic alkoxy carbonyl on nitrogen independently, or is replaced by oxygen or low alkyl group on sulphur.Preferred heterocyclic radical includes but not limited to epoxy group(ing), aziridinyl, tetrahydrofuran base, pyrrolidyl, piperidyl, piperazinyl, thiazolidyl, oxazolidinyl, oxazole ketone group and morpholino.Some preferred embodiment in, heterocyclic radical is fused on aryl, heteroaryl or the cycloalkyl.The example of this type of annelated heterocycles includes but not limited to tetrahydroquinoline and Dihydrobenzofuranes.Especially getting rid of extraneous at this term is O or S atom and another O or the adjacent compound of S atom of those Cheng Huan.

[0031]

In some preferred implementation, heterocyclic radical is a heteroaryl.Term used herein " heteroaryl " is meant the group of following optional replacement---it contains 5 to 14 annular atomses, preferred 5,6,9 or 10 annular atomses; In annular array (array), contain 6,10 or 14 pi electronics; And, also contain the heteroatoms of one or more N of being selected from, O and S except carbon atom.For example, heteroaryl can be pyrimidyl, pyridyl, benzimidazolyl-, thienyl, benzothiazolyl, benzofuryl and indolinyl.Preferred heteroaryl groups includes but not limited to thienyl, benzothienyl, furyl, benzofuryl, dibenzofuran base, pyrryl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, indyl, quinolyl, isoquinolyl, quinoxalinyl, tetrazyl, oxazolyl, thiazolyl, with isoxazolyl.

[0032]

" heteroaralkyl " or " heteroarylalkyl " group comprises the heteroaryl covalently bound with alkyl, and any all can randomly be substituted or not be substituted independently.Preferred assorted alkyl comprises C ₁-C ₆Alkyl and the heteroaryl that contains 5,6,9 or 10 annular atomses.Especially getting rid of at the extraneous compound of this term is to contain the adjacent one-tenth ring O and/or the compound of S atom.The example of preferred heteroaralkyl comprises pyridylmethyl, pyridyl ethyl, pyrryl methyl, pyrryl ethyl, imidazolyl methyl, imidazolyl ethyl, thiazolyl methyl and thiazolyl ethyl.

[0033]

" arylidene ", " inferior heteroaryl " or " inferior heterocyclic radical " group are between two other chemical groups and are used to connect the aryl as preceding definition, heteroaryl or the heterocyclic radical of these two groups.

[0034]

Preferred heterocyclic radical and heteroaryl include but not limited to acridyl, the azocine base, benzimidazolyl-, benzofuryl, benzothienyl (benzothiofuranyl), benzothienyl (benzothiophenyl) benzoxazolyl, benzothiazolyl, the benzotriazole base, the benzo tetrazyl, the benzoisoxazole base, the benzisothiazole base, the benzimidazoline base, carbazyl, the 4aH-carbazyl, carbolinyl, chromanyl, benzopyranyl, the cinnolines base, decahydroquinolyl, 2H, 6H-1,5,2-dithiazine base, dihydrofuran also [2,3-b] tetrahydrofuran (THF), furyl, the furazan base, imidazolidyl, imidazolinyl, imidazolyl, the 1H-indazolyl, pseudoindolyl (indolenyl), indolinyl, the indolizine base, indyl, the 3H-indyl, isobenzofuran-base, the isochroman base, iso indazolyl, isoindolinyl, isoindolyl, isoquinolyl, isothiazolyl isoxazolyl, methylenedioxyphenyl, morpholinyl, 1, the 5-phthalazinyl, octahydro isoquinolyl oxadiazole base, 1,2,3-oxadiazole base, 1,2,4-oxadiazole base, 1,2,5-oxadiazole base, 1,3,4-oxadiazole base, oxazolidinyl oxazolyl, oxazolidinyl, pyrimidyl, phenanthridinyl, the phenanthroline base, phenazinyl, phenothiazinyl, fen oxathiin base (phenoxathiinyl) phenoxazinyl, 2, the 3-phthalazinyl, piperazinyl, piperidyl, piperidone base, the 4-piperidone base, piperonyl, pteridyl, purine radicals, pyranyl, pyrazinyl, pyrazolidyl, pyrazolinyl, pyrazolyl, pyridazinyl, Bi Ding Bing oxazole, pyridine-imidazole, the pyrido thiazole, pyridyl (pyridinyl), pyridyl (pyridyl), pyrimidyl, pyrrolidyl, pyrrolinyl, the 2H-pyrryl, pyrryl, quinazolyl, quinolyl, the 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydric quinoline group, tetrazyl, 6H-1,2,5-thiadiazine base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, thianthrenyl, thiazolyl, thienyl, the thieno-thiazolyl, thiophene Bing oxazolyl, the Thienoimidazole base, thiophenyl, triazinyl, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, 1,2, the 5-triazolyl, 1,3, the 4-triazolyl, and xanthenyl.

[0035]

In this article, when a part (for example, cycloalkyl, alkyl, aryl, heteroaryl, heterocyclic radical, urea, or the like) when being described as " optional replacement ", this is meant that this group is optional and has one to four, preferred one to three, and more preferably one or two non-hydrogen substituting group.Suitable substituting group include but not limited to halogen, hydroxyl, oxo (for example, Cheng Huan-CH-replaced by oxygen be-C (O)-), nitro, halo alkyl, alkyl, aryl, aralkyl, alkoxyl group, aryloxy, amino, amido, alkyl-carbamoyl, aryl-amino-carbonyl, aminoalkyl group, acyl group, carboxyl, hydroxyalkyl, alkanesulfonyl, aryl sulfonyl, alkanesulfonamide base, aryl sulphur amido, aralkyl sulfahydantoin, alkyl-carbonyl, acyloxy, cyano group and urea groups.The preferred substituted that itself is further replaced (unless otherwise noted) clearly is:

(a) halogen, cyano group, oxo, carboxyl, formyl radical, nitro, amino, amidino groups, guanidine radicals,

(b) C ₁-C ₅Alkyl or alkenyl or aralkyl imino-, formamyl, azido-, amide group, sulfydryl, hydroxyl, hydroxyalkyl, alkylaryl, arylalkyl, C ₁-C ₈Alkyl, C ₁-C ₈Alkenyl, C ₁-C ₈Alkoxyl group, C ₁-C ₈Alkoxy carbonyl, aryloxycarbonyl, C ₂-C ₈Acyl group, C ₂-C ₈Amido, C ₁-C ₈Alkyl sulfenyl, arylalkyl sulfenyl, arylthio, C ₁-C ₈Alkyl sulfinyl, arylalkyl sulfinyl, aryl sulfinyl, C ₁-C ₈Alkyl sulphonyl, aryl alkylsulfonyl, aryl sulfonyl, C ₀-C ₆N-alkyl-carbamoyl, C ₂-C ₁₅N, N-dialkyl amido formyl radical, C ₃-C ₇Cycloalkyl, aroyl, aryloxy, aryl alkyl ethers, aryl, be fused to aryl, C on cycloalkyl or heterocycle or other aryl rings ₃-C ₇Heterocyclic radical, C ₅-C ₁₅Heteroaryl or be fused to or spiral shell-be fused to any these rings on cycloalkyl, heterocyclic radical or the aryl, wherein above-mentioned every kind of group further optional again by one above in (a) listed part replace; And

(c)-(CH ₂) _s-NR ³⁰R ³¹, wherein s be 0 (in the case, nitrogen is bonded directly on the substituted part) to 6, and R ³⁰And R ³¹Be hydrogen, cyano group, oxo, amide group, amidino groups, C independently of one another ₁-C ₈Hydroxyalkyl, C ₁-C ₃Alkylaryl, aryl-C ₁-C ₃Alkyl, C ₁-C ₈Alkyl, C ₁-C ₈Alkenyl, C ₁-C ₈Alkoxyl group, C ₁-C ₈Alkoxy carbonyl, aryloxycarbonyl, aryl-C ₁-C ₃Alkoxy carbonyl, C ₂-C ₈Acyl group, C ₁-C ₈Alkyl sulphonyl, aryl alkylsulfonyl, aryl sulfonyl, aroyl, aryl, cycloalkyl, heterocyclic radical or heteroaryl, wherein above-mentioned each group further optional again by one above in (a) listed part replace; Or

R ³⁰And R ³¹Follow the N that links to each other with them to form heterocyclic radical or heteroaryl, they are chosen wantonly by 1 to 3 separately from the above substituting group replacement of (a).

[0036]

In addition, the substituting group on circular part (that is, cycloalkyl, heterocyclic radical, aryl, heteroaryl) comprises and is fused on this loop section-or 5-6 unit monocycle and 9-14 unit dicyclo part of three-ring condensed ring system two to form.For example, the optional phenyl that replaces includes but not limited to following:

[0037]

" halo alkyl " is one of them hydrocarbyl portion that has been replaced by one or more halogens to all hydrogen.

[0038]

Term used herein " halogen " or " halo " are meant chlorine, bromine, fluorine or iodine.Term used herein " acyl group " is meant alkyl-carbonyl or aryl carbonyl substituting group.Term " amide group " is meant that the amide group that is connected on the nitrogen-atoms (that is, R-CO-NH-).Term " formamyl " is meant amide group (that is NH, that is connected on the carbonylic carbon atom ₂-CO-).The substituent nitrogen-atoms of amido or formamyl further is substituted.Term " sulfonamido " is meant the sulfinyl substituting group that connects by sulphur or nitrogen-atoms.Term " amino " is to comprise NH ₂, alkylamino, arylamino and ring be amino.Term used herein " urea groups " is meant and replaces or unsubstituted urea part.

[0039]

Term used herein " group (radical) " is meant the chemical part that contains one or more unpaired electrons.

[0040]

Substituted part is the part that wherein one or more hydrogen have been replaced by another chemical substituting group independently.As nonrestrictive example, substituted-phenyl comprises 2-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2-fluoro-3-propyl group phenyl.As another nonrestrictive example, replace the N-octyl group and comprise 2,4-dimethyl-5-ethyl-octyl group and 3-cyclopentyl-octyl group.Be included in and replace formed carbonyl (methylene radical (CH CO-) by oxygen in this definition ₂-).

[0041]

Aforesaid " replace " partly (for example unsubstituted ring alkyl, substituted heteroaryl not, or the like) is meant and do not contain any optional substituent part as defined above, all it used the above definition of this part in others.Therefore, for example, when " aryl " comprises phenyl and during the phenyl that replaced by halogen, " unsubstituting aromatic yl " do not comprise the phenyl that is replaced by halogen.

[0042]

In whole specification sheets, one or more chemical substituent preferred implementations have been determined.The further preferably combination of preferred implementation.For example, paragraph [0055] has been described Cy in the compound of formula (1) ²Preferred implementation, paragraph [0071] has been described the R of the compound of formula (1) ²To R ⁴Preferred implementation.Therefore, also comprise Cy in the scope of the present invention ²As described in the paragraph [0055] and Ay ²And R ¹To R ⁴The compound of the formula (1) as described in the paragraph [0071] time.

[0043]

Compounds more of the present invention can have chiral centre and/or rotamerism center (E-and Z-isomer), and it being understood that and the present invention includes all these optics, diastereomer and geometrical isomer.The present invention also comprises all tautomeric forms of compound disclosed herein.

[0044]

Compound of the present invention can be used with the form of hydrolyzable acid amides in hydrolyzable ester in the body or the body.The interior hydrolyzable ester of body that contains the compound of the present invention of carboxyl or hydroxyl is that for example, hydrolysis is to produce the acceptable ester of pharmacy of parent acid or alcohol in human body or animal body.Comprise C for the acceptable ester of the suitable pharmacy of carboxyl _1-6-alkoxy methyl ester (for example, methoxymethyl), C _1-6-alkanoyloxymethyl ester (for example, oxy acid methyl neopentyl), phthalidyl ester, C _3-8-cyclo alkoxy carbonyl oxygen base C _1-6-alkyl ester (for example, 1-cyclohexyl-carbonyl oxygen base ethyl); 1,3-dioxole-2-ketone group methyl ester (1,3-dioxolen-2-onlymethyl esters) (for example, 5-methyl isophthalic acid, 3-dioxole-2-ketone group methyl); And C _1-6-alkoxy-carbonyl oxy ethyl ester (for example, 1-methoxycarbonyl oxygen base ethyl), and can form on any carboxyl in the compound of this invention.

[0045]

Contain that hydrolyzable ester comprises for example inorganic ester and the a-acyloxy alkyl oxide of phosphoric acid ester in the body of compound of the present invention of hydroxyl, and because the rupture related compound of generation parent hydroxy of hydrolysis in the body of ester.The example of alpha-acyloxy alkyl oxide comprises acetoxyl group methoxyl group and 2,2-dimethyl propylene acyloxy-methoxyl group.The selection that forms group for hydrolyzable ester in the body of hydroxyl comprises alkyloyl, benzoyl, phenyl acetyl and substituted benzoyl and phenyl acetyl, alkoxy carbonyl (to produce alkyl carbonate), dialkyl amido formyl radical and N-(N; N-dialkyl amido ethyl)-and N-alkyl-carbamoyl (to produce carbamate), N, N-dialkyl amido ethanoyl and carboxyl ethanoyl.Substituent example on the benzoyl comprises from theheterocyclic nitrogen atom and is connected to the 3-of benzoyl basic ring or morpholino and the piperazinyl on the 4-position via methylene radical.For the meaning that the hydrolyzable acid amides is suitable in the body of the compound of the present invention that contains carboxyl be, for example, N-C _1-6-alkyl or N, N-two-C _1-6-alkylamide, for example N-methyl, N-ethyl, N-propyl group, N, N-dimethyl, N-ethyl-N-methyl or N, N-diethylamide.

Compound

[0046]

In first aspect, the present invention includes histone deacetylase inhibitors or its pharmacologically acceptable salts of formula (1):

Wherein

Ar ²Be saturated or single-or poly--unsaturation C ₅-C ₁₄-single-or condense poly--cyclic hydrocarbon radical, and each ring is chosen wantonly and is contained one, two, three or four one-tenth ring hetero atom, and each ring is optional by one or more C that are selected from ₁-C ₇-alkyl, hydroxyl, C ₁-C ₇-alkoxyl group, halogen and amino group replace, and condition is one and becomes ring O or S not to become ring O or S adjacent with another;

R ⁵And R ⁶Be independently selected from hydrogen, C ₁-C ₇-alkyl, aryl and aralkyl;

R ², R ³And R ⁴Be independently selected from hydrogen, halogen ,-NH ₂, nitro, hydroxyl, aryl, heterocyclic radical, C ₃-C ₈-cycloalkyl, heteroaryl, C ₁-C ₇-alkyl, haloalkyl, C ₁-C ₇-thiazolinyl, C ₁-C ₇-alkynyl, C ₁-C ₇-acyl group, C ₁-C ₇-alkyl-aryloxy, C ₁-C ₇-alkyl-sulfur alkyl aryl, C ₁-C ₇-alkyl-aryl sulfinyl, C ₁-C ₇-alkyl-aryl sulfonyl, C ₁-C ₇-alkyl-n-aryl sulfonyl, C ₁-C ₇-alkyl-arylamines, C ₁-C ₇-alkynyl-C (O)-amine, C ₁-C ₇-thiazolinyl-C (O)-amine, C ₁-C ₇-alkynyl-R ⁹, C ₁-C ₇-alkenyl-R ⁹, R wherein ⁹Be hydrogen, hydroxyl, amino, C ₁-C ₇-alkyl or C ₁-C ₇-alkoxyl group;

Q is 0 or 1;

R ¹Be single-, two-or three cyclophane base or heteroaryls, their optional separately being substituted;

Ф is-NH ₂Or-OH, and

Y is any acceptable chemical part of pharmacy that contains 1 to 50 atom; Condition is

Work as R ¹When being the TMSIM N imidazole base, R ²-R ⁴Be H, q is 0, Ar ²Be pyridine, Y is not Cl; And

Work as R ¹When being p-aminophenyl, R ²-R ⁴Be H, q is 0, and Ar ²Be phenyl, Y is not H.

[0047]

The atom that comprises the Y part is preferably the atom that those are found in medicine, include but not limited to H, C, N, O, S, F, Cl, Br, I and P.A large amount of exemplary of Y see paragraph [0050]-[0088], [0098]-[0110] and [0115]-[0207].The Y of compound of the present invention part also is found in following publication (be disclosed molecule itself or its a part of): WO03/024448, US 6,174,905, JP 11-269146 (1999), JP 11-302173 (1999), JP 2001131130, EP 0847992, JP 10152462, JP 2002332267, JP 11302173 and JP 2003137866.For example, in these publications, at structure Y-Ar ²-(CH=CH) _aDetermine many different Y parts, wherein Ar in the molecule of-C (O)-NH-Z easily ²As definition herein, a is 0 or 1, and Z is-OH or aryl, and such as in the publication suggestion, Ar ²,-CH=CH-and aryl moiety can be chosen wantonly and be substituted.

[0048]

In preferred implementation according to the compound of paragraph [0046], R ¹It is the aryl that is selected from phenyl, naphthyl, anthryl and fluorenyl.Another preferred embodiment in, R ¹Be to be selected from the heteroaryl described in the paragraph [0034].Other preferred R ¹Part comprises azoles base (azolyls) (for example, thiazolyl, oxazolyl, oxadiazole base, thiadiazolyl group or the like), pyridyl (pyridyl) and pyridyl (pyridinyl).R ¹More preferably furyl or thienyl.

[0049]

In the preferred implementation of all compounds of the present invention, R ², R ³And R ⁴Be hydrogen.Equally preferably Ф is-NH ₂Or-compound of OH.

[0050]

In the preferred implementation of the compound of paragraph [0046], [0048] and [0049], Y is Cy ²-X ¹-, wherein,

Cy ²Be hydrogen, cycloalkyl, aryl, heteroaryl or heterocyclic radical, their optional separately being substituted, and optional separately being fused on one or two aryl or the heteroaryl ring, or be fused on one or two saturated or the undersaturated cycloalkyl of part or heterocyclic ring, and wherein any aforementioned ring is optional is substituted; And

X ¹Be selected from covalent linkage, M ¹-L ²-M ¹, and L ²-M ²-L ², wherein

L ²Be independently selected from chemical bond, C in each case ₀-C ₄-alkyl, C ₀-C ₄-alkyl-(NH)-C ₀-C ₄-alkyl, C ₀-C ₄-alkyl-(S)-C ₀-C ₄-alkyl and C ₀-C ₄-alkyl-(O)-C ₀-C ₄-alkyl, condition are to work as X ¹Be M ¹-L ²-M ¹The time, L ²It or not chemical bond;

M ¹Be independently selected from each case-O-,-N (R ⁷)-,-S-,-S (O)-,-S (O) ₂-,-S (O) ₂N (R ⁷)-,-N (R ⁷)-S (O) ₂-,-C (O)-,-C (O)-NH-,-NH-C (O)-,-NH-C (O)-O-and-O-C (O)-NH-,-NH-C (O)-NH-,

R ⁷Be selected from hydrogen, C ₁-C ₆-alkyl, aryl, aralkyl, acyl group, C ₀-C ₆-alkyl-heterocyclic radical and C ₀-C ₆-alkyl-heteroaryl, wherein the optional quilt-OH of hydrocarbyl portion ,-NH ₂,-N (H) CH ₃,-N (CH ₃) ₂, or halogen replace; And

M ²Be selected from M ¹, inferior heteroaryl and inferior heterocyclic radical, any optional being substituted in these rings.

[0051]

According to paragraph [0050] some preferred embodiment in, Cy ²Optional substituting group be selected from C ₁-C ₇-alkyl, C ₁-C ₇-alkoxyl group, halogen, two-C ₁-C ₇-alkylamino-C ₁-C ₇-alkoxyl group and heteroaryl.

[0052]

According to paragraph [0050] some preferred embodiment in, X ¹Be selected from-N (Z)-C ₀-C ₇-alkyl-,-O-C ₀-C ₇-alkyl-,-C (H)=CH-C ₀-C ₇-alkyl-,-S-C ₀-C ₇-alkyl-or-C ₁-C ₇-alkyl-, wherein Z be-H or optional quilt-OH ,-NH ₂, or halogen replace-C ₁-C ₇-alkyl-.

[0053]

In some embodiments according to the compound of paragraph [0050], X ¹It is chemical bond.In some embodiments, X ¹Be L ²-M ²-L ², and M ²Be selected from-NH-,-N (CH ₃)-,-S-,-C (O)-N (H)-and-O-C (O)-N (H)-.In some embodiments, X ¹Be L ²-M ²-L ², L wherein ²Under at least a situation, be chemical bond.In other embodiments, X ¹Be L ²-M ²-L ², L wherein ²Under at least a situation, be alkylidene group, preferred methylene radical.In another embodiment, X ¹Be L ²-M ²-L ², L wherein ²Under at least a situation, be alkenylene.In some embodiments, X ¹Be M ¹-L ²-M ¹, and M ¹Be selected from-NH-,-N (CH ₃)-,-S-and-C (O)-N (H)-.Preferred X ¹Be selected from methylene radical, amino methyl and sulphomethyl.

[0054]

In some embodiments according to the compound of paragraph [0050], Cy ²Be aryl or heteroaryl, for example, phenyl, pyridyl, imidazolyl or quinolyl, their optional separately being substituted.In some embodiments, Cy ²Be heterocyclic radical, for example

Their optional separately being substituted, and optional being fused on one or more aromatic rings.In some embodiments, Cy ²Has one to three substituting group that is independently selected from alkyl, alkoxyl group, amino, nitro, halogen, haloalkyl and halogenated alkoxy.The example of preferred substituted comprise methyl, methoxyl group, fluorine, trifluoromethyl, trifluoromethoxy, nitro, amino, aminomethyl, and methylol.

[0055]

In some preferred implementations according to the compound of paragraph [0050], Cy ²Be phenyl, pyrimidyl, benzimidazolyl-or benzothiazolyl, they are optional separately by one to three CH ₃O-, dimethylamino-oxyethyl group, chlorine, fluorine and pyridyl replace.In preferred embodiment, Cy ²By one to three CH ₃The phenyl that O-replaces.

[0056]

In some embodiments according to paragraph [0046], Y be (V '-L ⁴) _t-V-L ³-, wherein

L ³Be direct key ,-C ₁-C ₆-alkyl ,-(C ₁-C ₃-alkyl) _M1-X '-(C ₁-C ₃-alkyl) _M2,-NH-(C ₀-C ₃-alkyl), (C ₁-C ₃-alkyl)-NH-or-NH-(C ₁-C ₃-alkyl)-NH-;

M1 and m2 are 0 or 1 independently;

X ' is-N (R ²¹)-,-C (O) N (R ²¹)-, N (R ²¹) C (O)-,-O-or-S-;

R ²¹Be-H, V "-(C ₁-C ₆-alkyl) _a

L ⁴Be (C ₁-C ₆-alkyl) _a-M-(C ₁-C ₆-alkyl) _b

A and b are 0 or 1 independently;

M is-NH-,-NHC (O)-,-C (O) NH-,-C (O)-,-SO ₂-,-NHSO ₂-or-SO ₂NH-;

V, V ' and V " be independently selected from cycloalkyl, heterocyclic radical, aryl and heteroaryl;

T is 0 or 1.

[0057]

In some embodiments according to paragraph [0056], Y is V-L ³, L wherein ³Be-NH-CH-or-CH-NH-;

V chooses wantonly to be independently selected from halogen, hydroxyl, C by 1 to 3 ₁-C ₆-alkyl, C ₁-C ₆-alkyl-oxygen base or-phenyl that the part of sulfenyl (particularly methoxyl group or methylthio group) replaces, wherein each hydrocarbyl portion is optional is replaced by one or more parts that are independently selected from halogen, nitro, nitroso-group, formyl radical, ethanoyl, amino, sulfonamido and cyano group.

[0058]

In some preferred implementations according to the compound of paragraph [0056], V is the optional loop section that replaces, and is selected from:

[0059]

In another preferred implementation according to the compound of paragraph [0046], Y is selected from:

[0060]

In other embodiment according to the compound of paragraph [0046],

X ¹Be selected from-CH ₂-,-NH-CH ₂-and-S-CH ₂-; And

Cy ²Be to choose wantonly to be selected from CH by one to three ₃-, CH ₃Monocycle or condensed bicyclic aryl or heteroaryl that the substituting group of O-replaces, optional by one to three CH ₃The phenyl that O-replaces, morphylinyl, morphylinyl-C ₁-C ₃-alkoxyl group, cyano group and CH ₃C (O) NH-.

[0061]

In other embodiment according to the compound of paragraph [0046],

X ¹Be selected from-OCH ₂,-CH ₂O-,-CH ₂-NH ₂-and-CH ₂S-; And

[0062]

In a embodiment according to paragraph [0060], Cy ²Be phenyl, pyridyl, pyrimidyl, benzimidazolyl-, benzothiazolyl, thienyl, tetrahydroquinozolinyl or 1,3-dihydroquinazoline-2, the 4-diketone, optional separately by one to three CH ₃O-replaces.More preferably, Cy ²By one to three CH ₃The phenyl that O-replaces.

[0063]

In another embodiment according to the compound of paragraph [0046],

Cy ²Be cycloalkyl, aryl, heteroaryl or heterocyclic radical, their optional separately being substituted, and optional separately being fused on one or more aryl or the heteroaryl ring, or be fused on one or more saturated or undersaturated cycloalkyl of part or the heterocycles, each ring is optional to be substituted, and condition is to work as Cy ²Be the ring in contain-C (O)-,-C (S)-,-S (O)-or-S (O) ₂-circular part the time, Cy ²The group that can not comprised aryl or heteroaryl ring again replaces; And

X ¹Be selected from chemical bond, L ³, W ¹-L ³, L ³-W ¹, W ¹-L ³-W ¹, and L ³-W ¹-L ³, wherein

W ¹All be S, O or N (R in each case ⁹), R wherein ⁹Be selected from hydrogen, alkyl, aryl or aralkyl; And

L ³Be C ₁-C ₄Alkylidene group, C ₂-C ₄Alkenylene or C ₂-C ₄Alkynylene.

[0064]

Preferably, in compound according to paragraph [0063], X ²Be selected from L ³, W ¹-L ³, L ³-W ¹, W ¹-L ³-W ¹, and L ³-W ¹-L ³

[0065]

In some embodiments according to the compound of paragraph [0063], X ¹It is chemical bond.In other embodiments, X ¹It is non-cyclic hydrocarbon group.In some such embodiments, X ¹Be alkylidene group, preferred methylene radical or ethylidene.In other such embodiment, X ¹It is alkenylene.In another such embodiment, carbon quilt-NH-in the hydrocarbyl chain or-S-replaces quilt-O-replacement in other.Some preferred embodiment in, X ¹Be W ¹-L ³-W ¹And W ¹Be-NH-or-N (CH ₃)-.

[0066]

In some embodiments according to the compound of paragraph [0063], Cy ²Be cycloalkyl, preferred cyclohexyl.In other embodiments, Cy ²Be aryl or heteroaryl, for example phenyl, pyridyl, pyrimidyl, imidazolyl, thiazolyl, oxadiazole base, quinolyl or fluorenyl, their optional separately being substituted and optional being fused on one or more aryl rings.In some embodiments, Cy ²Circular part be fused on the phenyl ring.In some embodiments, Cy ²Has one to three substituting group that is independently selected from alkyl, alkoxyl group, aryl, aralkyl, amino, halogen, haloalkyl and hydroxyalkyl.The example of preferred substituted comprise methyl, methoxyl group, fluorine, trifluoromethyl, amino, nitro, aminomethyl, methylol and phenyl.Some other preferred substituted have formula-K ¹-N (H) (R ¹⁰), wherein

K ¹Be chemical bond or C ₁-C ₄Alkylidene group;

R ¹⁰Be selected from Z ' and-Ak ²-Z ', wherein

Ak ²Be C ₁-C ₄Alkylidene group; And

Z ' is cycloalkyl, aryl, heteroaryl or heterocyclic radical, their optional separately being substituted, and optional separately being fused on one or more aryl or the heteroaryl ring, or be fused on one or more saturated or undersaturated cycloalkyl of part or the heterocycles.

[0067]

Example according to the preferred substituents of paragraph [0066] comprises

[0068]

In some embodiments according to the compound of paragraph [0063], Cy ²Be heterocyclic radical, as

Their optional separately being substituted and optional being fused on one or more aryl rings.In some embodiments, Cy ²Heterocyclic fused to phenyl ring.

[0069]

In some preferred implementation according to the compound of paragraph [0046], Cy ²-X ¹-generally speaking be selected from

A) A ₁-L ₁-B ₁-, A wherein ₁Be the optional aryl that replaces, the optional heteroaryl that replaces or the optional heterocyclic radical that replaces; L wherein ₁Be-(CH ₂) _0-1NH (CH ₂) _0-1-,-NHC (O)-or-NHCH ₂-; And B wherein ₁Be phenyl or covalent linkage;

B) A ₂-L ₂-B ₂-, A wherein ₂Be CH ₃(C=CH ₂The cycloalkyl of optional replacement)-,, the optional alkyl that replaces or the optional aryl that replaces; L wherein ₂Be-C ≡ C-; And B wherein ₂It is covalent linkage;

C) A ₃-L ₃-B ₃-, A wherein ₃Be the optional aryl that replaces, the optional heteroaryl that replaces or the optional heterocyclic radical that replaces; L wherein ₃It is covalent linkage; And B wherein ₃Be-CH ₂NH-;

D) A ₄-L ₄-B ₄-, A wherein ₄It is the optional aryl that replaces; L wherein ₄Be-NHCH ₂-; And B wherein ₄It is thienyl;

E) A ₅-L ₅-B ₅-, A wherein ₅Be optional heteroaryl that replaces or the optional heterocyclic radical that replaces; L wherein ₅It is covalent linkage; And B wherein ₅Be-SCH ₂-;

F) morpholinyl-CH ₂-;

G) the optional aryl that replaces;

H) A ₆-L ₆-B ₆-, A wherein ₆Be the optional aryl that replaces, the optional heteroaryl that replaces or the optional heterocyclic radical that replaces; L wherein ₆It is covalent linkage; And B wherein ₆Be-NHCH ₂-;

I) A ₇-L ₇-B ₇-, A wherein ₇Be optional heteroaryl that replaces or the optional heterocyclic radical that replaces; L wherein ₇It is covalent linkage; And B wherein ₇Be-CH ₂-;

I) optional heteroaryl that replaces or the optional heterocyclic radical that replaces;

K) A ₈-L ₈-B ₈-, A wherein ₈It is the optional phenyl that replaces; L wherein ₈It is covalent linkage; And B wherein ₈Be-O-;

L) A ₉-L ₉-B ₉-, A wherein ₉It is the optional aryl that replaces; L wherein ₉It is covalent linkage; And B wherein ₉It is furyl;

M) A ₁₀-L ₁₀-B ₁₀-, A wherein ₁₀Be optional heteroaryl that replaces or the optional heterocyclic radical that replaces; L wherein ₁₀Be-CH (CH ₂CH ₃)-; And B wherein ₁₀Be-NHCH ₂-;

N) A ₁₁-L ₁₁-B ₁₁-, A wherein ₁₁Be optional heteroaryl that replaces or the optional heterocyclic radical that replaces; L wherein ₁₁It is covalent linkage; And B wherein ₁₁Be-OCH ₂-;

O) A ₁₂-L ₁₂-B ₁₂-, A wherein ₁₂Be the optional aryl that replaces, the optional heteroaryl that replaces or the optional heterocyclic radical that replaces; L wherein ₁₂Be-NHC (O)-; And B wherein ₁₂Be-N (optional substituted aryl) CH ₂-;

P) A ₁₃-L ₁₃-B ₁₃-, A wherein ₁₃Be the optional aryl that replaces, the optional heteroaryl that replaces or the optional heterocyclic radical that replaces; L wherein ₁₃It is covalent linkage; And B wherein ₁₃Be-NHC (O)-;

Q) A ₁₄-L ₁₄-B ₁₄-, A wherein ₁₄Be the optional aryl that replaces, the optional heteroaryl that replaces or the optional heterocyclic radical that replaces; L wherein ₁₄Be-NHC (O) (optional heteroaryl that replaces); And B wherein ₁₄Be-S-S-;

r)F ₃CC(O)NH-；

S) A ₁₅-L ₁₅-B ₁₅-, A wherein ₁₅Be the optional aryl that replaces, the optional heteroaryl that replaces or the optional heterocyclic radical that replaces; L wherein ₁₅Be-(CH ₂) _0-1NH (the optional heteroaryl that replaces)-; And B wherein ₁₅Be-NHCH ₂-;

T) A ₁₆-L ₁₆-B ₁₆-, A wherein ₁₆Be the optional aryl that replaces, the optional heteroaryl that replaces or the optional heterocyclic radical that replaces; L wherein ₁₆It is covalent linkage; And B wherein ₁₆Be-N (the optional alkyl that replaces) CH ₂-; And

U) A ₁₇-L ₁₇-B ₁₇-, A wherein ₁₇Be the optional aryl that replaces, the optional heteroaryl that replaces or the optional heterocyclic radical that replaces; L wherein ₁₇It is covalent linkage; And B wherein ₁₇Be-(optional aryl-the CH that replaces ₂) ₂-N-.

[0070]

In another preferred implementation according to the compound of paragraph [0046], Cy ²-X ¹Be selected from general

A) D ₁-E ₁-F ₁-, D wherein ₁Be the optional aryl that replaces, the optional heteroaryl that replaces or the optional heterocyclic radical that replaces; E wherein ₁Be-CH ₂-or covalent linkage; And F wherein ₁It is covalent linkage;

B) D ₂-E ₂-F ₂-, D wherein ₂Be the optional aryl that replaces, the optional heteroaryl that replaces or the optional heterocyclic radical that replaces; E wherein ₂Be-NH (CH ₂) _0-2-; And F wherein ₂It is covalent linkage;

C) D ₃-E ₃-F ₃-, D wherein ₃Be the optional aryl that replaces, the optional heteroaryl that replaces or the optional heterocyclic radical that replaces; E wherein ₃Be-(CH ₂) _0-2NH-; And F wherein ₃It is covalent linkage;

D) D ₄-E ₄-F ₄-, D wherein ₄Be the optional aryl that replaces, the optional heteroaryl that replaces or the optional heterocyclic radical that replaces; E wherein ₄Be-S (CH ₂) _0-2-; And F wherein ₄It is covalent linkage;

E) D ₅-E ₅-F ₅-, D wherein ₅Be the optional aryl that replaces, the optional heteroaryl that replaces or the optional heterocyclic radical that replaces; E wherein ₅Be-(CH ₂) _0-2S-; And F wherein ₅It is covalent linkage; And

F) D ₆-E ₆-F ₆-, D wherein ₆Be the optional aryl that replaces, the optional heteroaryl that replaces or the optional heterocyclic radical that replaces; E wherein ₆Be-NH (CH ₂) _0-2NH-; And F wherein ₆It is covalent linkage.

[0071]

In some embodiments according to paragraph [0046] and [0048]-[0063], R ²To R ⁴Be independently hydrogen ,-NH ₂, nitro, furyl, chlorine, fluorine, butyl, trifluoromethyl, bromine, thienyl, phenyl ,-CHCHC (O)-NH ₂,-C ≡ CCH ₂-R ⁹, R wherein ⁹Be hydrogen, C ₁-C ₇-alkyl, hydroxyl, amino or C ₁-C ₇-alkoxyl group.

[0072]

In some preferred implementations according to the compound of paragraph [0046] and [0048]-[0071], q is 0 and X ¹Be independently selected from-NH-CH ₂-,-S-CH ₂-and-CH ₂-.

[0073]

In some preferred implementations according to the compound of paragraph [0046] and [0048]-[0071], q is 0 and X ¹Be independently selected from-OCH ₂-,-CH ₂O-,-CH ₂-NH ₂-and CH ₂S-.

[0074]

In some embodiments according to the compound of paragraph [0046] and [0048]-[0072], this compound has the Ar of following formula ²

Wherein G is N or C in each case independently, and C is optional is substituted.

[0075]

In some embodiments according to the compound of paragraph [0074], G is C (R in each case ⁸), R wherein ⁸Be selected from hydrogen and C ₁-C ₇-alkyl.In some preferred embodiments, G is-CH-.

[0076]

Some preferred embodiment in, be Ar according to the compound of paragraph [0074] ²Be selected from the compound of phenylene, benzo furylidene (benzofuranylene) and indolylidene (indolinylene).

[0077]

Some preferred embodiment in, Cy ²Be aryl or heteroaryl, their optional separately being substituted.More preferably, Cy ²Be phenyl, pyrimidyl, benzimidazolyl-or benzothiazolyl, their optional separately being substituted.Cy ²Preferred substituents be independently selected from C from one to three ₁-C ₇-alkyl, C ₁-C ₇-alkoxyl group, halogen, two-C ₁-C ₇-alkylamino-C ₁-C ₇The substituting group of-alkoxyl group and heteroaryl.More preferably, Cy ²Substituting group be selected from methyl, methoxyl group, fluorine, chlorine, pyridyl and dimethylamino-oxyethyl group.

[0078]

Some preferred embodiment in, by Cy ²-X ¹The part that forms is selected from following:

[0079]

In preferred embodiment, the compound of paragraph [0050] is shown in general formula (2):

Or be its pharmacologically acceptable salts, wherein

R ²And R ³Be independently selected from hydrogen, trifluoromethyl, butyl ,-(CH ₂) ₃-OH, chlorine, fluorine, amino, phenyl, thienyl, furyl ,-CH=CHC (O) NH ₂,-C ≡ CCH ₂-OH ,-C ≡ CCH ₂-OCH ₃And

The A ring is optional further to be independently selected from methyl, hydroxyl, methoxyl group, halogen and amino substituting group replacement by 1 to 3.

[0080]

Some preferred embodiment in, in compound according to paragraph [0079], Cy ²Be selected from:

[0081]

In other preferred implementation according to the compound of paragraph [0079] and [0080], the A ring is not further replaced.

[0082]

In another preferred implementation according to the compound of paragraph [0079] to [0081], R ²And R ³All be-H.

[0083]

In another embodiment in this regard, the present invention includes the compound of general formula (3):

Or its pharmacologically acceptable salts or interior hydrolyzable ester of body or acid amides; Wherein:

Ф is-NH ₂Or-OH;

Ring A is a heterocyclic radical, if wherein described heterocyclic radical contains-the NH-part, then the optional group that is selected from K of nitrogen replaces;

R ⁵Be the substituting group on the carbon, and be selected from halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulphonamide, C _1-6-alkyl, C _2-6-alkenyl, C _2-6-alkynyl, C _1-6-alkoxyl group, C _1-6-alkyloyl, C _1-6-alkanoyloxy, N-(C _1-6-alkyl) amino, N, N-(C _1-6-alkyl) ₂Amino, C _1-6-alkyl amido, N-(C _1-6-alkyl) formamyl, N, N-(C _1-6-alkyl) ₂Formamyl, C _1-6-alkyl S (O) _a---wherein a be 0 to 2, C _1-6-alkoxy carbonyl, N-(C _1-6-alkyl) sulphonamide, N, N-(C _1-6-alkyl) ₂Sulphonamide, aryl, aryloxy, aryl C _1-6-alkyl, heterocyclic radical, (heterocyclic radical) C _1-6-alkyl, or group (B-E-); R wherein ⁵, comprise group (B-E-), choose wantonly on carbon and replaced by one or more W; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen is optional is replaced by J;

W is halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulphonamide, C _1-6-alkyl, C _2-6-alkenyl, C _2-6-alkynyl, C _1-6-alkoxyl group, C _1-6-alkyloyl, C _1-6-alkanoyloxy, N-(C _1-6-alkyl) amino, N, N-(C _1-6-alkyl) ₂Amino, C _1-6-alkyl amido, N-(C _1-6-alkyl) formamyl, N, N-(C _1-6-alkyl) ₂Formamyl, C _1-6-alkyl S (O) _a---wherein a be 0 to 2, C _1-6-alkoxy carbonyl, N-(C _1-6-alkyl) sulphonamide, N, N-(C _1-6-alkyl) ₂Sulphonamide or group (B '-E '-); W wherein comprises group (B '-E '-), chooses wantonly on carbon to be replaced by one or more Y;

Y and Z are independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulphonamide, C _1-6-alkyl, C _2-6-alkenyl, C _2-6-alkynyl, C _1-6-alkoxyl group, C _1-6-alkyloyl, C _1-6-alkanoyloxy, N-(C _1-6-alkyl) amino, N, N-(C _1-6-alkyl) ₂Amino, C _1-6-alkyl amido, N-(C _1-6-alkyl) formamyl, N, N-(C _1-6-alkyl) ₂Formamyl, C _1-6-alkyl S (O) _a---wherein a be 0 to 2, C _1-6-alkoxy carbonyl, N-(C _1-6-alkyl) sulphonamide or N, N-(C _1-6-alkyl) ₂Sulphonamide;

G, J and K are independently selected from C _1-8-alkyl, C _1-8-alkenyl, C _1-8-alkyloyl, C _1-8-alkyl sulphonyl, C _1-8-alkoxy carbonyl, formamyl, N-(C _1-8-alkyl) formamyl, N, N-(C _1-8-alkyl) formamyl, benzyloxycarbonyl, benzoyl, phenyl sulfonyl, aryl, aryl C _1-6-alkyl or (heterocyclic radical) C _1-6-alkyl; Wherein G, J and K choose wantonly on carbon and are replaced by one or more Q; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen is optional by hydrogen or C ₁₆Alkyl replaces;

Q is halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulphonamide, C _1-6-alkyl, C _2-6-alkenyl, C _2-6-alkynyl, C _1-6-alkoxyl group, C _1-6-alkyloyl, C _1-6-alkanoyloxy, N-(C _1-6-alkyl) amino, N, N-(C _1-6-alkyl) ₂Amino, C _1-6-alkyl amido, N-(C _1-6-alkyl) formamyl, N, N-(C _1-6-alkyl) ₂Formamyl, C _1-6-alkyl S (O) _a---wherein a be 0 to 2, C _1-6-alkoxy carbonyl, C _1-6-alkoxycarbonyl amino, N-(C _1-6-alkyl) sulphonamide, N, N-(C _1-6-alkyl) ₂Sulphonamide, aryl, aryloxy, aryl C _1-6-alkyl, aryl C _1-6-alkoxyl group, heterocyclic radical, (heterocyclic radical) C _1-6-alkyl, (heterocyclic radical) C _1-6-alkoxyl group or group (B "-E "-); Q wherein, comprise group (B "-E "-), choose wantonly on carbon and replaced by one or more Z;

B, B ' and B " be independently selected from C _1-6-alkyl, C _2-6-alkenyl, C _2-6-alkynyl, C _3-8-cycloalkyl, C _3-8-cycloalkyl C _1-6-alkyl, aryl, aryl C _1-6-alkyl, heterocyclic radical, (heterocyclic radical) C _1-6-alkyl, phenyl or phenyl C _1-6-alkyl; Wherein B, B ' and B " choose wantonly on carbon and replaced by one or more D; And if wherein described heterocyclic radical contains-the NH-part the then optional group replacement that is selected from G of nitrogen;

E, E ' and E " be independently selected from-N (R ^a)-,-O-,-C (O) O-,-OC (O)-,-C (O)-,-N (R ^a) C (O)-,-N (R ^a) C (O) N (R ^b)-,-N (R ^a) C (O) O-,-OC (O) N (R ^a)-,-C (O) N (R ^aS)-, (O) _r,-SO ₂N (R ^a)-,-N (R ^a) SO ₂-, R wherein ^aAnd R ^bBe independently selected from hydrogen or the optional C that is replaced by one or more F _1-6-alkyl, and r is 0-2;

D and F are independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulphonamide, C _1-6-alkyl, C _2-6-alkenyl, C _2-6-alkynyl, C _1-6-alkoxyl group, C _1-6-alkyloyl, C _1-6-alkanoyloxy, N-(C _1-6-alkyl) amino, N, N-(C _1-6-alkyl) ₂Amino, C _1-6-alkyl amido, N-(C _1-6-alkyl) formamyl, N, N-(C _1-6-alkyl) ₂Formamyl, C _1-6-alkyl S (O) _a---wherein a be 0 to 2, C _1-6-alkoxy carbonyl, N-(C _1-6-alkyl) sulphonamide or N, N-(C _1-6-alkyl) ₂Sulphonamide;

M is 0,1,2,3 or 4; R wherein ⁵Value can be identical or different;

R ⁶It is halogen;

N is 0,1 or 2; R wherein ⁶Value can be identical or different; And

R ¹, R ², R ³And R ⁴Such as in the paragraph [0046] definition.

[0084]

Ring A, R ⁵, R ⁶, m and n certain sense comprise following:

Ring A:

(a) pyridyl, quinolyl, indyl, pyrimidyl, morpholinyl, piperidyl, piperazinyl, pyradazinyl, pyrazinyl, thiazolyl, thienyl, Thienopyrimidine base, thienopyridine base, purine radicals, triazinyl, oxazolyl, pyrazolyl or furyl; If wherein ring A contains-the NH-part, then the optional group that is selected from K of nitrogen replaces;

(b) pyridin-4-yl, pyridin-3-yl, pyridine-2-base, quinoline-8-base, pyrimidine-6-base, pyrimidine-5-base, pyrimidine-4-base, morpholine-4-base, piperidin-4-yl, piperidines-3-base, piperidines-2-base, piperazine-4-base, pyridazine-5-base, pyrazine-6-base, thiazol-2-yl, thiophene-2-base, thieno-[3,2b] pyrimidyl, thieno-[3,2b] pyrimidyl, thieno-[3,2b] pyridyl, purine-6-base or triazine-6-base; If wherein ring A contains-the NH-part, then the optional group that is selected from K of nitrogen replaces;

(c) pyridyl, quinolyl, pyrimidyl, morpholinyl, piperidyl, piperazinyl, pyradazinyl, pyrazinyl, thiazolyl or furyl;

(d) pyridin-4-yl, pyridin-3-yl, pyridine-2-base, quinoline-8-base, pyradizin-2-yl, furans-3-base, morpholinyl, thiazol-2-yl, pyrimidine-6-base, piperidin-4-yl or piperazine-4-base; And

(e) pyridin-4-yl, pyridin-3-yl, quinoline-8-base, piperidin-4-yl or piperazine-4-base.

R ⁵：

(a) substituting group on the carbon, and be selected from halogen, amino, C _1-6-alkyl, C _1-6-alkoxyl group, N-(C _1-6-alkyl) amino, aryl, aryloxy, aryl C _1-6-alkyl, heterocyclic radical, (heterocyclic radical) C _1-6-alkyl or group (B-E-); R wherein ⁵, comprise group (B-E-), choose wantonly on carbon and replaced by one or more W; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen is optional is replaced by J;

W is hydroxyl, sulfydryl, C _1-6-alkyl, C _1-6-alkoxyl group, N, N-(C _1-6-alkyl) ₂Amino or group (B '-E '); W wherein comprises group (B '-E '-), chooses wantonly on carbon to be replaced by one or more Y;

Y and Z are independently selected from halogen, nitro, cyano group, hydroxyl, C _1-6-alkoxyl group, N, N-(C _1-6-alkyl) ₂Amino or C _1-6-alkyl amido;

G, J and K are independently selected from C _1-8-alkyl, C _2-8-thiazolinyl, C _1-8-alkyloyl, aryl, aryl C _1-6-alkyl or (heterocyclic radical) C _1-6-alkyl; Wherein G, J and K choose wantonly on carbon and are replaced by one or more Q; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen is optional by hydrogen or C _1-6-alkyl replaces;

Q is cyano group, hydroxyl, C _1-6-alkoxyl group, C _1-6-alkanoyloxy, C _1-6-alkoxy carbonyl, C _1-6-alkoxycarbonyl amino, aryl, aryloxy or group (B " E "-); Q wherein, comprise group (B "-E "-), choose wantonly on carbon and replaced by one or more Z;

D and F are independently selected from halogen, C _1-6-alkoxyl group or N, N-(C _1-6-alkyl) ₂Amino.

(b) substituting group on the carbon, and be selected from fluorine, chlorine, amino, methyl, ethyl, propyl group, methoxyl group, N-methylamino, N-ethylamino, N-propyl group amino, N-butyl amino, phenyl, naphthyl ethyl, piperazine-4-base, piperidines-1-base, piperidin-4-yl, 2-(sulphomethyl)-pyrimidine-4-base, tetrahydrofuran (THF)-2-ylmethyl, tetrahydropyrans-2-ylmethyl, 1,2,5-thiadiazoles-3-base ethyl, piperidines-1-ylmethyl, pyridine-2-ylmethyl or group (B-B-); R wherein ⁵, comprise group (B-E-), choose wantonly on carbon and replaced by one or more W; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen is optional is replaced by J;

W is hydroxyl, methyl, ethyl, oxyethyl group, N, and N-(diethyl) is amino, N, N-(dibutyl) amino or group (B '-E '); W wherein comprises group (B '-E '-), chooses wantonly on carbon to be replaced by one or more Y;

Y and Z are independently selected from fluorine, chlorine, bromine, nitro, cyano group, hydroxyl, methoxyl group, N, N-(dimethyl) amino or methyl carbonylamino;

G, J and K are independently selected from methyl, ethyl, propyl group, amyl group, 2-methyl butyl, butyl, ethanoyl, benzyl, 3-(pyrroles-1-yl) propyl group or pyrrolidin-2-one-(5S)-methyl; Wherein G, J and K choose wantonly on carbon and are replaced by one or more Q; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen is optional by hydrogen or methyl substituted;

Q be cyano group, hydroxyl, methoxyl group, oxyethyl group, methyl ketonic oxygen base, methoxycarbonyl, tert-butoxycarbonyl amino, phenyl or group (B "-E "-); Q wherein, comprise group (B "-E "-), choose wantonly on carbon and replaced by one or more Z;

B, B ' and B " be independently selected from methyl, ethyl, propyl group, cyclohexyl, phenyl, benzyl, 1; 2; 3,4-tetrahydric quinoline group, 3-morpholino propyl group, 2-morpholino ethyl, 2-tetramethyleneimine-1-base ethyl, 3-morpholino propyl group, 3-(the 4-methyl send piperazine-1-yl) propyl group, 2-piperidines-1-base ethyl, 3-piperidines-1-base propyl group, pyridin-3-yl methyl or the basic propyl group of imidazoles-1-; Wherein B, B ' and B " choose wantonly on carbon and replaced by one or more D; And if wherein described heterocyclic radical contains-the NH-part the then optional group replacement that is selected from G of nitrogen;

E, E ' and E " be independently selected from-N (R ^a)-,-O-,-C (O)-,-NHC (O)-,-N (R ^a) C (O) O-; R wherein ^aBe hydrogen or the optional methyl that is replaced by one or more F;

D and F are independently selected from fluorine, methoxy or ethoxy;

(c) fluorine, chlorine, amino, methyl, methoxyl group, 3-morpholine-4-base propyl group amino, (3-morpholine-4-yl) ethylamino, ethanoyl, benzyl, the methoxycarbonyl methyl, 2-tetramethyleneimine-1-base oxethyl, 3-morpholino propoxy-, N-(2-fluorophenyl) propionic acid amide, 4-(diethylamino) phenylcarbonyl group methyl, 3-(4-methylpiperazine-1-yl) propyl group amino, 2-pyridine-1-base ethylamino, 2-[N, N-(diethyl) amino-ethyl amino, the pyridin-3-yl methylamino, 3-piperidines-1-base propyl group amino, imidazoles-1-base propyl group amino, 3-methoxy-propyl amino, 3-morpholine and propyl group amino, piperazine-1-base, the N-ethylamino, the 4-methyl is sent piperazine-1-base, 1-(3-phenoxy group) propyl group, 1-(3-cyano-phenyl) methyl, 1-(4-cyano-phenyl) methyl, tetrahydrofuran (THF)-2-ylmethyl, 1-(3-benzyloxy) propyl group, the 3-methoxy-benzyl, 2, the 3-dihydroxypropyl, 2-(methyl ketonic oxygen base) ethyl, 3-(pyrroles-1-yl) propyl group, 1-[3-(2-methoxy ethoxy)] propyl group, 2-(4-acetamido phenoxy group) ethyl, 2-(tert-butoxycarbonyl amino) ethyl, 2-(tert-butoxycarbonyl amino) propyl group, the 2-[(2-p-methoxy-phenyl) oxygen base] ethyl, (1,2,3,4-tetrahydroquinoline-1-yl) ethanoyl, 2-[N-(2-fluorophenyl) ethanamide] ethyl, the methoxycarbonyl methyl, 2-(oxyethyl group) ethyl, 4-methylpent-3-thiazolinyl, tetrahydropyrans-2-ylmethyl, 1-(2S)-2-methyl butyl, 4-(benzyloxy) butyl, 2-[4-(nitro) phenoxy group] ethyl, 2-[N, N-(dibutyl) amino] ethylamino, 3-[(N-methyl-N-phenyl) amino] propyl group amino, N-3-[2-(dimethylamino) oxyethyl group] propyl group amino, 2-[4-(acetamido) phenoxy group] ethyl, 2-[4-(hydroxyphenoxy)] ethyl, 1,2,5-thiadiazoles-3-base ethyl, piperidines-1-ylmethyl, 2-[4-(chlorine) phenoxy group] ethyl, pyrrolidin-2-one-(5S)-methyl, phenyl amino ketonic oxygen ylmethyl, cyclohexyl aminocarboxyl oxygen ylmethyl, 2-(sulphomethyl)-pyrimidine-4-base or pyridine-2-ylmethyl;

(d) halogen, amino, C _1-6-alkyl, C _1-6-alkoxyl group, C _1-3-alkanoyloxy, N-(C _1-3-alkyl) amino, N, N-(C _1-3-alkyl) ₂Axnino, C _1-3-alkyl amido, N-(C _1-3-alkyl) formamyl, N, N-(C _1-3-alkyl) ₂Formamyl;

(e) halogen, amino, C _1-6-alkyl or C _1-6-alkoxyl group; And

(f) halogen, amino, methyl or methoxy.

m：

(a) 0,1,2,3 or 4; R wherein ⁵Value can be identical or different;

(b) 0,1 or 2; R wherein ⁵Value can be identical or different;

(c) 0 or 1;

(d) 0; And

(e)1。

R ⁶：

(a) halogen;

(b) fluorine or chlorine; And

(c) fluorine.

n：

(a) 0,1 or 2, R wherein ⁶Value can be identical or different;

(b) 0 or 1;

(c) 0; And

(d)1。

[0085]

Other embodiment according to the compound of paragraph [0083] comprises following compound, wherein:

Ring A is a heterocyclic radical;

R ⁵Be halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulphonamide, C _1-6-alkyl, C _2-6-alkenyl, C _2-6-alkynyl, C _1-6-alkoxyl group, C _1-6-alkyloyl, C _1-6-alkanoyloxy, N-(C _1-6-alkyl) amino, N, N-(C _1-6-alkyl) ₂Amino, C _1-6-alkyl amido, N-(C _1-6-alkyl) formamyl, N, N-(C _1-6-alkyl) ₂Formamyl, C _1-6-alkyl S (O) _a---wherein a be 0 to 2, C _1-6-alkoxy carbonyl, N-(C _1-6-alkyl) sulphonamide, N, N-(C _1-6-alkyl) ₂Sulphonamide or group (B-E-); Wherein, B is selected from C _1-6-alkyl, C _2-6-alkenyl, C _2-6-alkynyl, C _3-8-cycloalkyl, C _3-8-cycloalkyl C _1-6-alkyl, phenyl, heterocyclic radical, phenyl C _1-6-alkyl or heterocyclic radical C _1-6-alkyl; Wherein B chooses wantonly on carbon and is replaced by one or more D; And if wherein described heterocyclic radical contains-the NH-part the then optional group replacement that is selected from G of nitrogen;

E is-N (R ^a)-,-O-,-C (O) O-,-OC (O)-,-C (O)-,-N (R ^a) C (O)-,-C (O) N (R ^aS)-, (O) _r,-SO ₂N (R ^a)-,-N (R ^a) SO ₂-, R wherein ^aBe hydrogen or the optional C that is replaced by one or more D _1-6-alkyl, and r is 0-2;

D is independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulphonamide, C _1-6-alkyl, C _2-6-alkenyl, C _2-6-alkynyl, C _1-6-alkoxyl group, C _1-6-alkyloyl, C _1-6-alkanoyloxy, N-(C _1-6-alkyl) amino, N, N-(C _1-6-alkyl) ₂Amino, C _1-6-alkyl amido, N-(C _1-6-alkyl) formamyl, N, N-(C _1-6-alkyl) ₂Formamyl, C _1-6-alkyl S (O) _a, wherein a be 0 to 2, C _1-6-alkoxy carbonyl, N-(C _1-6-alkyl) sulphonamide and N, N-(C _1-6-alkyl) ₂Sulphonamide;

G is selected from C _1-4-alkyl, C _1-4-alkyloyl, C _1-4-alkyl sulphonyl, C _1-4-alkoxy carbonyl, formamyl, N-(C _1-4-alkyl) formamyl, N, N-(C _1-4-alkyl) formamyl, benzyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl;

M is 0,1,2,3 or 4; R wherein ⁵Value identical or different;

R ⁶It is halogen; And

N is 0,1 or 2; R wherein ⁶Value can be identical or different.

[0086]

In another embodiment according to the compound of paragraph [0083],

Ring A is pyridyl, quinolyl, indyl, pyrimidyl, morpholinyl, piperidyl, piperazinyl, pyradazinyl, pyrazinyl, thiazolyl, thienyl, Thienopyrimidine base, thienopyridine base, purine radicals, triazinyl, oxazolyl, pyrazolyl or furyl; If wherein ring A contains-the NH-part, then the optional group that is selected from K of nitrogen replaces;

R ⁵Be the substituting group on the carbon, and be selected from halogen, amino, C _1-6-alkyl, C _1-6-alkoxyl group, N-(C _1-6-alkyl) amino, aryl, aryloxy, aryl C _1-6-alkyl, heterocyclic radical, (heterocyclic radical) C _1-6-alkyl, or group (B-E-); R wherein ⁵, comprise group (B-E-), choose wantonly on carbon and replaced by one or more W; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen is optional is replaced by J;

W is hydroxyl, sulfydryl, C _1-6-alkyl, C _1-6-alkoxyl group, N, N-(C _1-6-alkyl) ₂Amino or group (B '-E '-); W wherein comprises group (B '-E '-), chooses wantonly on carbon to be replaced by one or more Y;

G, J and K are independently selected from C _1-8-alkyl, C _2-8-alkenyl, C _1-8-alkyloyl, aryl, aryl C _1-6-alkyl or (heterocyclic radical) C _1-6-alkyl; Wherein G, J and K choose wantonly on carbon and are replaced by one or more Q; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen is optional by hydrogen or C _1-6-alkyl replaces;

Q is cyano group, hydroxyl, C _1-6-alkoxyl group, C _1-6-alkanoyloxy, C _1-6-alkoxy carbonyl, C _1-6-alkoxycarbonyl amino, aryl, aryloxy or group (B "-E "-); Q wherein, comprise group (B "-E "-) choose wantonly on carbon and replaced by one or more Z;

D and F are independently selected from halogen, C _1-6-alkoxyl group or N, N-(C _1-6-alkyl) ₂Amino;

M is 0,1,2,3 or 4; R wherein ⁵Value identical or different;

R ⁶It is fluorine or chlorine; And

N is 0,1 or 2; R wherein ⁶Value identical or different;

[0087]

In another embodiment according to the compound of paragraph [0083],

Ring A is pyridin-4-yl, pyridin-3-yl, pyridine-2-base, quinoline-8-base, pyrimidine-6-base, pyrimidine-5-base, pyrimidine-4-base, morpholine-4-base, piperidin-4-yl, piperidines-3-base, piperidines-2-base, piperazine-4-base, pyridazine-5-base, pyrazine-6-base, thiazol-2-yl, thiophene-2-base, thieno-[3,2d] pyrimidyl, thieno-[3,2b] pyrimidyl, thieno-[3,2b] pyridyl, purine-6-base or triazine-6-base; If wherein ring A contains-the NH-part, then the optional group that is selected from K of nitrogen replaces;

R ⁵It is the substituting group on the carbon, and be selected from fluorine, chlorine, amino, methyl, ethyl, propyl group, methoxyl group, N-methylamino, N-ethylamino, N-propyl group amino, N-butyl amino, phenyl, naphthyl ethyl, piperazine-1-base, piperidines-1-base, piperidin-4-yl, 2-(sulphomethyl)-pyrimidine-4-base, tetrahydrofuran (THF)-2-ylmethyl, tetrahydropyrans-2-ylmethyl, 1,2,5-thiadiazoles-3-base ethyl, piperidines-1-ylmethyl, pyridine-2-ylmethyl or group (B-B-); R wherein ⁵, comprise group (B-B-), choose wantonly on carbon and replaced by one or more W; If described heterocyclic radical contains-the NH-part, then nitrogen is optional is replaced by J;

D and F are independently selected from fluorine, methoxy or ethoxy;

M is 0,1 or 2; R wherein ⁵Value identical or different;

R ⁶It is fluorine; And

N is 0 or 1.

[0088]

In embodiment according to the compound of paragraph [0083] and [0085]-[0087], R ¹, R ², R ³And R ⁴Such as in paragraph [0048] and [0049] definition.In other preferred implementation, be by using according to the compound of paragraph [0083] Replace terminal portions

And the table 1-8 of the WO 03/087057 of modification and 13 compound, wherein Ф, R ¹, R ², R ³And R ⁴Such as paragraph [0046] definition, and preferably such as [0048] and [0049] definition.

[0089]

Definition in paragraph [0090]-[0097] is applicable to the R in paragraph [0083]-[0088] ⁵And R ⁶, and replenished definition in paragraph [0020]-[0042].If exist any inconsistently between the definition in paragraph [0020]-[0042] and paragraph [0090]-[0097], the definition in paragraph [0090]-[0097] is only for the compound prior applicability of paragraph [0083]-[0088].

[0090]

" alkyl " comprises straight chain and branched-chain alkyl.For example, " C _1-8-alkyl " and " C _1-6-alkyl " comprise methyl, ethyl, propyl group, sec.-propyl, amyl group, hexyl, heptyl and the tertiary butyl.But, when mentioning the single alkyl of " propyl group " and so on, only specially at linear form, when mentioning the single branched-chain alkyl of " sec.-propyl " and so on, only specially at the side chain form.

[0091]

Term " halogen " is meant fluorine, chlorine, bromine and iodine.

[0092]

When from " one or more " group, selecting optional substituting group, it being understood that its definition comprises all substituting groups that are selected from a special groups, or be selected from the substituting group of two or more special groups.

[0093]

" heterocyclic radical " is saturated, fractional saturation or undersaturated list or the dicyclo that contains 3-12 atom, wherein at least one atom is selected from nitrogen, sulphur or oxygen, unless otherwise noted, it can be that carbon or nitrogen connect, and wherein the epithio atom is optional oxidized to form the S-oxide compound.Preferably " heterocyclic radical " is saturated, fractional saturation or undersaturated list or the dicyclo that contains 5 or 6 atoms, wherein at least one atom is selected from nitrogen, sulphur or oxygen, or 8-10 unit dicyclo, unless otherwise noted, it can be that carbon or nitrogen connect, and wherein the epithio atom is optional oxidized to form the S-oxide compound.The example of term " heterocyclic radical " and suitable meaning are thiazolidyl, pyrrolidyl, 1,3-benzo dioxolyl, 1,2,4-oxadiazole base, 2-azabicyclo [2.2.1] heptyl, morpholinyl, tetrahydrofuran base, furyl, THP trtrahydropyranyl, piperidyl, piperazinyl, thio-morpholinyl, 1, the 3-dioxolanyl, high piperazinyl, thienyl, pyrryl, pyrazolyl oxadiazole base, tetrazyl oxazolyl, the Thienopyrimidine base, the thienopyridine base, thieno-[3,2d] pyrimidyl, 1,3, the 5-triazinyl, purine radicals, 1,2,3, the 4-tetrahydric quinoline group, benzimidazolyl-, benzothiazolyl benzoxazolyl, benzothienyl, benzofuryl, indazolyl, quinazolyl, the cinnolines base, 2, the 3-phthalazinyl, quinoxalinyl, 1,5-phthalazinyl (napthyridinyl), the benzotriazole base, the pyrrolo-thienyl, imidazo thienyl isoxazolyl, imidazolyl, thiadiazolyl group, isothiazolyl, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, pyranyl, indyl, pyrimidyl, thiazolyl, pyrazinyl, pyridazinyl, pyridyl, quinolyl, quinazolyl, and 1-isoquinolyl.

[0094]

" heterocyclic group " is saturated, fractional saturation or undersaturated list or the dicyclo that contains 3-12 atom, and wherein at least one atom is selected from nitrogen, sulphur or oxygen, unless otherwise noted, it can be that carbon or nitrogen connect, wherein CH ₂Group is optional to be replaced by C (O), and wherein the epithio atom is optional oxidized to form the S-oxide compound.Preferably " heterocyclic group " is saturated, fractional saturation or undersaturated list or the dicyclo that contains 5 or 6 atoms, and wherein at least one atom is selected from nitrogen, sulphur or oxygen, or 9 or 10 yuan of dicyclos, unless otherwise noted, it can be that carbon or nitrogen connect, wherein CH ₂Group is optional to be replaced by C (O), and wherein the epithio atom is optional oxidized to form the S-oxide compound.The example of term " heterocyclic radical " and suitable meaning are pyrrolidyl, the 2-Pyrrolidone base, 2,5-dioxo pyrrolidyl, 2,4-dioxo alkyl imidazole base, 2-oxo-1,3,4-triazoline base (triazolinyl), oxazolidinyl, 2-oxazolidine ketone group, 5,6-dihydro-uracil base, 1,3-benzo dioxolyl, 1,2,4-oxadiazole base, 2-azabicyclo [2.2.1] heptyl, morpholinyl, 2-oxo-tetrahydrofuran base, tetrahydrofuran base, furyl, THP trtrahydropyranyl, piperidyl, piperazinyl, thio-morpholinyl, 1,1-dioxo thio-morpholinyl, 1, the 3-dioxolanyl, high piperazinyl, thiophenyl, the thienopyridine base, the Thienopyrimidine base, thieno-[3,2d] pyrimidyl, 1,3, the 5-triazinyl, purine radicals, quinolyl, isoquinolyl, 1,2,3, the 4-tetrahydric quinoline group, tetrahydro isoquinolyl, imidazolyl, benzimidazolyl-, benzothiazolyl benzoxazolyl, benzothienyl, benzofuryl, indazolyl, quinazolyl, the cinnolines base, 2, the 3-phthalazinyl, quinoxalinyl, 1,5-phthalazinyl oxazolyl isoxazolyl, pyrryl, tetrazyl, thiadiazolyl group, isothiazolyl, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, pyranyl, indyl, pseudoindoyl, pyrimidyl, thiazolyl, pyrazolyl, the 3-pyrrolinyl, pyrazinyl, pyridazinyl, pyridyl, pyriconyl, pyrimidine ketone group and 1-isoquinolyl.

[0095]

" aryl " group is for example phenyl, indenyl, indanyl, naphthyl, tetralyl or fluorenyl, preferred phenyl.

[0096]

" C _1-6-alkanoyloxy " example be acetoxyl group." C _1-8-alkoxy carbonyl ", " C _1-6-alkoxy carbonyl " and C _1-4The example of-alkoxy carbonyl comprises methoxycarbonyl, ethoxy carbonyl, N-and t-butoxy carbonyl.C _2-6The example of-alkynyl is ethynyl and 2-propynyl." C _1-6-alkoxyl group " example comprise methoxyl group, oxyethyl group and propoxy-." C _1-6-alkyl amido " and C _1-3The example of-alkyl amido comprises formamido-, acetamido and propionamido-." C _1-6-alkyl S (O) _a---wherein a is 0 to 2 " example comprise C _1-6-alkyl sulphonyl, C _1-3-alkyl S (O) _a, methylthio group, ethylmercapto group, methylsulfinyl, ethyl sulfinyl, methylsulfonyl and ethylsulfonyl." C _1-8-alkyloyl ", " C _1-6-alkyloyl " and C _1-4The example of-alkyloyl comprises C _1-3-alkyloyl, propionyl and ethanoyl." N-C _1-6-alkylamino " and N-(C _1-3-alkyl) An Ji example comprises methylamino-and ethylamino." N, N-(C _1-6-alkyl) ₂Amino " and N, N-(C _1-2-alkyl) ₂Amino example comprises amino, two-(N-butyl) the amino and N-ethyl-N-methylaminos of two-N-methylamino, two-(N-ethyl)." C _2-8-alkenyl " example be C _1-6-alkenyl and C _2-3-alkenyl, and comprise vinyl, allyl group and 1-propenyl." N-(C _1-3-alkyl) sulphonamide " and " N-(Ci ₅Alkyl) sulphonamide " example be N-(C _1-3-alkyl) sulphonamide, N-(methyl) sulphonamide and N-(ethyl) sulphonamide." N-(C _1-6-alkyl) ₂Sulphonamide " example be N, N-(C _1-3-alkyl) ₂Sulphonamide, N, N-(dimethyl) sulphonamide and N-(methyl)-N-(ethyl) sulphonamide." N-(C _1-8-alkyl) formamyl " and " N-(C _1-6-alkyl) formamyl " example be N-(C _1-4-alkyl) formamyl, N-(C _1-3-alkyl) formamyl, methylamino carbonyl and ethylamino carbonyl." N, N-(C _1-8-alkyl) ₂Formamyl " and " N, N-(C _1-6-alkyl) ₂Formamyl " example be N, N-(C _1-4-alkyl) ₂Formamyl, N, N-(C _1-2-alkyl) ₂Formamyl, dimethylamino carbonyl and methylethyl aminocarboxyl." (heterocyclic radical) C _1-6-alkyl " example comprise piperidines-1-ylmethyl, piperidines-1-base ethyl, piperidines-1-base propyl group, pyridylmethyl, 3-morpholino propyl group, 2-morpholino ethyl and 2-pyrimidine-2-base ethyl." (heterocyclic radical) C _1-6-alkoxyl group " example comprise (heterocyclic radical) methoxyl group, (heterocyclic radical) oxyethyl group and (heterocyclic radical) propoxy-." aryl C _1-6-alkyl " example comprise benzyl, 2-phenylethyl, 2-phenyl propyl and 3-phenyl propyl.The example of " aryloxy " comprises phenoxy group and naphthyloxy." C _3-8-cycloalkyl " example comprise cyclopropyl and cyclohexyl." C _3-8-cycloalkyl C _1-6-alkyl " example comprise cyclopropyl methyl and 2-cyclohexyl propyl group." C _1-6-alkoxycarbonyl amino " example comprise the amino and tert-butoxycarbonyl amino of methoxycarbonyl.

[0097]

Use compound term description to contain the group of an above functional group, for example aryl C _1-4-alkyl.Explain these terms according to those skilled in the art's understanding.For example, aryl C _1-6-alkyl comprises the C that is replaced by aryl _1-6-alkyl, this type of group comprise benzyl, 2-phenylethyl, 2-phenyl propyl and 3-phenyl propyl.

[0098]

In another embodiment in this regard, the present invention includes compound, its N-oxide form, its pharmacy acceptable addition salt and stereochemistry heterogeneous forms thereof of following general formula (4):

Wherein

Ф is-NH ₂Or-OH;

N is 0,1,2 or 3, wherein when n is 0, is meant direct key;

T is 0,1,2,3 or 4, wherein when t is 0, is meant direct key;

Q, X, Y and Z are N or CH independently;

R ¹Be H or such as in the paragraph [0046] definition,

R ², R ³And R ⁴Such as in the paragraph [0046] definition;

R ¹²Be hydrogen, halogen, hydroxyl, amino, nitro, C _1-6-alkyl, C _1-6-alkoxyl group, trifluoromethyl, two (C _1-6-alkyl) amino, hydroxyl amino and naphthyl alkylsulfonyl pyrazinyl;

-L-is direct key or is selected from C _1-6-alkane 2 basis, amino, carbonyl and aminocarboxy divalent group;

Each R ¹³Be hydrogen atom, wherein when t is 2,3 or 4, R ¹³In one optional be aryl;

R ¹⁴Be hydrogen, hydroxyl, amino, hydroxyl C _1-6-alkyl, C _1-6-alkyl, C _1-6-alkoxyl group, aryl C _1-6-alkyl, aminocarboxyl, hydroxycarbonyl group, amino C _1-6-alkyl, aminocarboxyl C _1-6-alkyl, hydroxycarbonyl group C _1-6-alkyl, hydroxyl amino carbonyl, C _1-6-alkoxy carbonyl, C _1-6-alkylamino C _1-6-alkyl or two (C _1-6-alkyl) amino C _1-6-alkyl;

Ring A is selected from

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

R ⁵And R⁶Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C_1-6-alkyl; Three halo C_1-6-alkoxyl; C_1-6-alkyl; By aryl and C_3-10The C that-cycloalkyl replaces_1-6-alkyl; C_1-6-alkoxyl; C_1-6-alkoxy C_1-6-alkoxyl; C_1-6-alkyl carbonyl; C_1-6-alkoxyl carbonyl; C_1-6-alkyl sulfonyl base; Cyano group C_1-6-alkyl; Hydroxyl C_1-6-alkyl; Hydroxyl C_1-6-alkoxyl; Hydroxyl C_1-6-alkyl is amino; Amino C_1-6-alkoxyl; Two (C_1-6-alkyl) amino carbonyl; Two (hydroxyl C_1-6-alkyl) amino; (aryl) (C_1-6-alkyl) amino; Two (C_1-6-alkyl) amino C_1-6-alkoxyl; Two (C_1-6-alkyl) amino C_1-6-alkyl is amino; Two (C_1-6-alkyl) amino C_1-6The amino C of-alkyl_1-6-alkyl; Aryl sulfonyl; Arlysulfonylamino; Aryloxy group; Aryloxy group C_1-6-alkyl; Aryl C_2-6-olefin 2 base; Two (C_1-6-alkyl) amino; Two (C_1-6-alkyl) amino C_1-6-alkyl; Two (C_1-6-alkyl) amino (C_1-6-alkyl) amino; Two (C_1-6-alkyl) amino (C_1-6-alkyl) amino C_1-6-alkyl; Two (C_1-6-alkyl) amino C_1-6-alkyl (C_1-6-alkyl) amino; Two (C_1-6-alkyl) amino C_1-6-alkyl (C_1-6-alkyl) amino C_1-6-alkyl; Amino (the C of amino-sulfonyl_1-6-alkyl) amino; Amino (the C of amino-sulfonyl_1-6-alkyl) amino C_1-6-alkyl; Two (C_1-6-alkyl) amino (C of amino-sulfonyl_1-6-alkyl) amino; Two (C_1-6-alkyl) amino (C of amino-sulfonyl_1-6-alkyl) amino C_1-6-alkyl; Cyano group; Thiophenyl; By two (C_1-6-alkyl) amino C_1-6-alkyl (C_1-6-alkyl) amino C_1-6-alkyl replaces, two (C_1-6-alkyl) amino C_1-6-alkyl, C_1-6-alkylpiperazinyl C_1-6-alkyl, hydroxyl C_1-6-alkylpiperazinyl C_1-6-alkyl, hydroxyl C_1-6-alkoxy C_1-6-alkylpiperazinyl C_1-6-alkyl, two (C_1-6-alkyl) amino-sulfonyl piperazinyl C_1-6-alkyl, C_1-6-alkoxyl piperazinyl, C_1-6-alkoxyl piperazinyl C_1-6-alkyl, morpholinyl C_1-6-alkyl, hydroxyl C_1-6-alkyl (C_1-6-alkyl) amino C_1-6-alkyl or two (hydroxyl C_1-6-alkyl) amino C_1-6The thiophenyl that-alkyl replaces; Furyl; By hydroxyl C_1-6The furyl that-alkyl replaces; Benzofuranyl; Imidazole radicals; Oxazolyl; By aryl and C_1-6-alkyl replaces the De oxazolyl; C_1-6-alkyl triazolyl; Tetrazole radical; Pyrrolidinyl; Pyrrole radicals; Piperidyl C_1-6-alkoxyl; Morpholinyl; C_1-6-alkyl morpholine base; Morpholinyl C_1-6-alkoxyl; Morpholinyl C_1-6-alkyl; Morpholinyl C_1-6-alkyl is amino; Morpholinyl C_1-6The amino C of-alkyl_1-6-alkyl; Piperazinyl; C_1-6-alkylpiperazinyl; C_1-6-alkylpiperazinyl C_1-6-alkoxyl; Piperazinyl C_1-6-alkyl; Naphthyl sulfonyl piperazinyl; Naphthyl sulfonyl piperidyl; The naphthyl sulfonyl; C_1-6-alkylpiperazinyl C_1-6-alkyl; C_1-6-alkylpiperazinyl C_1-6-alkyl is amino; C_1-6-alkylpiperazinyl C_1-6The amino C of-alkyl_1-6-alkyl; C_1-6-alkylpiperazinyl sulfonyl; Amino-sulfonyl piperazinyl C_1-6-alkoxyl; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C_1-6-alkyl; Two (C_1-6-alkyl) amino-sulfonyl piperazinyl; Two (C_1-6-alkyl) amino-sulfonyl piperazinyl C_1-6-alkyl; Hydroxyl C_1-6-alkylpiperazinyl; Hydroxyl C_1-6-alkylpiperazinyl C_1-6-alkyl; C_1-6-alkoxyl piperidyl; C_1-6-alkoxyl piperidyl C_1-6-alkyl; The amino C of piperidyl_1-6-alkyl is amino; The amino C of piperidyl_1-6The amino C of-alkyl_1-6-alkyl; (C_1-6-Alkylpiperidine base) (hydroxyl C_1-6-alkyl) amino C_1-6-alkyl is amino; (C_1-6-Alkylpiperidine base) (hydroxyl C_1-6-alkyl) amino C_1-6The amino C of-alkyl_1-6-alkyl; Hydroxyl C_1-6-alkoxy C_1-6-alkylpiperazinyl; Hydroxyl C_1-6-alkoxy C_1-6-alkylpiperazinyl C_1-6-alkyl; (hydroxyl C_1-6-alkyl) (C_1-6-alkyl) amino; (hydroxyl C_1-6-alkyl) (C_1-6-alkyl) amino C_1-6-alkyl; Hydroxyl C_1-6The amino C of-alkyl_1-6-alkyl; Two (hydroxyl C_1-6-alkyl) amino C_1-6-alkyl; Pyrrolidinyl C_1-6-alkyl; Pyrrolidinyl C_1-6-alkoxyl; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two_1-6-alkyl and three halo C_1-6The pyrazolyl that the substituting group of-alkyl replaces; Pyridine radicals; By C_1-6The pyridine radicals that-alkoxyl, aryloxy group or aryl replace; Pyrimidine radicals; The tetrahydro-pyrimidine base piperazinyl; Tetrahydro-pyrimidine base piperazinyl C_1-6-alkyl; Quinolyl; Indyl; Phenyl; By one, two or three are independently selected from the phenyl that the substituting group of following group replaces, these substituting groups are selected from halogen, amino, nitro, C_1-6-alkyl, C_1-6-alkoxyl, hydroxyl C_1-4-alkyl, trifluoromethyl, trifluoro methoxyl group, hydroxyl C_1-4-alkoxyl, C_1-4-alkyl sulfonyl base, C_1-4-alkoxy C_1-4-alkoxyl, C_1-4-alkoxyl carbonyl, amino C_1-4-alkoxyl, two (C_1-4-alkyl) amino C_1-4-alkoxyl, two (C_1-4-alkyl) amino, two (C_1-4-alkyl) amino carbonyl, two (C_1-4-alkyl) amino C_1-4-alkyl, two (C_1-4-alkyl) amino C_1-4The amino C of-alkyl_1-4-alkyl, two (C_1-4-alkyl) amino (C_1-4-alkyl) amino, two (C_1-4-alkyl) amino (C_1-4-alkyl) amino C_1-4-alkyl, two (C_1-4-alkyl) amino C_1-4-alkyl (C_1-4-alkyl) amino, two (C_1-4-alkyl) amino C_1-4-alkyl (C_1-4-alkyl) amino C_1-4-alkyl, the amino (C of amino-sulfonyl_1-4-alkyl) amino, the amino (C of amino-sulfonyl_1-4-alkyl) amino C_1-4-alkyl, two (C_1-4-alkyl) amino (C of amino-sulfonyl_1-4-alkyl) amino, two (C_1-4-alkyl) amino (C of amino-sulfonyl_1-4-alkyl) amino C_1-4-alkyl, cyano group, piperidyl C_1-4-alkoxyl, pyrrolidinyl C_1-4-alkoxyl, amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C_1-4-alkyl, two (C_1-4-alkyl) amino-sulfonyl piperazinyl, two (C_1-4-alkyl) amino-sulfonyl piperazinyl C_1-4-alkyl, hydroxyl C_1-4-alkylpiperazinyl, hydroxyl C_1-4-alkylpiperazinyl C_1-4-alkyl, C_1-4-alkoxyl piperidyl, C_1-4-alkoxyl piperidyl C_1-4-alkyl, hydroxyl C_1-4-alkoxy C_1-4-alkylpiperazinyl, hydroxyl C_1-4-alkoxy C_1-4-alkylpiperazinyl C_1-4-alkyl, (hydroxyl C_1-4-alkyl) (C_1-4-alkyl) amino, (hydroxyl C_1-4-alkyl) (C_1-4-alkyl) amino C_1-4-alkyl, two (hydroxyl C_1-4-alkyl) amino, two (hydroxyl C_1-4-alkyl) amino C_1-4Furyl, pyrrolidinyl C that-alkyl, furyl, quilt-CH=CH-CH=CH-replace_1-4-alkyl, pyrrolidinyl C_1-4-alkoxyl, morpholinyl, morpholinyl C_1-4-alkoxyl, morpholinyl C_1-4-alkyl, morpholinyl C_1-4-alkyl is amino, morpholinyl C_1-4The amino C of-alkyl_1-4-alkyl, piperazinyl, C_1-4-alkylpiperazinyl, C_1-4-alkylpiperazinyl C_1-4-alkoxyl, piperazinyl C_1-4-alkyl, C_1-4-alkylpiperazinyl C_1-4-alkyl, C_1-4-alkylpiperazinyl C_1-4-alkyl is amino, C_1-4-alkylpiperazinyl C_1-4The amino C of-alkyl_1-6-alkyl, tetrahydro-pyrimidine base piperazinyl, tetrahydro-pyrimidine base piperazinyl C_1-4-alkyl, the amino C of piperidyl_1-4-alkyl is amino, the amino C of piperidyl_1-4The amino C of-alkyl_1-4-alkyl, (C_1-4-Alkylpiperidine base) (hydroxyl C_1-4-alkyl) amino C_1-4-alkyl is amino, (C_1-4-Alkylpiperidine base) (hydroxyl C_1-4-alkyl) amino C_1-4The amino C of-alkyl_1-4-alkyl, pyridine radicals C_1-4-alkoxyl, hydroxyl C_1-4-alkyl is amino, hydroxyl C_1-4The amino C of-alkyl_1-4-alkyl, two (C_1-4-alkyl) amino C_1-4-alkyl amino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C_1-4-alkoxyl and thiophenyl C_1-4-alkyl is amino;

Centre portions

Optional with methylene radical, ethylidene or the bridging of propylidene bridge (that is, forming the dicyclo part);

Each R ⁵And R ⁶Can be positioned on the nitrogen to replace hydrogen;

Aryl above is a phenyl, or by one or more halogen, C of being selected from independently of one another _1-6-alkyl, C _1-6The phenyl that the substituting group of-alkoxyl group, trifluoromethyl, cyano group and hydroxycarbonyl group replaces.

[0099]

In a embodiment, be suitable for following one or multinomial according to the compound of paragraph [0098]:

A) n is 1 or 2;

B) t is 0,1 or 2;

C) Z is a nitrogen;

D) R ¹²Be hydrogen, nitro, C _1-6-alkoxyl group, trifluoromethyl, two (C _1-6-alkyl) amino, hydroxyl amino or naphthyl alkylsulfonyl pyrazinyl;

E)-L-is direct key or is selected from C _1-6-alkane 2 basis, carbonyl and aminocarboxy divalent group;

F) each R ¹³Be hydrogen;

G) R ¹⁴Be hydrogen, hydroxyl C _1-6-alkyl, aminocarboxyl, hydroxyl amino carbonyl or two (C _1-6-alkyl) amino C _1-6-alkyl;

H) the A ring is to be selected from (a-1), (a-7), (a-9), (a-10), (a-12), (a-14), (a-19), (a-20), (a-21), (a-22), (a-23), (a-30), (a-34), (a-49) and group (a-50);

I) each s is 0,1,2 or 5 independently;

J) each R ⁵And R ⁶Be independently selected from hydrogen; Halogen; Nitro; Three halo C _1-6-alkyl; Three halo C _1-6-alkoxyl group; C _1-6-alkyl; C _1-6-alkoxyl group; C _1-6-alkyl sulphonyl; (aryl) (C _1-6-alkyl) amino; Aryl sulfonyl; Aryloxy; Aryl C _2-6-olefin 2 base; Two (C _1-6-alkyl) amino; Thiophenyl; By two (C _1-6-alkyl) amino C _1-6-alkyl (C _1-6-alkyl) amino C _1-6-alkyl, two (C _1-6-alkyl) amino C _1-6-alkyl, C _1-6-alkylpiperazine base C _1-6-alkyl, hydroxyl C _1-6-alkylpiperazine base C _1-6-alkyl, hydroxyl C _1-6-alkoxy C _1-6-alkylpiperazine base C _1-6-alkyl, two (C _1-6-alkyl) amino-sulfonyl piperazinyl C _1-6-alkyl, C _1-6-alkoxyl group piperidyl C _1-6-alkyl, morpholinyl C _1-6-alkyl, hydroxyl C _1-6-alkyl (C _1-6-alkyl) amino C _1-6-alkyl or two (hydroxyl C _1-6-alkyl) amino C _1-6The thiophenyl that-alkyl replaces; Furyl; Oxazolyl; Pyrryl; Pyrazolyl; Pyridyl; By C _1-6The pyridyl that-alkoxyl group replaces; Quinolyl; Indyl; Phenyl; And by one, two or three are independently selected from halogen, amino, C _1-6-alkyl, C _1-6-alkoxyl group, hydroxyl C _1-4-alkyl, trifluoromethyl, trifluoromethoxy, two (C _1-4-alkyl) amino C _1-4-alkoxyl group, two (C _1-4-alkyl) amino, two (C _1-4-alkyl) amino C _1-4-alkyl, two (C _1-4-alkyl) amino C _1-4-alkyl (C _1-4-alkyl) amino, two (C _1-4-alkyl) amino C _1-4-alkyl (C _1-4-alkyl) amino C _1-4-alkyl, hydroxyl C _1-4-alkylpiperazine base C _1-4-alkyl, hydroxyl C _1-4-alkoxy C _1-4-alkylpiperazine base C _1-4-alkyl, two (hydroxyl C _1-4-alkyl) amino C _1-4-alkyl, pyrrolidyl C _1-4-alkyl, pyrrolidyl C _1-4-alkoxyl group, morpholinyl C _1-4-alkoxyl group, morpholinyl C _1-4-alkyl and C _1-4-alkylpiperazine base C _1-4The phenyl that the substituting group of-alkyl replaces, and

K) centre portions

Optional with methylene bridge bridging (that is, forming the dicyclo part).

[0100]

In another embodiment, be suitable for following one or multinomial according to the compound of paragraph [0098]:

L) n is 1 or 2;

M) t is 0 or 2;

N) Z is a nitrogen;

O) R ¹²Be hydrogen;

P)-L-is direct key;

Q) each R ¹³Be hydrogen;

R) R ¹⁴Be hydrogen;

S) the A ring is to be selected from (a-1), (a-9), (a-19), (a-20), (a-21), (a-22), (a-23), (a-49) and group (a-50);

T) each s is 0,1,2 or 5 independently;

U) each R ⁵And R ⁶Be independently selected from hydrogen; Halogen; Three halo C _1-6-alkyl; Three halo C _1-6-alkoxyl group; C _1-6-alkyl; C _1-6-alkoxyl group; Aryl C _2-6-olefin 2 base; Two (C _1-6-alkyl) amino; Thiophenyl; By two (C _1-6-alkyl) amino C _1-6-alkyl (C _1-6-alkyl) amino C _1-6-alkyl, two (C _1-6-alkyl) amino C _1-6-alkyl, C _1-6-alkylpiperazine base C _1-6-alkyl, hydroxyl C _1-6-alkylpiperazine base C _1-6-alkyl, hydroxyl C _1-6-alkoxy C _1-6-alkylpiperazine base C _1-6-alkyl, C _1-6-alkoxyl group piperidyl C _1-6-alkyl, morpholinyl C _1-6-alkyl, hydroxyl C _1-6-alkyl (C _1-6-alkyl) amino C _1-6-alkyl or two (hydroxyl C _1-6-alkyl) amino C _1-6The thiophenyl that-alkyl replaces; Furyl; Oxazolyl; Pyrazolyl; Pyridyl; By C _1-6The pyridyl that-alkoxyl group replaces; Quinolyl; Indyl; Phenyl; And by one, two or three are independently selected from halogen, amino, C _1-6-alkyl, C _1-6-alkoxyl group, hydroxyl C _1-4-alkyl, trifluoromethyl, trifluoromethoxy, two (C _1-4-alkyl) amino C _1-4-alkoxyl group, two (C _1-4-alkyl) amino, two (C _1-4-alkyl) amino C _1-4-alkyl, two (C _1-4-alkyl) amino C _1-4-alkyl (C _1-4-alkyl) amino C _1-4-alkyl, hydroxyl C _1-4-alkylpiperazine base C _1-4-alkyl, hydroxyl C _1-4-alkoxy C _1-4-alkylpiperazine base C _1-4-alkyl, two (hydroxyl C _1-4-alkyl) amino C _1-4-alkyl, pyrrolidyl C _1-4-alkyl pyrrolidine base C _1-4-alkoxyl group, morpholinyl C _1-4-alkoxyl group, morpholinyl C _1-4-alkyl, C _1-4-alkylpiperazine base C _1-4The phenyl that the substituting group of-alkyl replaces, and

V) centre portions

Optional with methylene bridge bridging (that is, forming the dicyclo part).

[0101]

W) n is 1;

X) t is 0;

Y) Z is a nitrogen;

Z) R ¹²Be hydrogen;

Aa)-L-is direct key;

Bb) each R ¹³Be hydrogen;

Cc) R ¹⁴Be hydrogen;

Dd) the A ring is for being selected from (a-1) and group (a-20);

Ee) each s is 0 or 1 independently;

Ff) each R ⁵And R ⁶Be independently selected from hydrogen; Thiophenyl; By two (C _1-6-alkyl) amino C _1-6-alkyl or C _1-6-alkylpiperazine base C _1-6The thiophenyl that-alkyl replaces; Furyl; Phenyl; And be independently selected from two (C by one _1-4-alkyl) amino C _1-4-alkoxyl group, two (C _1-4-alkyl) amino, two (C _1-4-alkyl) amino C _1-4-alkyl, two (C _1-4-alkyl) amino C _1-4-alkyl (C _1-4-alkyl) amino C _1-4-alkyl, pyrrolidyl C _1-4-alkyl, pyrrolidyl C _1-4-alkoxyl group and C _1-4-alkylpiperazine base C _1-4The phenyl that the substituting group of-alkyl replaces.

[0102]

In another embodiment according to the compound of paragraph [0098], L is direct key and/or R ¹²Be H.

[0103]

A) t is 0;

B) R ¹²Be hydrogen, halogen, hydroxyl, amino, nitro, C _1-6-alkyl, C _1-6-alkoxyl group, trifluoromethyl or two (C _1-6-alkyl) amino;

C)-L-is direct key or is selected from C _1-6The divalent group of-alkane 2 basis, amino and carbonyl;

D) R ¹⁴Be hydrogen, hydroxyl, amino, hydroxyl C _1-6-alkyl, C _1-6-alkyl, C _1-6-alkoxyl group, aryl C _1-6-alkyl, aminocarboxyl, amino C _1-6-alkyl, C _1-6-alkylamino C _1-6-alkyl or two (C _1-6-alkyl) amino C _1-6-alkyl;

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

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

G) R ⁵Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6-alkyl; Three halo C _1-6-alkoxyl group; C _1-6-alkyl; C _1-6-alkoxyl group; C _1-6-alkyl-carbonyl; C _1-6-alkoxy carbonyl; C _1-6-alkyl sulphonyl; Hydroxyl C _1-6-alkyl; Aryloxy; Two (C _1-6-alkyl) amino; Cyano group; Thiophenyl; Furyl; By hydroxyl C _1-6The furyl that-alkyl replaces; Benzofuryl; Imidazolyl; Oxazolyl; By aryl and C _1-6-alkyl replaces the De oxazolyl; C _1-6-alkyl triazolyl; Tetrazyl; Pyrrolidyl; Pyrryl; Morpholinyl; C _1-6-alkyl morpholine base; Piperazinyl; C _1-6-alkylpiperazine base; Hydroxyl C _1-6-alkylpiperazine base; C _1-6-alkoxyl group piperidyl; Pyrazolyl; Be selected from C by one or two _1-6-alkyl and three halo C _1-6The pyrazolyl that the substituting group of-alkyl replaces; Pyridyl; By C _1-6The pyridyl that-alkoxyl group, aryloxy or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; Or be independently selected from halogen, C by one or two _1-6-alkyl, C _1-6The phenyl that the substituting group of-alkoxyl group or trifluoromethyl replaces;

H) R ⁶Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6-alkyl; Three halo C _1-6-alkoxyl group; C _1-6-alkyl; C _1-6-alkoxyl group; C _1-6-alkyl-carbonyl; C _1-6-alkoxy carbonyl; C _1-6-alkyl sulphonyl; Hydroxyl C _1-6-alkyl; Aryloxy; Two (C _1-6-alkyl) amino; Cyano group; Pyridyl; Phenyl; Or be independently selected from halogen, C by one or two _1-6-alkyl, C _1-6The phenyl that the substituting group of-alkoxyl group and trifluoromethyl replaces, and

I) centre portions

Optional with ethylene bridge bridging (that is, forming the dicyclo part).

[0104]

A) R ¹²Be hydrogen, halogen, hydroxyl, amino, nitro, C _1-6-alkyl, C _1-6-alkoxyl group, trifluoromethyl, hydroxyl amino or naphthyl alkylsulfonyl pyrazinyl;

B) R ¹⁴Be hydrogen, hydroxyl, amino, hydroxyl C _1-6-alkyl, C _1-6-alkoxyl group, aryl C _1-6-alkyl, aminocarboxyl, hydroxycarbonyl group, amino C _1-6-alkyl, aminocarboxyl C _1-6-alkyl, hydroxycarbonyl group C _1-6-alkyl, hydroxyl amino carbonyl, C _1-6-alkyl-carbonyl, C _1-6-alkylamino C _1-6-alkyl or two (C _1-6-alkyl) amino C _1-6-alkyl;

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

D) each R ⁵And R ⁶Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6-alkyl; Three halo C _1-6-alkoxyl group; C _1-6-alkyl; C _1-6-alkoxyl group; C _1-6-alkoxy C _1-6-alkoxyl group; C _1-6-alkyl-carbonyl; C _1-6-alkyl sulphonyl; Cyano group C _1-6-alkyl; Hydroxyl C _1-6-alkyl; Hydroxyl C _1-6-alkoxyl group; Hydroxyl C _1-6-alkylamino; Amino C _1-6-alkoxyl group; Two (C _1-6-alkyl) aminocarboxyl; Two (hydroxyl C _1-6-alkyl) amino; Two (C _1-6-alkyl) amino C _1-6-alkoxyl group; Two (C _1-6-alkyl) amino C _1-6-alkylamino; Aryl sulfonyl; Arlysulfonylamino; Aryloxy; Aryl C _2-6-olefin 2 base; Two (C _1-6-alkyl) amino; Cyano group; Thiophenyl; By two (C _1-6-alkyl) amino C _1-6-alkyl (C _1-6-alkyl) amino C _1-6-alkyl, two (C _1-6-alkyl) amino C _1-6-alkyl, C _1-6-alkylpiperazine base C _1-6-alkyl or two (hydroxyl C _1-6-alkyl) amino C _1-6The thiophenyl that-alkyl replaces; Furyl; Imidazolyl; C _1-6-alkyl triazolyl; Tetrazyl; Piperidyl C _1-6-alkoxyl group; Morpholinyl; C _1-6-alkyl morpholine base; Morpholinyl C _1-6-alkoxyl group; Morpholinyl C _1-6-alkyl; C _1-6-alkylpiperazine base C _1-6-alkoxyl group; C _1-6-alkylpiperazine base C _1-6-alkyl; C _1-6-alkylpiperazine base alkylsulfonyl; Amino-sulfonyl piperazinyl C _1-6-alkoxyl group; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C _1-6-alkyl; Two (C _1-6-alkyl) amino-sulfonyl piperazinyl; Two (C _1-6-alkyl) amino-sulfonyl piperazinyl C _1-6-alkyl; Hydroxyl C _1-6-alkylpiperazine base; Hydroxyl C _1-6-alkylpiperazine base C _1-6-alkyl; C _1-6-alkoxyl group piperidyl; C _1-6-alkoxyl group piperidyl C _1-6-alkyl; Hydroxyl C _1-6-alkoxy C _1-6-alkylpiperazine base; Hydroxyl C _1-6-alkoxy C _1-6-alkylpiperazine base C _1-6-alkyl; (hydroxyl C _1-6-alkyl) (C _1-6-alkyl) amino; (hydroxyl C _1-6-alkyl) (C _1-6-alkyl) amino C _1-6-alkyl; Pyrrolidyl C _1-6-alkoxyl group; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two _1-6-alkyl or three halo C _1-6The pyrazolyl that the substituting group of-alkyl replaces; Pyridyl; By C _1-6The pyridyl that-alkoxyl group or aryl replace; Pyrimidyl; Quinolyl; Phenyl; And by one, two or three are independently selected from halogen, amino, C _1-6-alkyl, C _1-6-alkoxyl group, hydroxyl C _1-4-alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl C _1-4-alkoxyl group, C _1-4-alkoxy C _1-4-alkoxyl group, amino C _1-4-alkoxyl group, two (C _1-4-alkyl) amino C _1-4-alkoxyl group, two (C _1-4-alkyl) amino, piperidyl C _1-4-alkoxyl group, pyrrolidyl C _1-4-alkoxyl group, amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C _1-4-alkyl, two (C _1-4-alkyl) amino-sulfonyl piperazinyl, two (C _1-4-alkyl) amino-sulfonyl piperazinyl C _1-4-alkyl, hydroxyl C _1-4-alkylpiperazine base, hydroxyl C _1-4-alkylpiperazine base C _1-4-alkyl, C _1-4-alkoxyl group piperidyl, C _1-4-alkoxyl group piperidyl C _1-4-alkyl, hydroxyl C _1-4-alkoxy C _1-4-alkylpiperazine base, hydroxyl C _1-4-alkoxy C _1-4-alkylpiperazine base C _1-4-alkyl, hydroxyl C _1-4-alkyl) (C _1-4-alkyl) amino, (hydroxyl C _1-4-alkyl) (C _1-4-alkyl) amino C _1-4-alkyl, pyrrolidyl C _1-4-alkoxyl group, morpholinyl C _1-4-alkoxyl group, morpholinyl C _1-4-alkyl, C _1-4-alkylpiperazine base C _1-4-alkoxyl group, C _1-4-alkylpiperazine base C _1-4-alkyl, hydroxyl C _1-4-alkylamino, two (hydroxyl C _1-4-alkyl) amino, two (C _1-4-alkyl) amino C _1-4-alkylamino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C _1-4-alkoxyl group and thiophenyl C _1-4The phenyl that the substituting group of-alkylamino replaces.

[0105]

In another embodiment according to the compound of paragraph [0098],

R ¹²Be hydrogen, halogen, hydroxyl, amino, nitro, C _1-6-alkyl, C _1-6-alkoxyl group, trifluoromethyl, hydroxyl amino or naphthyl alkylsulfonyl pyrazinyl;

R ¹⁴Be hydrogen, hydroxyl, amino, hydroxyl C _1-6-alkyl, C _1-6-alkoxyl group, aryl C _1-6-alkyl, aminocarboxyl, hydroxycarbonyl group, amino C _1-6-alkyl, aminocarboxyl C _1-6-alkyl, hydroxycarbonyl group C _1-6-alkyl, hydroxyl amino carbonyl, C _1-6-alkoxy carbonyl, C _1-6-alkylamino C _1-6-alkyl or two (C _1-6-alkyl) amino C _1-6-alkyl;

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

Each R ⁵And R ⁶Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6-alkyl; Three halo C _1-6-alkoxyl group; C _1-6-alkyl; C _1-6-alkoxyl group; C _1-6-alkoxy C _1-6-alkoxyl group; C _1-6-alkyl-carbonyl; C _1-6-alkyl sulphonyl; Cyano group C _1-6-alkyl; Hydroxyl C _1-6-alkyl; Hydroxyl C _1-6-alkoxyl group; Hydroxyl C _1-6-alkylamino; Amino C _1-6-alkoxyl group; Two (C _1-6-alkyl) aminocarboxyl; Two (hydroxyl C _1-6-alkyl) amino; Two (C _1-6-alkyl) amino C _1-6-alkoxyl group; Two (C _1-6-alkyl) amino C _1-6-alkylamino; Aryl sulfonyl; Arlysulfonylamino; Aryloxy; Aryl C _2-6-olefin 2 base; Two (C _1-6-alkyl) amino; Cyano group; Thiophenyl; By two (C _1-6-alkyl) amino C _1-6-alkyl (C _1-6-alkyl) amino C _1-6-alkyl, two (C _1-6-alkyl) amino C _1-6-alkyl, C _1-6-alkylpiperazine base C _1-6-alkyl or two (hydroxyl C _1-6-alkyl) amino C _1-6The thiophenyl that-alkyl replaces; Furyl; Imidazolyl; C _1-6-alkyl triazolyl; Tetrazyl; Piperidyl C _1-6-alkoxyl group; Morpholinyl; C _1-6-alkyl morpholine base; Morpholinyl C _1-6-alkoxyl group; Morpholinyl C _1-6-alkyl; C _1-6-alkylpiperazine base C _1-6-alkoxyl group; C _1-6-alkylpiperazine base C _1-6-alkyl; C _1-6-alkylpiperazine base alkylsulfonyl; Amino-sulfonyl piperazinyl C _1-6-alkoxyl group; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C _1-6-alkyl; Two (C _1-6-alkyl) amino-sulfonyl piperazinyl; Two (C _1-6-alkyl) amino-sulfonyl piperazinyl C _1-6-alkyl; Hydroxyl C _1-6-alkylpiperazine base; Hydroxyl C _1-6-alkylpiperazine base C _1-6-alkyl; C _1-6-alkoxyl group piperidyl; C _1-6-alkoxyl group piperidyl C _1-6-alkyl; Hydroxyl C _1-6-alkoxy C _1-6-alkylpiperazine base; Hydroxyl C _1-6-alkoxy C _1-6-alkylpiperazine base C _1-6-alkyl; (hydroxyl C _1-6-alkyl) (C _1-6-alkyl) amino; (hydroxyl C _1-6-alkyl) (C _1-6-alkyl) amino C _1-6-alkyl; Pyrrolidyl C _1-6-alkoxyl group; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two _1-6-alkyl and three halo C _1-6The pyrazolyl that the substituting group of-alkyl replaces; Pyridyl; By C _1-6The pyridyl that-alkoxyl group or aryl replace; Pyrimidyl; Quinolyl; Phenyl; And by one, two or three are independently selected from halogen, amino, C _1-6-alkyl, C _1-6-alkoxyl group, hydroxyl C _1-6-alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl C _1-6-alkoxy C _1-6-alkoxyl group, amino C _1-4-alkoxyl group, two (C _1-4-alkyl) amino C _1-4-alkoxyl group, two (C _1-4-alkyl) amino, piperidyl C _1-4-alkoxyl group, pyrrolidyl C _1-4-alkoxyl group, amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C _1-4-alkyl, two (C _1-4-alkyl) amino-sulfonyl piperazinyl, two (C _1-4-alkyl) amino-sulfonyl piperazinyl C _1-4-alkyl, hydroxyl C _1-4-alkylpiperazine base, hydroxyl C _1-4-alkylpiperazine base C _1-4-alkyl, C _1-4-alkoxyl group piperidyl, C _1-4-alkoxyl group piperidyl C _1-4-alkyl, hydroxyl C _1-4-alkoxy C _1-4-alkylpiperazine base, hydroxyl C _1-4-alkoxy C _1-4-alkylpiperazine base C _1-4-alkyl, (hydroxyl C _1-4-alkyl) (C _1-4-alkyl) amino, (hydroxyl C _1-4-alkyl) (C _1-4-alkyl) amino C _1-4-alkyl, pyrrolidyl C _1-4-alkoxyl group, morpholinyl C _1-4-alkoxyl group, morpholinyl C _1-4-alkyl, C _1-4-alkylpiperazine base C _1-4-alkoxyl group, C _1-4-alkylpiperazine base C _1-4-alkyl, hydroxyl C _1-4-alkylamino, two (hydroxyl C _1-4-alkyl) amino, two (C _1-4-alkyl) amino C _1-4-alkylamino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C _1-4-alkoxyl group and thiophenyl C _1-4The phenyl that the substituting group of-alkylamino replaces.

[0106]

In another embodiment according to the compound of paragraph [0098],

T is 0;

R ¹²Be hydrogen, halogen, hydroxyl, amino, nitro, C _1-6-alkyl, C _1-6-alkoxyl group, trifluoromethyl or two (C _1-6-alkyl) amino;

-L-is direct key or is selected from C _1-6The divalent group of-alkane 2 basis, amino and carbonyl;

R ¹⁴Be hydrogen, hydroxyl, amino, hydroxyl C _1-6-alkyl, C _1-6-alkyl, C _1-6-alkoxyl group, aryl C _1-6-alkyl, aminocarboxyl, amino C _1-6-alkyl, C _1-6-alkylamino C _1-6-alkyl or two (C _1-6-alkyl) amino C _1-6-alkyl;

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

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

R ⁵Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6-alkyl; Three halo C _1-6-alkoxyl group; C _1-6-alkyl; C _1-6-alkoxyl group; C _1-6-alkyl-carbonyl; C _1-6-alkoxy carbonyl; C _1-6-alkyl sulphonyl; Hydroxyl C _1-6-alkyl; Aryloxy; Two (C _1-6-alkyl) amino; Cyano group; Thiophenyl; Furyl; By hydroxyl C _1-6The furyl that-alkyl replaces; Benzofuryl; Imidazolyl; Oxazolyl; By aryl and C _1-6-alkyl replaces the De oxazolyl; C _1-6-alkyl triazolyl; Tetrazyl; Pyrrolidyl; Pyrryl; Morpholinyl; C _1-6-alkyl morpholine base; Piperazinyl; C _1-6-alkylpiperazine base; Hydroxyl C _1-6-alkylpiperazine base; C _1-6-alkoxyl group piperidyl; Pyrazolyl; Be selected from C by one or two _1-6-alkyl and three halo C _1-6The pyrazolyl that the substituting group of-alkyl replaces; Pyridyl; By C _1-6The pyridyl that-alkoxyl group, aryloxy or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; And be independently selected from halogen, C by one or two _1-6-alkyl, C _1-6The phenyl that the substituting group of-alkoxyl group and trifluoromethyl replaces.

R ⁶Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6-alkyl; Three halo C _1-6-alkoxyl group; C _1-6-alkyl; C _1-6-alkoxyl group; C _1-6-alkyl-carbonyl; C _1-6-alkoxy carbonyl; C _1-6-alkyl sulphonyl; Hydroxyl C _1-6-alkyl; Aryloxy; Two (C _1-6-alkyl) amino; Cyano group; Pyridyl; Phenyl; Or be independently selected from halogen, C by one or two _1-6-alkyl, C _1-6The phenyl that the substituting group of-alkoxyl group and trifluoromethyl replaces; And

Centre portions

Optional with ethylene bridge bridging (that is, forming the dicyclo part).

[0107]

In another embodiment according to the compound of paragraph [0098],

N is 1 or 2;

T is 0,1 or 2;

Z is a nitrogen;

R ¹²Be hydrogen, nitro, C _1-6-alkoxyl group, trifluoromethyl, two (C _1-6-alkyl) amino, hydroxyl amino or naphthyl alkylsulfonyl pyrazinyl;

-L-is direct key or is selected from C _1-6-alkane 2 basis, carbonyl and aminocarboxy divalent group;

Each R ¹³Represent hydrogen atom;

R ¹⁴Be hydrogen, hydroxyl C _1-6-alkyl, aminocarboxyl, hydroxyl amino carbonyl or two (C _1-6-alkyl) amino C _1-6-alkyl;

The A ring is to be selected from (a-1), (a-7), (a-9), (a-10), (a-12), (a-14), (a-19), (a-20), (a-21), (a-22), (a-23), (a-30), (a-34), (a-49) and group (a-50);

Each s is 0,1,2 or 5 independently;

Each R ⁵And R ⁶Be independently selected from hydrogen; Halogen; Nitro; Three halo C _1-6-alkyl; Three halo C _1-6-alkoxyl group; C _1-6-alkyl; C _1-6-alkoxyl group; C _1-6-alkyl sulphonyl; (aryl) (C _1-6-alkyl) amino; Aryl sulfonyl; Aryloxy; Aryl C _2-6-olefin 2 base; Two (C _1-6-alkyl) amino; Thiophenyl; By two (C _1-6-alkyl) amino C _1-6-alkyl (C _1-6-alkyl) amino C _1-6-alkyl, two (C _1-6-alkyl) amino C _1-6-alkyl, C _1-6-alkylpiperazine base C _1-6-alkyl, hydroxyl C _1-6-alkylpiperazine base C _1-6-alkyl, hydroxyl C _1-6-alkoxy C _1-6-alkylpiperazine base C _1-6-alkyl, two (C _1-6-alkyl) amino-sulfonyl piperazinyl C _1-6-alkyl, C _1-6-alkoxyl group piperidyl C _1-6-alkyl, morpholinyl C _1-6-alkyl, hydroxyl C _1-6-alkyl (C _1-6-alkyl) amino C _1-6-alkyl or two (hydroxyl C _1-6-alkyl) amino C _1-6The thiophenyl that-alkyl replaces; Furyl; Oxazolyl; Pyrryl; Pyrazolyl; Pyridyl; By C _1-6The pyridyl that-alkoxyl group replaces; Quinolyl; Indyl; Phenyl; And by one, two or three are independently selected from halogen, amino, C _1-6-alkyl, C _1-6-alkoxyl group, hydroxyl C _1-4-alkyl, trifluoromethyl, trifluoromethoxy, two (C _1-4-alkyl) amino C _1-4-alkoxyl group, two (C _1-4-alkyl) amino, two (C _1-4-alkyl) amino C _1-4-alkyl, two (C _1-4-alkyl) amino C _1-4-alkyl (C _1-4-alkyl) amino, two (C _1-4-alkyl) amino C _1-4-alkyl (C _1-4-alkyl) amino C _1-4-alkyl, hydroxyl 4 alkylpiperazine base C _1-4-alkyl, hydroxyl C _1-4-alkoxy C _1-4-alkylpiperazine base C _1-4-alkyl, two (hydroxyl C _1-4-alkyl) amino C _1-4-alkyl, pyrrolidyl C _1-4-alkyl, pyrrolidyl C _1-4-alkoxyl group, morpholinyl C _1-4-alkoxyl group and morpholinyl C _1-4-alkyl and C _1-4-alkylpiperazine base C _1-4The phenyl that the substituting group of-alkyl replaces, and

Centre portions

Optional with methylene bridge bridging (that is, forming the dicyclo part).

[0108]

In another embodiment according to the compound of paragraph [0098],

N is 1 or 2;

T is 0 or 2;

Z is a nitrogen;

R ¹²Be hydrogen;

-L-is direct key;

Each R ¹³Be hydrogen;

R ¹⁴Be hydrogen;

The A ring is to be selected from (a-1), (a-9), (a-19), (a-20), (a-21), (a-22), (a-23), (a-49) and group (a-50);

Each s is 0,1,2 or 5 independently;

Each R ⁵And R ⁶Be independently selected from hydrogen; Halogen; Three halo C _1-6-alkyl; Three halo C _1-6-alkoxyl group; C _1-6-alkyl; C _1-6-alkoxyl group; Aryl C _2-6-olefin 2 base; Two (C _1-6-alkyl) amino; Thiophenyl; By two (C _1-6-alkyl) amino C _1-6-alkyl (C _1-6-alkyl) amino C _1-6-alkyl two (C _1-6-alkyl) amino C _1-6-alkyl, C _1-6-alkylpiperazine base C _1-6-alkyl, hydroxyl C _1-6-alkylpiperazine base C _1-6-alkyl, hydroxyl C _1-6-alkoxy C _1-6-alkylpiperazine base C _1-6-alkyl, C _1-6-alkoxyl group piperidyl C _1-6-alkyl, morpholinyl C _1-6-alkyl, hydroxyl C _1-6-alkyl (C _1-6-alkyl) amino C _1-6-alkyl or two (hydroxyl C _1-6-alkyl) amino C _1-6The thiophenyl that-alkyl replaces; Furyl; Oxazolyl; Pyrazolyl; Pyridyl; By C _1-6The pyridyl that-alkoxyl group replaces; Quinolyl; Indyl; Phenyl; And by one, two or three are independently selected from halogen, amino, C _1-6-alkyl, C _1-6-alkoxyl group, hydroxyl C _1-4-alkyl, trifluoromethyl, trifluoromethoxy, two (C _1-4-alkyl) amino C _1-4-alkoxyl group, two (C _1-4-alkyl) amino, two (C _1-4-alkyl) amino C _1-4-alkyl, two (C _1-4-alkyl) amino C _1-4-alkyl (C _1-4-alkyl) amino C _1-4-alkyl, hydroxyl C _1-4-alkylpiperazine base C _1-4-alkyl, hydroxyl C _1-4-alkoxy C _1-4-alkylpiperazine base C _1-4-alkyl, two (hydroxyl C _1-4-alkyl) amino C _1-4-alkyl, pyrrolidyl C _1-4-alkyl, pyrrolidyl C _1-4-alkoxyl group, morpholinyl C _1-4-alkoxyl group, morpholinyl C _1-4-alkyl and C _1-4-alkylpiperazine base C _1-4The phenyl that the substituting group of-alkyl replaces, and

Centre portions

Optional with methylene bridge bridging (that is, forming the dicyclo part).

[0109]

In another embodiment according to the compound of paragraph [0098],

N is 1;

T is 0;

Z is a nitrogen;

R ¹²Be hydrogen;

-L-is direct key;

Each R ¹³Be hydrogen;

R ¹⁴Be hydrogen;

The A ring is for being selected from (a-1) and group (a-20);

Each s is 0 or 1 independently;

Each R ⁵And R ⁶Be independently selected from hydrogen; Thiophenyl; By two (C _1-6-alkyl) amino C _1-6-alkyl or C _1-6-alkylpiperazine base C _1-6The thiophenyl that-alkyl replaces; Furyl; Phenyl; And be independently selected from two (C by one _1-4-alkyl) amino C _1-4-alkoxyl group, two (C _1-4-alkyl) amino, two (C _1-4-alkyl) amino C _1-4-alkyl, two (C _1-4-alkyl) amino C _1-4-alkyl (C _1-4-alkyl) amino C _1-4-alkyl, pyrrolidyl C _1-4-alkyl, pyrrolidyl C _1-4-alkoxyl group and C _1-4-alkylpiperazine base C _1-4The phenyl that the substituting group of-alkyl replaces.

[0110]

In the compound of paragraph [0098]-[0109], R ¹, R ², R ³And R ⁴Preferably such as in paragraph [0048] and [0049] definition.In other embodiment of the compound of paragraph [0098]-[0109], R ¹, R ², R ³And R ⁴Be H.Other preferred implementation of the compound of paragraph [0098]-[0109] comprises the 21st and 22 page and the compound of table F-1 of WO03/076422, wherein terminal hydroxamic acid part (HO-NH-C (O)-) quilt

Replace, wherein Ф, R ¹, R ², R ³And R ⁴According to paragraph [0046] definition, and preferably define according to [0048] and [0049].

[0111]

In paragraph [0098]-[0110], the definition in paragraph [0112]-[0114] has replenished the definition in paragraph [0020]-[0042].If exist any inconsistently between the definition in paragraph [0020]-[0042] and paragraph [0112]-[0114], the definition in paragraph [0112]-[0114] is only for the compound prior applicability of paragraph [0098]-[0110].

[0112]

Halogen generally is meant fluorine, chlorine, bromine and iodine; C _1-4-alkyl is meant straight chain and the branched saturated hydrocarbon group that contains 1 to 4 carbon atom, for example methyl, ethyl, propyl group, butyl, 1-methylethyl, 2-methyl-propyl etc.; C _1-6-alkyl comprises C _1-4-alkyl and contain the higher homologue of 5 to 6 carbon atoms, for example amyl group, 2-methyl butyl, hexyl, 2-methyl amyl etc.; C _1-6-alkane 2 basis is meant divalence straight chain and the branched saturated hydrocarbon group that contains 1 to 6 carbon atom, methylene radical, 1 for example, 2-ethane two bases, 1,3-propane two bases, 1,4-butane two bases, 1,5-pentane two bases, 1,6-hexane two bases and branched chain isomer thereof, for example 2-methylpentane two bases, 3-methylpentane two bases, 2,2-dimethylbutane two bases, 2,3-dimethylbutane two bases etc.; Three halo C _1-6-alkyl is meant the C that contains three identical or different halogenic substituents _1-6-alkyl, for example trifluoromethyl; C _2-6-olefin 2 base is meant divalence straight chain and the branched hydrocarbyl that contains two keys and have 2 to 6 carbon atoms, for example ethene two bases, 2-propylene two bases, 3-butylene two bases, 2-amylene two bases, 3-amylene two bases, 3-methyl-2-butene two bases etc.; Aryl is meant phenyl and by one or more halogen, C of being selected from independently of one another _1-6-alkyl, C _1-6The phenyl that the substituting group of-alkoxyl group or trifluoromethyl, cyano group, hydroxycarbonyl group replaces; Aminoaryl is meant the aryl that is replaced by amino; C _3-10-cycloalkyl comprises the cyclic hydrocarbon radical that contains 3 to 10 carbon, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, suberyl, ring octyl group etc.

[0113]

Term " another Zn chelation group " be meant can with Zn ²⁺The group of-ionic interaction, it may reside in enzyme binding site.

[0114]

The N-oxide form of the compound of paragraph [0098] comprise one of them or several nitrogen-atoms be oxidized to those compounds of so-called N-oxide compound, particularly one or more piperidines-, piperazine or pyridazinyl-nitrogen is by those N-oxide compounds of N-oxidation.

[0115]

In another embodiment, the present invention includes compound or its pharmacologically acceptable salts of following structural (5):

Wherein

Ф is-NH ₂Or-OH;

R ¹Be H or such as in the paragraph [0046] definition;

R ², R ³And R ⁴Such as in the paragraph [0046] definition;

N is 0,1,2 or 3, and when n was 0, it was meant direct key;

Q be nitrogen or Or

X be nitrogen or

Y be nitrogen or

Z be nitrogen or

R be selected from hydrogen, halogen ,-NH ₂, nitro, hydroxyl, aryl, heterocyclic radical, C ₃-C ₈-cycloalkyl, heteroaryl, C ₁-C ₇-alkyl, haloalkyl, C ₁-C ₇-alkenyl, C ₁-C ₇-alkynyl, C ₁-C ₇-acyl group, C ₁-C ₇-alkyl-aryloxy, C ₁-C ₇-alkyl-sulfur alkyl aryl, C ₁-C ₇-alkyl-aryl sulfonyl kia, C ₁-C ₇-alkyl-aryl sulfonyl, C ₁-C ₇-alkyl-n-aryl sulfonyl, C ₁-C ₇-alkyl-arylamines, C ₁-C ₇-alkynyl-C (O)-amine, C ₁-C ₇-alkenyl-C (O)-amine, C ₁-C ₇-alkynyl-R ⁹, C ₁-C ₇-alkenyl-R ⁹, R wherein ⁹Be hydrogen, hydroxyl, amino, C ₁-C ₇-alkyl or C ₁-C ₇-alkoxyl group;

R ¹²Be hydrogen, halogen, hydroxyl, amino, nitro, C _1-6Alkyl, C _1-6Alkoxyl group, trifluoromethyl, two (C _1-6Alkyl) amino, hydroxyl amino or naphthyl alkylsulfonyl pyrazinyl;

R ¹³Be hydrogen, C _1-6Alkyl, aryl C _2-6Olefin 2 base, furyl carbonyl, naphthyl carbonyl ,-C (O) phenyl R ⁹, C _1-6Alkyl amino-carbonyl, amino-sulfonyl, n-aryl sulfonyl, amino-sulfonyl amino, two (C _1-6Alkyl) amino-sulfonyl amino, n-aryl sulfonyl amino, the amino C of amino-sulfonyl _1-6Alkyl, two (C _1-6Alkyl) the amino C of amino-sulfonyl _1-6Alkyl, the amino C of n-aryl sulfonyl _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl, C _1-12Alkyl sulphonyl, two (C _1-6Alkyl) amino-sulfonyl, three halo C _1-6Alkyl sulphonyl, two (aryl) C _1-6Alkyl-carbonyl, thiophenyl C _1-6Alkyl-carbonyl, pyridyl carbonyl or aryl C _1-6Alkyl-carbonyl

Each R wherein ⁹Be independently selected from phenyl; By one, two or three are independently selected from halogen, amino, C _1-6Alkyl, C _1-6Alkoxyl group, hydroxyl C _1-4Alkyl, hydroxyl C _1-4Alkoxyl group, amino C _1-4Alkoxyl group, two (C _1-4Alkyl) amino C _1-4Alkoxyl group, two (C _1-6Alkyl) amino C _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl (C _1-6Alkyl) amino C _1-6Alkyl, hydroxyl C _1-4Alkylpiperazine base C _1-4Alkyl, C _1-4Alkoxyl group piperidyl C _1-4Alkyl, hydroxyl C _1-4Alkoxy C _1-4Alkylpiperazine base, C _1-4Alkylpiperazine base C _1-4Alkyl, two (hydroxyl C _1-4Alkyl) amino C _1-4Alkyl, pyrrolidyl C _1-4Alkoxyl group, morpholinyl C _1-4Alkoxyl group or morpholinyl C _1-4The phenyl that the substituting group of alkyl replaces; Thiophenyl; Or by two (C _1-4Alkyl) amino C _1-4Alkoxyl group, two (C _1-6Alkyl) amino C _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl (C _1-6Alkyl) amino C _1-6Alkyl, pyrrolidyl C _1-4Alkoxyl group, C _1-4Alkylpiperazine base C _1-4Alkyl, two (hydroxyl C _1-4Alkyl) amino C _1-4Alkyl or morpholinyl C _1-4The thiophenyl that alkoxyl group replaces.

R ¹⁴Be hydrogen, hydroxyl, amino, hydroxyl C _1-6Alkyl, C _1-6Alkyl, C _1-6Alkoxyl group, aryl C _1-6Alkyl, aminocarboxyl, hydroxycarbonyl group, amino C _1-6Alkyl, aminocarboxyl C _1-6Alkyl, hydroxycarbonyl group C _1-6Alkyl, hydroxyl amino carbonyl, C _1-6Alkoxy carbonyl, C _1-6Alkylamino C _1-6Alkyl or two (C _1-6Alkyl) amino C _1-6Alkyl;

Work as R ¹³And R ¹⁴When being present on the identical carbon atom, R ¹³And R ¹⁴Can form divalent group together, it is a following formula

-C(O)-NH-CH ₂-NR ¹⁰- (a-1)

R wherein ¹⁰Be hydrogen or aryl;

Work as R ¹³And R ¹⁴When being present on the adjacent carbon atom, R ¹³And R ¹⁴Can form divalent group together, it is a following formula

＝CH-CH＝CH-CH＝ (b-1)；

Aryl above is a phenyl or by one or more halogen, C of being selected from independently of one another _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group, trifluoromethyl, cyano group or hydroxycarbonyl group replaces.

[0116]

In some embodiments, use in the following restricted condition one or multinomial according to the compound of paragraph [0115]:

N is 0 or 1;

Q is

Or

R ¹²Be hydrogen or nitro;

R ¹³Be C _1-6Alkyl, aryl C _2-6Olefin 2 base, furyl carbonyl, naphthyl carbonyl, C _1-6Alkyl amino-carbonyl, amino-sulfonyl, two (C _1-6Alkyl) the amino C of amino-sulfonyl _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl, C _1-12Alkyl sulphonyl, two (C _1-6Alkyl) amino-sulfonyl, three halo C _1-6Alkyl sulphonyl, two (aryl) C _1-6Alkyl-carbonyl, thiophenyl C _1-6Alkyl-carbonyl, pyridyl carbonyl or aryl C _1-6Alkyl-carbonyl;

R ¹⁴Be hydrogen;

Work as R ¹³And R ¹⁴When being present on the identical carbon atom, R ¹³And R ¹⁴Can form the divalent group of formula (a-1) together, wherein R ¹⁰Be aryl;

Work as R ¹³And R ¹⁴When being present on the adjacent carbon atom, R ¹³And R ¹⁴Can form the divalent group of formula (b-1) together.

[0117]

In other embodiment, use in the following restricted condition one or multinomial according to the compound of paragraph [0115]:

N is 1;

Q is

Or

Z is a nitrogen;

R ¹²Be hydrogen;

R ¹³Be naphthyl carbonyl, C _1-12Alkyl sulphonyl or two (aryl) C _1-6Alkyl-carbonyl;

R ¹⁴Be hydrogen.

[0118]

In another embodiment according to the compound of paragraph [0115], R ¹²Be H.

[0119]

In another embodiment according to the compound of paragraph [0115]:

R ¹²Be hydrogen, halogen, hydroxyl, amino, nitro, C _1-6Alkyl, C _1-6Alkoxyl group, trifluoromethyl or two (C _1-6Alkyl) amino;

R ¹³Be hydrogen, C _1-6Alkyl, aryl C _2-6Olefin 2 base, furyl carbonyl, naphthyl carbonyl ,-C (O) phenyl R ⁹, C _1-6Alkyl amino-carbonyl, amino-sulfonyl, n-aryl sulfonyl, amino-sulfonyl amino, two (C _1-6Alkyl) amino-sulfonyl amino, two (C _1-6Alkyl) amino C _1-6Alkyl, C _1-12Alkyl sulphonyl, two (C _1-6Alkyl) amino-sulfonyl or pyridyl carbonyl, wherein each R ⁹Be independently selected from phenyl; By one, two or three are independently selected from halogen, C _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group replaces; Or thiophenyl; And

R ¹⁴Be hydrogen, hydroxyl, amino, hydroxyl C _1-6Alkyl, C _1-6Alkyl, C _1-6Alkoxyl group, aryl C _1-6Alkyl, aminocarboxyl, amino C _1-6Alkyl, C _1-6Alkylamino C _1-6Alkyl or two (C _1-6Alkyl) amino C _1-6Alkyl.

[0120]

In some embodiments according to the compound of paragraph [0115],

[0121]

In some embodiments according to the compound of paragraph [0115],

N is 0 or 1; Q is Or-NHC (O) C _1-6Alkane 2 basis SH; R ¹²Be hydrogen or nitro; R ¹³Be C _1-6Alkyl, aryl C _2-6Olefin 2 base, furyl carbonyl, naphthyl carbonyl, C _1-6Alkyl amino-carbonyl, amino-sulfonyl, two (C _1-6Alkyl) the amino C of amino-sulfonyl _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl, C _1-12Alkyl sulphonyl, two (C _1-6Alkyl) amino-sulfonyl, three halo C _1-6Alkyl sulphonyl, two (aryl) C _1-6Alkyl-carbonyl, thiophenyl C _1-6Alkyl-carbonyl, pyridyl carbonyl or aryl C _1-6Alkyl-carbonyl; R ¹⁴Be hydrogen; Work as R ¹³And R ¹⁴When being present on the identical carbon atom, R ¹³And R ¹⁴Can form the divalent group of formula (a-1) together, wherein R ¹⁰It is aryl; Or work as R ¹³And R ¹⁴When being present on the adjacent carbon atom, R ¹³And R ¹⁴Can form the divalent group of formula (b-1) together.

[0122]

In some embodiments according to the compound of paragraph [0115],

N is 1; Q is Z is a nitrogen; R ¹²Be hydrogen; R ¹³Be naphthyl carbonyl, C _1-12Alkyl sulphonyl or two (aryl) C _1-6Alkyl-carbonyl; And R ¹⁴Be hydrogen.

[0123]

Specific implementations according to the compound of paragraph [0115] comprises following

Wherein terminal hydroxamic acid part (C (O)-NH-OH) quilt

[0124]

In the compound of paragraph [0115]-[0123], R ¹, R ², R ³And R ⁴Preferably such as in paragraph [0048] and [0049] definition, in other embodiment of the compound of paragraph [0115]-[0123], R ¹, R ², R ³And R ⁴Be H.

[0125]

In another embodiment, the present invention includes compound or its pharmacologically acceptable salts of following structural (6):

Wherein

Ф is-NH ₂Or-OH;

R ¹Be H or such as in the paragraph [0046] definition;

R ², R ³And R ⁴Such as in the paragraph [0046] definition;

N is 0,1,2 or 3, and when n was 0, it was meant direct key;

M is 0 or 1, and when m was 0, it was meant direct key;

T is 0,1,2,3 or 4, and when t was 0, it was meant direct key;

Q be nitrogen or

Or

X be nitrogen or

Y be nitrogen or

R be selected from hydrogen, halogen ,-NH ₂, nitro, hydroxyl, aryl, heterocyclic radical, C ₃-C ₈-cycloalkyl, heteroaryl, C ₁-C ₇-alkyl, haloalkyl, C ₁-C ₇-alkenyl, C ₁-C ₇-alkynyl, C ₁-C ₇-acyl group, C ₁-C ₇-alkyl-aryloxy, C ₁-C ₇-alkyl-sulfur alkyl aryl, C ₁-C ₇-alkyl-aryl sulfonyl kia, C ₁-C ₇-alkyl-aryl sulfonyl, C ₁-C ₇-alkyl-n-aryl sulfonyl, C ₁-C ₇-alkyl-arylamine, C ₁-C ₇-alkynyl-C (O)-amine, C ₁-C ₇-alkenyl-C (O)-amine, C ₁-C ₇-alkynyl-R ⁹, C ₁-C ₇-alkenyl-R ⁹, R wherein ⁹Be hydrogen, hydroxyl, amino, C ₁-C ₇-alkyl or C ₁-C ₇-alkoxyl group;

-L-is direct key or is selected from C _1-6Alkane 2 basis, C _1-6Alkane 2 basis oxygen base, amino, carbonyl or aminocarboxy divalent group;

Each R ¹³Represent hydrogen atom independently, and a hydrogen atom can be replaced by a substituting group that is selected from aryl;

R ¹⁵Be hydrogen, C _1-6Alkyl, C _3-10Cycloalkyl, hydroxyl C _1-6Alkyl, C _1-6Alkoxy C _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl or aryl;

For being selected from following group

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

Each R⁶And R⁷Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C_1-6Alkyl; Three halo C_1-6Alkoxyl; C_1-6Alkyl; By aryl and C_3-10The C that cycloalkyl replaces_1-6Alkyl; C_1-6Alkoxyl; C_1-6Alkoxy C_1-6Alkoxyl; C_1-6The alkyl carbonyl; C_1-6The alkoxyl carbonyl; C_1-6The alkyl sulfonyl base; Cyano group C_1-6Alkyl; Hydroxyl C_1-6Alkyl; Hydroxyl C_1-6Alkoxyl; Hydroxyl C_1-6Alkyl is amino; Amino C_1-6Alkoxyl; Two (C_1-6Alkyl) amino carbonyl; Two (hydroxyl C_1-6Alkyl) amino; (aryl) (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkoxyl; Two (C_1-6Alkyl) amino C_1-6Alkyl is amino; Two (C_1-6Alkyl) amino C_1-6The amino C of alkyl_1-6Alkyl; Aryl sulfonyl; Arlysulfonylamino; Aryloxy group; Aryloxy group C_1-6Alkyl; Aryl C_2-6Olefin 2 base; Two (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino (C_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl; Amino (the C of amino-sulfonyl_1-6Alkyl) amino; Amino (the C of amino-sulfonyl_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino (C of amino-sulfonyl_1-6Alkyl) amino; Two (C_1-6Alkyl) amino (C of amino-sulfonyl_1-6Alkyl) amino C_1-6Alkyl; Cyano group; Thiophenyl; By two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl, two (C_1-6Alkyl) amino C_1-6Alkyl, C_1-6Alkylpiperazinyl C_1-6Alkyl, hydroxyl C_1-6Alkylpiperazinyl C_1-6Alkyl, hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl C_1-6Alkyl, two (C_1-6Alkyl) amino-sulfonyl piperazinyl C_1-6Alkyl, C_1-6Alkoxyl piperidyl, C_1-6Alkoxyl piperidyl C_1-6Alkyl, morpholinyl C_1-6Alkyl, hydroxyl C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl or two (hydroxyl C_1-6Alkyl) amino C_1-6The thiophenyl that alkyl replaces; Furyl; By hydroxyl C_1-6The furyl that-alkyl replaces; Benzofuranyl; Imidazole radicals; Oxazolyl; By aryl and C_1-6Alkyl replaces the De oxazolyl; C_1-6The alkyl triazolyl; Tetrazole radical; Pyrrolidinyl; Pyrrole radicals; Piperidyl C_1-6Alkoxyl; Morpholinyl; C_1-6The alkyl morpholine base; Morpholinyl C_1-6Alkoxyl; Morpholinyl C_1-6Alkyl; Morpholinyl C_1-6Alkyl is amino; Morpholinyl C_1-6The amino C of alkyl_1-6Alkyl; Piperazinyl; C_1-6Alkylpiperazinyl; C_1-6-alkylpiperazinyl C_1-6-alkoxyl; Piperazinyl C_1-6-alkyl; Naphthyl sulfonyl piperazinyl; Naphthyl sulfonyl piperidyl; The naphthyl sulfonyl; C_1-6Alkylpiperazinyl C_1-6Alkyl; C_1-6Alkylpiperazinyl C_1-6Alkyl is amino; C_1-6Alkylpiperazinyl C_1-6The amino C of alkyl_1-6Alkyl; C_1-6-alkylpiperazinyl sulfonyl; Amino-sulfonyl piperazinyl C_1-6Alkoxyl; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C_1-6Alkyl; Two (C_1-6Alkyl) amino-sulfonyl piperazinyl; Two (C_1-6Alkyl) amino-sulfonyl piperazinyl C_1-6Alkyl; Hydroxyl C_1-6Alkylpiperazinyl; Hydroxyl C_1-6Alkylpiperazinyl C_1-6-alkyl; C_1-6The alkoxyl piperidyl; C_1-6-alkoxyl piperidyl C_1-6Alkyl; The amino C of piperidyl_1-6Alkyl is amino; The amino C of piperidyl_1-6The amino C of alkyl_1-6Alkyl; (C_1-6The Alkylpiperidine base) (hydroxyl C_1-6Alkyl) amino C_1-6Alkyl is amino; (C_1-6The Alkylpiperidine base) (hydroxyl C_1-6Alkyl) amino C_1-6The amino C of alkyl_1-6Alkyl; Hydroxyl C_1-6-alkoxy C_1-6Alkylpiperazinyl; Hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl C_1-6Alkyl; (hydroxyl C_1-6Alkyl) (C_1-6Alkyl) amino; (hydroxyl C_1-6Alkyl) (C_1-6Alkyl) amino C_1-6Alkyl; Hydroxyl C_1-6The amino C of alkyl_1-6Alkyl; Two (hydroxyl C_1-6Alkyl) amino C_1-6Alkyl; Pyrrolidinyl C_1-6Alkyl; Pyrrolidinyl C_1-6Alkoxyl; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two_1-6Alkyl or three halo C_1-6The pyrazolyl that the substituting group of alkyl replaces; Pyridine radicals; By C_1-6The pyridine radicals that alkoxyl, aryloxy group or aryl replace; Pyrimidine radicals; The tetrahydro-pyrimidine base piperazinyl; Tetrahydro-pyrimidine base piperazinyl C_1-6Alkyl; Quinolyl; Indoles; Phenyl; By the phenyl that, two or three substituting groups replace, these substituting groups are independently selected from halogen, amino, nitro, C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-4Alkyl, trifluoromethyl, trifluoro methoxyl group, hydroxyl C_1-4Alkoxyl, C_1-4Alkyl sulfonyl base, C_1-4Alkoxy C_1-4Alkoxyl, C_1-4Alkoxyl carbonyl, amino C_1-4Alkoxyl, two (C_1-4Alkyl) amino C_1-4Alkoxyl, two (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino carbonyl, two (C_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4The amino C of alkyl_1-4Alkyl, two (C_1-4Alkyl) amino (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino (C_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4Alkyl (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino C_1-4Alkyl (C_1-4Alkyl) amino C_1-4Alkyl, the amino (C of amino-sulfonyl_1-4Alkyl) amino, the amino (C of amino-sulfonyl_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino (C of amino-sulfonyl_1-4Alkyl) amino, two (C_1-4Alkyl) amino (C of amino-sulfonyl_1-4Alkyl) amino C_1-6Alkyl, cyano group, piperidyl C_1-4Alkoxyl, pyrrolidinyl C_1-4Alkoxyl; Amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C_1-4Alkyl, two (C_1-4Alkyl) amino-sulfonyl piperazinyl, two (C_1-4Alkyl) amino-sulfonyl piperazinyl C_1-4Alkyl, hydroxyl C_1-4Alkylpiperazinyl, hydroxyl C_1-4Alkylpiperazinyl C_1-4Alkyl, C_1-4Alkoxyl piperidyl, C_1-4Alkoxyl piperidyl C_1-4Alkyl, hydroxyl C_1-4Alkoxy C_1-4Alkylpiperazinyl, hydroxyl C_1-4Alkoxy C_1-4Alkylpiperazinyl C_1-4Alkyl, (hydroxyl C_1-4Alkyl) (C_1-4Alkyl) amino, (hydroxyl C_1-4Alkyl) (C_1-4Alkyl) amino C_1-4Alkyl, two (hydroxyl C_1-4Alkyl) amino, two (hydroxyl C_1-4Alkyl) amino C_1-4Furyl, pyrrolidinyl C that alkyl, furyl, quilt-CH=CH-CH=CH-replace_1-4Alkyl, pyrrolidinyl C_1-4Alkoxyl, morpholinyl, morpholinyl C_1-4Alkoxyl, morpholinyl C_1-4Alkyl, morpholinyl C_1-4Alkyl is amino, morpholinyl C_1-4The amino C of alkyl_1-4Alkyl, piperazinyl, C_1-4Alkylpiperazinyl, C_1-4Alkylpiperazinyl C_1-4Alkoxyl, piperazinyl C_1-4Alkyl, C_1-4Alkylpiperazinyl C_1-4Alkyl, C_1-4Alkylpiperazinyl C_1-4Alkyl is amino, C_1-4Alkylpiperazinyl C_1-4The amino C of alkyl_1-6Alkyl, tetrahydro-pyrimidine base piperazinyl, tetrahydro-pyrimidine base piperazinyl C_1-4Alkyl, the amino C of piperidyl_1-4Alkyl is amino, the amino C of piperidyl_1-4The amino C of alkyl_1-4Alkyl, (C_1-4The Alkylpiperidine base) (hydroxyl C_1-4Alkyl) amino C_1-4Alkyl is amino, (C_1-4The Alkylpiperidine base) (hydroxyl C_1-4Alkyl) amino C_1-4The amino C of alkyl_1-4Alkyl, piperidyl C_1-4Alkoxyl, hydroxyl C_1-4Alkyl is amino, hydroxyl C_1-4The amino C of alkyl_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4Alkyl amino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C_1-4Alkoxyl or thiophenyl C_1-4-alkyl is amino;

Each R ⁶And R ⁷Can be positioned on the nitrogen to replace hydrogen;

Aryl above is a phenyl, or by one or more halogen, C of being selected from independently of one another _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group, trifluoromethyl, cyano group or hydroxycarbonyl group replaces.

[0126]

In some embodiments, use in the following restricted condition one or multinomial according to the compound of paragraph [0125]:

N is 1;

M is 0 or 1;

T is 0,1 or 2;

Q is

Or

R ¹²Be hydrogen or C _1-6Alkyl;

-L-is direct key;

R ¹⁴Be hydrogen;

R ¹⁵Be hydrogen;

Be to be selected from (a-1), (a-20), (a-25), (a-27), (a-28), (a-29), (a-41) or group (a-42);

Each s is 0,1,2 or 3 independently;

Each R ⁶Be independently selected from hydrogen, halogen, C _1-6Alkyl or C _1-6Alkoxyl group.

[0127]

In other embodiment, use in the following restricted condition one or multinomial according to the compound of paragraph [0125]:

N is 1;

M is 0 or 1;

T is 0,1 or 2;

Q is Or

R ¹²Be hydrogen;

-L-is direct key;

R ¹⁴Be hydrogen;

R ¹⁵Be hydrogen;

Each s is 0,1,2 or 3 independently;

[0128]

R ¹⁵Be hydrogen, C _1-6Alkyl, C _3-10Cycloalkyl, hydroxyl C _1-6Alkyl, C _1-6Alkoxy C _1-6Alkyl or two (C _1-6Alkyl) amino C _1-6Alkyl;

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

Each R ⁶And R ⁷Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkoxy C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkyl sulphonyl; Cyano group C _1-6Alkyl; Hydroxyl C _1-6Alkyl; Hydroxyl C _1-6Alkoxyl group; Hydroxyl C _1-6Alkylamino; Amino C _1-6Alkoxyl group; Two (C _1-6Alkyl) aminocarboxyl; Two (hydroxyl C _1-6Alkyl) amino; Aryl C _1-6Alkyl) amino; Two (C _1-6Alkyl) amino C _1-6Alkoxyl group; Two (C _1-6Alkyl) amino C _1-6Alkylamino; Aryl sulfonyl; Arlysulfonylamino; Aryloxy; Aryl C _2-6Olefin 2 base; Two (C _1-6-alkyl) amino; Two (C _1-6-alkyl) amino C _1-6-alkyl; Two (C _1-6-alkyl) amino C _1-6Alkyl (C _1-6Alkyl) amino C _1-6Alkyl; Cyano group; Thiophenyl; By two (C _1-6Alkyl) amino C _1-6Alkyl (C _1-6Alkyl) amino C _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl, C _1-6Alkylpiperazine base C _1-6Alkyl or two (hydroxyl C _1-6Alkyl) amino C _1-6The thiophenyl that alkyl replaces; Furyl; Imidazolyl; C _1-6The alkyl triazolyl; Tetrazyl; Pyrrolidyl; Piperidyl C _1-6Alkoxyl group; Morpholinyl; C _1-6The alkyl morpholine base; Morpholinyl C _1-6Alkoxyl group; Morpholinyl C _1-6Alkyl; C _1-6The alkylpiperazine base; C _1-6Alkylpiperazine base C _1-6Alkoxyl group; C _1-6Alkylpiperazine base C _1-6Alkyl; C _1-6Alkylpiperazine base alkylsulfonyl; Amino-sulfonyl piperazinyl C _1-6Alkoxyl group; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C _1-6Alkyl; Two (C _1-6Alkyl) amino-sulfonyl piperazinyl; Two (C _1-6Alkyl) amino-sulfonyl piperazinyl C _1-6Alkyl; Hydroxyl C _1-6The alkylpiperazine base; Hydroxyl C _1-6Alkylpiperazine base C _1-6Alkyl; C _1-6-alkoxyl group piperidyl; C _1-6-alkoxyl group piperidyl C _1-6Alkyl; Hydroxyl C _1-6Alkoxy C _1-6The alkylpiperazine base; Hydroxyl C _1-6Alkoxy C _1-6Alkylpiperazine base C _1-6Alkyl; (hydroxyl C _1-6Alkyl) (C _1-6Alkyl) amino; (hydroxyl C _1-6Alkyl) (C _1-6Alkyl) amino C _1-6-alkyl; Pyrrolidyl C _1-6Alkoxyl group; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two _1-6Alkyl or three halo C _1-6The pyrazolyl that the substituting group of alkyl replaces; Pyridyl; By C _1-6The pyridyl that alkoxyl group or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; By one, two or three are independently selected from halogen, amino, C _1-6Alkyl, C _1-6Alkoxyl group, hydroxyl C _1-4Alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl C _1-4Alkoxyl group, C _1-4Alkoxy C _1-4Alkoxyl group, amino C _1-4Alkoxyl group, two (C _1-4Alkyl) amino C _1-4Alkoxyl group, two (C _1-4Alkyl) amino, two (C _1-4Alkyl) amino C _1-4Alkyl, two (C _1-4Alkyl) amino C _1-4Alkyl (C _1-4Alkyl) amino C _1-4Alkyl, piperidyl C _1-4Alkoxyl group, pyrrolidyl C _1-4Alkoxyl group, amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C _1-4-alkyl, two (C _1-4Alkyl) amino-sulfonyl piperazinyl, two (C _1-4Alkyl) amino-sulfonyl piperazinyl C _1-4Alkyl, hydroxyl C _1-4Alkylpiperazine base, hydroxyl C _1-4Alkylpiperazine base C _1-4Alkyl, C _1-4Alkoxyl group piperidyl, C _1-4Alkoxyl group piperidyl C _1-4Alkyl, hydroxyl C _1-4Alkoxy C _1-4Alkylpiperazine base, hydroxyl C _1-4Alkoxy C _1-4Alkylpiperazine base C _1-4Alkyl, (hydroxyl C _1-4Alkyl) (C _1-4Alkyl) amino, (hydroxyl C _1-4Alkyl) (C _1-4Alkyl) amino C _1-4Alkyl, pyrrolidyl C _1-4-alkoxyl group, morpholinyl C _1-4Alkoxyl group, morpholinyl C _1-4Alkyl, C _1-4Alkylpiperazine base, C _1-4Alkylpiperazine base C _1-4Alkoxyl group, C _1-4Alkylpiperazine base C _1-4Alkyl, hydroxyl C _1-4-alkylamino, two (hydroxyl C _1-4Alkyl) amino, two (C _1-4-alkyl) amino C _1-4Alkylamino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C _1-4Alkoxyl group or thiophenyl C _1-4The phenyl that the substituting group of alkylamino replaces.

[0129]

t＝0；

m＝0；

-L-is direct key or is selected from C _1-6Alkane 2 basis, C _1-6The divalent group of alkane 2 basis oxygen base, amino or carbonyl;

R ¹⁴Be hydrogen, hydroxyl, amino, hydroxyl C _1-6Alkyl, C _1-6Alkyl, C _1-6Alkoxyl group, aryl C _1-6Alkyl, aminocarboxyl, amino C _1-6Alkyl, C _1-6Alkylamino C _1-6Alkyl or two (C _1-6Alkyl) amino C _1-6Alkyl;

R ¹⁵Be hydrogen;

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

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

R ⁶Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkoxy carbonyl; C _1-6Alkyl sulphonyl; Hydroxyl C _1-6Alkyl; Aryloxy; Two (C _1-6Alkyl) amino; Cyano group; Thiophenyl; Furyl; By hydroxyl C _1-6The furyl that alkyl replaces; Benzofuryl; Imidazolyl; Oxazolyl; By aryl and C _1-6Alkyl replaces the De oxazolyl; C _1-6-alkyl triazolyl; Tetrazyl; Pyrrolidyl; Pyrryl; Morpholinyl; C _1-6The alkyl morpholine base; Piperazinyl; C _1-6The alkylpiperazine base; Hydroxyl C _1-6-alkylpiperazine base; C _1-6The alkoxyl group piperidyl; Pyrazolyl; Be selected from C by one or two _1-6Alkyl or three halo C _1-6The pyrazolyl that alkyl replaces; Pyridyl; By C _1-6The pyridyl that-alkoxyl group, aryloxy or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; Or be independently selected from halogen, C by one or two _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group or trifluoromethyl replaces;

R ⁷Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkoxy carbonyl; C _1-6Alkyl sulphonyl; Hydroxyl C _1-6Alkyl; Aryloxy; Two (C _1-6Alkyl) amino; Cyano group; Pyridyl; Phenyl; Or be independently selected from halogen, C by one or two _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group or trifluoromethyl replaces.

[0130]

In some embodiments according to the compound of paragraph [0125]:

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

Each R ⁶And R ⁷Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkoxy C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkyl sulphonyl; Cyano group C _1-6Alkyl; Hydroxyl C _1-6Alkyl; Hydroxyl C _1-6Alkoxyl group; Hydroxyl C _1-6Alkylamino; Amino C _1-6Alkoxyl group; Two (C _1-6Alkyl) aminocarboxyl; Two (hydroxyl C _1-6Alkyl) amino; Aryl C _1-6Alkyl) amino; Two (C _1-6Alkyl) amino C _1-6Alkoxyl group; Two (C _1-6Alkyl) amino C _1-6Alkylamino; Aryl sulfonyl; Arlysulfonylamino; Aryloxy; Aryl C _2-6Olefin 2 base; Two (C _1-6Alkyl) amino; Two (C _1-6Alkyl) amino C _1-6-alkyl; Two (C _1-6Alkyl) amino C _1-6Alkyl (C _1-6Alkyl) amino C _1-6Alkyl; Cyano group; Thiophenyl; By two (C _1-6Alkyl) amino C _1-6Alkyl (C _1-6Alkyl) amino C _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl, C _1-6Alkylpiperazine base C _1-6Alkyl or two (hydroxyl C _1-6Alkyl) amino C _1-6The thiophenyl that alkyl replaces; Furyl; Imidazolyl; C _1-6The alkyl triazolyl; Tetrazyl; Pyrrolidyl; Piperidyl C _1-6Alkoxyl group; Morpholinyl; C _1-6The alkyl morpholine base; Morpholinyl C _1-6Alkoxyl group; Morpholinyl C _1-6Alkyl; C _1-6The alkylpiperazine base; C _1-6Alkylpiperazine base C _1-6Alkoxyl group; C _1-6Alkylpiperazine base C _1-6Alkyl; C _1-6Alkylpiperazine base alkylsulfonyl; Amino-sulfonyl piperazinyl C _1-6Alkoxyl group; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C _1-6Alkyl; Two (C _1-6Alkyl) amino-sulfonyl piperazinyl; Two (C _1-6Alkyl) amino-sulfonyl piperazinyl C _1-6Alkyl; Hydroxyl C _1-6The alkylpiperazine base; Hydroxyl C _1-6Alkylpiperazine base C _1-6Alkyl; C _1-6-alkoxyl group piperidyl; C _1-6-alkoxyl group piperidyl C _1-6Alkyl; Hydroxyl C _1-6Alkoxy C _1-6The alkylpiperazine base; Hydroxyl C _1-6Alkoxy C _1-6Alkylpiperazine base C _1-6Alkyl; (hydroxyl C _1-6Alkyl) (C _1-6Alkyl) amino; (hydroxyl C _1-6Alkyl) (C _1-6Alkyl) amino C _1-6Alkyl pyrrolidine base C _1-6Alkoxyl group; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two _1-6Alkyl or three halo C _1-6The pyrazolyl that the substituting group of alkyl replaces; Pyridyl; By C _1-6The pyridyl that alkoxyl group or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; By one, two or three are independently selected from halogen, amino, C _1-6Alkyl, C _1-6Alkoxyl group, hydroxyl C _1-4Alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl C _1-4Alkoxyl group, C _1-4Alkoxy C _1-4Alkoxyl group, amino C _1-4Alkoxyl group, two (C _1-4Alkyl) amino C _1-4Alkoxyl group, two (C _1-4Alkyl) amino, two (C _1-4Alkyl) amino C _1-4Alkyl, two (C _1-4Alkyl) amino C _1-4Alkyl (C _1-4Alkyl) amino C _1-4Alkyl, piperidyl C _1-4Alkoxyl group, pyrrolidyl C _1-4Alkoxyl group, amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C _1-4-alkyl, two (C _1-4Alkyl) amino-sulfonyl piperazinyl, two (C _1-4Alkyl) amino-sulfonyl piperazinyl C _1-4Alkyl, hydroxyl C _1-4Alkylpiperazine base, hydroxyl C _1-4Alkylpiperazine base C _1-4Alkyl, C _1-4Alkoxyl group piperidyl, C _1-4Alkoxyl group piperidyl C _1-4Alkyl, hydroxyl C _1-4Alkoxy C _1-4Alkylpiperazine base, hydroxyl C _1-4Alkoxy C _1-4Alkylpiperazine base C _1-4Alkyl, (hydroxyl C _1-4Alkyl) (C _1-4Alkyl) amino, (hydroxyl C _1-4Alkyl) (C _1-4Alkyl) amino C _1-4Alkyl, pyrrolidyl C _1-4Alkoxyl group, morpholinyl C _1-4Alkoxyl group, morpholinyl C _1-4-alkyl, C _1-4Alkylpiperazine base, C _1-4Alkylpiperazine base C _1-4Alkoxyl group, C _1-4Alkylpiperazine base C _1-4Alkyl, hydroxyl C _1-4Alkylamino, two (hydroxyl C _1-4Alkyl) amino, two (C _1-4Alkyl) amino C _1-4Alkylamino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C _1-4Alkoxyl group or thiophenyl C _1-4The phenyl that the substituting group of alkylamino replaces.

[0131]

In some embodiments according to the compound of paragraph [0125], t is 0, and m is 0, and:

R ¹⁵Be hydrogen;

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

R ⁶Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkoxy carbonyl; C _1-6Alkyl sulphonyl; Hydroxyl C _1-6Alkyl; Aryloxy; Two (C _1-6Alkyl) amino; Cyano group; Thiophenyl; Furyl; By hydroxyl C _1-6The furyl that alkyl replaces; Benzofuryl; Imidazolyl; Oxazolyl; By aryl and C _1-6Alkyl replaces the De oxazolyl; C _1-6-alkyl triazolyl; Tetrazyl; Pyrrolidyl; Pyrryl; Morpholinyl; C _1-6-alkyl morpholine base; Piperazinyl; C _1-6The alkylpiperazine base; Hydroxyl C _1-6-alkylpiperazine base; C _1-6-alkoxyl group piperidyl; Pyrazolyl; Be selected from C by one or two _1-6Alkyl or three halo C _1-6The pyrazolyl that alkyl replaces; Pyridyl; By C _1-6The pyridyl that-alkoxyl group or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; Or be independently selected from halogen, C by one or two _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group or trifluoromethyl replaces;

And R ⁷Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkoxy carbonyl; C _1-6Alkyl sulphonyl; Hydroxyl C _1-6Alkyl; Aryloxy; Two (C _1-6Alkyl) amino; Cyano group; Pyridyl; Phenyl; Or be independently selected from halogen, C by one or two _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group or trifluoromethyl replaces.

[0132]

In some embodiments according to the compound of paragraph [0125],

N is 1; M is 0 or 1; T is 0,1 or 2; Q is Or

R ¹²Be hydrogen or C _1-6Alkyl;-L-is direct key;

R ¹⁴And R ¹⁵Be hydrogen;

Be to be selected from (a-1), (a-20), (a-25), (a-27), (a-28), (a-29), (a-41) or group (a-42); Each s is 0,1 or 2 independently; And each R ⁶Be independently selected from hydrogen, halogen, C _1-6Alkyl or C _1-6Alkoxyl group.

[0133]

In some embodiments according to the compound of paragraph [0125],

N is 1; M is 0 or 1; T is 0,1 or 2; Q is

Or

R ¹²Be hydrogen;-L-is direct key;

R ¹⁴And R ¹⁵Be hydrogen;

Be to be selected from (a-1), (a-20), (a-27), (a-28), (a-29), (a-41) or group (a-42); Each s is 0,1 or 2 independently; And each R ⁶Be independently selected from hydrogen, halogen, C _1-6Alkyl or C _1-6Alkoxyl group.

[0134]

Specific implementations according to the compound of paragraph [0125] comprises following

Wherein terminal hydroxamic acid part (C (O)-NH-OH) quilt

[0135]

In the compound of paragraph [0125]-[0134], R ¹, R ², R ³And R ⁴Preferably such as in paragraph [0048] and [0049] definition, in other embodiment of the compound of paragraph [0125]-[0134], R ¹, R ², R ³And R ⁴Be H.

[0136]

In another embodiment, the present invention includes compound or its pharmacologically acceptable salts of following structural (7):

Wherein

Ф is-NH ₂Or-OH;

R ¹Be H or such as in the paragraph [0046] definition;

R ², R ³And R ⁴Such as in the paragraph [0046] definition;

N is 0,1,2 or 3, and when n was 0, it was meant direct key;

T is 0,1,2,3 or 4, and when t was 0, it was meant direct key;

Q be nitrogen or

Or

X be nitrogen or

Y be nitrogen or

Z be nitrogen or

-L-is direct key or is selected from C _1-6Alkane 2 basis, C _1-6Alkoxyl group, amino, carbonyl or aminocarboxy divalent group;

Each R ¹³Represent hydrogen atom independently, and the substituting group that hydrogen atom can be selected from aryl replaces;

For being selected from following group

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

Each R⁵And R⁶Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C_1-6Alkyl; Three halo C_1-6Alkoxyl; C_1-6Alkyl; By aryl and C_3-10The C that cycloalkyl replaces_1-6Alkyl; C_1-6Alkoxyl; C_1-6Alkoxy C_1-6Alkoxyl; C_1-6The alkyl carbonyl; C_1-6The alkoxyl carbonyl; C_1-6The alkyl sulfonyl base; Cyano group C_1-9Alkyl; Hydroxyl C_1-6Alkyl; Hydroxyl C_1-6Alkoxyl; Hydroxyl C_1-6Alkyl is amino; Amino C_1-6Alkoxyl; Two (C_1-6Alkyl) amino carbonyl; Two (hydroxyl C_1-6Alkyl) amino; (aryl) (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkoxyl; Two (C_1-6Alkyl) amino C_1-6Alkyl amino; Two (C_1-6Alkyl) amino C_1-6Alkyl amino C_1-6Alkyl; Aryl sulfonyl; Arlysulfonylamino; Aryloxy group; Aryloxy group C_1-6Alkyl; Aryl C_2-6Olefin 2 base; Two (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino (C_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl; Amino (the C of amino-sulfonyl_1-6Alkyl) amino; Amino (the C of amino-sulfonyl_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino (C of amino-sulfonyl_1-6Alkyl) amino; Two (C_1-6Alkyl) amino (C of amino-sulfonyl_1-6Alkyl) amino C_1-6Alkyl; Cyano group; Thiophenyl; By two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl, two (C_1-6Alkyl) amino C_1-6Alkyl, C_1-6Alkylpiperazinyl C_1-6Alkyl, hydroxyl C_1-6Alkylpiperazinyl C_1-6Alkyl, hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl C_1-6Alkyl, two (C_1-6Alkyl) amino-sulfonyl piperazinyl C_1-6Alkyl, C_1-6Alkoxyl piperidyl, C_1-6Alkoxyl piperidyl C_1-6Alkyl, morpholinyl C_1-6Alkyl, hydroxyl C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl or two (hydroxyl C_1-6Alkyl) amino C_1-6The thiophenyl that alkyl replaces; Furyl; By hydroxyl C_1-6The furyl that-alkyl replaces; Benzofuranyl; Imidazole radicals; Oxazolyl; By aryl and C_1-6Alkyl replaces the De oxazolyl; C_1-6-alkyl triazolyl; Tetrazole radical; Pyrrolidinyl; Pyrrole radicals; Piperidyl C_1-6Alkoxyl; Morpholinyl; C_1-6-alkyl morpholine base; Morpholinyl C_1-6Alkoxyl; Morpholinyl C_1-6Alkyl; Morpholinyl C_1-6Alkyl is amino; Morpholinyl C_1-6The amino C of alkyl_1-6Alkyl; Piperazinyl; C_1-6Alkylpiperazinyl; C_1-6Alkylpiperazinyl C_1-6Alkoxyl; Piperazinyl C_1-6-alkyl; Naphthyl sulfonyl piperazinyl; Naphthyl sulfonyl piperidyl; The naphthyl sulfonyl; C_1-6Alkylpiperazinyl C_1-6Alkyl; C_1-6Alkylpiperazinyl C_1-6Alkyl is amino; C_1-6Alkylpiperazinyl C_1-6The amino C of alkyl_1-6Alkyl; C_1-6The alkylpiperazinyl sulfonyl; Amino-sulfonyl piperazinyl C_1-6Alkoxyl; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C_1-6Alkyl; Two (C_1-6Alkyl) amino-sulfonyl piperazinyl; Two (C_1-6-alkyl) amino-sulfonyl piperazinyl C_1-6Alkyl; Hydroxyl C_1-6Alkylpiperazinyl; Hydroxyl C_1-6Alkylpiperazinyl C_1-6Alkyl; C_1-6The alkoxyl piperidyl; C_1-6Alkoxyl piperidyl C_1-6Alkyl; The amino C of piperidyl_1-6Alkyl is amino; The amino C of piperidyl_1-6The amino C of alkyl_1-6Alkyl; (C_1-6The Alkylpiperidine base) (hydroxyl C_1-6Alkyl) amino C_1-6Alkyl is amino; (C_1-6The Alkylpiperidine base) (hydroxyl C_1-6Alkyl) amino C_1-6The amino C of alkyl_1-6Alkyl; Hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl; Hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl C_1-6Alkyl; (hydroxyl C_1-6Alkyl) (C_1-6Alkyl) amino; (hydroxyl C_1-6Alkyl) (C_1-6Alkyl) amino C_1-6Alkyl; Hydroxyl C_1-6The amino C of alkyl_1-6Alkyl; Two (hydroxyl C_1-6Alkyl) amino C_1-6Alkyl; Pyrrolidinyl C_1-6Alkyl; Pyrrolidinyl C_1-6Alkoxyl; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two_1-6Alkyl or three halo C_1-6The pyrazolyl that the substituting group of alkyl replaces; Pyridine radicals; By C_1-6The pyridine radicals that alkoxyl, aryloxy group or aryl replace; Pyrimidine radicals; The tetrahydro-pyrimidine base piperazinyl; Tetrahydro-pyrimidine base piperazinyl C_1-6Alkyl; Quinolyl; Indoles; Phenyl; By the phenyl that, two or three substituting groups replace, these substituting groups are independently selected from halogen, amino, nitro, C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-4Alkyl, trifluoromethyl, trifluoro methoxyl group, hydroxyl C_1-4Alkoxyl, C_1-4Alkyl sulfonyl base, C_1-4Alkoxy C_1-4Alkoxyl, C_1-4Alkoxyl carbonyl, amino C_1-4Alkoxyl, two (C_1-4Alkyl) amino C_1-4Alkoxyl, two (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino carbonyl, two (C_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4The amino C of alkyl_1-4Alkyl, two (C_1-4Alkyl) amino (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino (C_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4Alkyl (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino C_1-4Alkyl (C_1-4Alkyl) amino C_1-4Alkyl, the amino (C of amino-sulfonyl_1-4Alkyl) amino, the amino (C of amino-sulfonyl_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino (C of amino-sulfonyl_1-4Alkyl) amino, two (C_1-4Alkyl) amino (C of amino-sulfonyl_1-4Alkyl) amino C_1-6Alkyl, cyano group, piperidyl C_1-4Alkoxyl, pyrrolidinyl C_1-4Alkoxyl, amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C_1-4Alkyl, two (C_1-4Alkyl) amino-sulfonyl piperazinyl, two (C_1-4Alkyl) amino-sulfonyl piperazinyl C_1-4Alkyl, hydroxyl C_1-4Alkylpiperazinyl, hydroxyl C_1-4Alkylpiperazinyl C_1-4Alkyl, C_1-4Alkoxyl piperidyl, C_1-4Alkoxyl piperidyl C_1-4Alkyl, hydroxyl C_1-4Alkoxy C_1-4Alkylpiperazinyl, hydroxyl C_1-4Alkoxy C_1-4Alkylpiperazinyl C_1-4Alkyl, (hydroxyl C_1-4Alkyl) (C_1-4Alkyl) amino, (hydroxyl C_1-4Alkyl) (C_1-4Alkyl) amino C_1-4Alkyl, two (hydroxyl C_1-4Alkyl) amino, two (hydroxyl C_1-4Alkyl) amino C_1-4Furyl, pyrrolidinyl C that alkyl, furyl, quilt-CH=CH-CH=CH-replace_1-4Alkyl, pyrrolidinyl C_1-4Alkoxyl, morpholinyl, morpholinyl C_1-4Alkoxyl, morpholinyl C_1-4Alkyl, morpholinyl C_1-4Alkyl is amino, morpholinyl C_1-4The amino C of alkyl_1-4Alkyl, piperazinyl, C_1-4Alkylpiperazinyl, C_1-4Alkylpiperazinyl C_1-4Alkoxyl, piperazinyl C_1-4Alkyl, C_1-4Alkylpiperazinyl C_1-4Alkyl, C_1-4Alkylpiperazinyl C_1-4Alkyl is amino, C_1-4Alkylpiperazinyl C_1-4The amino C of alkyl_1-6Alkyl, tetrahydro-pyrimidine base piperazinyl, tetrahydro-pyrimidine base piperazinyl C_1-4Alkyl, the amino C of piperidyl_1-4Alkyl is amino, the amino C of piperidyl_1-4The amino C of alkyl_1-4Alkyl, (C_1-4The Alkylpiperidine base) (hydroxyl C_1-4Alkyl) amino C_1-4Alkyl is amino, (C_1-4The Alkylpiperidine base) (hydroxyl C_1-4Alkyl) amino C_1-4The amino C of alkyl_1-4Alkyl, piperidyl C_1-4Alkoxyl, hydroxyl C_1-4Alkyl is amino, hydroxyl C_1-4The amino C of alkyl_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4Alkyl amino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C_1-4Alkoxyl or thiophenyl C_1-4Alkyl is amino,

Each R ⁵And R ⁶Can be positioned on the nitrogen to replace hydrogen;

[0137]

In other embodiment, be suitable for following one or the multinomial (R in this section wherein according to the compound of paragraph [0136] ², R ³And R ⁴Correspond respectively to the R in the paragraph [0136] separately ¹², R ¹³And R ¹⁴):

N is 1 or 2;

T is 0,1,2 or 4;

Q is Or

R ²Be hydrogen or nitro;

-L-is direct key or is selected from C _1-6The divalent group of alkane 2 basis;

R ⁴Be hydrogen;

Be to be selected from (a-1), (a-2), (a-3), (a-5), (a-6), (a-11), (a-1 8), (a-20), (a-21), (a-32), (a-33), (a-47) or group (a-51);

Each s is 0,1,2 or 4 independently;

Each R ⁵And R ⁶Be independently selected from hydrogen; Halogen; Three halo C _1-6Alkyl; C _1-6Alkyl; By aryl and C _3-10The C of cycloalkyl substituted _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; Cumarone; The naphthyl alkylsulfonyl; The pyridyl that is replaced by aryloxy; Phenyl; Or be independently selected from hydroxyl C by one _1-4Alkyl or morpholinyl C _1-4The phenyl that the substituting group of alkyl replaces.

[0138]

N is 1;

T is 0,1 or 2;

Q is Or

X is a nitrogen;

Y is a nitrogen;

R ²Be hydrogen;

-L-is direct key;

Each R ³Represent hydrogen atom independently;

R ⁴Be hydrogen;

Be to be selected from (a-6), (a-11), (a-20), (a-47) or group (a-51);

Each s is 0,1 or 4 independently;

Each R ⁵And R ⁶Be independently selected from hydrogen; C _1-6Alkyl; C _1-6Alkoxyl group; The naphthyl alkylsulfonyl; Or by hydroxyl C _1-4Alkyl or morpholinyl C _1-4The phenyl that alkyl replaces.

[0139]

In other embodiment according to the compound of paragraph [0136], L is direct key.

[0140]

T is 1,2,3 or 4;

R ²Be hydrogen, halogen, hydroxyl, amino, nitro, C _1-6Alkyl, C _1-6Alkoxyl group, trifluoromethyl or two (C _1-6Alkyl) amino;

R ⁴Be hydrogen, hydroxyl, amino, hydroxyl C _1-6Alkyl, C _1-6Alkyl, C _1-6Alkoxyl group, aryl C _1-6Alkyl, aminocarboxyl, amino C _1-6Alkyl, C _1-6Alkylamino C _1-6Alkyl or two (C _1-6Alkyl) amino C _1-6Alkyl;

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

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

R ⁵Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkoxy carbonyl; C _1-6Alkyl sulphonyl; Hydroxyl C _1-6Alkyl; Aryloxy; Two (C _1-6Alkyl) amino; Cyano group; Thiophenyl; Furyl; By hydroxyl C _1-6The furyl that alkyl replaces; Benzofuryl; Imidazolyl; Oxazolyl; By aryl and C _1-6Alkyl replaces the De oxazolyl; C _1-6-alkyl triazolyl; Tetrazyl; Pyrrolidyl; Pyrryl; Morpholinyl; C _1-6-alkyl morpholine base; Piperazinyl; C _1-6The alkylpiperazine base; Hydroxyl C _1-6The alkylpiperazine base; C _1-6The alkoxyl group piperidyl; Pyrazolyl; Be selected from C by one or two _1-6Alkyl or three halo C _1-6The pyrazolyl that alkyl replaces; Pyridyl; By C _1-6The pyridyl that-alkoxyl group, aryloxy or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; Or be independently selected from halogen, C by one or two _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group or trifluoromethyl replaces;

R ⁶Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkoxy carbonyl; C _1-6Alkyl sulphonyl; Hydroxyl C _1-6Alkyl; Aryloxy; Two (C _1-6Alkyl) amino; Cyano group; Pyridyl; Phenyl; Or be independently selected from halogen, C by one or two _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group or trifluoromethyl replaces.

[0141]

Comprise the compound that the meets following condition (R in this section wherein according to other embodiment of the compound of paragraph [0136] ², R ³And R ⁴Correspond respectively to the R in the paragraph [0136] separately ¹², R ¹³And R ¹⁴):

T is 1,2,3 or 4;

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

R ⁵Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkoxy carbonyl; C _1-6Alkyl sulphonyl; Hydroxyl C _1-6Alkyl; Aryloxy; Two (C _1-6Alkyl) amino; Cyano group; Thiophenyl; Furyl; By hydroxyl C _1-6The furyl that alkyl replaces; Benzofuryl; Imidazolyl; Oxazolyl; By aryl and C _1-6Alkyl replaces the De oxazolyl; C _1-6-alkyl triazolyl; Tetrazyl; Pyrrolidyl; Pyrryl; Morpholinyl; C _1-6-alkyl morpholine base; Piperazinyl; C _1-6The alkylpiperazine base; Hydroxyl C _1-6The alkylpiperazine base; C _1-6The alkoxyl group piperidyl; Pyrazolyl; Be selected from C by one or two _1-6Alkyl or three halo C _1-6The pyrazolyl that the substituting group of alkyl replaces; Pyridyl; By C _1-6The pyridyl that-alkoxyl group, aryloxy or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; Or be independently selected from halogen, C by one or two _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group or trifluoromethyl replaces;

[0142]

Following (the R in this section wherein of other embodiment according to the compound of paragraph [0136] ², R ³And R ⁴Correspond respectively to the R in the paragraph [0136] separately ¹², R ¹³And R ¹⁴):

N is 1 or 2;

T is 1,2,3 or 4;

Q is

Or

R ²Be H or nitro;

-L-is direct key or is selected from C _1-6The divalent group of alkane 2 basis; R ⁴Be hydrogen; Be to be selected from (a-1), (a-2), (a-3), (a-5), (a-6), (a-11), (a-18), (a-20), (a-21), (a-32), (a-33), (a-47) or group (a-51); Each s is 0,1,2 or 4 independently; Each R ⁵And R ⁶Be independently selected from hydrogen; Halogen; Three halo C _1-6Alkyl; C _1-6Alkyl; By aryl and C _3-10The C of cycloalkyl substituted _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; Benzofuryl; The naphthyl alkylsulfonyl; The pyridyl that is replaced by aryloxy; Phenyl; Or be independently selected from hydroxyl C by one _1-4Alkyl or morpholinyl C _1-4The phenyl that the substituting group of alkyl replaces.

[0143]

N is 1;

T is 0 or 1; X is a nitrogen; Y is a nitrogen;

Q is

Or

R ²Be hydrogen;-L-is direct key; Each R ³Represent hydrogen atom independently; R ⁴Be hydrogen; Be to be selected from (a-6), (a-11), (a-20), (a-47) or group (a-51); Each s is 0,1 or 4 independently; And each R ⁵And R ⁶Be independently selected from hydrogen; C _1-6Alkyl; C _1-6Alkoxyl group; The naphthyl alkylsulfonyl; Or by hydroxyl C _1-4Alkyl or morpholinyl C _1-4The aryl that alkyl replaces.

[0144]

Specific implementations according to the compound of paragraph [0136] comprises following

Wherein terminal hydroxamic acid part (C (O)-NH-OH) quilt

[0145]

In the compound of paragraph [0136]-[0144], R ¹, R ², R ³And R ⁴Preferably such as in paragraph [0048] and [0049] definition, in other embodiment of the compound of paragraph [0136]-[0144], R ¹, R ², R ³And R ⁴Be H.

[0146]

In another embodiment, the present invention includes compound or its pharmacologically acceptable salts of following structural (8):

Wherein

Ф is-NH ₂Or-OH;

R ¹Be H or such as in the paragraph [0046] definition;

R ², R ³And R ⁴Such as in the paragraph [0046] definition;

N is 0,1,2 or 3, and when n was 0, it was meant direct key;

T is 0,1,2,3 or 4, and when t was 0, it was meant direct key;

Q be nitrogen or Or

X be nitrogen or

Y be nitrogen or

Z be nitrogen or

For being selected from following group

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

Each R⁶And R⁷Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C_1-6Alkyl; Three halo C_1-6Alkoxyl; C_1-6Alkyl; By aryl and C_3-10The C that cycloalkyl replaces_1-6Alkyl; C_1-6Alkoxyl; C_1-6Alkoxy C_1-6Alkoxyl; C_1-6The alkyl carbonyl; C_1-6The alkoxyl carbonyl; C_1-6The alkyl sulfonyl base; Cyano group C_1-6Alkyl; Hydroxyl C_1-6Alkyl; Hydroxyl C_1-6Alkoxyl; Hydroxyl C_1-6Alkyl is amino; Amino C_1-6Alkoxyl; Two (C_1-6Alkyl) amino carbonyl; Two (hydroxyl C_1-6Alkyl) amino; (aryl) (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkoxyl; Two (C_1-6Alkyl) amino C_1-6Alkyl is amino; Two (C_1-6Alkyl) amino C_1-6The amino C of alkyl_1-6Alkyl; Aryl sulfonyl; Arlysulfonylamino; Aryloxy group; Aryloxy group C_1-6Alkyl; Aryl C_2-6Olefin 2 base; Two (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino (C_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl; Amino (the C of amino-sulfonyl_1-6Alkyl) amino; Amino (the C of amino-sulfonyl_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino (C of amino-sulfonyl_1-6Alkyl) amino; Two (C_1-6Alkyl) amino (C of amino-sulfonyl_1-6Alkyl) amino C_1-6Alkyl; Cyano group; Thiophenyl; By two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl, two (C_1-6Alkyl) amino C_1-6Alkyl, C_1-6Alkylpiperazinyl C_1-6Alkyl, hydroxyl C_1-6Alkylpiperazinyl C_1-6Alkyl, hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl C_1-6Alkyl, two (C_1-6Alkyl) amino-sulfonyl piperazinyl C_1-6Alkyl, C_1-6Alkoxyl piperidyl, C_1-6Alkoxyl piperidyl C_1-6Alkyl, morpholinyl C_1-6Alkyl, hydroxyl C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl or two (hydroxyl C_1-6Alkyl) amino C_1-6The thiophenyl that alkyl replaces; Furyl; By hydroxyl C_1-6The furyl that-alkyl replaces; Benzofuranyl; Imidazole radicals; Oxazolyl; By aryl and C_1-6Alkyl replaces the De oxazolyl; C_1-6The alkyl triazolyl; Tetrazole radical; Pyrrolidinyl; Pyrrole radicals; Piperidyl C_1-6-alkoxyl; Morpholinyl; C_1-6-alkyl morpholine base; Morpholinyl C_1-6Alkoxyl; Morpholinyl C_1-6Alkyl; Morpholinyl C_1-6Alkyl is amino; Morpholinyl C_1-6The amino C of alkyl_1-6Alkyl; Piperazinyl; C_1-6Alkylpiperazinyl; C_1-6Alkylpiperazinyl C_1-6Alkoxyl; Piperazinyl C_1-6Alkyl; Naphthyl sulfonyl piperazinyl; Naphthyl sulfonyl piperidyl; The naphthyl sulfonyl; C_1-6Alkylpiperazinyl C_1-6Alkyl; C_1-6Alkylpiperazinyl C_1-6Alkyl is amino; C_1-6Alkylpiperazinyl C_1-6The amino C of alkyl_1-6Alkyl; C_1-6The alkylpiperazinyl sulfonyl; Amino-sulfonyl piperazinyl C_1-6Alkoxyl; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C_1-6Alkyl; Two (C_1-6Alkyl) amino-sulfonyl piperazinyl; Two (C_1-6Alkyl) amino-sulfonyl piperazinyl C_1-6Alkyl; Hydroxyl C_1-6Alkylpiperazinyl; Hydroxyl C_1-6Alkylpiperazinyl C_1-6Alkyl; C_1-6The alkoxyl piperidyl; C_1-6Alkoxyl piperidyl C_1-6Alkyl; The amino C of piperidyl_1-6Alkyl is amino; The amino C of piperidyl_1-6The amino C of alkyl_1-6Alkyl; (C_1-6The Alkylpiperidine base) (hydroxyl C_1-6Alkyl) amino C_1-6Alkyl is amino; (C_1-6The Alkylpiperidine base) (hydroxyl C_1-6Alkyl) amino C_1-6The amino C of alkyl_1-6Alkyl; Hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl; Hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl C_1-6Alkyl; (hydroxyl C_1-6Alkyl) (C_1-6Alkyl) amino; (hydroxyl C_1-6Alkyl) (C_1-6Alkyl) amino C_1-6Alkyl; Hydroxyl C_1-6The amino C of alkyl_1-6Alkyl; Two (hydroxyl C_1-6Alkyl) amino C_1-6Alkyl; Pyrrolidinyl C_1-6Alkyl; Pyrrolidinyl C_1-6Alkoxyl; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two_1-6Alkyl or three halo C_1-6The pyrazolyl that the substituting group of alkyl replaces; Pyridine radicals; By C_1-6The pyridine radicals that alkoxyl, aryloxy group or aryl replace; Pyrimidine radicals; The tetrahydro-pyrimidine base piperazinyl; Tetrahydro-pyrimidine base piperazinyl C_1-6Alkyl; Quinolyl; Indoles; Phenyl; By the phenyl that, two or three substituting groups replace, these substituting groups are independently selected from halogen, amino, nitro, C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-4Alkyl, trifluoromethyl, trifluoro methoxyl group, hydroxyl C_1-4Alkoxyl, C_1-4Alkyl sulfonyl base, C_1-4Alkoxy C_1-4Alkoxyl, C_1-4Alkoxyl carbonyl, amino C_1-4Alkoxyl, two (C_1-4Alkyl) amino C_1-4Alkoxyl, two (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino carbonyl, two (C_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4The amino C of alkyl_1-4Alkyl, two (C_1-4Alkyl) amino (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino (C_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4Alkyl (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino C_1-4Alkyl (C_1-4Alkyl) amino C_1-4Alkyl, the amino (C of amino-sulfonyl_1-4Alkyl) amino, the amino (C of amino-sulfonyl_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino (C of amino-sulfonyl_1-4Alkyl) amino, two (C_1-4Alkyl) amino (C of amino-sulfonyl_1-4Alkyl) amino C_1-6Alkyl, cyano group, piperidyl C_1-4Alkoxyl, pyrrolidinyl C_1-4Alkoxyl; Amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C_1-4Alkyl, two (C_1-4Alkyl) amino-sulfonyl piperazinyl, two (C_1-4Alkyl) amino-sulfonyl piperazinyl C_1-4Alkyl, hydroxyl C_1-4Alkylpiperazinyl, hydroxyl C_1-4Alkylpiperazinyl C_1-4Alkyl, C_1-4Alkoxyl piperidyl, C_1-4Alkoxyl piperidyl C_1-4Alkyl, hydroxyl C_1-4Alkoxy C_1-4Alkylpiperazinyl, hydroxyl C_1-4Alkoxy C_1-4Alkylpiperazinyl C_1-4Alkyl, (hydroxyl C_1-4Alkyl) (C_1-4Alkyl) amino, (hydroxyl C_1-4Alkyl) (C_1-4Alkyl) amino C_1-4Alkyl, two (hydroxyl C_1-4Alkyl) amino, two (hydroxyl C_1-4Alkyl) amino C_1-4Furyl, pyrrolidinyl C that alkyl, furyl, quilt-CH=CH-CH=CH-replace_1-4Alkyl, pyrrolidinyl C_1-4Alkoxyl, morpholinyl, morpholinyl C_1-4Alkoxyl, morpholinyl C_1-4Alkyl, morpholinyl C_1-4Alkyl is amino, morpholinyl C_1-4The amino C of alkyl_1-4Alkyl, piperazinyl, C_1-4Alkylpiperazinyl, C_1-4Alkylpiperazinyl C_1-4Alkoxyl, piperazinyl C_1-4Alkyl, C_1-4Alkylpiperazinyl C_1-4Alkyl, C_1-4Alkylpiperazinyl C_1-4Alkyl is amino, C_1-4Alkylpiperazinyl C_1-4The amino C of alkyl_1-6Alkyl, tetrahydro-pyrimidine base piperazinyl, tetrahydro-pyrimidine base piperazinyl C_1-4Alkyl, the amino C of piperidyl_1-4Alkyl is amino, the amino C of piperidyl_1-4The amino C of alkyl_1-4Alkyl, (C_1-4The Alkylpiperidine base) (hydroxyl C_1-4Alkyl) amino C_1-4Alkyl is amino, (C_1-4The Alkylpiperidine base) (hydroxyl C_1-4Alkyl) amino C_1-4The amino C of alkyl_1-4Alkyl, piperidyl C_1-4Alkoxyl, hydroxyl C_1-4Alkyl is amino, hydroxyl C_1-4The amino C of alkyl_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4Alkyl amino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C_1-4Alkoxyl or thiophenyl C_1-4Alkyl is amino;

Each R ⁶And R ⁷Can be positioned on the nitrogen to replace hydrogen;

[0147]

In other embodiment, be suitable for following one or the multinomial (R in this section wherein according to the compound of paragraph [0146] ², R ³, R ⁴And R ⁵Correspond respectively to the R in the paragraph [0146] separately ¹², R ¹³, R ¹⁴And R ¹⁵):

N is 0,1 or 2;

T is 0,1,2 or 3;

Q

Or

R ²Be hydrogen, C _1-6Alkyl or naphthyl alkylsulfonyl pyrazinyl;

Each R ³Represent hydrogen atom independently;

R ⁴Be hydrogen, hydroxyl, hydroxyl C _1-6Alkyl or C _1-6Alkoxyl group;

R ⁵Be hydrogen, C _1-6Alkyl, hydroxyl C _1-6Alkyl or C _1-6Alkoxy C _1-6Alkyl;

Be to be selected from (a-1), (a-7) or group (a-20);

Each s is 0 or 1 independently;

Each R ⁶Be independently selected from hydrogen; Thiophenyl; Furyl; Benzofuryl; Phenyl; Or be independently selected from C by one _1-6Alkyl, C _1-6Alkoxyl group, hydroxyl C _1-4Alkyl, C _1-4Alkyl sulphonyl or two (C _1-4Alkyl) phenyl of amino substituting group replacement;

Each R ⁷Be independently selected from hydrogen.

[0148]

N is 1 or 2;

T is 0,1,2 or 3;

Q is Or

R ²Be hydrogen or C _1-6Alkyl;

Each R ³Represent hydrogen atom independently;

R ⁴Be hydrogen;

R ⁵Be hydrogen or C _1-6Alkoxy C _1-6Alkyl;

Be to be selected from (a-1) or group (a-20);

Each s is 0 or 1 independently;

Each R ⁶Be independently selected from hydrogen; Thiophenyl; Furyl; Benzofuryl; Phenyl; Or be independently selected from C by one _1-6Alkyl, C _1-6Alkoxyl group, hydroxyl C _1-4Alkyl or two (C _1-4Alkyl) phenyl of amino substituting group replacement.

[0149]

According to other embodiment of the compound of paragraph [0146] is R wherein ¹²Compound during for H.

[0150]

T is 0;

R ⁵Be hydrogen;

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

R ⁶Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkoxy carbonyl; C _1-6Alkyl sulphonyl; Hydroxyl C _1-6Alkyl; Aryloxy; Two (C _1-6Alkyl) amino; Cyano group; Thiophenyl; Furyl; By hydroxyl C _1-6The furyl that alkyl replaces; Benzofuryl; Imidazolyl; Oxazolyl; By aryl and C _1-6Alkyl replaces the De oxazolyl; C _1-6-alkyl triazolyl; Tetrazyl; Pyrrolidyl; Pyrryl; Morpholinyl; C _1-6-alkyl morpholine base; Piperazinyl; C _1-6The alkylpiperazine base; Hydroxyl C _1-6The alkylpiperazine base; C _1-6The alkoxyl group piperidyl; Pyrazolyl; Be selected from C by one or two _1-6Alkyl or three halo C _1-6The pyrazolyl that alkyl replaces; Pyridyl; By C _1-6The pyridyl that-alkoxyl group, aryloxy or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; Or be independently selected from halogen, C by one or two _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group or trifluoromethyl replaces;

[0151]

R ⁵Be hydrogen, C _1-6Alkyl, C _3-10Cycloalkyl, hydroxyl C _1-6Alkyl, C _1-6Alkoxy C _1-6Alkyl or two (C _1-6Alkyl) amino C _1-6Alkyl;

Each R ⁶And R ⁷Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkoxy C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkyl sulphonyl; Cyano group C _1-6Alkyl; Hydroxyl C _1-6Alkyl; Hydroxyl C _1-6Alkoxyl group; Hydroxyl C _1-6Alkylamino; Amino C _1-6Alkoxyl group; Two (C _1-6Alkyl) aminocarboxyl; Two (hydroxyl C _1-6Alkyl) amino; Aryl C _1-6Alkyl) amino; Two (C _1-6Alkyl) amino C _1-6Alkoxyl group; Two (C _1-6Alkyl) amino C _1-6Alkylamino; Aryl sulfonyl; Arlysulfonylamino; Aryloxy; Aryl C _2-6Olefin 2 base; Two (C _1-6Alkyl) amino; Two (C _1-6Alkyl) amino C _1-6Alkyl; Two (C _1-6Alkyl) amino C _1-6Alkyl (C _1-6Alkyl) amino C _1-6Alkyl; Cyano group; Thiophenyl; By two (C _1-6Alkyl) amino C _1-6Alkyl (C _1-6Alkyl) amino C _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl, C _1-6Alkylpiperazine base C _1-6Alkyl or two (hydroxyl C _1-6Alkyl) amino C _1-6The thiophenyl that alkyl replaces; Furyl; Imidazolyl; C _1-6The alkyl triazolyl; Tetrazyl; Pyrrolidyl; Piperidyl C _1-6-alkoxyl group; Morpholinyl; C _1-6-alkyl morpholine base; Morpholinyl C _1-6Alkoxyl group; Morpholinyl C _1-6Alkyl; C _1-6The alkylpiperazine base; C _1-6Alkylpiperazine base C _1-6Alkoxyl group; C _1-6Alkylpiperazine base C _1-6Alkyl; C _1-6Alkylpiperazine base alkylsulfonyl; Amino-sulfonyl piperazinyl C _1-6Alkoxyl group; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C _1-6Alkyl; Two (C _1-6Alkyl) amino-sulfonyl piperazinyl; Two (C _1-6Alkyl) amino-sulfonyl piperazinyl C _1-6Alkyl; Hydroxyl C _1-6The alkylpiperazine base; Hydroxyl C _1-6Alkylpiperazine base C _1-6Alkyl; C _1-6The alkoxyl group piperidyl; C _1-6Alkoxyl group piperidyl C _1-6Alkyl; Hydroxyl C _1-6Alkoxy C _1-6The alkylpiperazine base; Hydroxyl C _1-6Alkoxy C _1-6Alkylpiperazine base C _1-6Alkyl; (hydroxyl C _1-6Alkyl) (C _1-6Alkyl) amino; (hydroxyl C _1-6Alkyl) (C _1-6Alkyl) amino C _1-6Alkyl; Pyrrolidyl C _1-6Alkoxyl group; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two _1-6Alkyl or three halo C _1-6The pyrazolyl that the substituting group of alkyl replaces; Pyridyl; By C _1-6The pyridyl that alkoxyl group or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; By one, two or three are independently selected from halogen, amino, C _1-6Alkyl, C _1-6Alkoxyl group, hydroxyl C _1-4Alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl C _1-4Alkoxyl group, C _1-4Alkoxy C _1-4Alkoxyl group, amino C _1-4Alkoxyl group, two (C _1-4Alkyl) amino C _1-4Alkoxyl group, two (C _1-4Alkyl) amino, two (C _1-4Alkyl) amino C _1-4Alkyl, two (C _1-4Alkyl) amino C _1-4Alkyl (C _1-4Alkyl) amino C _1-4Alkyl, piperidyl C _1-4Alkoxyl group, pyrrolidyl C _1-4Alkoxyl group, amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C _1-4Alkyl, two (C _1-4Alkyl) amino-sulfonyl piperazinyl, two (C _1-4Alkyl) amino-sulfonyl piperazinyl C _1-4Alkyl, hydroxyl C _1-4Alkylpiperazine base, hydroxyl C _1-4Alkylpiperazine base C _1-4Alkyl, C _1-4Alkoxyl group piperidyl, C _1-4Alkoxyl group piperidyl C _1-4Alkyl, hydroxyl C _1-4Alkoxy C _1-4Alkylpiperazine base, hydroxyl C _1-4Alkoxy C _1-4Alkylpiperazine base C _1-4Alkyl, (hydroxyl C _1-4Alkyl) (C _1-4Alkyl) amino, (hydroxyl C _1-4Alkyl) (C _1-4Alkyl) amino C _1-4Alkyl, pyrrolidyl C _1-4Alkoxyl group, morpholinyl C _1-4Alkoxyl group, morpholinyl C _1-4Alkyl, C _1-4Alkylpiperazine base, C _1-4Alkylpiperazine base C _1-4Alkoxyl group, C _1-4Alkylpiperazine base C _1-4Alkyl, hydroxyl C _1-4Alkylamino, two (hydroxyl C _1-4Alkyl) amino, two (C _1-4Alkyl) amino C _1-4Alkylamino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C _1-4Alkoxyl group or thiophenyl C _1-4The phenyl that the substituting group of alkylamino replaces.

[0152]

Comprise the compound that the meets following condition (R in this section wherein according to other embodiment of the compound of paragraph [0146] ², R ³, R ⁴And R ⁵Correspond respectively to the R in the paragraph [0146] separately ¹², R ¹³, R ¹⁴And R ¹⁵):

Each R ⁶And R ⁷Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkoxy C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkyl sulphonyl; Cyano group C _1-6Alkyl; Hydroxyl C _1-6Alkyl; Hydroxyl C _1-6Alkoxyl group; Hydroxyl C _1-6Alkylamino; Amino C _1-6Alkoxyl group; Two (C _1-6Alkyl) aminocarboxyl; Two (hydroxyl C _1-6Alkyl) amino; Aryl (C _1-6Alkyl) amino; Two (C _1-6Alkyl) amino C _1-6Alkoxyl group; Two (C _1-6Alkyl) amino C _1-6Alkylamino; Aryl sulfonyl; Arlysulfonylamino; Aryloxy; Aryl C _2-6Olefin 2 base; Two (C _1-6Alkyl) amino; Two (C _1-6Alkyl) amino C _1-6Alkyl; Two (C _1-6Alkyl) amino C _1-6Alkyl (C _1-6Alkyl) amino C _1-6Alkyl; Cyano group; Thiophenyl; By two (C _1-6Alkyl) amino C _1-6Alkyl (C _1-6Alkyl) amino C _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl, C _1-6Alkylpiperazine base C _1-6Alkyl or two (hydroxyl C _1-6Alkyl) amino C _1-6The thiophenyl that alkyl replaces; Furyl; Imidazolyl; C _1-6The alkyl triazolyl; Tetrazyl; Pyrrolidyl; Piperidyl C _1-6Alkoxyl group; Morpholinyl; C _1-6The alkyl morpholine base; Morpholinyl C _1-6Alkoxyl group; Morpholinyl C _1-6Alkyl; C _1-6The alkylpiperazine base; C _1-6Alkylpiperazine base C _1-6Alkoxyl group; C _1-6Alkylpiperazine base C _1-6Alkyl; C _1-6Alkylpiperazine base alkylsulfonyl; Amino-sulfonyl piperazinyl C _1-6Alkoxyl group; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C _1-6Alkyl; Two (C _1-6Alkyl) amino-sulfonyl piperazinyl; Two (C _1-6Alkyl) amino-sulfonyl piperazinyl C _1-6Alkyl; Hydroxyl C _1-6The alkylpiperazine base; Hydroxyl C _1-6Alkylpiperazine base C _1-6Alkyl; C _1-6The alkoxyl group piperidyl; C _1-6Alkoxyl group piperidyl C _1-6Alkyl; Hydroxyl C _1-6Alkoxy C _1-6The alkylpiperazine base; Hydroxyl C _1-6Alkoxy C _1-6Alkylpiperazine base C _1-6Alkyl; (hydroxyl C _1-6Alkyl) (C _1-6Alkyl) amino; (hydroxyl C _1-6Alkyl) (C _1-6Alkyl) amino C _1-6Alkyl; Pyrrolidyl C _1-6Alkoxyl group; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two _1-6Alkyl or three halo C _1-6The pyrazolyl that the substituting group of alkyl replaces; Pyridyl; By C _1-6The pyridyl that alkoxyl group or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; By one, two or three are independently selected from halogen, amino, C _1-6Alkyl, C _1-6Alkoxyl group, hydroxyl C _1-4Alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl C _1-4Alkoxyl group, C _1-4Alkoxy C _1-4Alkoxyl group, amino C _1-4Alkoxyl group, two (C _1-4Alkyl) amino C _1-4Alkoxyl group, two (C _1-4Alkyl) amino, two (C _1-4Alkyl) amino C _1-4Alkyl, two (C _1-4Alkyl) amino C _1-4Alkyl (C _1-4Alkyl) amino C _1-4Alkyl, piperidyl C _1-4Alkoxyl group, pyrrolidyl C _1-4Alkoxyl group; Amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C _1-4Alkyl, two (C _1-4Alkyl) amino-sulfonyl piperazinyl, two (C _1-4Alkyl) amino-sulfonyl piperazinyl C _1-4Alkyl, hydroxyl C _1-4Alkylpiperazine base, hydroxyl C _1-4Alkylpiperazine base C _1-4Alkyl, C _1-4Alkoxyl group piperidyl, C _1-4Alkoxyl group piperidyl C _1-4Alkyl, hydroxyl C _1-4Alkoxy C _1-4Alkylpiperazine base, hydroxyl C _1-4Alkoxy C _1-4Alkylpiperazine base C _1-4Alkyl, (hydroxyl C _1-4Alkyl) (C _1-4Alkyl) amino, (hydroxyl C _1-4Alkyl) (C _1-4Alkyl) amino C _1-4Alkyl, pyrrolidyl C _1-4Alkoxyl group, morpholinyl C _1-4Alkoxyl group, morpholinyl C _1-4Alkyl, C _1-4Alkylpiperazine base, C _1-4Alkylpiperazine base C _1-4Alkoxyl group, C _1-4Alkylpiperazine base C _1-4Alkyl, hydroxyl C _1-4Alkylamino, two (hydroxyl C _1-4Alkyl) amino, two (C _1-4Alkyl) amino C _1-4Alkylamino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C _1-4Alkoxyl group or thiophenyl C _1-4The phenyl that the substituting group of alkylamino replaces.

[0153]

T is 0;

R ⁵Be hydrogen;

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

R ⁶Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkoxy carbonyl; C _1-6Alkyl sulphonyl; Hydroxyl C _1-6Alkyl; Aryloxy; Two (C _1-6Alkyl) amino; Cyano group; Thiophenyl; Furyl; By hydroxyl C _1-6The furyl that alkyl replaces; Benzofuryl; Imidazolyl; Oxazolyl; By aryl and C _1-6Alkyl replaces the De oxazolyl; C _1-6-alkyl triazolyl; Tetrazyl; Pyrrolidyl; Pyrryl; Morpholinyl; C _1-6-alkyl morpholine base; Piperazinyl; C _1-6The alkylpiperazine base; Hydroxyl C _1-6The alkylpiperazine base; C _1-6The alkoxyl group piperidyl; Pyrazolyl; Be selected from C by one or two _1-6Alkyl or three halo C _1-6The pyrazolyl that alkyl replaces; Pyridyl; By C _1-6The pyridyl that alkoxyl group, aryloxy or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; Or be independently selected from halogen, C by one or two _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group or trifluoromethyl replaces; And

[0154]

N is 0,1 or 2, t is 0,1,2 or 3; Q is Or

R ²Be hydrogen, C _1-6Alkyl or naphthyl alkylsulfonyl pyrazinyl; Each R ³Represent hydrogen atom independently;

R ⁴Be hydrogen, hydroxyl, hydroxyl C _1-6Alkyl or C _1-6Alkoxyl group; R ⁵Be hydrogen, C _1-6Alkyl, hydroxyl C _1-6Alkyl or C _1-6Alkoxy C _1-6Alkyl; Be to be selected from (a-1), (a-7) or group (a-20); Each s is 0 or 1 independently; Each R ⁶Be independently selected from hydrogen; Thiophenyl; Furyl; Benzofuryl; Phenyl; Or be independently selected from C by one _1-6Alkyl, C _1-6Alkoxyl group, hydroxyl C _1-4Alkyl, C _1-4Alkyl sulphonyl or two (C _1-4Alkyl) phenyl of amino substituting group replacement; Each R ⁷Be independently selected from hydrogen.

[0155]

N is 1 or 2; T is 0,1,2 or 3; Q is Or

R ²Be hydrogen or C _1-6Alkyl; Each R ³Represent hydrogen atom independently; R ⁴Be hydrogen; R ⁵Be hydrogen or C _1-6Alkoxy C _1-6Alkyl; Be to be selected from (a-1) or group (a-20); Each s is 0 or 1 independently; Each R ⁶Be independently selected from hydrogen; Thiophenyl; Furyl; Benzofuryl; Phenyl; Or be independently selected from C by one _1-6Alkyl, C _1-6Alkoxyl group, hydroxyl C _1-4Alkyl or two (C _1-4Alkyl) phenyl of amino substituting group replacement.

[0156]

Wherein terminal hydroxamic acid part (C (O)-NH-OH) quilt

[0157]

In the compound of paragraph [0146]-[0156], R ¹, R ², R ³And R ⁴Preferably such as in paragraph [0048] and [0049] definition, in other embodiment of the compound of paragraph [0146]-[0156], R ¹, R ², R ³And R ⁴Be H.

[0158]

In another embodiment, the present invention includes compound or its pharmacologically acceptable salts of following structural (9):

Wherein

Ф is-NH ₂Or-OH;

R ¹Be H or such as in the paragraph [0046] definition;

R ², R ³And R ⁴Such as in the paragraph [0046] definition;

N is 0,1,2 or 3, and when n was 0, it was meant direct key;

Q be nitrogen or

Or

X be nitrogen or

Y be nitrogen or

Z be nitrogen or

R ¹³Be hydrogen, hydroxyl, amino, hydroxyl C _1-6Alkyl, C _1-6Alkyl, C _1-6Alkoxyl group, aryl C _1-6Alkyl, aminocarboxyl, hydroxycarbonyl group, amino C _1-6Alkyl, aminocarboxyl C _1-6Alkyl, hydroxycarbonyl group C _1-6Alkyl, hydroxyl amino carbonyl, C _1-6Alkoxy carbonyl, C _1-6Alkylamino C _1-6Alkyl or two (C _1-6Alkyl) amino C _1-6Alkyl;

When Z equaled nitrogen ,-L-was direct key;

When Z equals The time ,-L-is-NH-or divalent group-C _1-6Alkane 2 basis NH-;

R ¹⁴Be hydrogen, C _1-6Alkyl, C _3-10Cycloalkyl, hydroxyl C _1-6Alkyl, C _1-6Alkoxy C _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl or aryl;

For being selected from following group

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

Each R⁵And R⁶Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C_1-6Alkyl; Three halo C_1-6Alkoxyl; C_1-6Alkyl; By aryl and C_3-10The C that cycloalkyl replaces_1-6Alkyl; C_1-6Alkoxyl; C_1-6Alkoxy C_1-6Alkoxyl; C_1-6The alkyl carbonyl; C_1-6The alkoxyl carbonyl; C_1-6The alkyl sulfonyl base; Cyano group C_1-6Alkyl; Hydroxyl C_1-6Alkyl; Hydroxyl C_1-6Alkoxyl; Hydroxyl C_1-6Alkyl is amino; Amino C_1-6Alkoxyl; Two (C_1-6Alkyl) amino carbonyl; Two (hydroxyl C_1-6Alkyl) amino; (aryl) (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkoxyl; Two (C_1-6Alkyl) amino C_1-6Alkyl is amino; Two (C_1-6Alkyl) amino C_1-6The amino C of alkyl_1-6Alkyl; Aryl sulfonyl; Arlysulfonylamino; Aryloxy group; Aryloxy group C_1-6Alkyl; Aryl C_2-6Olefin 2 base; Two (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino (C_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl; Amino (the C of amino-sulfonyl_1-6Alkyl) amino; Amino (the C of amino-sulfonyl_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino (C of amino-sulfonyl_1-6Alkyl) amino; Two (C_1-6Alkyl) amino (C of amino-sulfonyl_1-6Alkyl) amino C_1-6Alkyl; Cyano group; Thiophenyl; By two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl, two (C_1-6Alkyl) amino C_1-6Alkyl, C_1-6Alkylpiperazinyl C_1-6Alkyl, hydroxyl C_1-6Alkylpiperazinyl C_1-6Alkyl, hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl C_1-6Alkyl, two (C_1-6Alkyl) amino-sulfonyl piperazinyl C_1-6Alkyl, C_1-6Alkoxyl piperidyl, C_1-6Alkoxyl piperidyl C_1-6Alkyl, morpholinyl C_1-6Alkyl, hydroxyl C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl or two (hydroxyl C_1-6Alkyl) amino C_1-6The thiophenyl that alkyl replaces; Furyl; By hydroxyl C_1-6The furyl that-alkyl replaces; Benzofuranyl; Imidazole radicals; Oxazolyl; By aryl and C_1-6Alkyl replaces the De oxazolyl; C_1-6The alkyl triazolyl; Tetrazole radical; Pyrrolidinyl; Pyrrole radicals; Piperidyl C_1-6-alkoxyl; Morpholinyl; C_1-6-alkyl morpholine base; Morpholinyl C_1-6Alkoxyl; Morpholinyl C_1-6Alkyl; Morpholinyl C_1-6Alkyl is amino; Morpholinyl C_1-6The amino C of alkyl_1-6Alkyl; Piperazinyl; C_1-6Alkylpiperazinyl; C_1-6Alkylpiperazinyl C_1-6Alkoxyl; Piperazinyl C_1-6Alkyl; Naphthyl sulfonyl piperazinyl; Naphthyl sulfonyl piperidyl; The naphthyl sulfonyl; C_1-6Alkylpiperazinyl C_1-6Alkyl; C_1-6Alkylpiperazinyl C_1-6Alkyl is amino; C_1-6Alkylpiperazinyl C_1-6The amino C of alkyl_1-6Alkyl; C_1-6The alkylpiperazinyl sulfonyl; Amino-sulfonyl piperazinyl C_1-6Alkoxyl; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C_1-6Alkyl; Two (C_1-6Alkyl) amino-sulfonyl piperazinyl; Two (C_1-6Alkyl) amino-sulfonyl piperazinyl C_1-6Alkyl; Hydroxyl C_1-6Alkylpiperazinyl; Hydroxyl C_1-6Alkylpiperazinyl C_1-6Alkyl; C_1-6The alkoxyl piperidyl; C_1-6Alkoxyl piperidyl C_1-6Alkyl; The amino C of piperidyl_1-6Alkyl is amino; The amino C of piperidyl_1-6The amino C of alkyl_1-6Alkyl; (C_1-6The Alkylpiperidine base) (hydroxyl C_1-6Alkyl) amino C_1-6Alkyl is amino; (C_1-6The Alkylpiperidine base) (hydroxyl C_1-6Alkyl) amino C_1-6The amino C of alkyl_1-6Alkyl; Hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl; Hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl C_1-6Alkyl; (hydroxyl C_1-6Alkyl) (C_1-6Alkyl) amino; (hydroxyl C_1-6Alkyl) (C_1-6Alkyl) amino C_1-6Alkyl; Hydroxyl C_1-6The amino C of alkyl_1-6Alkyl; Two (hydroxyl C_1-6Alkyl) amino C_1-6Alkyl; Pyrrolidinyl C_1-6Alkyl; Pyrrolidinyl C_1-6Alkoxyl; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two_1-6Alkyl or three halo C_1-6The pyrazolyl that the substituting group of alkyl replaces; Pyridine radicals; By C_1-6The pyridine radicals that alkoxyl, aryloxy group or aryl replace; Pyrimidine radicals; The tetrahydro-pyrimidine base piperazinyl; Tetrahydro-pyrimidine base piperazinyl C_1-6Alkyl; Quinolyl; Indyl; Phenyl; By the phenyl that, two or three substituting groups replace, these substituting groups are independently selected from halogen, amino, nitro, C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-4Alkyl, trifluoromethyl, trifluoro methoxyl group, hydroxyl C_1-4Alkoxyl, C_1-4Alkyl sulfonyl base, C_1-4Alkoxy C_1-4Alkoxyl, C_1-4Alkoxyl carbonyl, amino C_1-4Alkoxyl, two (C_1-4Alkyl) amino C_1-4Alkoxyl, two (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino carbonyl, two (C_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4The amino C of alkyl_1-4Alkyl, two (C_1-4Alkyl) amino (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino (C_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4Alkyl (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino C_1-4Alkyl (C_1-4Alkyl) amino C_1-4Alkyl, the amino (C of amino-sulfonyl_1-4Alkyl) amino, the amino (C of amino-sulfonyl_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino (C of amino-sulfonyl_1-4Alkyl) amino, two (C_1-4Alkyl) amino (C of amino-sulfonyl_1-4Alkyl) amino C_1-6Alkyl, cyano group, piperidyl C_1-4Alkoxyl, pyrrolidinyl C_1-4Alkoxyl; Amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C_1-4Alkyl, two (C_1-4Alkyl) amino-sulfonyl piperazinyl, two (C_1-4Alkyl) amino-sulfonyl piperazinyl C_1-4Alkyl, hydroxyl C_1-4Alkylpiperazinyl, hydroxyl C_1-4Alkylpiperazinyl C_1-4Alkyl, C_1-4Alkoxyl piperidyl, C_1-4Alkoxyl piperidyl C_1-4Alkyl, hydroxyl C_1-4Alkoxy C_1-4Alkylpiperazinyl, hydroxyl C_1-4Alkoxy C_1-4Alkylpiperazinyl C_1-4Alkyl, (hydroxyl C_1-4Alkyl) (C_1-4Alkyl) amino, (hydroxyl C_1-4Alkyl) (C_1-4Alkyl) amino C_1-4Alkyl, two (hydroxyl C_1-4Alkyl) amino, two (hydroxyl C_1-4Alkyl) amino C_1-4Furyl, pyrrolidinyl C that alkyl, furyl, quilt-CH=CH-CH=CH-replace_1-4Alkyl, pyrrolidinyl C_1-4Alkoxyl, morpholinyl, morpholinyl C_1-4Alkoxyl, morpholinyl C_1-4Alkyl, morpholinyl C_1-4Alkyl is amino, morpholinyl C_1-4The amino C of alkyl_1-4Alkyl, piperazinyl, C_1-4Alkylpiperazinyl, C_1-4Alkylpiperazinyl C_1-4Alkoxyl, piperazinyl C_1-4Alkyl, C_1-4Alkylpiperazinyl C_1-4Alkyl, C_1-4Alkylpiperazinyl C_1-4Alkyl is amino, C_1-4Alkylpiperazinyl C_1-4The amino C of alkyl_1-6Alkyl, tetrahydro-pyrimidine base piperazinyl, tetrahydro-pyrimidine base piperazinyl C_1-4Alkyl, the amino C of piperidyl_1-4Alkyl is amino, the amino C of piperidyl_1-4The amino C of alkyl_1-4Alkyl, (C_1-4The Alkylpiperidine base) (hydroxyl C_1-4Alkyl) amino C_1-4Alkyl is amino, (C_1-4The Alkylpiperidine base) (hydroxyl C_1-4Alkyl) amino C_1-4The amino C of alkyl_1-4Alkyl, piperidyl C_1-4Alkoxyl, hydroxyl C_1-4Alkyl is amino, hydroxyl C_1-4The amino C of alkyl_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4Alkyl amino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C_1-4Alkoxyl or thiophenyl C_1-4Alkyl is amino;

Each R ⁵And R ⁶Can be positioned on the nitrogen to replace hydrogen;

[0159]

In other embodiment, be suitable for following one or the multinomial (R in this section wherein according to the compound of paragraph [0158] ², R ³And R ⁴Correspond respectively to the R in the paragraph [0158] separately ¹², R ¹³And R ¹⁴):

N is 1;

Q is Or

R ²Be hydrogen or nitro;

R ³Be hydrogen;

When Z equals The time ,-L-is divalent group-C _1-6Alkane 2 basis NH-;

R ⁴Be hydrogen, C _1-6Alkyl or aryl;

Be to be selected from (a-1) or group (a-21);

Each s is 0,1 or 2 independently;

Each R ⁵Be independently selected from hydrogen; Halogen; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; Aryloxy; Cyano group or phenyl.

[0160]

N is 1;

Q is Or

X is a nitrogen;

Y is a nitrogen;

R ²Be hydrogen;

R ³Be hydrogen;

When Z equals

The time ,-L-is divalent group-C _1-6Alkane 2 basis NH-;

R ⁴Be hydrogen, C _1-6Alkyl or aryl;

Be group (a-1);

Each s is 0 or 1 independently;

Each R ⁵Be independently selected from hydrogen or phenyl.

[0161]

Z is N;

R ³Be hydrogen, hydroxyl, amino, hydroxyl C _1-6Alkyl, C _1-6Alkyl, C _1-6Alkoxyl group, aryl C _1-6Alkyl, aminocarboxyl, amino C _1-6Alkyl, C _1-6Alkylamino C _1-6Alkyl or two (C _1-6Alkyl) amino C _1-6Alkyl;

R ⁴Be hydrogen;

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

R ⁵Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkoxy carbonyl; C _1-6Alkyl sulphonyl; Hydroxyl C _1-6Alkyl; Aryloxy; Two (C _1-6Alkyl) amino; Cyano group; Thiophenyl; Furyl; By hydroxyl C _1-6The furyl that alkyl replaces; Benzofuryl; Imidazolyl; Oxazolyl; By aryl and C _1-6Alkyl replaces the De oxazolyl; C _1-6-alkyl triazolyl; Tetrazyl; Pyrrolidyl; Pyrryl; Morpholinyl; C _1-6The alkyl morpholine base; Piperazinyl; C _1-6The alkylpiperazine base; Hydroxyl C _1-6The alkylpiperazine base; C _1-6The alkoxyl group piperidyl; Pyrazolyl; Be selected from C by one or two _1-6Alkyl or three halo C _1-6The pyrazolyl that alkyl replaces; Pyridyl; By C _1-6The pyridyl that alkoxyl group, aryloxy or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; Or be independently selected from halogen, C by one or two _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group or trifluoromethyl replaces;

[0162]

Comprise the following (R in this section wherein according to other embodiment of the compound of paragraph [0158] ², R ³And R ⁴Correspond respectively to the R in the paragraph [01 58] separately ¹², R ¹³And R ¹⁴):

Z is N;

R ⁴Be hydrogen;

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

R ⁵Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkoxy carbonyl; C _1-6Alkyl sulphonyl; Hydroxyl C _1-6Alkyl; Aryloxy; Two (C _1-6Alkyl) amino; Cyano group; Thiophenyl; Furyl; By hydroxyl C _1-6The furyl that alkyl replaces; Benzofuryl; Imidazolyl; Oxazolyl; By aryl and C _1-6Alkyl replaces the De oxazolyl; C _1-6-alkyl triazolyl; Tetrazyl; Pyrrolidyl; Pyrryl; Morpholinyl; C _1-6-alkyl morpholine base; Piperazinyl; C _1-6The alkylpiperazine base; Hydroxyl C _1-6The alkylpiperazine base; C _1-6The alkoxyl group piperidyl; Pyrazolyl; Be selected from C by one or two _1-6Alkyl or three halo C _1-6The pyrazolyl that alkyl replaces; Pyridyl; By C _1-6The pyridyl that alkoxyl group, aryloxy or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; Or be independently selected from halogen, C by one or two _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group or trifluoromethyl replaces; And

[0163]

Comprise the following (R in this section wherein according to other embodiment of the compound of paragraph [0158] ², R ³And R ⁴Correspond respectively to the R in the paragraph [0158] separately ¹², R ¹³And R ¹⁴):

N is 1; Q is Or R ²Be hydrogen or nitro; R ³Be hydrogen; When Z equals

The time ,-L-is divalent group-C _1-6Alkane 2 basis NH-; R ⁴Be hydrogen, C _1-6Alkyl or aryl; Be to be selected from (a-1) or group (a-21); Each s is 0,1 or 2 independently; Each R ⁵Be independently selected from hydrogen; Halogen; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; Aryloxy; Cyano group or phenyl.

[0164]

N is 1; X is a nitrogen; Y is a nitrogen; Q is Or R ²Be hydrogen; R ³Be hydrogen; When Z equals

The time ,-L-is divalent group-C _1-6Alkane 2 basis NH-; R ⁴Be hydrogen, C _1-6Alkyl or aryl;

Be group (a-1); Each s is 0 or 1 independently; Each R ⁵Be independently selected from hydrogen or phenyl.

[0165]

Specific implementations according to the compound of paragraph [0158] comprises following

Wherein terminal hydroxamic acid part (C (O)-NH-OH) quilt

[0166]

In the compound of paragraph [0158]-[0165], R ¹, R ², R ³And R ⁴Preferably such as in paragraph [0048] and [0049] definition, in other embodiment of the compound of paragraph [0158]-[0165], R ¹, R ², R ³And R ⁴Be H.

[0167]

In another embodiment, the present invention includes compound or its pharmacologically acceptable salts of following structural (10):

Wherein

Ф is-NH ₂Or-OH;

R ¹Be H or such as in the paragraph [0046] definition;

R ², R ³And R ⁴Such as in the paragraph [0046] definition;

N is 0,1,2 or 3, and when n was 0, it was meant direct key;

M is 0,1,2 or 3, and when m was 0, it was meant direct key;

T is 0 or 1, and when t was 0, it was meant direct key;

Q be nitrogen or Or

X be nitrogen or

Y be nitrogen or

Z is-CH ₂-or-O-;

R ¹²Be hydrogen, hydroxyl, amino, hydroxyl C _1-6Alkyl, C _1-6Alkyl, C _1-6Alkoxyl group, aryl C _1-6Alkyl, aminocarboxyl, hydroxycarbonyl group, amino C _1-6Alkyl, aminocarboxyl C _1-6Alkyl, hydroxycarbonyl group C _1-6Alkyl, hydroxyl amino carbonyl, C _1-6Alkoxy carbonyl, C _1-6Alkylamino C _1-6Alkyl or two (C _1-6Alkyl) amino C _1-6Alkyl;

-L-is selected from C _1-6Alkane 2 basis, carbonyl, alkylsulfonyl or the C that is replaced by phenyl _1-6The divalent group of alkane 2 basis;

For being selected from following group

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

Each R⁵And R⁶Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C_1-6Alkyl; Three halo C_1-6Alkoxyl; C_1-6Alkyl; By aryl and C_3-10The C that cycloalkyl replaces_1-6Alkyl; C_1-6Alkoxyl; C_1-6Alkoxy C_1-6Alkoxyl; C_1-6The alkyl carbonyl; C_1-6The alkoxyl carbonyl; C_1-6The alkyl sulfonyl base; Cyano group C_1-6Alkyl; Hydroxyl C_1-6Alkyl; Hydroxyl C_1-6Alkoxyl; Hydroxyl C_1-6Alkyl is amino; Amino C_1-6Alkoxyl; Two (C_1-6Alkyl) amino carbonyl; Two (hydroxyl C_1-6Alkyl) amino; (aryl) (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkoxyl; Two (C_1-6Alkyl) amino C_1-6Alkyl is amino; Two (C_1-6Alkyl) amino C_1-6The amino C of alkyl_1-6Alkyl; Aryl sulfonyl; Arlysulfonylamino; Aryloxy group; Aryloxy group C_1-6Alkyl; Aryl C_2-6Olefin 2 base; Two (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino (C_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl; Amino (the C of amino-sulfonyl_1-6Alkyl) amino; Amino (the C of amino-sulfonyl_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino (C of amino-sulfonyl_1-6Alkyl) amino; Two (C_1-6Alkyl) amino (C of amino-sulfonyl_1-6Alkyl) amino C_1-6Alkyl; Cyano group; Thiophenyl; By two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl, two (C_1-6Alkyl) amino C_1-6Alkyl, C_1-6Alkylpiperazinyl C_1-6Alkyl, hydroxyl C_1-6Alkylpiperazinyl C_1-6Alkyl, hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl C_1-6Alkyl, two (C_1-6Alkyl) amino-sulfonyl piperazinyl C_1-6Alkyl, C_1-6Alkoxyl piperidyl, C_1-6Alkoxyl piperidyl C_1-6Alkyl, morpholinyl C_1-6Alkyl, hydroxyl C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl or two (hydroxyl C_1-6Alkyl) amino C_1-6The thiophenyl that alkyl replaces; Furyl; By hydroxyl C_1-6The furyl that-alkyl replaces; Benzofuranyl; Imidazole radicals; Oxazolyl; By aryl and C_1-6Alkyl replaces the De oxazolyl; C_1-6The alkyl triazolyl; Tetrazole radical; Pyrrolidinyl; Pyrrole radicals; Piperidyl C_1-6Alkoxyl; Morpholinyl; C_1-6The alkyl morpholine base; Morpholinyl C_1-6Alkoxyl; Morpholinyl C_1-6Alkyl; Morpholinyl C_1-6Alkyl is amino; Morpholinyl C_1-6The amino C of alkyl_1-6Alkyl; Piperazinyl; C_1-6Alkylpiperazinyl; C_1-6Alkylpiperazinyl C_1-6Alkoxyl; Piperazinyl C_1-6Alkyl; Naphthyl sulfonyl piperazinyl; Naphthyl sulfonyl piperidyl; The naphthyl sulfonyl; C_1-6Alkylpiperazinyl C_1-6Alkyl; C_1-6Alkylpiperazinyl C_1-6Alkyl is amino; C_1-6Alkylpiperazinyl C_1-6The amino C of alkyl_1-6Alkyl; C_1-6The alkylpiperazinyl sulfonyl; Amino-sulfonyl piperazinyl C_1-6Alkoxyl; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C_1-6Alkyl; Two (C_1-6Alkyl) amino-sulfonyl piperazinyl; Two (C_1-6Alkyl) amino-sulfonyl piperazinyl C_1-6Alkyl; Hydroxyl C_1-6Alkylpiperazinyl; Hydroxyl C_1-6Alkylpiperazinyl C_1-6Alkyl; C_1-6The alkoxyl piperidyl; C_1-6Alkoxyl piperidyl C_1-6Alkyl; The amino C of piperidyl_1-6Alkyl is amino; The amino C of piperidyl_1-6The amino C of alkyl_1-6Alkyl; (C_1-6The Alkylpiperidine base) (hydroxyl C_1-6Alkyl) amino C_1-6Alkyl is amino; (C_1-6The Alkylpiperidine base) (hydroxyl C_1-6Alkyl) amino C_1-6The amino C of alkyl_1-6Alkyl; Hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl; Hydroxyl C_1-6Alkoxy C_1-6-alkylpiperazinyl C_1-6Alkyl; (hydroxyl C_1-6Alkyl) (C_1-6Alkyl) amino; (hydroxyl C_1-6Alkyl) (C_1-6Alkyl) amino C_1-6Alkyl; Hydroxyl C_1-6The amino C of alkyl_1-6Alkyl; Two (hydroxyl C_1-6Alkyl) amino C_1-6Alkyl; Pyrrolidinyl C_1-6Alkyl; Pyrrolidinyl C_1-6Alkoxyl; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two_1-6Alkyl or three halo C_1-6The pyrazolyl that the substituting group of alkyl replaces; Pyridine radicals; By C_1-6The pyridine radicals that alkoxyl, aryloxy group or aryl replace; Pyrimidine radicals; The tetrahydro-pyrimidine base piperazinyl; Tetrahydro-pyrimidine base piperazinyl C_1-6Alkyl; Quinolyl; Indyl; Phenyl; By the phenyl that, two or three substituting groups replace, these substituting groups are independently selected from halogen, amino, nitro, C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-4Alkyl, trifluoromethyl, trifluoro methoxyl group, hydroxyl C_1-4Alkoxyl, C_1-4Alkyl sulfonyl base, C_1-4Alkoxy C_1-4Alkoxyl, C_1-4Alkoxyl carbonyl, amino C_1-4Alkoxyl, two (C_1-4Alkyl) amino C_1-4Alkoxyl, two (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino carbonyl, two (C_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4The amino C of alkyl_1-4Alkyl, two (C_1-4Alkyl) amino (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino (C_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4Alkyl (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino C_1-4Alkyl (C_1-4Alkyl) amino C_1-4Alkyl, the amino (C of amino-sulfonyl_1-4Alkyl) amino, the amino (C of amino-sulfonyl_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino (C of amino-sulfonyl_1-4Alkyl) amino, two (C_1-4Alkyl) amino (C of amino-sulfonyl_1-4Alkyl) amino C_1-6Alkyl, cyano group, piperidyl C_1-4Alkoxyl, pyrrolidinyl C_1-4Alkoxyl; Amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C_1-4Alkyl, two (C_1-4Alkyl) amino-sulfonyl piperazinyl, two (C_1-4Alkyl) amino-sulfonyl piperazinyl C_1-4Alkyl, hydroxyl C_1-4Alkylpiperazinyl, hydroxyl C_1-4Alkylpiperazinyl C_1-4Alkyl, C_1-4Alkoxyl piperidyl, C_1-4Alkoxyl piperidyl C_1-4Alkyl, hydroxyl C_1-4Alkoxy C_1-4Alkylpiperazinyl, hydroxyl C_1-4Alkoxy C_1-4Alkylpiperazinyl C_1-4Alkyl, (hydroxyl C_1-4Alkyl) (C_1-4Alkyl) amino, (hydroxyl C_1-4Alkyl) (C_1-4Alkyl) amino C_1-4Alkyl, two (hydroxyl C_1-4Alkyl) amino, two (hydroxyl C_1-4Alkyl) amino C_1-4Furyl, pyrrolidinyl C that alkyl, furyl, quilt-CH=CH-CH=CH-replace_1-4Alkyl, pyrrolidinyl C_1-4Alkoxyl, morpholinyl, morpholinyl C_1-4Alkoxyl, morpholinyl C_1-4Alkyl, morpholinyl C_1-4Alkyl is amino, morpholinyl C_1-4The amino C of alkyl_1-4Alkyl, piperazinyl, C_1-4Alkylpiperazinyl, C_1-4Alkylpiperazinyl C_1-4Alkoxyl, piperazinyl C_1-4Alkyl, C_1-4Alkylpiperazinyl C_1-4Alkyl, C_1-4Alkylpiperazinyl C_1-4Alkyl is amino, C_1-4Alkylpiperazinyl C_1-4The amino C of alkyl_1-6Alkyl, tetrahydro-pyrimidine base piperazinyl, tetrahydro-pyrimidine base piperazinyl C_1-4Alkyl, the amino C of piperidyl_1-4Alkyl is amino, the amino C of piperidyl_1-4The amino C of alkyl_1-4Alkyl, (C_1-4The Alkylpiperidine base) (hydroxyl C_1-4Alkyl) amino C_1-4Alkyl is amino, (C_1-4The Alkylpiperidine base) (hydroxyl C_1-4Alkyl) amino C_1-4The amino C of alkyl_1-4Alkyl, piperidyl C_1-4Alkoxyl, hydroxyl C_1-4Alkyl is amino, hydroxyl C_1-4The amino C of alkyl_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4Alkyl amino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C_1-4Alkoxyl or thiophenyl C_1-4Alkyl is amino;

Each R ⁵And R ⁶Can be positioned on the nitrogen to replace hydrogen;

[0168]

In other embodiment, be suitable for following one or the multinomial (R in this section wherein according to the compound of paragraph [0167] ², R ³And R ⁴Correspond respectively to the R in the paragraph [01 67] separately ¹², R ¹³And R ¹⁴):

N is 0,1 or 2;

M is 0,1 or 2;

Q is

Or

X is a nitrogen;

R ²Be hydrogen;

-L-is the C that is selected from carbonyl, alkylsulfonyl or is replaced by phenyl _1-6The divalent group of alkane 2 basis;

Be to be selected from (a-1), (a-20) or group (a-43);

Each s is 0 or 1 independently;

Each R ⁵Be independently selected from hydrogen or phenyl.

[0169]

In other embodiment, be suitable for following one or the multinomial (R in this section wherein according to the compound of paragraph [0167] ², R ³And R ⁴Correspond respectively to the R in the paragraph [0167] separately ¹², R ¹³And R ¹⁴):

N is 0,1 or 2;

M is 1 or 2;

Q is

Or

X is a nitrogen;

R ²Be hydrogen;

-L-is the divalent group that is selected from carbonyl or alkylsulfonyl;

Be to be selected from (a-1) or group (a-20);

Each s is 0 or 1 independently;

Each R ⁵Be independently selected from hydrogen or aryl.

[0170]

T is 0;

R ²Be hydrogen, hydroxyl, amino, hydroxyl C _1-6Alkyl, C _1-6Alkyl, C _1-6Alkoxyl group, aryl C _1-6Alkyl, aminocarboxyl, amino C _1-6Alkyl, C _1-6Alkylamino C _1-6Alkyl or two (C _1-6Alkyl) amino C _1-6Alkyl;

-L-is selected from C _1-6The divalent group of alkane 2 basis, carbonyl or alkylsulfonyl;

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

[0171]

Comprise the following (R in this section wherein according to other embodiment of the compound of paragraph [0167] ², R ³And R ⁴Correspond respectively to the R in the paragraph [0167] separately ¹², R ¹³And R ¹⁴):

T is 0;

S is 0,1,2,3 or 4;

[0172]

N is 0,1 or 2; M is 0,1 or 2; Q is Or X is nitrogen alkylsulfonyl or the C that replaced by phenyl _1-6Alkane 2 basis;

Be to be selected from (a-1), (a-20) or group (a-43); S is 0 or 1; Each R ⁵Be independently selected from hydrogen or phenyl.

[0173]

N is 0,1 or 2; M is 0,1 or 2; Q is

Or X is a nitrogen; R ²Be hydrogen;-L-is the divalent group that is selected from carbonyl or alkylsulfonyl;

Be to be selected from (a-1) or group (a-20); Each s is 0 or 1 independently; Each R ⁵Be independently selected from hydrogen or aryl.

[0174]

Specific implementations according to the compound of paragraph [0167] comprises following

Wherein terminal hydroxamic acid part (C (O)-NH-OH) quilt

[0175]

In the compound of paragraph [0167]-[0174], R ¹, R ², R ³And R ⁴Preferably such as in paragraph [0048] and [0049] definition.In other embodiment of the compound of paragraph [0167]-[0174], R ¹, R ², R ³And R ⁴Be H.

[0176]

In another embodiment, the present invention includes compound or its pharmacologically acceptable salts of following structural (11):

Wherein

Ф is-NH ₂Or-OH;

R ¹Be H or such as in the paragraph [0046] definition;

R ², R ³And R ⁴Such as in the paragraph [0046] definition;

T is 0,1,2,3 or 4, and when t was 0, it was meant direct key;

Q be nitrogen or Or

X be nitrogen or

Y be nitrogen or

Z is-NH-,-O-or-CH ₂-;

-L-is selected from-NR ⁹C (O)-,-NR ⁹SO ₂-or-NR ⁹CH ₂-divalent group, R wherein ⁹Be hydrogen, C _1-6Alkyl, C _3-10Cycloalkyl, hydroxyl C _1-6Alkyl, C _1-6Alkoxy C _1-6Alkyl or two (C _1-6Alkyl) amino C _1-6Alkyl;

For being selected from following group

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

Each R⁵And R⁶Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C_1-6Alkyl; Three halo C_1-6Alkoxyl; C_1-6Alkyl; By aryl and C_3-10The C that cycloalkyl replaces_1-6Alkyl; C_1-6Alkoxyl; C_1-6Alkoxy C_1-6Alkoxyl; C_1-6The alkyl carbonyl; C_1-6The alkoxyl carbonyl; C_1-6The alkyl sulfonyl base; Cyano group C_1-6Alkyl; Hydroxyl C_1-6Alkyl; Hydroxyl C_1-6Alkoxyl; Hydroxyl C_1-6Alkyl is amino; Amino C_1-6Alkoxyl; Two (C_1-6Alkyl) amino carbonyl; Two (hydroxyl C_1-6Alkyl) amino; (aryl) (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkoxyl; Two (C_1-6Alkyl) amino C_1-6Alkyl is amino; Two (C_1-6Alkyl) amino C_1-6The amino C of alkyl_1-6Alkyl; Aryl sulfonyl; Arlysulfonylamino; Aryloxy group; Aryloxy group C_1-6Alkyl; Aryl C_2-6Olefin 2 base; Two (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino (C_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl; Amino (the C of amino-sulfonyl_1-6Alkyl) amino; Amino (the C of amino-sulfonyl_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino (C of amino-sulfonyl_1-6Alkyl) amino; Two (C_1-6Alkyl) amino (C of amino-sulfonyl_1-6Alkyl) amino C_1-6Alkyl; Cyano group; Thiophenyl; By two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl, two (C_1-6Alkyl) amino C_1-6Alkyl, C_1-6Alkylpiperazinyl C_1-6Alkyl, hydroxyl C_1-6Alkylpiperazinyl C_1-6Alkyl, hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl C_1-6Alkyl, two (C_1-6Alkyl) amino-sulfonyl piperazinyl C_1-6Alkyl, C_1-6Alkoxyl piperidyl, C_1-6Alkoxyl piperidyl C_1-6Alkyl, morpholinyl C_1-6Alkyl, hydroxyl C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl or two (hydroxyl C_1-6Alkyl) amino C_1-6The thiophenyl that alkyl replaces; Furyl; By hydroxyl C_1-6The furyl that alkyl replaces; Benzofuranyl; Imidazole radicals; Oxazolyl; By aryl and C_1-6Alkyl replaces the De oxazolyl; C_1-6The alkyl triazolyl; Tetrazole radical; Pyrrolidinyl; Pyrrole radicals; Piperidyl C_1-6Alkoxyl; Morpholinyl; C_1-6The alkyl morpholine base; Morpholinyl C_1-6Alkoxyl; Morpholinyl C_1-6Alkyl; Morpholinyl C_1-6Alkyl is amino; Morpholinyl C_1-6The amino C of alkyl_1-6Alkyl; Piperazinyl; C_1-6Alkylpiperazinyl; C_1-6Alkylpiperazinyl C_1-6Alkoxyl; Piperazinyl C_1-6Alkyl; Naphthyl sulfonyl piperazinyl; Naphthyl sulfonyl piperidyl; The naphthyl sulfonyl; C_1-6Alkylpiperazinyl C_1-6Alkyl; C_1-6Alkylpiperazinyl C_1-6Alkyl is amino; C_1-6Alkylpiperazinyl C_1-6The amino C of alkyl_1-6Alkyl; C_1-6The alkylpiperazinyl sulfonyl; Amino-sulfonyl piperazinyl C_1-6Alkoxyl; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C_1-6Alkyl; Two (C_1-6Alkyl) amino-sulfonyl piperazinyl; Two (C_1-6Alkyl) amino-sulfonyl piperazinyl C_1-6Alkyl; Hydroxyl C_1-6Alkylpiperazinyl; Hydroxyl C_1-6Alkylpiperazinyl C_1-6Alkyl; C_1-6The alkoxyl piperidyl; C_1-6Alkoxyl piperidyl C_1-6Alkyl; The amino C of piperidyl_1-6Alkyl is amino; The amino C of piperidyl_1-6The amino C of alkyl_1-6Alkyl; (C_1-6The Alkylpiperidine base) (hydroxyl C_1-6Alkyl) amino C_1-6Alkyl is amino; (C_1-6The Alkylpiperidine base) (hydroxyl C_1-6Alkyl) amino C_1-6The amino C of alkyl_1-6Alkyl; Hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl; Hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl C_1-6Alkyl; (hydroxyl C_1-6Alkyl) (C_1-6Alkyl) amino; (hydroxyl C_1-6Alkyl) (C_1-6Alkyl) amino C_1-6Alkyl; Hydroxyl C_1-6The amino C of alkyl_1-6Alkyl; Two (hydroxyl C_1-6Alkyl) amino C_1-6Alkyl; Pyrrolidinyl C_1-6Alkyl; Pyrrolidinyl C_1-6Alkoxyl; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two_1-6Alkyl or three halo C_1-6The pyrazolyl that the substituting group of alkyl replaces; Pyridine radicals; By C_1-6The pyridine radicals that alkoxyl, aryloxy group or aryl replace; Pyrimidine radicals; The tetrahydro-pyrimidine base piperazinyl; Tetrahydro-pyrimidine base piperazinyl C_1-6Alkyl; Quinolyl; Indoles; Phenyl; By the phenyl that, two or three substituting groups replace, these substituting groups are independently selected from halogen, amino, nitro, C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-4Alkyl, trifluoromethyl, trifluoro methoxyl group, hydroxyl C_1-4Alkoxyl, C_1-4Alkyl sulfonyl base, C_1-4Alkoxy C_1-4Alkoxyl, C_1-4Alkoxyl carbonyl, amino C_1-4Alkoxyl, two (C_1-4Alkyl) amino C_1-4Alkoxyl, two (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino carbonyl, two (C_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4The amino C of alkyl_1-4Alkyl, two (C_1-4Alkyl) amino (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino (C_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4Alkyl (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino C_1-4Alkyl (C_1-4Alkyl) amino C_1-4Alkyl, the amino (C of amino-sulfonyl_1-4Alkyl) amino, the amino (C of amino-sulfonyl_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino (C of amino-sulfonyl_1-4Alkyl) amino, two (C_1-4Alkyl) amino (C of amino-sulfonyl_1-4Alkyl) amino C_1-6Alkyl, cyano group, piperidyl C_1-4Alkoxyl, pyrrolidinyl C_1-4Alkoxyl; Amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C_1-4Alkyl, two (C_1-4Alkyl) amino-sulfonyl piperazinyl, two (C_1-4Alkyl) amino-sulfonyl piperazinyl C_1-4Alkyl, hydroxyl C_1-4Alkylpiperazinyl, hydroxyl C_1-4Alkylpiperazinyl C_1-4Alkyl, C_1-4Alkoxyl piperidyl, C_1-4Alkoxyl piperidyl C_1-4Alkyl, hydroxyl C_1-4Alkoxy C_1-4Alkylpiperazinyl, hydroxyl C_1-4Alkoxy C_1-4Alkylpiperazinyl C_1-4Alkyl, (hydroxyl C_1-4Alkyl) (C_1-4Alkyl) amino, (hydroxyl C_1-4Alkyl) (C_1-4Alkyl) amino C_1-4Alkyl, two (hydroxyl C_1-4Alkyl) amino, two (hydroxyl C_1-4Alkyl) amino C_1-4Furyl, pyrrolidinyl C that alkyl, furyl, quilt-CH=CH-CH=CH-replace_1-4Alkyl, pyrrolidinyl C_1-4Alkoxyl, morpholinyl, morpholinyl C_1-4Alkoxyl, morpholinyl C_1-4Alkyl, morpholinyl C_1-4Alkyl is amino, morpholinyl C_1-4The amino C of alkyl_1-4Alkyl, piperazinyl, C_1-4Alkylpiperazinyl, C_1-4Alkylpiperazinyl C_1-4Alkoxyl, piperazinyl C_1-4Alkyl, C_1-4Alkylpiperazinyl C_1-4Alkyl, C_1-4Alkylpiperazinyl C_1-4Alkyl is amino, C_1-4Alkylpiperazinyl C_1-4The amino C of alkyl_1-6Alkyl, tetrahydro-pyrimidine base piperazinyl, tetrahydro-pyrimidine base piperazinyl C_1-4Alkyl, the amino C of piperidyl_1-4Alkyl is amino, the amino C of piperidyl_1-4The amino C of alkyl_1-4Alkyl, (C_1-4The Alkylpiperidine base) (hydroxyl C_1-4Alkyl) amino C_1-4Alkyl is amino, (C_1-4The Alkylpiperidine base) (hydroxyl C_1-4Alkyl) amino C_1-4The amino C of alkyl_1-4Alkyl, piperidyl C_1-4Alkoxyl, hydroxyl C_1-4Alkyl is amino, hydroxyl C_1-4The amino C of alkyl_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4Alkyl amino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C_1-4Alkoxyl or thiophenyl C_1-4Alkyl is amino;

Each R ⁵And R ⁶Can be positioned on the nitrogen to replace hydrogen;

[0177]

In other embodiment, be suitable for following one or the multinomial (R in this section wherein according to the compound of paragraph [0176] ², R ³And R ⁴Correspond respectively to the R in the paragraph [0176] separately ¹², R ¹³And R ¹⁴):

T is 0 or 1;

Q is

Or

X is a nitrogen;

R ¹²Be hydrogen, hydroxyl, C _1-6Alkyl or aryl C _1-6Alkyl;

-L-be selected from-NHC (O)-or-NHSO ₂-divalent group;

Be to be selected from (a-1) or group (a-20);

Each s is 0 or 1 independently;

Each R ⁵Be independently selected from hydrogen or phenyl.

[0178]

T is 1;

Q is Or

X is a nitrogen;

Y is a nitrogen;

Z is-O-or-CH ₂-;

R ¹²Be H;

-L-be selected from-NHC (O)-or-NHSO ₂-divalent group;

Be to be selected from (a-1) or group (a-20);

Each s is 0 or 1 independently;

Each R ⁵Be independently selected from hydrogen or phenyl.

[0179]

T is 0;

R ¹²Be hydrogen, hydroxyl, amino, hydroxyl C _1-6Alkyl, C _1-6Alkyl, C _1-6Alkoxyl group, aryl C _1-6Alkyl, aminocarboxyl, amino C _1-6Alkyl, C _1-6Alkylamino C _1-6Alkyl or two (C _1-6Alkyl) amino C _1-6Alkyl;

-L-be selected from-NHC (O)-or-NHSO ₂-divalent group;

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

R ⁵Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkoxy carbonyl; C _1-6Alkyl sulphonyl; Hydroxyl C _1-6Alkyl; Aryloxy; Two (C _1-6Alkyl) amino; Cyano group; Thiophenyl; Furyl; By hydroxyl C _1-6The furyl that alkyl replaces; Benzofuryl; Imidazolyl; Oxazolyl; By aryl and C _1-6Alkyl replaces the De oxazolyl; C _1-6The alkyl triazolyl; Tetrazyl; Pyrrolidyl; Pyrryl; Morpholinyl; C _1-6The alkyl morpholine base; Piperazinyl; C _1-6The alkylpiperazine base; Hydroxyl C _1-6The alkylpiperazine base; C _1-6The alkoxyl group piperidyl; Pyrazolyl; Be selected from C by one or two _1-6Alkyl or three halo C _1-6The pyrazolyl that the substituting group of alkyl replaces; Pyridyl; By C _1-6The pyridyl that-alkoxyl group, aryloxy or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; Or be independently selected from halogen, C by one or two _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group or trifluoromethyl replaces;

[0180]

R ³And R ⁴Be selected from hydrogen, hydroxyl, hydroxyl C independently of one another _1-6Alkyl, amino C _1-6Alkyl or aminoaryl;

Each R ⁵And R ⁶Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkoxy C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkyl sulphonyl; Cyano group C _1-6Alkyl; Hydroxyl C _1-6Alkyl; Hydroxyl C _1-6Alkoxyl group; Hydroxyl C _1-6Alkylamino; Amino C _1-6Alkoxyl group; Two (C _1-6Alkyl) aminocarboxyl; Two (hydroxyl C _1-6Alkyl) amino; Aryl C _1-6Alkyl) amino; Two (C _1-6Alkyl) amino C _1-6Alkoxyl group; Two (C _1-6Alkyl) amino C _1-6Alkylamino; Aryl sulfonyl; Arlysulfonylamino; Aryloxy; Aryl C _2-6Olefin 2 base; Two (C _1-6Alkyl) amino; Two (C _1-6Alkyl) amino C _1-6Alkyl; Two (C _1-6Alkyl) amino C _1-6Alkyl (C _1-6Alkyl) amino C _1-6Alkyl; Cyano group; Thiophenyl; By two (C _1-6Alkyl) amino C _1-6Alkyl (C _1-6Alkyl) amino C _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl, C _1-6Alkylpiperazine base C _1-6Alkyl or two (hydroxyl C _1-6Alkyl) amino C _1-6The thiophenyl that alkyl replaces; Furyl; Imidazolyl; C _1-6The alkyl triazolyl; Tetrazyl; Pyrrolidyl; Piperidyl C _1-6Alkoxyl group; Morpholinyl; C _1-6The alkyl morpholine base; Morpholinyl C _1-6Alkoxyl group; Morpholinyl C _1-6Alkyl; C _1-6The alkylpiperazine base; C _1-6Alkylpiperazine base C _1-6Alkoxyl group; C _1-6Alkylpiperazine base C _1-6Alkyl; C _1-6Alkylpiperazine base alkylsulfonyl; Amino-sulfonyl piperazinyl C _1-6Alkoxyl group; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C _1-6Alkyl; Two (C _1-6Alkyl) amino-sulfonyl piperazinyl; Two (C _1-6Alkyl) amino-sulfonyl piperazinyl C _1-6Alkyl; Hydroxyl C _1-6The alkylpiperazine base; Hydroxyl C _1-6Alkylpiperazine base C _1-6Alkyl; C _1-6The alkoxyl group piperidyl; C _1-6Alkoxyl group piperidyl C _1-6Alkyl; Hydroxyl C _1-6Alkoxy C _1-6The alkylpiperazine base; Hydroxyl C _1-6Alkoxy C _1-6Alkylpiperazine base C _1-6Alkyl; (hydroxyl C _1-6Alkyl) (C _1-6Alkyl) amino; (hydroxyl C _1-6Alkyl) (C _1-6Alkyl) amino C _1-6Alkyl; Pyrrolidyl C _1-6Alkoxyl group; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two _1-6Alkyl or three halo C _1-6The pyrazolyl that the substituting group of alkyl replaces; Pyridyl; By C _1-6The pyridyl that alkoxyl group or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; By one, two or three are independently selected from halogen, amino, C _1-6Alkyl, C _1-6Alkoxyl group, hydroxyl C _1-4Alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl C _1-4Alkoxyl group, C _1-4Alkoxy C _1-4Alkoxyl group, amino C _1-4Alkoxyl group, two (C _1-4Alkyl) amino C _1-4Alkoxyl group, two (C _1-4Alkyl) amino, two (C _1-4Alkyl) amino C _1-4Alkyl, two (C _1-4Alkyl) amino C _1-4Alkyl (C _1-4Alkyl) amino C _1-4Alkyl, piperidyl C _1-4Alkoxyl group, pyrrolidyl C _1-4Alkoxyl group; Amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C _1-4Alkyl, two (C _1-4Alkyl) amino-sulfonyl piperazinyl, two (C _1-4Alkyl) amino-sulfonyl piperazinyl C _1-4Alkyl, hydroxyl C _1-4Alkylpiperazine base, hydroxyl C _1-4Alkylpiperazine base C _1-4Alkyl, C _1-4Alkoxyl group piperidyl, C _1-4Alkoxyl group piperidyl C _1-4Alkyl, hydroxyl C _1-4Alkoxy C _1-4Alkylpiperazine base, hydroxyl C _1-4Alkoxy C _1-4Alkylpiperazine base C _1-4Alkyl, (hydroxyl C _1-4Alkyl) (C _1-4Alkyl) amino, (hydroxyl C _1-4Alkyl) (C _1-4Alkyl) amino C _1-4Alkyl, pyrrolidyl C _1-4Alkoxyl group, morpholinyl C _1-4Alkoxyl group, morpholinyl C _1-4Alkyl, C _1-4Alkylpiperazine base, C _1-4Alkylpiperazine base C _1-4Alkoxyl group, C _1-4Alkylpiperazine base C _1-4Alkyl, hydroxyl C _1-4Alkylamino, two (hydroxyl C _1-4Alkyl) amino, two (C _1-4Alkyl) amino C _1-4Alkylamino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C _1-4Alkoxyl group or thiophenyl C _1-4The phenyl that the substituting group of alkylamino replaces.

[0181]

Comprise the following (R in this section wherein according to other embodiment of the compound of paragraph [0176] ², R ³And R ⁴Correspond respectively to the R in the paragraph [0176] separately ¹², R ¹³And R ¹⁴):

[0182]

T is 0;

-L-be selected from-NHC (O)-or-NHSO ₂-divalent group;

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

R ⁵Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkoxy carbonyl; C _1-6Alkyl sulphonyl; Hydroxyl C _1-6Alkyl; Aryloxy; Two (C _1-6Alkyl) amino; Cyano group; Thiophenyl; Furyl; By hydroxyl C _1-6The furyl that alkyl replaces; Benzofuryl; Imidazolyl; Oxazolyl; By aryl and C _1-6Alkyl replaces the De oxazolyl; C _1-6The alkyl triazolyl; Tetrazyl; Pyrrolidyl; Pyrryl; Morpholinyl; C _1-6The alkyl morpholine base; Piperazinyl; C _1-6The alkylpiperazine base; Hydroxyl C _1-6The alkylpiperazine base; C _1-6The alkoxyl group piperidyl; Pyrazolyl; Be selected from C by one or two _1-6Alkyl or three halo C _1-6The pyrazolyl that alkyl replaces; Pyridyl; By C _1-6The pyridyl that alkoxyl group or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; Or be independently selected from halogen, C by one or two _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group or trifluoromethyl replaces;

And R ⁶Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkoxy carbonyl; C _1-6Alkyl sulphonyl; Hydroxyl C _1-6Alkyl; Aryloxy; Two (C _1-6Alkyl) amino; Cyano group; Pyridyl; Phenyl; Or be independently selected from halogen, C by one or two _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group or trifluoromethyl replaces.

[0183]

T is 0 or 1; Q is Or X is a nitrogen; R ¹²Be hydrogen, hydroxyl, C _1-6Alkyl or aryl C _1-6Alkyl;-L-be selected from-NHC (O)-or-NHSO ₂-divalent group;

Be to be selected from (a-1) or group (a-20); Each s is 0 or 1 independently; Each R ⁵Be independently selected from hydrogen or phenyl.

[0184]

T is 1; Q is Or

X is a nitrogen; Y is a nitrogen; Z is-O-or-CH ₂-; R ¹²Be H;-L-be selected from-NHC (O)-or-NHSO ₂-divalent group;

[0185]

Specific implementations according to the compound of paragraph [0176] comprises following

Wherein terminal hydroxamic acid part (C (O)-NH-OH) quilt

[0186]

In the compound of paragraph [0176]-[0185], R ¹, R ², R ³And R ⁴Preferably such as in paragraph [0048] and [0049] definition, in other embodiment of the compound of paragraph [0176]-[0185], R ¹, R ², R ³And R ⁴Be H.

[0187]

In another embodiment, the present invention includes compound or its pharmacologically acceptable salts of following structural (12):

Wherein

Ф is-NH ₂Or-OH;

R ¹Be H or such as in the paragraph [0046] definition;

R ², R ³And R ⁴Such as in the paragraph [0046] definition;

Ring A is a heterocyclic radical, if wherein described heterocyclic radical contains-the NH-part, then the optional group that is selected from G of nitrogen replaces;

R ¹¹For the substituting group on the carbon and be selected from halogen, nitro, cyano group, hydroxyl, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulphonamide, C _1-6Alkyl, C _2-6Alkenyl, C _2-6Alkynyl, C _1-6Alkoxyl group, C _1-6Alkyloyl, C _1-6Alkanoyloxy, N-(C _1-6Alkyl) amino, N, N-(C _1-6Alkyl) ₂Amino, C _1-6Alkyl amido, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, C _1-6Alkyl S (O) _a---wherein a be 0 to 2, C _1-6Alkoxy carbonyl, N-(C _1-6Alkyl) sulphonamide, N, N-(C _1-6Alkyl) ₂Sulphonamide, aryl, aryloxy, aryl C _1-6Alkyl, heterocyclic radical, (heterocyclic radical) C _1-6Alkyl, or group (D-E-); R wherein ¹, comprise group (D-E-), can choose wantonly on carbon and replaced by one or more V; And if wherein described heterocyclic radical contains-the NH-part the then optional group replacement that is selected from J of nitrogen;

V is halogen, nitro, cyano group, hydroxyl, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulphonamide, C _1-6Alkyl, C _2-6Alkenyl, C _2-6Alkynyl, C _1-6Alkoxyl group, C _1-6Alkyloyl, C _1-6Alkanoyloxy, N-(C _1-6Alkyl) amino, N, N-(C _1-6Alkyl) ₂Amino, C _1-6Alkyl amido, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, C _1-6Alkyl S (O) _a---wherein a be 0 to 2, C _1-6Alkoxy carbonyl, N-(C _1-6Alkyl) sulphonamide, N, N-(C _1-6Alkyl) ₂Sulphonamide or group (D '-E '-); V wherein comprises group (D '-E '-), can choose wantonly on carbon to be replaced by one or more W;

W and Z are independently selected from halogen, nitro, cyano group, hydroxyl, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulphonamide, C _1-6Alkyl, C _2-6Alkenyl, C _2-6Alkynyl, C _1-6Alkoxyl group, C _1-6Alkyloyl, C _1-6Alkanoyloxy, N-(C _1-6Alkyl) amino, N, N-(C _1-6Alkyl) ₂Amino, C _1-6Alkyl amido, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, C _1-6Alkyl S (O) _a---wherein a be 0 to 2, C _1-6Alkoxy carbonyl, N-(C _1-6Alkyl) sulphonamide or N, N-(C _1-6Alkyl) ₂Sulphonamide;

G, J and K are independently selected from C _1-8Alkyl, C _2-8Alkenyl, C _2-8Alkynyl, C _1-8Alkyloyl, C _1-8Alkyl sulphonyl, C _1-8Alkoxy carbonyl, formamyl, N-(C _1-8Alkyl) formamyl, N, N-(C _1-8Alkyl) formamyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl, aryl, aryl C _1-6Alkyl or (heterocyclic radical) C _1-6Alkyl; Wherein G, J and K can choose wantonly on carbon and be replaced by one or more Q; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen wantonly and is selected from hydrogen or C _1-6The substituting group of alkyl replaces;

Q is halogen, nitro, cyano group, hydroxyl, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulphonamide, C _1-6Alkyl, C _2-6Alkenyl, C _2-6Alkynyl, C _1-6Alkoxyl group, C _1-6Alkyloyl, C _1-6Alkanoyloxy, N-(C _1-6Alkyl) amino, N, N-(C _1-6Alkyl) ₂Amino, C _1-6Alkyl amido, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, C _1-6Alkyl S (O) _a---wherein a be 0 to 2, C _1-6Alkoxy carbonyl, C _1-6Alkoxycarbonyl amino, N-(C _1-6Alkyl) sulphonamide, N, N-(C _1-6Alkyl) ₂Sulphonamide, aryl, aryloxy, aryl C _1-6Alkyl, aryl C _1-6Alkoxyl group, heterocyclic radical, (heterocyclic radical) C _1-6Alkyl, (heterocyclic radical) C _1-6Alkoxyl group or group (D "-E "-); Q wherein, comprise group (D "-E "-), can choose wantonly on carbon and replaced by one or more Z;

D, D ' and D " be independently selected from C _1-6-alkyl, C _2-6Alkenyl, C _2-6Alkynyl, C _3-8Cycloalkyl, C _3-8Cycloalkyl C _1-6-alkyl, aryl, aryl C _1-6Alkyl, heterocyclic radical, (heterocyclic radical) C _1-6Alkyl; Wherein D, D ' and D " can choose wantonly on carbon and replaced by one or more F '; And if wherein described heterocyclic radical contains-the NH-part, nitrogen can be chosen the group that is selected from K wantonly and replace;

E, E ' and E " be independently selected from-N (R ^a)-,-O-,-C (O) O-,-OC (O)-,-C (O)-,-N (R ^a) C (O)-,-N (R ^a) C (O) N (R ^b)-,-N (R ^a) C (O) O-,-OC (O) N (R ^a)-,-C (O) N (R ^a)-,-S (O) _r-,-SO ₂N (R ^a)-,-N (R ^a) SO ₂-; R wherein ^aAnd R ^bBe independently selected from hydrogen or the optional C that is replaced by one or more F _1-6Alkyl, and r is 0-2;

F and F ' are independently selected from halogen, nitro, cyano group, hydroxyl, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulphonamide, C _1-6Alkyl, C _2-6Alkenyl, C _2-6Alkynyl, C _1-6Alkoxyl group, C _1-6Alkyloyl, C _1-6Alkanoyloxy, N-(C _1-6Alkyl) amino, N, N-(C _1-6Alkyl) ₂Amino, C _1-6Alkyl amido, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, C _1-6Alkyl S (O) _a---wherein a be 0 to 2, C _1-6Alkoxy carbonyl, N-(C _1-6Alkyl) sulphonamide and N, N-(C _1-6Alkyl) ₂Sulphonamide;

M is 0,1,2,3 or 4; R wherein ¹Meaning can be identical or different;

Ring B is selected from following ring

Wherein,

X ¹And X ²Be selected from CH or N, and

Y ¹, Y ², Y ³And Y ⁴Be selected from CH or N, condition is Y ¹, Y ², Y ³And Y ⁴In at least one be N;

R ¹²It is halogen;

N is 0,1 or 2, wherein R ¹²Same meaning or difference.

[0188]

In some embodiments according to the compound of paragraph [0187],

Ring A is pyridyl, quinolyl, indyl, pyrimidyl, morpholinyl, piperidyl, piperazinyl, pyridazinyl, pyrazinyl, thiazolyl, thienyl, Thienopyrimidine base, thienopyridine base, purine radicals, 1 ', 2 ', 3 ', 6 '-tetrahydro pyridyl, triazinyl, oxazolyl, pyrazolyl or furyl; If wherein ring A contains-the NH-part, then nitrogen can be chosen the group replacement that is selected from G wantonly.

Ring A is pyridin-4-yl, pyridin-3-yl, pyridine-2-base, quinoline-8-base, pyrimidine-6-base, pyrimidine-5-base, pyrimidine-4-base, morpholine-4-base, piperidin-4-yl, piperidines-3-base, piperidines-2-base, piperazine-4-base, pyridazine-5-base, pyrazine-6-base, thiazol-2-yl, thiophene-2-base, thieno-[3,2d] pyrimidyl, thieno-[3,2b] pyrimidyl, thieno-[3,2b] pyridyl, purine-6-base, 1 ', 2 ', 3 ', 6 '-tetrahydropyridine-4-base.

Ring A is pyridin-4-yl, pyridin-3-yl, pyridine-2-base, quinoline-8-base, pyrimidine-6-base, pyrimidine-5-base, pyrimidine-4-base, morpholine-4-base, piperidin-4-yl, piperidines-3-base, piperidines-2-base, piperazine-4-base, pyridazine-5-base, pyrazine-6-base, thiazol-2-yl, thiophene-2-base, thieno-[3,2d] pyrimidyl, thieno-[3,2b] pyrimidyl, thieno-[3,2b] pyridyl, purine-6-base, 1 ', 2 ', 3 ', 6 '-tetrahydropyridine-4-base or triazine-6-base; If wherein ring A contains-the NH-part, then nitrogen can be chosen the group replacement that is selected from G wantonly.

Ring A is pyridin-4-yl, pyridin-3-yl, pyridine-2-base, morpholine-4-base, piperidin-4-yl, piperidines-3-base, piperidines-2-base, piperazine-4-base, thiazol-2-yl, thiophene-2-base, furans-3-base, tetramethyleneimine-1-base, piperidines-1-base, triazol-1-yl or 1 ', 2 ', 3 ', 6 '-tetrahydropyridine-4-base, if wherein ring A contains-the NH-part, then nitrogen can be chosen the group replacement that is selected from G wantonly.

Ring A is pyridyl, pyrimidyl, morpholinyl, piperidyl, piperazinyl, pyridazinyl, thienyl, pyrazinyl, thiazolyl, 1,2,4-triazolyl or furyl.

Ring A is pyridin-4-yl, pyridin-3-yl, pyridine-2-base or 1,2, the 4-triazolyl.

Ring B is thienyl, thiadiazolyl group, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl.

Ring B is thienyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl.

Ring B is thienyl or pyridyl.

Ring B is thienyl or pyridyl---wherein, thienyl all links to each other with ring A on the 2-position of thiophene basic ring or pyridyl ring with pyridyl, and links to each other with the amide group of formula (I) on the 5-position of thiophene basic ring or pyridyl ring.

R ¹¹Be halogen, amino, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-3Alkanoyloxy, N-(C _1-3Alkyl) amino, N, N-(C _1-3Alkyl) ₂Amino, C _1-3Alkyl amido, N-(C _1-3Alkyl) formamyl, N, N-(C _1-3Alkyl) ₂Formamyl.

R ¹¹Be halogen, amino, C _1-6Alkyl or C _1-6Alkoxyl group.

R ¹¹Be halogen, amino, methyl or methoxy.

R ¹¹For the substituting group on the carbon and be selected from halogen, nitro, cyano group, hydroxyl, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulphonamide, C _1-6Alkyl, C _2-6Alkenyl, C _2-6Alkynyl, C _1-6Alkoxyl group, C _1-6Alkyloyl, C _1-6Alkanoyloxy, N-(C _1-6Alkyl) amino, N, N-(C _1-6Alkyl) ₂Amino, C _1-6Alkyl amido, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, C _1-6-alkyl S (O) _a---wherein a be 0 to 2, C _1-6Alkoxy carbonyl, N-(C _1-6Alkyl) sulphonamide, N, N-(C _1-6Alkyl) ₂Sulphonamide, aryl, aryloxy, aryl C _1-6Alkyl, heterocyclic radical, (heterocyclic radical) C _1-6Alkyl, or group (D-E-); R wherein ¹, comprise group (D-E-), can choose wantonly on carbon and replaced by one or more V; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen the group that is selected from J wantonly and replaces;

G, J and K are independently selected from C _1-8Alkyl, C _2-8Alkenyl, C _2-8Alkynyl, C _1-8Alkyloyl, C _1-8Alkyl sulphonyl, C _1-8Alkoxy carbonyl, formamyl, N-(C _1-8Alkyl) formamyl, N, N-(C _1-8Alkyl) formamyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl, aryl, aryl C _1-6Alkyl or (heterocyclic radical) C _1-6Alkyl; Wherein G, J and K can choose wantonly on carbon and be replaced by one or more Q; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen wantonly and is selected from hydrogen or C _1-6The group of alkyl replaces;

D, D ' and D " be independently selected from C _1-6Alkyl, C _2-6Alkenyl, C _2-6Alkynyl, C _3-8Cycloalkyl, C _3-8Cycloalkyl C _1-6Alkyl, aryl, aryl C _1-6Alkyl, heterocyclic radical, (heterocyclic radical) C _1-6Alkyl; Wherein D, D ' and D " choose wantonly on carbon and replaced by one or more F '; If wherein described heterocyclic radical contains-the NH-part, nitrogen can be chosen the group that is selected from K wantonly and replace;

E, E ' and E " be independently selected from-N (R ^a)-,-O-,-C (O) O-,-OC (O)-,-C (O)-,-N (R ^a) C (O)-,-N (R ^a) C (O) N (R ^b)-,-N (R ^a) C (O) O-,-OC (O) N (R ^a)-,-C (O) N (R ^a)-,-S (O) _r-,-SO ₂N (R ^a)-,-N (R ^a) SO ₂-; R wherein ^aAnd R ^bBe independently selected from hydrogen or the optional C that is replaced by one or more F _1-6Alkyl, and r is 0-2; And

R ¹¹For the substituting group on the carbon and be selected from cyano group, hydroxyl, C _1-6Alkyl or group (D-E-); R wherein ¹¹, comprise group (D-E-), can choose wantonly on carbon and replaced by one or more V;

V is cyano group, hydroxyl or group (D '-E '-); V wherein comprises group (D '-E '-), can choose wantonly on carbon to be replaced by one or more W;

W and Z are independently selected from cyano group, C _1-6Alkyl or C _1-6Alkoxyl group;

G and K are independently selected from C _1-8Alkyl, C _2-8Alkenyl, C _2-8Alkynyl, aryl C _1-6Alkyl or (heterocyclic radical) C _1-6Alkyl; Wherein G and K can choose wantonly on carbon and be replaced by one or more Q;

Q is cyano group, hydroxyl, oxo, C _1-6Alkyl, C _2-6Alkenyl, C _1-6Alkoxyl group, C _1-6Alkyloyl, C _1-6Alkanoyloxy, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, C _1-6Alkoxy carbonyl, C _1-6Alkoxycarbonyl amino, aryl, aryloxy or group (D "-E "-); Q wherein, comprise group (D "-E "-), can choose wantonly on carbon and replaced by one or more Z;

D, D ' and D " be independently selected from aryl, aryl C _1-6Alkyl or heterocyclic radical; Wherein D, D ' and D " can choose wantonly on carbon and replaced by one or more F '; If wherein described heterocyclic radical contains-the NH-part, nitrogen can be chosen the group that is selected from K wantonly and replace;

E, E ' and E " be independently selected from-O-,-C (O) O-,-OC (O)-,-C (O)-,-N (R ^a) C (O)-,-C (O) N (R ^a)-,-S (O) _r-; R wherein ^aBe selected from hydrogen or the optional C that is replaced by one or more F _1-6Alkyl, and r is 0-2; And

F and F ' are independently selected from nitro, hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Alkyloyl, N-(C _1-6Alkyl) amino, N, N-(C _1-6Alkyl) ₂Amino, C _1-6Alkyl amido or C _1-6Alkoxy carbonyl.

M is 0,1,2,3 or 4; R wherein ¹¹Same meaning or difference.

M is 0,1 or 2; R wherein ¹¹Same meaning or difference.

M is 0.

M is 1.

R ¹²It is halogen.

R ¹²It is fluorine.

R ¹²Be chlorine.

N is 0,1 or 2; R wherein ¹²Same meaning or difference;

N is 0;

N is 1.

[0189]

Comprise following (each R in this section wherein according to other embodiment of the compound of paragraph [0187] ²Corresponding to the R in the paragraph [0187] ¹²):

Ring A is pyridyl, indyl, pyrimidyl, morpholinyl, piperidyl, piperazinyl, pyridazinyl, thienyl, piperazinyl, thiazolyl, oxazolyl, 1,2,4-triazolyl, isoxazolyl, isothiazolyl, pyrazolyl or furyl;

Ring B is thienyl, thiadiazolyl group, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl;

R ¹¹Be halogen, amino, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-3Alkanoyloxy, N-(C _1-3Alkyl) amino, N, N-(C _1-3Alkyl) ₂Amino, C _1-3Alkyl amido, N-(C _1-3Alkyl) formamyl, N, N-(C _1-3Alkyl) ₂Formamyl;

M is 0,1,2, wherein R ¹¹Same meaning or difference;

N is 0,1,2, wherein R ¹²Same meaning or difference;

R ¹²Be F or Cl.

[0190]

Ring A is pyridin-4-yl, pyridin-3-yl, pyridine-2-base or 1,2, the 4-triazolyl;

Ring B is thienyl or pyridyl;

R ¹¹Be halogen, amino, methyl or methoxy;

M is 0,1,2, wherein R ¹¹Same meaning or difference.

N is 0 or 1;

R ¹²Be F.

[0191]

Ring A is pyridyl, quinolyl, indyl, pyrimidyl, morpholinyl, piperidyl, piperazinyl, pyridazinyl, pyrazinyl, thiazolyl, thienyl, Thienopyrimidine base, thienopyridine base, purine radicals, 1 ', 2 ', 3 ', 6 '-tetrahydro pyridyl, triazinyl, oxazolyl, pyrazolyl or furyl; If wherein ring A contains-the NH-part, then nitrogen can be chosen the group replacement that is selected from G wantonly;

R ¹¹For the substituting group on the carbon and be selected from halogen, nitro, cyano group, hydroxyl, oxo, trifluoromethyl, trifluoromethoxy, amino, carboxyl, formamyl, sulfydryl, sulphonamide, C _1-6Alkyl, C _2-6Alkenyl, C _2-6Alkynyl, C _1-6Alkoxyl group, C _1-6Alkyloyl, C _1-6Alkanoyloxy, N-(C _1-6Alkyl) amino, N, N-(C _1-6Alkyl) ₂Amino, C _1-6Alkyl amido, N-(C _1-6Alkyl) formamyl, N, N-(C _1-6Alkyl) ₂Formamyl, C _1-6Alkyl S (O) _a---wherein a be 0 to 2, C _1-6Alkoxy carbonyl, N-(C _1-6Alkyl) sulphonamide, N, N-(C _1-6Alkyl) ₂Sulphonamide, aryl, aryloxy, aryl C _1-6Alkyl, heterocyclic radical, (heterocyclic radical) C _1-6Alkyl, or group (D-E-); R wherein ¹, comprise group (D-E-), choose wantonly on carbon and replaced by one or more V; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen the group that is selected from J wantonly and replaces;

G, J and K are independently selected from C _1-8Alkyl, C _2-8Alkenyl, C _2-8Alkynyl, C _1-8Alkyloyl, C _1-8Alkyl sulphonyl, C _1-8Alkoxy carbonyl, formamyl, N-(C _1-8Alkyl) formamyl, N, N-(C _1-8Alkyl) formamyl, benzyloxycarbonyl, benzoyl and phenyl sulfonyl, aryl, aryl C _1-6Alkyl or (heterocyclic radical) C _1-6Alkyl; Wherein G, J and K choose wantonly on carbon and are replaced by one or more Q; And if wherein described heterocyclic radical contains-the NH-part, then nitrogen can be chosen wantonly and is selected from hydrogen or C _1-6The group of alkyl replaces;

M is 0,1,2,3 or 4, wherein R ¹¹Same meaning or difference;

R ¹²Be F or Cl;

N is 0,1 or 2, wherein R ¹²Same meaning or difference.

[0192]

Ring A is pyridin-4-yl, pyridin-3-yl, pyridine-2-base, morpholine-4-base, piperidin-4-yl, piperidines-3-base, piperidines-2-base, piperazine-4-base, thiazol-2-yl, thiophene-2-base, furans-3-base, tetramethyleneimine-1-base, piperidines-1-base, triazol-1-yl or 1 ', 2 ', 3 ', 6 '-tetrahydropyridine-4-base, if wherein ring A contains-the NH-part, then nitrogen can be chosen the group replacement that is selected from G wantonly;

Ring B is thienyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl;

E, E ' and E " be independently selected from-O-,-C (O) O-,-OC (O)-,-C (O)-,-N (R ^a) C (O)-,-C (O) N (R ^a)-,-S (O) _r-; R wherein ^aBe selected from hydrogen or the optional C that is replaced by one or more F _1-6Alkyl, and r is 0-2;

F and F ' are independently selected from nitro, hydroxyl, C _1-6Alkyl, C _1-6Alkoxyl group, C _1-6Alkyloyl, N-(C _1-6Alkyl) amino, N, N-(C _1-6Alkyl) ₂Amino, C _1-6Alkyl amido or C _1-6Alkoxy carbonyl;

M is 0,1 or 2, wherein R ¹¹Same meaning or difference;

R ¹²Be F;

N is 0 or 1;

[0193]

Below be specific implementations according to the compound of paragraph [0187]:

R wherein ¹¹Be selected from:

[0194]

In the compound of paragraph [0187]-[0193], R ¹, R ², R ³And R ⁴Preferably such as in paragraph [0048] and [0049] definition.In other embodiment of the compound of paragraph [0187]-[0193], R ¹, R ², R ³And R ⁴Be H.

[0195]

In another embodiment, the present invention includes the compound of WO 03/024448, wherein terminal portions-C (O)-NH-Ay ¹,-C (O)-NH-Ay ²,-C (O)-NH-Ar ^a-NH ₂, and:

Replaced as the lower section:

Wherein Ф, R ¹, R ², R ³And R ⁴As institute's definition in the paragraph [0046], and preferred such as [0048] and [0049] middle definition.

[0196]

In another embodiment, the present invention includes compound or its pharmacologically acceptable salts of following structural (13):

Wherein

Ф is-NH ₂Or-OH;

R ¹Be H or such as in the paragraph [0046] definition;

R ², R ³And R ⁴Such as in the paragraph [0046] definition; And

Ar, A, D, E and G in the JP 2003137866 definition.

[0197]

In the compound of paragraph [0196], R ¹, R ², R ³And R ⁴Preferably such as in paragraph [0048] and [0049] definition.In other embodiment of the compound of paragraph [0196], R ¹, R ², R ³And R ⁴Be H.The specific implementations of the compound of paragraph [0196] is the terminal portions by the compound that makes JP2003137866:

Replaced as the lower section:

And those compounds that obtain, wherein Ф, R ¹, R ², R ³And R ⁴As institute's definition in the paragraph [0046], and preferred such as [0048] and [0049] middle definition.

[0198]

In another embodiment, the present invention includes compound or its pharmacologically acceptable salts of following structural (14):

Wherein

Ф is-NH ₂Or-OH;

R ¹Be H or such as in the paragraph [0046] definition;

R ², R ³And R ⁴Such as in the paragraph [0046] definition;

X, Y and A in the JP 11-269146 (1999) definition; And

R ¹¹R with JP 11-269146 (1999) ¹Identical.

[0199]

In the compound of paragraph [0198], R ¹, R ², R ³And R ⁴Preferably such as in paragraph [0048] and [0049] definition.In other embodiment of the compound of paragraph [0198], R ¹, R ², R ³And R ⁴Be H.The specific implementations of the compound of paragraph [0198] is the terminal portions by the compound 1-50 of the table 2-4 that makes JP11-269146 (1999):

Replaced as the lower section:

[0200]

In another embodiment, the present invention includes compound or its pharmacologically acceptable salts of following structural (15):

Wherein

Ф is-NH ₂Or-OH;

R ¹Be H or such as in the paragraph [0046] definition;

R ², R ³And R ⁴Such as in the paragraph [0046] definition;

N, X, Q and A in the JP 11-302173 (1999) definition; And

R ¹¹R with JP 11-302173 (1999) ¹Identical.

[0201]

In the compound of paragraph [0200], R ¹, R ², R ³And R ⁴Preferably such as in paragraph [0048] and [0049] definition.In other embodiment of the compound of paragraph [0200], R ¹, R ², R ³And R ⁴Be H.The specific implementations of the compound of paragraph [0200] is the terminal portions by the compound 1-67 that makes JP11-302173 (1999):

Replaced as the lower section:

[0202]

In another embodiment, the present invention includes compound or its pharmacologically acceptable salts of following structural (16):

Wherein

Ф is-NH ₂Or-OH;

R ¹Be H or such as in the paragraph [0046] definition;

R ², R ³And R ⁴Such as in the paragraph [0046] definition;

N, Q, X and A in the JP 2001131130 definition; And

R ¹¹R with JP 2001131130 ¹Identical.

[0203]

In the compound of paragraph [0202], R ¹, R ², R ³And R ⁴Preferably such as in paragraph [0048] and [0049] definition.In other embodiment of the compound of paragraph [0202], R ¹, R ², R ³And R ⁴Be H.The specific implementations of the compound of paragraph [0202] is the terminal portions by the compound that makes JP2001131130:

Replaced as the lower section:

[0204]

In another embodiment, the present invention includes compound or its pharmacologically acceptable salts of following structural (17):

Wherein

Ф is-NH ₂Or-OH;

R ¹Be H or such as in the paragraph [0046] definition;

R ², R ³And R ⁴Such as in the paragraph [0046] definition;

N, X, Q and A in JP 10152462, JP 2002332267 and the JP 11-302173 definition; And

R ¹¹R with JP 10152462, JP 2002332267 and JP 11-302173 ¹Identical.

[0205]

In the compound of paragraph [0204], R ¹, R ², R ³And R ⁴Preferably such as in paragraph [0048] and [0049] definition.In other embodiment of the compound of paragraph [0204], R ¹, R ², R ³And R ⁴Be H.The specific implementations of the compound of paragraph [0204] is the terminal portions by the compound that makes JP10152462, JP 2002332267 and JP 11-302173:

(particularly

Replaced as the lower section:

[0206]

In another embodiment, the present invention includes compound or its pharmacologically acceptable salts of following structural (18):

Wherein

Ф is-NH ₂Or-OH;

R ¹Be H or such as in the paragraph [0046] definition;

R ², R ³And R ⁴Such as in the paragraph [0046] definition;

Define among n, X, Q and A such as the US 6,174,905; And

R ¹¹With US 6,174,905 R ¹Identical.

[0207]

In the compound of paragraph [0206], R ¹, R ², R ³And R ⁴Preferably such as in paragraph [0048] and [0049] definition.In other embodiment of the compound of paragraph [0206], R ¹, R ², R ³And R ⁴Be H.The specific implementations of the compound of paragraph [0206] is by making US6, the terminal portions of the compound of 174,905 table 1:

With US 6,174, the terminal portions of the compound of 905 table 2-4:

Replaced as the lower section:

[0208]

In other embodiment according to paragraph [0046], the present invention includes the compound of WO01/70675, wherein end group part-C (the O)-NHOH of table 2 and 3 compound ,-C (O)-CH ₂-SC (O) CH ₃,-C (O)-CH ₂-SH ,-C (O)-CH ₂-SCH ₃,-C (O)-CH ₂-SCH ₂-phenyl ,-C (O)-CH ₂-S-phenyl ,-C (O)-CH ₂-SC (O)-phenyl and

Quilt is as the lower section

Replace, wherein Ф, R ¹, R ², R ³And R ⁴As institute's definition in the paragraph [0046], and preferred such as [0048] and [0049] middle definition.

[0209]

In second aspect, the invention provides and contain just like arbitrary section described or the compound as shown in the arbitrary form of this paper and the composition of the acceptable vehicle of pharmacy in paragraph [0046]-[0088], [0098]-[0110] and [0115]-[0207].

[0210]

A third aspect of the present invention provides a kind of method of inhibition of histone deacetylase, this method comprise make histone deacetylase with as described in paragraph [0046]-[0088], [0098]-[0110] and [0115]-[0207] arbitrary section the compound as shown in the arbitrary form of this paper or with contact as the described composition of paragraph [0209].Inhibition to histone deacetylase can be in cell or multicellular organisms.If in multicellular organisms, comprise according to the present invention's method in this respect this organism is used as described in paragraph [0046]-[0088], [0098]-[0110] and [0115]-[0207] arbitrary section or the compound as shown in the arbitrary form of this paper or as the described composition of paragraph [0209].Preferably, this organism is a Mammals, is more preferably the people.

[0211]

The data acknowledgement that this paper is listed the anticancer effect of hdac inhibitor of the present invention.Report about the human clinical experiment of hdac inhibitor shows recently, these inhibitor can effectively be treated human entity tumour or cancer (lung, colon, prostate gland (prostrate), stomach, mammary gland, leukemia), comprise and eliminate lymphoma (SAHA, the ASCO Abstract No.2321 that transforms fully, 2003) and outer rim T-cell lymphoma (depsipeptide/FR901228 ASCO Abstract No.88,2002).These data have confirmed inhibition HDAC-1 with the listed data of this paper and have suppressed the surprising effectiveness of tumor growth in vivo, estimate reasonably that thus HDAC-1 inhibitor of the present invention not only can be used for suppressing HDAC, can also be as the agent of treatment treatment for cancer.

Preferred compound according to the present invention comprises in the table 1 those, and they mainly are to use method preparation shown in the described herein and following synthetic schemes.All compounds among the application all are to use Chemdraw Ultra 6.0.2 version (available from Cambridgesoft.co, 100 CambridgePark Drive, Cambridge, MA 02140), Namepro 5.09 editions (available from ACD labs, 90 Adelaide Street West, Toronto, Ontario, M5H, 3V9, Canada) name, or by its derivation.

Table 1

[0213]

We are surprised to find that, when comprising the benzamide part:

Hdac inhibitor at the 5-position of aniline ring (NH ₂The contraposition of group) goes up when being planar ring or member ring systems (aryl or heteroaryl) replacement substantially, be not substituted with the aniline ring or replaced by less non-flat portion or the similar compound of planar section not on the 5-position of aniline ring the time compared, the HDAC of this compound suppresses, and active (suppressing assay method by following human HDAC-1 measures) improved 3 to 10 coefficients or higher.In addition, we have found that itself can replace this planar section.Therefore, the R in the compound of the present invention ¹Be single-, two-or three-cyclophane base or heteroaryl moieties, this part is optional to be substituted.In some preferred implementations, R ¹Further do not replaced.In other preferred implementation, R ¹The part that is contained 1-5 atom, for example replacements such as methyl, methylol, halogenated methyl, halogen, hydroxyl, amino.In other embodiments, R ¹By bigger part, the part that for example contains 6-25 atom replaces.

[0214]

In view of people such as T.Suzuki, J.Med.Chem, 1999,42,3001-3003, this point is wonderful, because the document points out that the substitute mode (the wherein amino ortho position that is positioned at amide nitrogen) on the pulsating aniline ring of the benzamide of known HDACs is extremely sensitive to replacing.And the substituting group that amino is the Me of an ortho position or a position and OMe and so on can damage HDAC and suppress active, and what cause that HDAC renders a service completely loses.The substituting group of the same type in amino contraposition can not cause the obvious reduction of effectiveness, only can infer like this and may allow small-substituent, for example Me, MeO, F, Cl.

[0215]

In addition, we are surprised to find that, the HDAC of these compounds (just contain the chemical part of paragraph [0046] and have basic compound for planar ring or member ring systems on the 5-position of aniline ring) suppresses active, basically with the carbonyl that is attached to acid amides in the paragraph [0046] on the characteristic of chemical part irrelevant.Therefore, in the compound of formula 1, any chemical part that Y is made up of 1 to 50 atom (non-reacted on the preferred physiology).

[0216]

Be exemplary below according to the compound of above-mentioned embodiment.

Table 1a

Table 1a (continuing)

Table 1a (continuing)

Synthetic schemes and experimental arrangement

Can use the known method of those of ordinary skills, prepare compound of the present invention according to the reaction scheme shown in the embodiment hereinafter.These schemes are used to illustrate the process that some can be used for making compound of the present invention.Those skilled in the art will appreciate that, can use other synthesis step commonly used.Can prepare compound of the present invention by the marketable material composition.Can carry out various replacements to obtain compound of the present invention according to the program of well known to a person skilled in the art to these material compositions.

Can be used in combination the argumentation of the techniques described herein and WO 03/087057, synthetic routinely compound according to paragraph [0083]-[0088].

Can be used in combination the argumentation of the techniques described herein and WO 03/076422, synthetic routinely compound according to paragraph [0098]-[0110].

Can be used in combination the argumentation of the techniques described herein and WO 03/075929, synthetic routinely compound according to paragraph [0115]-[0124].

Can be used in combination the argumentation of the techniques described herein and WO 03/076395, synthetic routinely compound according to paragraph [0125]-[0135].

Can be used in combination the argumentation of the techniques described herein and WO 03/076400, synthetic routinely compound according to paragraph [0136]-[0145].

Can be used in combination the argumentation of the techniques described herein and WO 03/076401, synthetic routinely compound according to paragraph [0146]-[0157].

Can be used in combination the argumentation of the techniques described herein and WO 03/076421, synthetic routinely compound according to paragraph [0158]-[0166].

Can be used in combination the argumentation of the techniques described herein and WO 03/076430, synthetic routinely compound according to paragraph [0167]-[0175].

Can be used in combination the argumentation of the techniques described herein and WO 03/076438, synthetic routinely compound according to paragraph [0176]-[0186].

Can be used in combination the argumentation of the techniques described herein and WO 03/92686, synthetic routinely compound according to paragraph [0187]-[0194].

Can be used in combination the argumentation of the techniques described herein and WO 03/024448, synthetic routinely compound according to paragraph [0195].

Can be used in combination the argumentation of the techniques described herein and JP 2003137866, synthetic routinely compound according to paragraph [0196]-[0197].

Can be used in combination the argumentation of the techniques described herein and JP 11-269146 (1999), synthetic routinely compound according to paragraph [0198]-[0199].

Can be used in combination the argumentation of the techniques described herein and JP 11-302173 (1999), synthetic routinely compound according to paragraph [0200]-[0201].

Can be used in combination the argumentation of the techniques described herein and JP 2001131130, synthetic routinely compound according to paragraph [0202]-[0203].

Can be used in combination the argumentation of the techniques described herein and JP 10152462, JP 2002332267 and JP 11-302173, synthetic routinely compound according to paragraph [0204]-[0205].

Can be used in combination the argumentation of the techniques described herein and US 6,174,905, synthetic routinely compound according to paragraph [0206]-[0207].

Can be used in combination the argumentation of the techniques described herein and WO 01/70675, synthetic routinely compound according to paragraph [0206].

Embodiment 1

N-[2-amino-5-(2-thienyl) phenyl]-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide (6)

Scheme 1

Step 1.5-bromo-2-nitro-aniline (2)

With potassium tert.-butoxide (14.5 grams; 129.2 mmole) and (301 milligrams of cupric chlorides (I); 3.04 in 0 ℃ of stirring, (1,6.141 restrains glycol dimethyl ether mmole) (120 milliliters) solution dropwise to add 1-bromo-4-nitro-benzene therein through 103 minutes under nitrogen; 30.4 mmole) and O-methyl-hydroxylamine hydrochloride (3.174 the gram; 38 mmoles) N, dinethylformamide (65 milliliters) solution removes cooling bath, and mixture was at room temperature reacted 3 hours, washs with ethyl acetate (600 milliliters) dilution and with saturated aqueous ammonium chloride.Dry (MgSO ₄) organic layer, filter and concentrate.By flash chromatography (eluent, 25% ethyl acetate is in hexane), obtain 4.96 gram (75% yield) compounds 2.

¹H NMR：(400.2MHz，CDCl ₃)δ(ppm)：7.98(d，J＝9.24，1H)；7.02(d，J＝1.98，1H)；6.82(dd，J＝1.98 and 9.24，1H)；6.12(bs，2H)。

Step 2.2-nitro-5-benzene sulphur-2-base-aniline (3)

With aryl bromide 2 (5.85 grams; Mmole) 26.9 (or optional any other halogenated aryl hydrocarbon); 2-thienyl boric acid (4.56 grams, 35.6 mmoles); (or optional any other aryl boric acid), three-o-tolyl phosphine (2.69 grams; 8.8 mmole) and salt of wormwood (11.1 the gram; 80 mmoles) (2.04 restrain the suspension in degassed ethylene glycol dme (70 milliliters) and water (35 milliliters) with four (triphenyl phosphine) palladium (0), 1.77 mmole) handle, and mixture stirred 18 hours on 80 ℃ pre-hot oil bath, dilute with methylene dichloride (300 milliliters), wash dry (MgSO with water ₄) and concentrate.Purify by flash chromatography (hexane solution of eluent 50% ether), obtain compound 3 (5.63 grams, 95% yield).

¹H NMR：(400.2MHz，DMSO)δ(ppm)：7.97(d，J＝9.0，1H)；7.69(dd，J＝1.2 and 5.1，1H)；7.60(dd，J＝1.2 and 3.6，1H)；7.49(bs，2H)；7.27(d，J＝2.0，1H)；7.18(dd，J＝3.6 and 5.1，1H)；6.97(dd，J＝2.0 and 9.0，1H)。

Step 3.4-[(3,4-dimethoxy-phenyl amino)-methyl]-N-(2-nitro-5-benzene sulphur-2-base-phenyl)-benzamide (5)

In N-methyl-p-nitroaniline (3,460 milligrams, 2.1 mmoles) (or optionally any other N-methyl-p-nitroaniline, 1 equivalent); 4-[(3,4-dimethoxy-phenyl amino)-methyl]-phenylformic acid (4, as follows, 761 milligrams, 2.65 mmoles) (or optionally any other acid, 1.3 equivalent) and the phosphofluoric acid benzotriazole-1-base oxygen base three ((1095 milligrams of dimethylamino) Phosphonium (BOP), 2.47 in pyridine mmole) (15 milliliters) solution, under nitrogen gas stream, be added on 60% sodium hydride (563 milligrams, 14.1 mmoles) in the oil by part, and reaction was at room temperature carried out 2.5 hours, and use dilution with toluene.With the excessive NaH of acetate cancellation, and whole mixture is concentrated, be dissolved in ethyl acetate again and use NaHCO ₃Salt brine solution washing, dry (MgSO ₄) and concentrate.Purify by flash chromatography (hexane solution of eluent 30% to 75% AcOEt), obtain the acid amides 5 of 883 milligrams (1.80 mmoles, 86% yields).

¹H NMR：(400.2MHz，DMSO)δ(ppm)：10.8(s，1H)；8.10(d，J＝2.0，1H)；8.06(d，J＝8.6，1H)；7.90(d，J＝8.2，2H)；7.74(dd，J＝1.0and 4.9，1H)；7.72(dd，J＝1.0 and 3.5，1H)；7.69(dd，J＝2.2 and 8.7，1H)；7.53(d，J＝8.2，2H)；7.22(dd，J＝3.5 and 4.9，1H)；6.64(d，J＝8.6，1H)；6.31(d，J＝2.0，1H)；6.01(t，J＝6.1，1H)；5.98(dd，J＝2.2 and 8.4，1H)；4.32(d，J＝6.1，2H)；3.66(s，3H)；3.59(s，3H)。

4-[(3,4-dimethoxy-phenyl amino)-methyl]-phenylformic acid (4)

3, (786 milligrams of 4-dimethoxy-aniline; 5.13 mmole) and (219 milligrams of dichloride dibutyl tins; 0.72 in glycol dimethyl ether mmole) (7 milliliters) solution, add (748 milligrams in 4-formyl radical-phenylformic acid; 4.98 mmole).This suspension was at room temperature stirred 10 minutes, with (1.0 milliliters of phenyl silanes; 7.9 mmole) handle, and mixture stirred 12 hours under identical temperature.Add methyl alcohol and several dripping, stirred 5 hours, concentrate in a vacuum, be suspended in the methylene dichloride and also at room temperature stirred one day.After the filtration, obtain pure sour 4 (1.13 grams of beige solid shape; 79% yield).

¹H NMR：(400.2MHz，DMSO)δ(ppm)：7.86(d，J＝8.2，2H)；7.44(d，J＝8.2，2H)；6.63(d，J＝8.5，1H)；6.29(d，J＝2.3，1H)；5.96(dd，J＝2.3，8.5，1H)；5.96(bs，1H)；4.28(s，2H)；3.64(s，3H)；3.58(s，3H)。

Step 4.N-(2-amino-5-benzene sulphur-2-base-phenyl)-4-[(3,4-dimethoxy-phenyl amino)-methyl]-benzamide (6)

In sealed tube, with (250 milligrams of compounds 5,0.511 (or optional any other nitro acid amides mmole), 1 equivalent) and two hydration tin chlorides (II) (2.30 the gram, 10.2 mmole) suspension in 1: 1: 1 mixture THF/MeOH/ water (18 milliliters) stirred 1 hour at 75 ℃, with the ethyl acetate dilution, and use saturated NaHCO ₃Solution washing is through Na ₂SO ₄Dry and purify by flash chromatography, eluent is the dichloromethane solution of 20% EtOAc, to produce the titled reference compound 6 of 138 milligrams (59% yields).

¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.66(s，1H)；7.92(d，J＝8.4，2H)；7.46(d，J＝8.4，2H)；7.44(d，J＝2.0，1H)；7.34(dd，J＝1.1；5.0，1H)；7.27(dd，J＝2.0；8.2，1H)；7.22(dd，J＝1.1 and 3.6，1H)；7.03(dd，J＝3.6，5.0，1H)；6.78(d，J＝8.5，1H)；6.64(d，J＝8.5，1H)；6.31(d，J＝2.5，1H)；6.01-5.97(m，2H)；5.14(bs，2H)；4.30(d，J＝6.1，2H)；3.66(s，3H)；3.58(s，3H)。

Table 2

Sign according to the compound of scheme 1 preparation

Embodiment 2

N-[2-amino-4-(2-thienyl) phenyl]-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide (16)

Scheme 2

Step 1.2-nitro-4-benzene sulphur-2-base-aniline (14)

According to embodiment 1, identical program described in the step 2, but compound 1 is replaced to compound 13, the yield with 89% obtains titled reference compound 14.

¹H NMR：(400.2MHz，DMSO)δ(ppm)：8.11(d，J＝2.15，1H)；7.73(dd，J＝2.15，8.8，1H)；7.59(bs，2H)；7.45(dd，J＝1.1，5.4，1H)；7.40(dd，J＝1.1，3.8，1H)；7.09(m，1H)；7.08(dd，J＝5.6，8.8，1H)。

Step 2.4-[(3,4-dimethoxy-phenyl amino)-methyl]-N-(2-nitro-4-benzene sulphur-2-base-phenyl)-benzamide (15)

According to embodiment 1, identical program described in the step 3, but compound 3 is replaced to compound 14, the yield with 68% obtains titled reference compound. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：10.7(s，1H)；8.19(d，J＝2.0，1H)；8.00(dd，J＝1.7，8.6，1H)；7.89(d，J＝8.0，2H)；7.80(d，J＝8.4，1H)；7.67(d，J＝3.8，1H)；7.64(d，J＝5.1，1H)；7.51(d，J＝8.0，2H)；7.18(t，J＝3.8，1H)；6.64(d，J＝8.6，1H)；6.31(d，J＝2.4，1H)；6.31-5.96(m，2H)；4.31(d，J＝6.1，2H)；3.66(s，3H)；3.59(s，3H)。

Step 3.N-(2-amino-4-benzene sulphur-2-base-phenyl)-4-[(3,4-dimethoxy-phenyl amino)-methyl]-benzamide (16)

According to embodiment 1, identical program described in the step 4, but compound 5 is replaced to compound 15, the yield with 47% obtains titled reference compound. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.59(s，1H)；7.90(d，J＝8.0，2H)；7.46(d，J＝8.0，2H)；7.45(d，J＝1.1，1H)；7.34(dd，J＝1.1，3.5，1H)；7.20(d，J＝8.1，1H)；7.09(dd，J＝3.5，4.9，1H)；6.89(dd，J＝2.2，8.1，1H)；6.64(d，J＝8.6，1H)；6.32(d，J＝2.5，1H)；6.00-5.97(m，2H)；5.07(bs，2H)；4.30(d，J＝6.1，2H)；3.66(s，3H)；3.59(s，3H)。

Embodiment 3

N-(2-amino-4-bromophenyl)-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide (18)

Scheme 2a

N-(4-bromo-2-nitro-phenyl)-4-[(3,4-dimethoxy-phenyl amino)-methyl]-benzamide (17)

According to embodiment 2, identical program described in the step 2, but compound 14 is replaced to compound 13, the yield with 92% obtains compound 17. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：10.72(s，1H)；8.17(d，J＝2.0，1H)；7.96(dd，J＝2.0，8.6，1H)；7.86(d，J＝7.9，2H)；7.69(d，J＝8.6，1H)；7.51(d，J＝7.9，2H)；6.63(d，J＝8.4，1H)；6.32(d，J＝2.0，1H)；6.01-5.96(m，2H)；4.31(d，J＝5.9，2H)；3.65(s，3H)；3.58(s，3H)。

N-(2-amino-4-bromo-phenyl)-4-[(3,4-dimethoxy-phenyl amino)-methyl]-benzamide (18)

According to embodiment 2, identical program described in the step 3, but compound 15 is replaced to compound 17, the yield with 46% obtains compound 18.

¹H NMR(400.2MHz，DMSO)δ(ppm)：9.55(s，1H)，7.89(d，J＝8.2Hz，2H)，7.45(d，J＝8.4Hz，2H)，7.07(d，J＝8.4Hz，1H)，6.92(d，J＝2.3Hz，1H)，6.69(dd，J＝8.4，2.3Hz，1H)，6.63(d，J＝8.4Hz，1H)，6.30(d，J＝2.5Hz，1H)，6.00-5.96(m，2H)，5.22(s，2H)，4.29(d，J＝6.3Hz，2H)，3.65(s，3H)，3.58(s，3H)。MS：(calc.)455.1；(obt.)456.4，458.4(MH) ⁺。

Embodiment 4

N-[2-amino-5-(2-thienyl) phenyl]-1-(3,4,5-trimethoxy benzyl) indoline-6-carboxylic acid amides (23)

Scheme 3

Step 1:2,3-dihydro-1H-indole-5-carboxylic acid methyl esters (20)

In the Glacial acetic acid cold soln of indole-5-carboxylic acid's methyl esters of 0 ℃ (2 grams, 11.4 mmoles), slowly add sodium cyanoborohydride (1.075 grams, 17.1 mmoles).This mixture heated up and restir 1 hour at room temperature, be cooled to 0 ℃ and use H again ₂The O cancellation.The interpolation NaOH aqueous solution is adjusted to 12 with the pH value of gained solution, with the DCM extraction, with the salt water washing and through MgSO ₄Dry.Purify with the titled reference compound 20 (1.62 grams, 80%) that produces the beige solid shape with exsiccant extract vacuum concentration and by flash chromatography (hexane solution of eluent 30%EtOAc). ¹H-NMR(DMSO)δ：2.94(t，J＝8.6Hz，2H)；3.51(dt，J＝1.2，8.6Hz，2H)；3.71(s，3H)；6.42(d，J＝8.0Hz，2H)；7.54(m，2H)。

Step 2:1-(3,4,5-trimethoxy-benzyl)-2,3-dihydro-1H-indole-5-carboxylic acid methyl esters (21)

At 20 (300 milligrams, 1.69 mmoles), 3,4, in THF (8 milliliters) solution of 5-TMB (365 milligrams, 1.86 mmoles) and dichloride dibutyl tin (51 milligrams, 0.17 mmole), add phenyl silane (229 microlitres, 1.86 mmoles).With this mixture under nitrogen in stirred overnight at room temperature.Add aldehyde and phenyl silane again, and continue to stir until starting material are exhausted.Evaporate THF in a vacuum and pass through flash chromatography (hexane solution of eluent 20% EtOAc) purification resistates.Also by secondary flash chromatography (hexane solution of eluent 20% EtOAc) compound is further purified at last by recrystallization in mixture E tOAc/ hexane, to produce the titled reference compound 21 (428 milligrams, 71%) of white solid. ¹H-NMR(DMSO)δ：2.96(t，J＝8.4Hz，2H)；3.45(t，J＝8.7Hz，2H)；3.61(s，3H)；3.71(s，6H)；3.72(s，3H)；4.30(s，2H)；6.59(s，2H)；6.61(d，J＝8.4Hz，1H)，7.54(d，J＝1.6Hz，1H)；7.63(dd，J＝1.8，8.4Hz，1H)。

Step 3:1-(3,4,5-trimethoxy-benzyl)-2,3-dihydro-1H-indole-5-carboxylic acid (22)

With LiOH * H ₂Water (5 milliliters) solution of O (75 milligrams, 1.78 mmoles) adds in THF (5 milliliters) solution of ester 21 (426 milligrams, 1.19 mmoles).This mixture at room temperature stirred spend the night.Remove THF in a vacuum, use 1N HCl that remaining aqueous solution is acidified to pH 1 then.The throw out that forms is filtered collection, use H ₂The O washing is also dry, produces the titled reference compound 22 (320 milligrams, 78%) of white solid. ¹H-NMR(DMSO)δ：2.96(t，J＝8.6Hz，2H)；3.43(t，J＝8.6Hz，2H)；3.62(s，3H)；3.72(s，6H)；4.29(s，2H)；6.58(s，1H)；6.60(s，2H)；7.53(s，1H)；7.61(d，J＝8.8Hz，1H)。

Step 4 and 5.1-(3,4,5-trimethoxy-benzyl)-2,3-dihydro-1H-Indole-6-carboxylic acid (2-amino-5-benzene sulphur-2-base-phenyl)-acid amides (23)

According to embodiment 1, the program described in the step 3 and 4, the titled reference compound 23 (294 milligrams, 41%) of acquisition yellow solid shape. ¹H NMR：(DMSO)δ(ppm)：9.37(s，1H)，7.73(d，J＝8.4Hz，1H)，7.70(s，1H)，7.44(d，J＝2.0Hz，1H)，7.33(d，J＝5.1Hz，1H)，7.25(dd，J＝8.2，2.0Hz，1H)，7.22(d，J＝3.3Hz，1H)，7.03(dd，J＝4.2，4.2Hz，1H)，6.78(d，J＝8.4Hz，1H)，6.66(d，J＝8.2Hz，1H)，6.64(s，2H)，5.06(s，2H)，4.32(s，2H)，3.75(s，6H)，3.64(s，3H)，3.45(t，J＝8.3Hz，2H)，3.00(t，J＝8.5Hz，2H)。MS：(calc.)515.2；(obt.)513.7(MH) ⁺。

Embodiment 5

N-[2-amino-5-(2-thienyl) phenyl]-5-{[(3,4, the 5-trimethoxyphenyl) amino] methyl }-1-cumarone-2-carboxylic acid amides (29)

Scheme 4

Step 1.5-methyl-cumarone-2-carboxylic acid, ethyl ester (25)

At 2-hydroxy-5-methyl benzaldehyde (5 grams, 36.7 mmoles) and K ₂CO ₃In (12.7 grams, 91.8 mmoles) stirred suspension in DMF (30 milliliters), dropwise add ethyl bromoacetate (4.07 milliliters, 36.7 mmoles).Make this mixture under nitrogen stirring at room 2 hours, be heated to 80 ℃ and stir and spend the night then.To react and use H ₂The O cancellation is filtered collection with it and is passed through flash chromatography (hexane solution of eluent 5% EtOAc) purification to produce titled reference compound 25 (2.30 grams, 31%) to form throw out. ¹H-NMR(CDCI ₃)δ：1.45(t，J＝7.0Hz，3H)；2.47(s，3H)；4.45(q，J＝7.0Hz，2H)；7.26(m，1H)；7.46(m，3H)。

Step 2-3.5-methylol-cumarone-2-carboxylic acid, ethyl ester (26)

Under nitrogen, with the mixture of ester 25 (2.26 gram, 11.1 mmoles), N-bromosuccinimide (2.37 grams, 13.3 mmoles) and VAZO (271 milligrams, 1.11 mmoles) at CCl ₄Reflux in (50 milliliters) and spend the night.Reaction mixture is cooled to room temperature, with methylene dichloride dilution and wash with water.With organic layer through anhydrous MgSO ₄Dry and concentrated in a vacuum.Resistates is purified to produce 5-brooethyl-cumarone-2-carboxylic acid, ethyl ester by flash chromatography (hexane solution of eluent 5% EtOAc).This compound is dissolved in diox (20 milliliters) and adds NaHCO ₃Water (20 milliliters) solution of (1.76 grams, 20.9 mmoles).To be reflected at 80 ℃ stirred 16 hours.Be dissolved in EtOAc and use the salt water washing with solvent evaporation and with product.With organic layer through anhydrous MgSO ₄Dry and concentrated in a vacuum.Resistates is purified with the titled reference compound 26 (2.55 grams, 61%) that produces white solid by flash chromatography (hexane solution of eluent 20-40% EtOAc). ¹H-NMR(DMSO)δ：7.74(d，J＝1.0Hz，1H)，7.71-7.70(m，1H)，7.65(d，J＝8.6Hz，1H)，7.44(dd，J＝8.6，1.8Hz，1H)，5.31(t，J＝5.8Hz，1H)，4.59(d，J＝5.7Hz，2H)，4.35(q，J＝7.1Hz，2H)；1.34(t，J＝7.0，3H)。

Step 4:5-formyl radical-cumarone-2-carboxylic acid, ethyl ester (27)

In DCM (70 milliliters) solution of compound 26 (2.53 grams, 11.49 mmoles), add MnO ₂(9.99 grams, 114.9 mmoles).Reaction mixture was at room temperature stirred 16 hours, filter by C salt pad then.Filtrate is concentrated in a vacuum to produce white solid titled reference compound 27 (2.19 grams, 87%). ¹H-NMR(DMSO)δ：10.07(s，1H)，8.40-8.39(m，1H)，8.03(dd，J＝8.6，1.6Hz，1H)，7.93-7.92(m，2H)，4.38(q，J＝7.1Hz，2H)；1.35(t，J＝7.0，3H)。

Step 5:5-[(3,4,5-trimethoxy-phenyl amino)-methyl]-cumarone-2-carboxylic acid, ethyl ester (28)

According to embodiment 4, identical program described in the step 2, but with

compound

20 and 3,4, the 5-TMB replaces to 3,4,5-trimethoxy-aniline and compound 27, the yield with 99% obtains titled reference compound. ¹H NMR：(DMSO)δ(ppm)：7.75(d，J＝1.0Hz，1H)，7.73(d，J＝1.0Hz，1H)，7.66(d，J＝8.6Hz，1H)，7.51(dd，J＝8.6，1.8Hz，1H)，6.11(t，J＝6.1Hz，1H)，5.89(s，2H)，4.37-4.32(m，4H)，3.63(s，6H)，3.49(s，3H)，1.33(t，J＝7.0，3H)。

Step 6-8:5-[(3,4,5-trimethoxy-phenyl amino)-methyl]-cumarone-2-carboxylic acid (2-amino-5-benzene sulphur-2-base-phenyl)-acid amides (29)

According to identical program described in embodiment 4 steps 3, then according to embodiment 1, the program of describing in the step 3 and 4, the yield with 73% obtains the titled reference compound 29 of orange solids shape. ¹H NMR：(DMSO)δ(ppm)：9.92(s，1H)，7.77(d，J＝1.0Hz，1H)，7.70(s，1H)，7.65(d，J＝8.6Hz，1H)，7.49(dd，J＝8.6，1.8Hz，1H)，7.46(d，J＝2.2Hz，1H)，7.34(dd，J＝5.1，1.0Hz，1H)，7.30(dd，J＝8.2，2.2Hz，1H)，7.23(dd，J＝3.5，1.2Hz，1H)，7.04(dd，J＝5.1，3.5Hz，1H)，6.80(d，J＝8.4Hz，1H)，6.12(t，J＝5.8Hz，1H)，5.91(s，2H)，4.35(d，J＝5.9Hz，2H)，3.64(s，6H)，3.50(s，3H)。MS：(calc.)529.2；(obt.)530.7(MH) ⁺。

Embodiment 6

4-{[(3, the 4-Dimethoxyphenyl) amino] methyl }-N-[3-(2-thienyl) phenyl] benzamide (32)

Scheme 5

Step 1:3-benzene sulphur-2-base-aniline (31)

According to identical program described in embodiment 1 step 2, but compound 2 is replaced to compound 30, obtain titled reference compound 31 with 50% yield. ¹H NMR：(DMSO)δ(ppm)：7.45(dd，J＝5.1，1.2Hz，1H)，7.32(dd，J＝3.7，1.2Hz，1H)，7.07(dd，J＝3.7，1.2Hz，1H)，7.02(dd，J＝7.7，7.7Hz，1H)，6.81(dd，J＝1.9，1.9Hz，1H)，6.78(ddd，J＝7.4，1.6，0.8Hz，1H)，6.48(ddd，J＝8.0，2.3，1.0Hz，1H)，5.20(s，2H)。MS：(calc.)176.4；(obt.)175.1(MH) ⁺。

Step 2:4-[(3,4-dimethoxy-phenyl amino)-methyl]-N-(3-benzene sulphur-2-base-phenyl)-benzamide (32)

In 31 (122 milligrams, 0.696 mmole), acid 4 (182 milligrams, 0.633 mmole) and the stirred solution of BOP (308 milligrams, 0.696 mmole) in DMF (4 milliliters), add Et ₃N (265 microlitres, 1.90 mmoles).To be reflected under the nitrogen stirring at room 3 hours, use H ₂O cancellation and evaporation.With the resistates ethyl acetate extraction, use NH ₄Cl, NaHCO ₃Saturated solution and salt water washing.With organic layer through anhydrous MgSO ₄Dry and concentrated in a vacuum, the material that forms is thus purified to produce the titled reference compound 32 (70 milligrams, 25%) of yellow solid shape by flash chromatography (hexane solution of eluent 40% EtOAc). ¹H NMR：(DMSO)δ(ppm)：10.25(s，1H)，8.09-8.08(m，1H)，7.73(ddd，J＝7.6，3.7，3.7Hz，1H)，7.54(dd，J＝5.1，1.0Hz，1H)，7.49(d，J＝8.2Hz，2H)，7.45(dd，J＝3.7，1.2Hz，1H)，7.42-7.32(m，2H)，7.13(dd，J＝5.1，3.7Hz，1H)，6.64(d，J＝8.6Hz，1H)，6.31(d，J＝2.5Hz，1H)，6.00-5.97(m，2H)，4.31(d，J＝6.1Hz，2H)，3.65(s，3H)，3.59(s，3H)。MS：(calc.)，444.2；(obt.)445.5(MH) ⁺。

Table 3

Sign according to the compound of scheme 5 preparation

Embodiment 7

N-[2-amino-5-(2-thienyl) phenyl]-4-{[(4-pyridin-3-yl pyrimidine-2-base) amino] methyl } benzamide (43)

Scheme 6

Step 1:3-dimethylamino-1-pyridin-3-yl-acrylketone (38)

At 3-acetylpyridine (37,30.0 gram, 247.6 mmoles) and N, the stirred solution of dinethylformamide dimethyl-acetal (65.8 milliliters, 495.2 mmoles) was refluxed under nitrogen 4 hours.Reaction mixture is concentrated into dried, and adds 50 milliliters of diethyl ether to produce brown suspension.The filtering separation solid is used Et ₂O rinsing and dry titled reference compound 38 (36.97 grams, 85% yield) to produce orange crystalline solid shape. ¹H NMR(400MHz，CDCl ₃)δ(ppm)：9.08(d，J＝2.2Hz，1H)，8.66(dd，J＝4.9，1.4Hz，1H)，8.26-8.23(m，1H)，7.85(d，J＝12.1Hz，1H)，7.40(dd，J＝7.8，4.9Hz，1H)，5.68(d，J＝12.1Hz，1H)，3.20(s，3H)，2.97(s，3H)。

Step 2:(4-guanidine methyl) methyl benzoate (40)

At 4-amino methyl-methyl benzoate hydrochloride (39,15.7 gram, 77.8 mmole) with (29.5 milliliters of diisopropylethylamine, 171.2 mmole) in the stirred suspension in DMF (85.6 milliliters), under room temperature and nitrogen, add pyrazoles-1-amitraz hydrochloride (12.55 grams, 85.6 mmoles).After 4 hours, the reaction mixture of settled solution form is concentrated in a vacuum dried, and adds NaHCO ₃Saturated aqueous solution (35 milliliters) to produce suspension.The filtering separation solid is also used cold water washing.With the concentrated solid material that produces again of mother liquor, it is filtered collect equally.Two parts of solids are merged, use H ₂O (50 milliliters) development leaches, and uses cold H ₂O and diethyl ether washing, and the dry titled reference compound 40 (12.32 grams, 77% yield) that obtains the white crystalline solid shape. ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：9.20-8.00(m，4H)，ABsystem(δ _A＝7.91，δ _B＝7.39，J _AB＝8.2Hz，4H)，4.39(bs，2H)，3.83(s，3H)。

Step 3:4-[(4-pyridin-3-yl-pyrimidine-2--amino)-methyl]-methyl benzoate (41)

In compound 38 (0.394 gram, 1.9 mmoles) and 40 (0.402 gram, 2.3 mmoles) stirred suspension in Virahol (3.8 milliliters), under room temperature and nitrogen, add molecular sieve (0.2 gram, 4_, powder).With reaction mixture refluxed 5 hours.Add MeOH (50 milliliters), and reaction mixture is refluxed once more.The turbid solution that forms is filtered by C salt pad, filtrate is concentrated into dried, and with resistates with ethyl acetate (3 milliliters) development, leach and dry, obtain the titled reference compound 41 (0.317 gram, 52%) of white crystalline solid shape. ¹H NMR(400MHz，DMSO-d ₆)δ(ppm)：9.17(bs，1H)，8.64(m，1H)，8.38(m，2H)，7.98(t，J＝6.3Hz，1H)，7.88(m，2H)，7.48(m，3H)，7.24(d，J＝5.1Hz，1H)，4.64(d，J＝6.1Hz，2H)，3.81(s，3H)。

Step 4:4-[(4-pyridin-3-yl-pyrimidine-2--amino)-methyl]-phenylformic acid (42)

At room temperature, in 41 (3.68 grams, 11.5 mmoles) stirred solution in the mixture of THF (23 milliliters) and MeOH (23 milliliters), add LiOH.H ₂Water (11.5 milliliters) solution of O (1.06 grams, 25.3 mmoles).Reaction mixture is spent the night 40 ℃ of stirrings, be cooled to room temperature, and the aqueous solution of adding HCl (12.8 milliliters, 2N) (the about 4-5 of pH).Mixture is concentrated into dried; Solid water development with forming leaches, with minimum H ₂The O washing is also dry, obtains the titled reference compound 42 (3.44 grams, 95%) of white solid. ¹H NMR (400MHz, DMSO-d ₆) δ (ppm): 12.83 (bs, 1H), 9.23 (bs, 1H), 8.73-8.66 (m, 1H), 8.46-8.36[m comprises 8.42 (d, J=5.1Hz), 2H], 8.02 (t, J=6.3Hz, 1H), 7.91 (d, J=8.2Hz, 2H), 7.60-7.40 (m, 3H), 7.28 (d, J=5.1Hz, 1H), 4.67 (d, J=6.3Hz, 2H).

Step 5:N-(2-amino-5-benzene sulphur-2-base-phenyl)-4-[(4-pyridin-3-yl-pyrimidine-2--amino)-methyl]-benzamide (43)

According to embodiment 1, identical method described in the step 3-4, but compound 4 is replaced to compound 42 obtains titled reference compound with 62% yield.

¹H NMR(400MHz，DMSO-d ₆)，δ(ppm)：9.65(s，1H)，9.22(s，1H)，8.66(d，J＝3.7Hz，1H)，8.39(d，J＝5.3Hz，2H)，8.01(t，J＝6.5Hz，1H)，7.93(d，J＝8.4Hz，2H)，7.53-7.44(m，4H)，7.32(dd，J＝5.1，1.2Hz，1H)，7.28-7.24(m，2H)，7.21(dd，J＝3.7，1.2Hz，1H)，6.02(dd，J＝5.1，3.5Hz，1H)，6.78(d，J＝8.4Hz，1H)，5.13(s，2H)，4.65(d，J＝5.7，2H)。MS：(calc.)478.2；(obt.)479.5(MH) ⁺。

Embodiment 8

4-[({6-[2-(dimethylamino) oxyethyl group]-1H-benzimidazolyl-2 radicals-yl } sulfenyl) methyl]-N-[2-nitro-5-(2-thienyl) phenyl] benzamide (50)

Scheme 7

Step 1:2-amino-benzothiazole-6-alcohol (45):

Obtain titled reference compound 45 according to program identical described in the U.S. Patent application 10/242,304 (it is incorporated herein by this reference fully).The yield of this titled reference compound is 49%. ¹H NMR：(CD ₃OD)δ(ppm)：7.93(d，J＝8.5Hz，2H)，7.50(d，J＝8.5Hz，2H)，7.31(bs，1H)，6.86(bs，1H)，6.76(dd，J＝8.8，2.47Hz，1H)，4.49(s，2H)，3.94(s，3H)。

Step 2:4-[(6-hydroxyl-benzothiazole-2-base is amino)-methyl] methyl benzoate (46):

Obtain titled reference compound 46 according to the program identical with the reductive amination described in the U.S. Patent application 10/242,304 (it is incorporated herein by this reference fully).The yield of this titled reference compound is 92%. ¹H NMR：(Acetone-d ₆)δ(ppm)：8.06(t，J＝7.9Hz，2H)，7.65(d，J＝8.4Hz，2H)，7.36(d，J＝8.8Hz，1H)，7.21(d，J＝2.2Hz，1H)，6.88(dd，J＝8.8，2.6Hz，1H)，4.87(s，2H)，3.95(s，3H)。m/z：315.2(MH ⁺)。

Step 3:4-{[6-(2-dimethylamino-oxyethyl group)-benzothiazole-2-base is amino]-methyl }-methyl benzoate (47):

According to obtaining titled reference compound 47 with the program together of the Mitsunobu reacting phase described in the U.S. Patent application 10/242,304 (it is incorporated herein by this reference fully).The yield of this titled reference compound is 61%. ¹H NMR：(CD ₃OD)δ(ppm)：7.98(d，J＝8.4Hz，2H)，7.48(d，J＝8.0Hz，2H)，7.31(d，J＝8.8Hz，1H)，7.22(d，J＝2.5Hz，1H)，6.89(dd，J＝8.8，2.7Hz，1H)，4.68(s，2H)，4.09(t，J＝5.5Hz，2H)，3.88(s，3H)，2.77(t，J＝5.5Hz，2H)，2.35(s，6H)。m/z：386.4(MH ⁺)。

Step 4:4-{[6-(2-dimethylamino-oxyethyl group)-benzothiazole-2-base is amino]-methyl }-phenylformic acid (48):

Obtain titled reference compound 48 according to the program identical with the ester hydrolysis described in the U.S. Patent application 10/242,304 (it is incorporated herein by this reference fully).The yield of this titled reference compound is 63%. ¹H NMR：(CD ₃OD)δ(ppm)：8.43(bs，1H)，7.92(d，J＝8.0Hz，2H)，7.48(d，J＝8.2Hz，2H)，7.38(s，1H)，7.30(d，J＝8.4Hz，1H)，6.87(d，J＝9.2Hz，1H)，4.66(d，J＝5.1Hz，2H)，4.17(t，J＝4.7Hz，2H)，3.06(bs，2H)，2.54(s，6H)。m/z：372.4(MH ⁺)。

Step 5:4-[6-(2-dimethylamino-oxyethyl group)-1H-benzimidazolyl-2 radicals-Ji sulfane ylmethyl]-N-(2-nitro-5-benzene sulphur-2-base-phenyl)-benzamide (49)

According to embodiment 1, the program that step 3 is identical, but compound 4 is replaced to compound 48 obtains titled reference compound 49 with 83% yield. ¹H NMR：(DMSO-d ₆)δ(ppm)：10.92(bs，1H)，8.26(bs，1H)，8.16(s，1H)，8.05(d，J＝9.0Hz，1H)，7.82(d，J＝7.4Hz，2H)，7.74-7.67(m，2H)，7.31-7.21(m，5H)，6.79(d，J＝8.4Hz，1H)，4.54(d，J＝4.7Hz，2H)，3.99(bs，2H)，2.59(t，J＝5.9Hz，2H)，2.20(s，6H)。

Step 6:N-[2-amino-5-(2-thienyl) phenyl]-4-[({6-[2-(dimethylamino) oxyethyl group]-1H-benzimidazolyl-2 radicals-yl } sulfenyl) methyl] benzamide N-(2-amino-5-benzene sulphur-2-base-phenyl)-4-{[6-(2-dimethylamino-oxyethyl group)-benzothiazole-2-base amino]-methyl }-benzamide (50)

According to embodiment 1, the program that step 4 is identical, but compound 5 is replaced to compound 49 obtains titled reference compound 50 with 7% yield. ¹H NMR：(DMSO-d ₆)δ(ppm)：9.68(s，1H)，8.39(bs，1H)，7.95(d，J＝7.4Hz，2H)，7.47(d，J＝8.4Hz，2H)，7.44(s，1H)，7.32(s，1H)，7.27-7.21(m，3H)，7.02(s，1H)，6.80(t，J＝9.8Hz，2H)，5.14(s，2H)，5.63(d，J＝4.5Hz，2H)，4.05(bs，2H)，2.76(bs，2H)，2.32(s，6H)。m/z：544.5(MH ⁺)。

Embodiment 9

N-[2-amino-5-(2-thienyl) phenyl]-sulfenyl of 4-{[(6-chloro-5-fluoro-1H-benzimidazolyl-2 radicals-yl)] methyl } benzamide (55)

Scheme 8

Step 1:4-(6-chloro-5-fluoro-1H-benzimidazolyl-2 radicals-Ji sulfane ylmethyl)-methyl benzoate (52)

Obtain titled reference compound 52 according to the program identical with the S-alkylation described in the U.S. Patent application 10/242,304 (it is incorporated herein by this reference fully).The yield of this titled reference compound is 55%.

¹H NMR：(DMSO-d ₆)δ(ppm)：7.85(d，J＝8.4Hz，2H)，7.55(d，J＝8.4Hz，2H)，3.80(s，2H)，3.34(s，3H)。m/z：351.2(MH ⁺)。

Step 2:4-{6-[(pyridin-3-yl methyl)-amino]-benzothiazole-2-base sulfane ylmethyl }-methyl benzoate (53):

Obtain titled reference compound 53 according to the program identical with the ester hydrolysis described in the U.S. Patent application 10/242,304 (it is incorporated herein by this reference fully).The yield of this titled reference compound is 83%.

¹H NMR：(DMSO-d ₆)δ(ppm)：7.88(d，J＝8.2Hz，2H)，7.67(d，J＝6.8Hz，1H)，7.55(d，J＝8.2Hz，2H)，7.53(d，J＝6.8Hz，1H)，4.65(s，2H)。Step 3:N-(2-amino-phenyl)-4-{6-[(pyridin-3-yl methyl)-amino]-benzothiazole-2-base sulfane ylmethyl }-benzamide (54):

According to embodiment 1, the program that step 3 is identical, but compound 4 is replaced to compound 53 obtains titled reference compound 54 with 66% yield.

¹H NMR：(DMSO-d ₆)δ(ppm)：12.89(bs，1H)，10.79(s，1H)，8.12(d，J＝2.0Hz，1H)，8.05(d，J＝8.8Hz，2H)，7.90-7.68(m，3H)，7.62(d，J＝8.4Hz，2H)，7.48(bs，1H)，7.21(dd，J＝4.9，3.7Hz，1H)，4.65(s，2H)。m/z：539.5。

Step 4:N-(2-amino-5-benzene sulphur-2-base-phenyl)-4-(6-chloro-5-fluoro-1H-benzimidazolyl-2 radicals-Ji sulfane ylmethyl)-benzamide (55):

According to embodiment 1, the program that step 4 is identical, but compound 5 is replaced to compound 54 obtains titled reference compound 55 with 14% yield. ¹H NMR：(DMSO-d ₆)δ(ppm)：12.96(s，0.5H)，12.92(s，0.5H)，9.71(s，1H)，7.96(d，J＝8.0Hz，2H)，8.35(s，0.5H)，7.79(d，J＝7.0Hz，0.5H)，7.64(d，J＝7.0Hz，0.5H)，7.62(d，J＝7.8Hz，2H)，7.50(s，0.5H)，7.48(s，1H)，7.38(d，J＝4.9Hz，1H)，7.32(d，J＝8.4Hz，1H)，7.27(d，J＝3.1Hz，1H)，7.08(t，J＝3.7Hz，1H)，6.83(d，J＝8.4Hz，1H)，5.19(s，2H)，4.69(d，J＝3.5Hz，2H)。m/z：509.5。

Embodiment 10

N-(4-amino-5-phenyl-3-thienyl)-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl }-benzamide (61)

Scheme 9

Step 1:(4-tert-butoxycarbonyl amino-benzene sulphur-3-yl)-t-butyl carbamate (57)

3, in the THF of the vigorous stirring of 4-diamino thiophene (40 milliliters) solution, add sherwood oil (300 milliliters) (1.00 grams, 8.77 mmoles).In this mixture, through adding sherwood oil (100 milliliters) solution of tert-Butyl dicarbonate (3.82 grams, 17.5 mmoles) in 30 minutes.Continue to stir 16 hours and solvent is distilled.Resistates is dissolved in DCM and uses the 1NHCl washed twice, through MgSO ₄Drying also is concentrated into about 20 ml volumes in a vacuum.When stirring, slowly add hexane and be settled out brown crystalline material.Filter to collect product, with hexane wash and make mother liquor once more crystallization to produce second batch of product.With two batches of merging, obtain titled reference compound 57 (2.19 grams, 80% yield) thus.This program is substantially as Brugier etc., and described in Tetrahedron (1997) 30:10331-10344, it is incorporated herein by this reference fully. ¹H NMR：(CDCl ₃)δ(ppm)：7.14(s，2H)，6.66(bs，1H)，1.54(s，18H)。

With 3,4-diamino thiophene dihydrochloride (Toronto Research) (2.0 grams, 10.7 mmoles) is dissolved in the minimum 1N HCl aqueous solution to obtain neutrality 3, and 4-diamino thieno-adds the 2N NaOH aqueous solution makes solution be alkalescence.With throw out EtOAc extracting twice, and with the organic layer that merges through MgSO ₄Dry and concentrated (1.00 grams, 82% rate of recovery).

Step 2:(2-bromo-4-tert-butoxycarbonyl amino-benzene sulphur-3-yl)-t-butyl carbamate

At room temperature, at the CCl of compound 57 (2.16 gram, 6.87 mmoles) ₄Add NBS (1.22 grams, 6.87 mmoles) in (137 milliliters) solution.Mixture was stirred 16 hours.Leach solid material, collection filtrate also washes with water.With organic layer through MgSO ₄Dry and concentrated in a vacuum.Make eluent by the flash chromatography resistates of purifying with DCM, obtain titled reference compound 58 (1.92 grams, 71% yield). ¹H NMR：(CDCl ₃)δ(ppm)：7.30(bs，1H)，6.00(s，1H)，1.45(s，9H)，1.43(s，9H)。m/z：415.4/417.4(M+Na/M+2+Na)。This program is substantially as Brugier etc., Tetrahedron, and described in the 56:2985-2993 (2000), it is incorporated herein by this reference fully.

Step 3:(4-tert-butoxycarbonyl amino-5-phenyl-benzene sulphur-3-yl)-t-butyl carbamate (59)

In flame-dried round-bottomed flask, four (triphenyl phosphine) palladium (59 milligrams, 0.051 mmole) is added in DME (5 milliliters) de-gassed solution of compound 58 (400 milligrams, 1.02 mmoles).Add phenyl-boron dihydroxide (186 milligrams, 1.53 mmoles), water (2.5 milliliters) and Na successively ₂CO ₃(324 milligrams, 3.06 mmoles) are outgasing between the interpolation at every turn and are using nitrogen purging.Mixture refluxed 3 hours under nitrogen atmosphere and at Et ₂Layering between O and the water.With organic layer through MgSO ₄Dry and concentrated in a vacuum.Obtain brown buttery titled reference compound 59 (398 milligrams, 100% yield). ¹H NMR：(CDCl ₃)δ(ppm)：7.51-7.31(m，6H)，1.54(s，18H)。m/z：413.5(M+Na ⁺)。This program is substantially as Brugier etc., Tetrahedron, and described in the 56:2985-2993 (2000), it is incorporated herein by this reference fully.

Step 4:2-phenyl-thiophene-3,4-diamines (60)

30% acetic acid solution (102 microlitre) that in Glacial acetic acid (102 microlitre) solution of compound 59, adds HBr.Mixture was at room temperature stirred 16 hours, and add Et ₂O (10 milliliters).Filtration collecting precipitation thing is existed side by side promptly water-soluble, adds the neutralization of the 2N NaOH aqueous solution and also uses Et ₂O extraction precipitation thing.With organic layer through MgSO ₄Dry and concentrated in a vacuum, obtain titled reference compound 60 (34 milligrams, 69% yield).This program is substantially as Brugier etc., Tetrahedron, and described in the 30:10331-10344 (1997), it is incorporated herein by this reference fully. ¹H NMR：(CDCl ₃)δ(ppm)：7.49(dd，J＝8.4，1.4Hz，2H)，7.41(t，J＝7.6Hz，2H)，7.26(dd，J＝10.2，7.2Hz，1H)，6.22(s，1H)，3.51(bs，4H)。m/z：191.3(MH ⁺)。

Step 5:N-(4-amino-5-phenyl-benzene sulphur-3-yl)-4-[(3,4-dimethoxy-phenyl amino)-methyl]-benzamide (61)

According to embodiment 6, identical program described in the step 2, but compound 31 is replaced to compound 60 obtains titled reference compound 61 with 73% yield.

¹H NMR：(CD ₃OD)δ(ppm)：7.91(d，J＝8.2Hz，2H)，7.52(d，J＝8.0Hz，2H)，7.51(dd，J＝7.0，1.2Hz，2H)，7.42(t，J＝7.4Hz，2H)，7.38(s，1H)，7.28(tt，J＝7.4，1.8Hz，1H)，6.71(d，J＝8.6Hz，1H)，6.37(d，J＝2.7Hz，1H)，6.13(dd，J＝8.6，2.5Hz，1H)，4.38(s，2H)，3.74(s，3H)，3.71(s，3H)。m/z：460.5(MH ⁺)。

Embodiment 11

N-(3-amino-2,2 '-thiophthene base)-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide (62)

Program according to identical with embodiment 10 replaces to the 2-thienyl boric acid with the phenyl-boron dihydroxide in the step 3, obtains titled reference compound 62 with 29% yield. ¹H NMR：(DMSO-d ₆)δ(ppm)：7.90(d，J＝8.4Hz，2H)，7.52(d，J＝8.4Hz，2H)，7.37(dd，J＝5.1，1.2Hz，1H)，7.36(s，1H)，7.14(dd，J＝3.7，1.2Hz，1H)，7.10(dd，J＝5.1，3.5Hz，1H)，6.71(d，J＝7.4Hz，1H)，6.36(d，J＝2.5Hz，1H)，4.38(s，2H)，3.74(s，3H)，3.71(s，3H)，m/z：466.5(MH ⁺)。

Embodiment 12

Trans-N-[2-amino-5-(2-thiophene) phenyl]-3-(4-{[(3,4,5-trimethoxyphenyl) amino] methyl } phenyl) acrylamide (67)

Scheme 10

Step 1-3:3-{4-[(3,4,5-trimethoxy-phenyl amino)-methyl]-phenyl }-vinylformic acid (66)

Described titled reference compound 66 and the synthesis path shown in the scheme 10 in United States Patent (USP) 10/242,304, this patent is incorporated herein by this reference fully.

Step 4-5:N-(2-amino-5-benzene sulphur-2-base-phenyl)-3-{4-[(3,4,5-trimethoxy-phenyl amino)-methyl]-phenyl }-acrylamide (67)

According to embodiment 1, step 3 and program identical described in 4, but compound 4 is replaced to compound 66 obtain titled reference compound 67 with 32% yield.

¹H NMR(400MHz，DMSO d ₆)：9.40(s，1H)；7.67(s，1H)；7.56(d，2H，J＝7.6Hz)；7.51(s，1H)；7.42(d，2H，J＝8.0Hz)；7.33(d，1H，J＝5.1Hz)；7.23-7.19(m，2H)；7.03(dd，1H，J＝3.7，4.9Hz)；6.85(d，1H，J＝15.7Hz)；6.76(d，1H，J＝8.2Hz)；6.08(dd，1H；J＝5.7，6.0Hz)；5.87(s，2H)；5.19(s，2H)；4.25(d，2H，J＝5.9Hz)，3.63(s，6H)；3.49(s，3H)。

Embodiment 13

N-(2-amino-5-butyl phenyl)-4-{[(3,4-Dimethoxyphenyl) amino] methyl benzamide (68) and

Embodiment 13a

N-(2-amino-5-butyl phenyl)-4-methyl benzamide

Scheme 11

With (430 milligrams of solid sodium borohydride; 11.4 mmole) handle 0 ℃ (207 milligrams of nitro-compounds 5; 0.42 mmole) and (595 milligrams of Nickel dichloride hexahydrates (II); 2.5 mmole) stirred solution in methyl alcohol (6 milliliters) stirs mixture 2 hours under uniform temp then, uses the acetone quenching, pours 5% NH in salt solution into ₄OH, and use dichloromethane extraction.With organic layer drying (Na ₂SO ₄), filter and concentrate.After flash chromatography on the silicagel column separates (dichloromethane solution of eluent 20% AcOEt), obtain (62 milligrams of compounds 68; 0.143 mmole, 34%) and 69 (22 milligrams, 0.078 mmole, 19%).

Compound 68: ¹H NMR:(400.2MHz, DMSO) δ (ppm): 9.58 (s, 1H); 7.89 (d, J=8.2,2H); 7.45 (d, J=8.2,2H); 6.97 (s, 1H); 6.78 (dd, J=2.0; 8.2,1H); 6.67 (d, J=8.0,1H); 6.64 (d, J=8.6,1H); 6.31 (d, J=2.5,1H); 5.99-5.96 (m, 2H); 4.68 (bs, 2H); 4.29 (d, J=6.3,2H); 3.65 (s, 3H); 3.58 (s, 3H); 2.43 (t, J=7.4,2H); 1.49 (m, J=7.4,2H); 1.30 (m, J=7.4,2H); 0.89 (t, J=7.4,3H).

Compound 69: ¹H NMR:(400.2MHz, DMSO) δ (ppm): 9.57 (s, 1H); 7.86 (d, J=8.1,2H); 7.30 (d, J=8.1,2H); 6.78 (dd, J=2.0; 8.0,1H); 6.68 (d, J=8.0,1H); 4.67 (bs, 2H); 2.44 (t, J=7.4,2H); 2.38 (s, 3H); 1.49 (m, J=7.4,2H); 1.31 (m, J=7.4,2H); 0.89 (t, J=7.4,3H).

Embodiment 14

N-(2-amino-4-butyl phenyl)-4-{[(3,4-Dimethoxyphenyl) amino] methyl benzamide (70) and

Embodiment 14a

N-(2-amino-4-butyl phenyl)-4-methyl benzamide (71)

According to identical program described in the embodiment 13, but compound 5 is replaced to compound 15, obtain compound 70 and 71 with 53% and 9% yield respectively.

Scheme 12

Compound 70: ¹H NMR:(400.2MHz, DMSO) δ (ppm): 9.51 (s, 1H); 7.88 (d, J=8.4,2H); 7.44 (d, J=8.4,2H); 7.00 (d, J=8.3,1H); 6.63 (d, J=8.3,1H); 6.58 (d, J=2.0,1H); 6.30 (d, J=2.5,1H); 5.99-5.96 (m, 2H); 4.79 (bs, 2H); 4.29 (d, J=6.1,2H); 3.65 (s, 3H); 3.59 (s, 3H); 2.45 (t, J=7.4,2H); 1.52 (m, J=7.4,2H); 1.30 (m, J=7.4,2H); 0.90 (t, J=7.4,3H).

Compound 71: ¹H NMR:(400.2MHz, DMSO) δ (ppm): 9.51 (s, 1H); 7.85 (d, J=8.0,2H); 7.28 (d, J=8.0,2H); 7.01 (d, J=8.5,1H); 6.58 (d, J=2.0,1H); 6.40 (d, J=2.0,8.5,1H); 4.78 (bs, 2H); 2.45 (t, J=7.4,2H); 2.38 (s, 3H); 1.53 (m, J=7.4,2H); 1.31 (m, J=7.4,2H); 0.90 (t, J=7.4,3H).

Embodiment 15

N-[2-amino-5-(3-hydroxypropyl-1-alkynes-1-yl) phenyl]-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide (76)

Scheme 13

Step 1:3-(3-amino-4-nitro-phenyl)-third-2-alkynes-1-alcohol (72)

With (447 milligrams of aryl bromides 2; 2.06 mmole); (145 milligrams of four (triphenyl phosphine) palladiums (0), 0.12 mmole) and (143 milligrams of cupric iodides (I), 0.75 mmole) suspension in degassed ethylene glycol dme (2.5 milliliters) and triethylamine (1.5 milliliters) is in the dark under nitrogen and stirring at room 10 minutes, use (0.7 milliliter in pure third-2-alkynes-1-alcohol then, 12 mmoles) (or optional any other alkynes, 5 equivalents) handle, and mixture stirred 48 hours under the same conditions, with methylene dichloride (50 milliliters) dilution, filter and concentrate through C salt pad.Provide compound 72 (328 milligrams, 83% yield) by flash chromatography (hexane solution of eluent 50 to 75%AcOEt).

¹H NMR：(400.2MHz，DMSO)δ(ppm)：7.92(d，J＝8.8，1H)；7.46(bs，2H)；7.04(d，J＝1.7，1H)；6.57(dd，J＝1.7，8.8，1H)；5.41(t，J＝6.1，1H)；4.30(d，J＝6.1，2H)。

Step 2:5-[3-(tertiary butyl-phenylbenzene-silanyloxy base)-third-1-alkynyl]-2-nitro-aniline (73)

With (328 milligrams of alcohol 72,1.71 mmole) and (308 milligrams of imidazoles, 4.5 N mmole), dinethylformamide (3 milliliters) solution is with (0.5 milliliter of the pure tertiary butyl-chloro-phenylbenzene-silane, 1.9 mmole) handle, and solution stirred 18 hours under nitrogen, with ethyl acetate (300 milliliters) dilution, use KHSO ₄5% aqueous solution, use saturated NaHCO then ₃Solution washes with water at last, dry (MgSO ₄), filter and concentrate in a vacuum.By flash chromatography (hexane solution of eluent 50% ether, the dichloromethane solution of 50% EtOAc then) purification crude mixture, to obtain compound 73 (691 milligrams, 94% yield).

¹H NMR：(400.2MHz，DMSO)δ(ppm)：7.91(d，J＝8.8，1H)；7.68-7.66(m，4H)；7.46-7.44(m，6H)；7.01(d，J＝1.7，1H)；6.46(dd，J＝1.7，8.8，1H)；4.61(d，2H)；1.03(d，9H)。

Step 3:N-{5-[3-(tertiary butyl-phenylbenzene-silanyloxy base)-third-1-alkynyl]-2-nitro-phenyl }-4-[(3,4-dimethoxy-phenyl amino)-methyl]-benzamide (74)

According to identical program described in the embodiment 1, but compound 3 is replaced to compound 73, obtain titled reference compound with 77% yield.

¹H NMR：(400.2MHz，DMSO)δ(ppm)：10.7(s，1H)；7.97(d，J＝8.6，1H)；7.88(d，J＝8.4，2H)；7.76(d，J＝1.8，1H)；7.70-7.67(m，4H)；7.52(d，J＝8.4，2H)；7.47-7.44(m，6H)；7.25(d，J＝7.4，1H)；6.64(d，J＝8.6，1H)；6.31(d，J＝2.8，1H)；6.01-5.96(m，2H)；4.65(s，2H)；4.31(d，J＝6.1，2H)；3.65(s，3H)；3.55(s，3H)；1.03(d，9H)。

Step 4:4-[(3,4-dimethoxy-phenyl amino)-methyl]-N-[5-(3-hydroxyl-third-1-alkynyl)-2-nitro-phenyl]-benzamide (75)

With (871 milligrams of compounds 74,1.24 (2.0 milliliters of the THF solution of THF mmole) (3 milliliters) solution usefulness 1.0M tetrabutylammonium fluoride, 2.0 mmole) handle, use 70% hydrofluoric pyridine solution (0.1 milliliter) to handle then, and solution stirred 12 hours under nitrogen, also use saturated NaHCO with ethyl acetate (200 milliliters) dilution ₃(50 milliliters), water (6 * 100 milliliters) washing then, dry (Na ₂SO ₄), filter and concentrate in a vacuum.Rough material (647 milligrams) is enough pure for next step, need not further purification.

Step 5:N-[2-amino-5-(3-hydroxyl-third-1-alkynyl)-phenyl]-4-[(3,4-dimethoxy-phenyl amino)-methyl]-benzamide (76)

According to embodiment 1, identical program described in the step 4, but compound 5 is replaced to compound 75 obtains 52% yield.

¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.51(s，1H)；7.88(d，J＝8.2，2H)；7.45(d，J＝8.2，2H)；7.22(d，J＝1.8，1H)；6.99(dd，J＝1.8，8.2，1H)；6.69(d，J＝8.4，1H)；6.63(d，J＝8.4，1H)；6.31(d，J＝2.3，1H)；5.99-5.96(m，2H)；5.30(s，2H)；5.19(d，J＝5.9，1H)；4.29(d，J＝5.9，2H)；4.23(d，J＝5.3，2H)；3.65(s，3H)；3.55(s，3H)。

Embodiment 16

N-{2-amino-5-[3-(dimethylamino) third-1-alkynes-1-yl] phenyl }-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide (79)

Scheme 14

Step 1:5-(3-dimethylamino-third-1-alkynyl)-2-nitro-aniline (77)

According to embodiment 15, identical program described in the step 1, but propargyl alcohol is replaced to N, N-dimethyl propargylamine obtains titled reference compound with 80% yield.

¹H NMR：(400.2MHz，DMSO)δ(ppm)：8.02(d，J＝8.8，1H)；6.87(d，J＝1.6，1H)；6.69(dd，J＝1.6，8.8，1H)；6.18(bs，2H)；3.48(s，2H)；2.38(s，6H)。

Step 2:4-[(3,4-dimethoxy-phenyl amino)-methyl]-N-[5-(3-dimethylamino-third-1-alkynyl)-2-nitro-phenyl]-benzamide (78)

According to embodiment 15, identical program described in the step 3, but compound 73 is replaced to compound 77, obtain titled reference compound with 86% yield.

¹H NMR：(400.2MHz，DMSO)δ(ppm)：10.74(s，1H)；8.0(d，J＝8.4，2H)；7.88(d，J＝8.4，2H)；7.83(d，J＝1.8，1H)；7.52(d，J＝8.4，2H)；7.41(dd，J＝1.8，8.4，1H)；6.64(d，J＝8.6，1H)；6.31(d，J＝2.6，1H)；6.30(d，J＝6.6，1H)；5.97(dd，J＝2.6，8.6，1H)；4.30(d，J＝6.6，2H)；3.65(s，3H)；3.64(s，3H)；3.58(s，2H)；2.25(s，6H)。

Step 3:N-[2-amino-5-(3-dimethylamino-third-1-alkynyl)-phenyl]-4-[(3,4-dimethoxy-phenyl amino)-methyl]-benzamide (79)

According to embodiment 15, identical program described in the step 5, but compound 75 is replaced to compound 78, obtain titled reference compound with 63% yield.

¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.53(s，1H)；7.89(d，J＝8.2，2H)；7.45(d，J＝8.2，2H)；7.22(d，J＝1.8，1H)；7.01(dd，J＝1.8，8.2，1H)；6.69(d，J＝8.2，1H)；6.63(d，J＝8.2，1H)；6.30(d，J＝2.5，1H)；5.99-5.96(m，2H)；5.28(s，2H)；4.29(d，J＝6.1，2H)；3.65(s，3H)；3.58(s，3H)；3.37(s，2H)；2.21(s，6H)。

Embodiment 17

N-[2-amino-5-(3-hydroxypropyl) phenyl]-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide (85)

Scheme 15

Step 1:3-(3-amino-4-nitro-phenyl)-propionic aldehyde (80)

Handle aryl bromide 2 (1.544 grams, 7.11 mmoles) (or optional any halogenated aryl hydrocarbon) with third-2-alkene-1-alcohol (3 milliliters, 40 mmoles) (or optionally any other alkene-1-alcohol, 6 equivalents); (280 milligrams of three adjacent toluene phosphines; 0.9 mmole) and (280 milligrams of three (dibenzalacetones), two palladiums (0); 0.3 N mmole), dinethylformamide (6 milliliters) and ethyl diisopropylamine solution (3 milliliters), and this solution stirred 3 hours at 120 ℃ under nitrogen.Reaction mixture is concentrated under high vacuum, and resistates is purified by flash chromatography (dichloromethane solution of eluent 5%MeOH), produce aldehyde 80 (253 milligrams, 18% yield).

¹H NMR：(400.2MHz，CDCl ₃)δ(ppm)：9.68(t，J＝0.8，1H)；7.89(d，J＝8.7，1H)；6.51(d，J＝1.6，1H)；6.39(dd，J＝2.0，8.7，1H)；6.02(bs，2H)；2.78(t，J＝6.7，2H)；2.69(m，J＝0.8，6.7，2H)。

Step 2:3-(3-amino-4-nitro-phenyl)-third-1-alcohol (81).

With the tetrahydrofuran (THF) (1 milliliter) and propan-2-ol (2 milliliters) solution of solid sodium borohydride (175 milligrams, 4.6 mmoles) processing aldehyde 80 (253 milligrams, 1.3 mmoles), and-5 ℃ of stirrings 15 minutes.Add acetone (5 milliliters), under uniform temp, stirred 10 minutes, use ethyl acetate (100 milliliters) dilution then, use 5% KHSO ₄The aqueous solution is used saturated NaHCO then ₃Solution washes with water at last, dry (MgSO ₄), and promptly be used for next step without purifying.

¹H NMR：(400.2MHz，CDCl ₃)δ(ppm)：8.01(d，J＝8.8，1H)；6.64(d，J＝1.8，1H)；6.54(dd，J＝1.8，8.8，1H)；6.18(bs，2H)；3.69(t，J＝7.2，2H)；2.68(t，J＝7.2，2H)；1.91(m，J＝7.2，2H)。

Step 3:5-[3-(tertiary butyl-phenylbenzene-silanyloxy base)-propyl group]-2-nitro-aniline (82)

According to embodiment 15, identical program described in the step 2, but compound 72 is replaced to compound 81, obtain titled reference compound with 78% yield.

¹H NMR：(400.2MHz，CDCl ₃)δ(ppm)：7.99(d，J＝8.8，1H)；7.73(d，J＝1.6，1H)；7.65-7.63(m，4H)；7.46-7.37(m，6H)；6.49(dd，J＝1.6，8.8，1H)；4.02(bs，2H)；3.71(t，J＝7.4，2H)；2.69(t，J＝7.2，2H)；1.87(m，J＝7.2，2H)；1.10(s，9H)。

Step 4:N-{5-[3-(tertiary butyl-phenylbenzene-silanyloxy base)-propyl group]-2-nitro-phenyl }-4-[(3,4-dimethoxy-phenyl amino)-methyl]-benzamide (83)

According to embodiment 15, identical program described in the step 3, but compound 73 is replaced to compound 82, obtain titled reference compound with 71% yield.

¹H NMR：(400.2MHz，CDCl ₃)δ(ppm)：11.3(s，1H)；8.75(d，J＝2.0，1H)；8.61(d，J＝8.6，1H)；7.86(d，J＝8.4，2H)；7.57-7.54(m，4H)；7.44(d，J＝8.4，2H)；7.34-7.27(m，6H)；6.88(dd，J＝2.0，8.4，1H)；6.62(d，J＝8.6，1H)；6.21(d，J＝2.5，1H)；6.08(dd，J＝2.5，8.6，1H)；4.32(s，2H)；3.72(s，3H)；3.71(s，3H)；3.62(t，J＝7.4，2H)；2.76(t，J＝7.2，2H)；1.84(m，J＝7.2，2H)；0.99(s，9H)。

Step 5:4-[(3,4-dimethoxy-phenyl amino)-methyl]-N-[5-(3-hydroxyl-propyl group)-2-nitro-phenyl]-benzamide (84)

According to embodiment 15, identical program described in the step 4, but compound 74 is replaced to compound 83, obtain titled reference compound with 99% yield.

¹H NMR：(400.2MHz，CDCl ₃)δ(ppm)：11.4(s，1H)；8.86(d，J＝2.0，1H)；8.21(d，J＝8.6，1H)；7.95(d，J＝8.4，2H)；7.57(d，J＝8.4，2H)；7.07(dd，J＝2.0，8.6，1H)；6.74(d，J＝8.6，1H)；6.42(d，J＝2.3，1H)；6.31(d，J＝8.6，1H)；4.43(s，2H)；3.83(s，3H)；3.82(s，3H)；3.74(t，J＝7.4，2H)；2.87(t，J＝7.2，2H)；2.01(m，J＝7.2，2H)；1.62(bs，1H)。

Step 6:N-[2-amino-5-(3-hydroxyl-propyl group)-phenyl]-4-[(3,4-dimethoxy-phenyl amino)-methyl]-benzamide (85)

According to embodiment 15, identical program described in the step 5, but compound 75 is replaced to compound 84, obtain titled reference compound with 62% yield.

¹H NMR：(400.2MHz，CDCl ₃)δ(ppm)：9.58(s，1H)；7.89(d，J＝8.1，2H)；7.45(d，J＝8.1，2H)；6.98(s，1H)；6.78(dd，J＝1.8，8.0，1H)；6.67(d，J＝8.0，1H)；6.64(d，J＝8.6，1H)；6.31(d，J＝2.5，1H)；5.98(m，1H)；4.68(bs，2H)；4.40(t，J＝5.1，1H)；4.29(d，J＝6.4，2H)；3.65(s，3H)；3.58(s，3H)；3.37(dt，J＝5.1，7.6，2H)；2.46(t，J＝7.6，2H)；1.65(m，J＝7.2，2H)。

Embodiment 18

N-{2-amino-5-[(1E)-3-amino-3-oxygen third-1-alkene-1-yl] phenyl }-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide (88)

Scheme 16

Step 1:N-(5-bromo-2-nitro-phenyl)-4-[(3,4-dimethoxy-phenyl amino)-methyl]-benzamide (86)

According to embodiment 1, identical program described in the step 3, but compound 3 is replaced to compound 2, obtain titled reference compound, it is used without further purification.

¹H NMR：(400.2MHz，DMSO)δ(ppm)：10.4(s，1H)；8.08(d，J＝2.2，1H)；7.96(d，J＝8.6，1H)；7.87(d，J＝8.4，2H)；7.60(dd，J＝2.2，8.6，1H)；7.52(d，J＝8.4，2H)；6.64(d，J＝8.4，1H)；6.30(d，J＝2.5，1H)；5.97(m，2H)；4.31(d，J＝6.1，2H)；3.65(s，3H)；3.58(s，3H)。

Step 2:N-(2-amino-5-bromo-phenyl)-4-[(3,4-dimethoxy-phenyl amino)-methyl]-benzamide (87)

According to embodiment 1, identical program described in the step 4, but compound 5 is replaced to compound 86, obtain titled reference compound (through two steps) with 28% yield.

¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.58(s，1H)，7.89(d，J＝8.2Hz，2H)，7.46(d，J＝8.4Hz，2H)，7.35(d，J＝2.3Hz，1H)，7.08(dd，J＝8.4，2.3Hz，1H)，6.70(d，J＝8.6Hz，1H)，6.64(d，J＝8.6Hz，1H)，6.31(d，J＝2.5Hz，1H)，5.99-5.96(m，2H)，5.12(s，2H)，4.29(d，J＝6.1Hz，2H)，3.65(s，3H)，3.58(s，3H)。

Step 3:N-[2-amino-5-(2-formamyl-vinyl)-phenyl]-4-[(3,4-dimethoxy-phenyl amino)-methyl]-benzamide (88)

According to embodiment 17, identical program described in the step 1, but compound 2 is replaced to compound 87, obtain titled reference compound with 18% yield.

¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.57(s，1H)，7.91(d，J＝8.2Hz，2H)，7.46(d，J＝8.2Hz，2H)，7.38(d，J＝2.0Hz，1H)，7.32(bs，1H)；7.23(d，J＝16Hz，1H)，7.15(dd，J＝2.0，8.4Hz，1H)；6.82(bs，1H)；6.74(d，J＝8.4Hz，1H)，6.64(d，J＝8.6Hz，1H)，6.32(m，1H)，6.29(d，J＝16Hz，1H)，5.98(m，2H)，5.39(bs，2H)，4.30(d，J＝6.1Hz，2H)，3.66(s，3H)，3.59(s，3H)。

Embodiment 19

N-(2-amino-5-(2-((t-butyldimethylsilyl oxygen base) methyl) benzene sulphur-3-yl) phenyl)-4-methoxy benzamide (93) and

Embodiment 20

N-(2-amino-5-(2-(methylol) benzene sulphur-3-yl) phenyl)-4-methoxy benzamide (94)

Scheme 17

Step 1. (3-(3-amino-4-nitrophenyl) benzene sulphur-2-yl) methyl alcohol (90)

Suspension in Virahol (5 milliliters) stirred 3 hours at 0 ℃ with aldehyde 89 (500 milligrams, 3.21 mmoles) and sodium borohydride (121 milligrams, 3.21 mmoles).Remove excess cyanide with acetone, and with solvent evaporation.With gained boric acid (or any other boric acid), 5-bromo-2-N-methyl-p-nitroaniline (2) (697 milligrams, 3.21 mmoles) (scheme 1, embodiment 1), POT (305 milligrams, 1.00 mmoles), Pd (PPh ₃) ₄(241 milligrams, 0.209 mmole) and K ₂CO ₃(1.33 grams, 9.63 mmoles) suspension in DME (12 milliliters) and water (4 milliliters) stirred 16 hours at 80 ℃.With solvent evaporation; Add ethyl acetate also with saturated NaCl solution washing.With organic layer through MgSO ₄Drying is filtered and is concentrated.After passing through flash chromatography (hexane solution of eluent 40% EtOAc) purification on the silica gel, obtain 605 milligrams (75%) orange buttery compound 90. ¹H NMR：(400MHz，DMSO)δ(ppm)：7.98(d，J＝9.0Hz，1H)，7.52(d，J＝5.3Hz，1H)，7.44(s，2H)，7.15(d，J＝5.3Hz，1H)，7.02(d，J＝1.8Hz，1H)，6.73(dd，J＝9.0，2.0Hz，1H)，5.72(t，J＝5.4Hz，1H)，4.70(d，J＝5.5Hz，2H)。

Step 2.5-(2-((t-butyldimethylsilyl oxygen base) methyl) benzene sulphur-3-yl)-2-N-methyl-p-nitroaniline (91)

DMF (20 milliliters) solution of 90 (600 milligrams, 2.39 mmoles), imidazoles (245 milligrams, 3.60 mmoles) and TBDMSCI (543 milligrams, 3.60 mmoles) was at room temperature stirred 16 hours.With solvent evaporation, add ethyl acetate also with saturated NaCl solution washing.With organic layer through MgSO ₄Drying is filtered and is concentrated.After resistates purified by flash chromatography (hexane solution of eluent 5-10%EtOAc), obtain the compound 91 of 674 milligrams of (77%) yellow oilies. ¹H NMR：(400MHz，DMSO)δ(ppm)：7.97(d，J＝8.8Hz，1H)，7.53(d，J＝5.1Hz，1H)，7.45(s，2H)，7.15(d，J＝5.3Hz，1H)，6.98(d，J＝1.8Hz，1H)，6.70(dd，J＝8.8，2.0Hz，1H)，4.91(s，2H)，0.89(s，9H)，0.07(s，6H)。

Step 3.5N-(5-(2-((t-butyldimethylsilyl oxygen base) methyl) benzene sulphur-3-yl)-2-nitrophenyl)-4-methoxy benzamide (92)

Pyridine (10 milliliters) solution of 91 (636 milligrams, 1.74 mmoles) and 4-methoxy benzoyl chloride (446 milligrams, 2.62 mmoles) was at room temperature stirred 16 hours.With solvent evaporation, add ethyl acetate and use NH ₄Saturated NaCl solution washing is used in the saturated solution washing of Cl then.Organic layer is through MgSO ₄Drying is filtered and is concentrated.After passing through flash chromatography (hexane solution of eluent 5-10%EtOAc) purification on the silica gel, obtain the compound 92 of 804 milligrams of (93%) yellow oilies. ¹H NMR：(400MHz，DMSO)δ(ppm)：10.64(s，1H)，8.05(d，J＝8.6Hz，1H)，7.95-7.93(m，3H)，7.59(d，J＝5.3Hz，1H)，7.46(dd，J＝8.6，2.0Hz，1H)，7.28(d，J＝5.3Hz，1H)，7.10(dt，J＝9.0，2.2Hz，2H)，4.95(s，2H)，3.85(s，3H)，0.88(s，9H)，0.09(s，6H)。

Step 4.N-(2-amino-5-(2-((t-butyldimethylsilyl oxygen base) methyl) benzene sulphur-3-yl) phenyl)-4-methoxy benzamide (93) and N-(2-amino-5-(2-(methylol) benzene sulphur-3-yl) phenyl)-4-methoxy benzamide (94)

With 92 (800 milligrams, 1.60 mmoles), SnCl ₂.2H ₂O (2.17 grams, 9.63 mmoles) and NH ₄The suspension of OAc (1.23 grams, 16.0 mmoles) in 1: 1: 1 mixture of MeOH/THF/ water at room temperature stirred 16 hours.Leach salt and use the EtOAc rinsing.With solvent evaporation, add ethyl acetate and use NaHCO ₃Saturated solution washing, use saturated NaCl solution washing then.With organic layer through MgSO ₄Drying is filtered and is concentrated.After passing through flash chromatography (the DCM solution of eluent 0.5-5% MeOH) purification on the silica gel, obtain 200 milligrams of (27%) cream-coloured powder shape compounds 93 and 92 milligrams of (16%) cream-coloured powder shape compounds 94.

Compound 93: ¹H NMR:(DMSO) δ (ppm): 9.54 (s, 1H), 7.96 (d, J=8.8Hz, 2H), 7.43 (d, J=5.1Hz, 1H), 7.28 (d, J=1.8Hz, 1H), and 7.09-7.02 (m, 4H), 6.81 (d, J=8.2Hz, 1H), 5.05 (s, 2H), 4.82 (s, 2H), 3.83 (s, 3H), 0.87 (s, 9H), 0.06 (s, 6H).MS：(calc.)468.2；(obt.)491.2(M+Na) ⁺。

Compound 94: ¹H NMR:(DMSO) δ (ppm): 9.57 (s, 1H), 7.96 (d, J=8.8Hz, 2H), 7.40 (d, J=5.1Hz, 1H), 7.23 (d, J=1.8Hz, 1H), and 7.09-7.02 (m, 4H), 6.81 (d, J=8.0Hz, 1H), 5.51 (t, J=5.4Hz, 1H), 5.01 (s, 2H), 4.64 (d, J=5.3Hz, 2H), 3.83 (s, 3H).MS：(calc.)354.1；(obt.)354.1(M+Na) ⁺。

Embodiment 21

N-(2-amino-5-(4-((t-butyldimethylsilyl oxygen base) methyl) phenyl) phenyl)-4-((3,4-Dimethoxyphenyl amino) methyl) benzamide (99) and

Embodiment 21-1

N-(2-amino-5-(4-(methylol) phenyl) phenyl)-4-((3,4-Dimethoxyphenyl amino) methyl) benzamide (100)

Scheme 18

Step 1 and 2.2-nitro-5-((4-(t-butyldimethylsilyl oxygen base) methyl) phenyl) aniline (97)

According to as embodiment 19 and 20, the described identical program of step 1 and 2 (scheme 17) obtains compound 97 with 78% yield. ¹H NMR：(400MHz，DMSO)δ(ppm)：8.01(d，J＝9.0Hz，1H)，7.61(d，J＝8.2Hz，2H)，7.46(s，2H)，7.41(d，J＝8.0Hz，2H)，7.27(d，J＝2.0Hz，1H)，6.91(dd，J＝9.0，2.0Hz，1H)，0.92(s，9H)，0.11(s，6H)。

Step 3.N-(2-nitro-5-(4-((t-butyldimethylsilyl oxygen base) methyl) phenyl) phenyl)-4-((3,4-Dimethoxyphenyl amino) methyl) benzamide (98)

According to embodiment 1, identical program obtains compound 98 with 28% yield in the step 3 (scheme 1). ¹H NMR：(DMSO)δ(ppm)：10.77(s，1H)，8.14(d，J＝2.0Hz，1H)，8.09(d，J＝8.6Hz，2H)，7.91(d，J＝8.4Hz，2H)，7.72(d，J＝8.2Hz，2H)，7.68(dd，J＝8.6，2.2Hz，1H)，7.53(d，J＝8.4Hz，2H)，7.45(d，J＝8.4Hz，2H)，6.65(d，J＝8.6Hz，2H)，5.99-5.97(m，2H)，4.78(s，2H)，4.32(d，J＝6.3Hz，2H)，3.66(s，3H)，3.59(s，3H)，0.93(s，9H)，0.11(s，6H)。

Step 4.N-(2-amino-5-(4-((t-butyldimethylsilyl oxygen base) methyl) phenyl) phenyl)-4-((3,4-Dimethoxyphenyl amino) benzamide (99) and N-(2-amino-5-(4-(methylol) phenyl) phenyl)-4-((3,4-Dimethoxyphenyl amino) methyl) benzamide (100) methyl)

According to embodiment 19 and 20, identical program obtains compound 99 and 100 in the step 4 (scheme 17).

Compound 99: ¹H NMR:(DMSO) δ (ppm): 9.66 (s, 1H), 7.93 (d, J=8.0Hz, 2H), 7.52-7.46 (m, 5H), 7.31-7.29 (m, 3H), 6.84 (d, J=7.6Hz, 1H), 6.64 (d, J=8.6Hz, 1H), 6.32 (s, 1H), 6.00-5.98 (m, 2H), 5.06 (s, 2H), 4.70 (s, 2H), 4.30 (d, J=5.9Hz, 2H), 3.66 (s, 3H), 3.59 (s, 3H), 0.91 (s, 9H), 0.10 (s, 6H).MS：(calc.)597.2(obt.)598.5(MH) ⁺。

Compound 100: ¹H NMR:(DMSO) δ (ppm): 9.67 (s, 1H), 7.93 (d, J=7.8Hz, 2H), 7.50-7.46 (m, 5H), 7.31-7.29 (m, 3H), 6.84 (d, J=8.0Hz, 1H), 6.64 (d, J=8.4Hz, 1H), 6.32 (d, J=2.0Hz, 1H), 6.00-5.98 (m, 2H), 5.15 (t, J=5.5Hz, 1H), 5.06 (s, 2H), 4.49 (d, J=5.7Hz, 2H), 4.31 (d, J=5.9Hz, 2H), 3.66 (s, 3H), 3.59 (s, 3H).MS：(calc.)483.2；(obt.)484.4(MH) ⁺。

Embodiment 22

N-(2-amino-5-(4-methoxycarbonyl phenyl) phenyl)-4-methoxy benzamide (104) and

Embodiment 23

N-(2-amino-5-(4-carboxyl phenyl) phenyl)-4-methoxy benzamide (105)

Scheme 19

Step 1.2-nitro-5-(4-methoxycarbonyl phenyl) aniline (102)

According to embodiment 19 and 20, identical program in the step 1 (scheme 17), but boric acid 89 is replaced to boric acid 101 obtains compound 102 with 70% yield. ¹H NMR：(400MHz，DMSO)δ(ppm)：8.07-8.04(m，3H)，7.78(d，J＝8.2Hz，2H)，7.50(s，2H)，7.34(d，J＝2.0Hz，1H)，6.96(dd，J＝9.0，2.2Hz，1H)，3.88(s，3H)。

Step 2.N-(2-nitro-5-(4-methoxycarbonyl phenyl) phenyl)-4-methoxy benzamide (103)

102 (599 milligrams, 2.20 mmoles), NaH 60% (141 milligrams, 3.52 mmoles) and the suspension of 4-methoxy benzoyl chloride (450 milligrams, 2.64 mmoles) in pyridine (5 milliliters) and DMF (12 milliliters) were at room temperature stirred 48 hours.Leach solid, and use the MeOH rinsing, produce the titled reference compound 103 of 584 milligrams of (82%) yellow solid shapes. ¹H NMR：(400MHz，DMSO)δ(ppm)：10.72(s，1H)，8.13-8.08(m，3H)，7.96(d，J＝8.8Hz，2H)，7.90(d，J＝8.6Hz，2H)，7.74(dd，J＝8.6，2.2Hz，1H)，7.11(d，J＝8.8Hz，1H)，3.89(s，3H)，3.86(s，3H)。

Step 3.N-(2-amino-5-(4-methoxycarbonyl phenyl) phenyl)-4-methoxy benzamide (104)

According to embodiment 19 and 20, identical program obtains compound 104 with 10% yield in the step 4 (scheme 17). ¹H NMR：(DMSO)δ(ppm)：9.61(s，1H)，7.98(d，J＝8.8Hz，2H)，7.95(d，J＝8.4Hz，2H)，7.71(d，J＝8.4Hz，2H)，7.60(d，J＝2.2Hz，1H)，7.43(dd，J＝8.4，2.2Hz，1H)，7.04(d，J＝8.8Hz，2H)，6.86(d，J＝8.4Hz，1H)，5.27(sb，2H)，3.85(s，3H)，3.84(s，3H)。MS：(calc.)376.1；(obt.)377.1(MH) ⁺。

Step 4.N-(2-amino-5-(4-carboxyl phenyl) phenyl)-4-methoxy benzamide (105)

THF (1 milliliter) and water (1 milliliter) solution of 104 (44 milligrams, 0.117) and NaOH 1M (0.24 milliliter, 0.24 mmole) were stirred 48 hours at 40 ℃.Add HCl 1M, and throw out is leached.Solid is further purified by flash chromatography (the DCM solution of eluent 3-5% MeOH), produce compound 205 (34 milligrams, 80% yield). ¹H NMR：(DMSO)δ(ppm)：9.61(s，1H)，7.98(d，J＝8.6Hz，2H)，7.93(d，J＝8.2Hz，2H)，7.66(d，J＝8.2Hz，2H)，7.58(d，J＝2.0Hz，1H)，7.40(dd，J＝8.2，2.0Hz，1H)，7.04(d，J＝8.8Hz，2H)，6.86(d，J＝8.4Hz，1H)，5.23(s，2H)，3.84(s，3H)。MS：(calc.)362.1；(obt.)363.1(MH) ⁺。

Embodiment 24

4-amino-3-(4-methoxybenzoyl amino) methyl benzoate

Scheme 20

Step 1.4-amino-3-(4-methoxybenzoyl amino) methyl benzoate (107)

CH with 4-methoxy benzoyl chloride (1.03 grams, 6.02 mmoles) ₃CN (6 milliliters) solution dropwise add to 0 ℃ 3, the CH of 4-diamino-methyl benzoate (106) (1.00 gram, 6.02 mmoles) and pyridine (0.49 milliliter, 6.02 mmoles) ₃In CN (25 milliliters) solution.Reaction mixture was stirred 3 hours and with solvent evaporation at 0 ℃.Add ethyl acetate and organic layer is used NH successively ₄Cl, NaHCO ₃With the saturated solution washing of NaCl, through MgSO ₄Drying is filtered and is concentrated.After passing through flash chromatography (the DCM solution of eluent 1-3% MeOH) purification on the silica gel, obtain the compound 107 of 1.03 gram (56%) pale solid shapes. ¹H NMR：(DMSO)δ(ppm)：9.51(s，1H)，7.96(d，J＝8.8Hz，2H)，7.75(d，J＝2.0Hz，1H)，7.56(dd，J＝8.4，2.0Hz，1H)，7.03(d，J＝9.0Hz，2H)，6.75(d，J＝8.4Hz，1H)，5.80(s，2H)，3.83(s，3H)，3.75(s，3H)。MS：(calc.)300.1；(obt.)301.1(MH) ⁺。

Embodiment 25

4-amino-3-(4-methoxybenzoyl amino) phenylformic acid (108)

Step 1.4-amino-3-(4-methoxybenzoyl amino) phenylformic acid (108)

Suspension in 1: 1 THF: MeOH (6 milliliters) was 50 ℃ of heating 16 hours with 107 (400 milligrams, 1.33 mmoles) and 1M NaOH (2.7 milliliters, 2.66 mmoles).Add HCl 1M with reach pH=4 and with solid filtering to produce the compound 108 of 370 milligrams of (97%) white solid. ¹H NMR：(DMSO)δ(ppm)：9.52(s，1H)，7.96(d，J＝8.8Hz，2H)，7.71(d，J＝2.0Hz，1H)，7.54(dd，J＝8.4，2.0Hz，1H)，7.02(d，J＝9.0Hz，2H)，6.74(d，J＝8.4Hz，1H)，5.69(s，2H)，3.83(s，3H)。MS：(calc.)361.1；(obt.)362.3(MH) ⁺。

Embodiment 26

N-(2-amino-5-formamyl phenyl)-4-methoxy benzamide (109) step 1.N-(2-amino-5-formamyl phenyl)-4-methoxy benzamide (109)

With 108 (200 milligrams, 0.70 mmole), NH ₄Cl (74 milligrams, 1.40 mmoles), HOBT-hydrate (104 milligrams, 0.77 mmole), EDC (119 milligrams, 0.77 mmole) and Et ₃DMF (3 milliliters) solution of N (0.29 milliliter, 2.1 mmoles) at room temperature stirred 16 hours.With solvent evaporation, add ethyl acetate, and organic layer is used NH successively ₄Cl, NaHCO ₃With the saturated solution washing of NaCl, through MgSO ₄Drying is filtered and is concentrated.Crude product is developed and is filtered generation compound 109 (60 milligrams, 30%) in ethyl acetate. ¹H NMR：(DMSO)δ(ppm)：9.57(s，1H)，7.96(d，J＝8.8Hz，2H)，7.67(d，J＝2.2Hz，1H)，7.59(sb，1H)，7.52(dd，J＝8.2，2.0Hz，1H)，7.02(d，J＝8.8Hz，2H)，6.90(sb，1H)，6.72(d，J＝8.4Hz，1H)，5.41(s，2H)，3.83(s，3H)。MS：(calc.)285.1；(obt.)286.1(MH) ⁺。

Embodiment 27

N-(2-amino-5-phenyl formamyl phenyl)-4-methoxy benzamide (112) step 1.4-(tert-butoxycarbonyl)-3-(4-methoxybenzoyl amino) phenylformic acid (110)

With 108 (700 milligrams, 2.45 mmoles), Boc ₂O (801 milligrams, 3.67 mmoles) and Et ₃N (0.51 milliliter, 3.67 mmoles) was at 2: 1 dioxs: the solution in the water (15 milliliters) at room temperature stirred 16 hours.Solvent is concentrated and add HCl 1M to reach pH=5.Filtering precipitate is to produce the titled reference compound 110 of 736 milligrams of (78%) beige solid shapes. ¹H NMR：(DMSO)δ(ppm)：9.81(s，1H)，8.87(s，1H)，8.02(d，J＝1.6Hz，1H)，7.95(dt，J＝9.0，2.2Hz，2H)，7.75-7.74(m，2H)，7.07(dt，J＝9.0，2.2Hz，2H)，3.84(s，3H)，1.46(s，9H)。

Step 2.2-(4-methoxybenzoyl amino)-4-(phenyl amino formyl radical) the phenylcarbamic acid tert-butyl ester (111)

With 110 (373 milligrams, 0.965 mmole), aniline (0.11 milliliter, 1.16 mmoles), BOP (640 milligrams, 1.45 mmoles) and Et ₃DMF (3 milliliters) solution of N (0.40 milliliter, 1.45 mmoles) at room temperature stirred 16 hours.With solvent evaporation, add ethyl acetate, and with organic layer NH ₄Cl, NaHCO ₃With the saturated solution washing of NaCl, through MgSO ₄Drying is filtered and is concentrated.After passing through flash chromatography (hexane solution of eluent 30-40%AcOEt) purification on the silica gel, obtain the compound 111 of 352 milligrams of (79%) white solid. ¹H NMR：(DMSO)δ(ppm)：10.17(s，1H)，9.86(s，1H)，8.83(s，1H)，7.97(dt，J＝9.0，2.2Hz，2H)，7.84-7.73(m，4H)，7.35-7.31(m，2H)，7.10-7.05(m，3H)，3.85(s，3H)，1.47(s，9H)。

Step 3.N-(2-amino-5-phenyl formamyl phenyl)-4-methoxy benzamide (112)

DCM (3 milliliters) solution of 111 (343 milligrams, 0.743 mmole) and TFA (0.5 milliliter) was at room temperature stirred 16 hours.Purify by flash chromatography (eluent 2-3% MeOH/DCM) with solvent evaporation and with solid, produce the titled reference compound 112 (230 milligrams, 86% yield) of pale solid shape. ¹H NMR：(DMSO)δ(ppm)：9.83(s，1H)，9.62(s，1H)，7.99(d，J＝8.8Hz，2H)，7.82(d，J＝2.0Hz，1H)，7.73(dd，J＝8.8，1.2Hz，2H)，7.67(dd，J＝8.4，2.2Hz，1H)，7.31-7.27(m，2H)，7.05-7.01(m，3H)，6.80(d，J＝8.4Hz，1H)，3.84(s，3H)。MS：(calc.)361.1；(obt.)362.1(MH) ⁺。

Embodiment 28

N-(2-amino-5-bromo-phenyl)-4-methoxyl group-benzamide (114)

Scheme 21

Step 1 and 2.N-(2-amino-5-bromo-phenyl)-4-methoxyl group-benzamide (114)

In flame-dried round-bottomed flask, add 5-bromo-2-nitro-aniline (2) (10.66 grams, 49.09 mmoles) (scheme 1, embodiment 1) and 4-methoxy benzoyl chloride (8.37 grams, 49.09 mmoles).With mixture heating up to 90 ℃.The molten solids stirring is spent the night to produce Huang-brown solid.Add THF (250 milliliters) then and use SnCl ₂.2H ₂O (55.38 grams, 245.45 mmoles, 5.0 equivalents) handles this solution and at room temperature stirred 2 hours.Evaporate only about half of THF, add 200 milliliters of EtOAc and 100 milliliters of saturated NaHCO then ₃Filter out sedimentary pink salt and on filtrate, carry out work-up with EtOAc.With organic layer water and the salt water washing that merges, and through MgSO ₄Dry.Evaporate most of EtOAc, add hexane then, and filter the titled reference compound 114 (13.40 grams, 85% yield) of collecting precipitation thing to produce the cream-coloured powder shape. ¹H NMR(DMSO-d ₆)δ(ppm)：9.52(s，1H)，7.93(d，J＝9.0Hz，2H)，7.34(d，J＝2.3Hz，1H)，7.08(dd，J＝8.6，2.3Hz，1H)，7.02(d，J＝9.0Hz，2H)，6.71(d，J＝8.6Hz，1H)，5.10(s，2H)，3.82(s，3H)。

Embodiment 29

N-(2-amino-5-(3-chloro-4-fluorophenyl) phenyl)-4-methoxy benzamide (115) step 1.N-(2-amino-5-(3-chloro-4-fluorophenyl) phenyl)-4-methoxy benzamide (115)

According to embodiment 19 and 20 steps 1 (scheme 17) in identical Suzuki coupling program obtain compound 115 with 84% yield. ¹H NMR：(DMSO)δ(ppm)：9.59(s，1H)，7.97(d，J＝8.8Hz，2H)，7.71(dd，J＝7.2，2.3Hz，1H)，7.56-7.52(m，1H)，7.51(d，J＝2.2Hz，1H)，7.40(t，J＝9.0，1H)，7.33(dd，J＝8.2，2.3，1H)，7.04(d，J＝9.0Hz，2H)，6.84(d，J＝8.4Hz，1H)，5.16(sb，2H)，3.84(s，3H)。MS：(calc.)370.1；(obt.)371.1(MH) ⁺。

Embodiment 30

N-[2-amino-5-(4,4,5,5-tetramethyl--[1,3,2] dioxaborolan-2-yl)-phenyl]-4-methoxyl group-benzamide (116)

Step 1.N-[2-amino-5-(4,4,5,5-tetramethyl--[1,3,2] dioxaborolan-2-yl)-phenyl]-4-methoxyl group-benzamide (116)

In 75 milliliters pressurized vessel, add N-(2-amino-5-bromo-phenyl)-4-methoxy benzamide (114) (2.95 grams, 9.19 mmole), duplex tetramethyl ethylene ketone boric acid ester (bis (pinacolato) diboron) (2.80 grams, 11.03 mmoles) and THF (25 milliliters).Vacuum is removed air then, uses nitrogen purging container then.Add Pd (P (t-Bu) then ₃) ₂(0.070 gram, 0.14 mmole), Pd ₂(dba) ₃(0.063 gram, 0.07 mmole) and KF (1.76 grams, 30.34 mmoles, 3.3 equivalents), and behind each the interpolation, remove air.Stir a week with sealing for pressure vessels and with mixture at 50 ℃.After 2 and 4 days, add two kinds of palladium catalysts once more.After reaction is finished, mixture is extracted with EtOAc.With organic layer water and the salt water rinse and concentrated that merges.On silica gel, by column chromatography gained oil is purified then, produce the titled reference compound 116 (1.53 grams, 45%) of light yellow solid shape with EtOAc/ hexane (50: 50). ¹H NMR(DMSO-d ₆)δ(ppm)：9.47(s，1H)，7.95(d，J＝8.8Hz，2H)，7.41(d，J＝1.4Hz，1H)，7.24(dd，J＝7.8，1.4Hz，1H)，7.01(d，J＝8.8Hz，2H)，6.70(d，J＝7.8Hz，1H)，5.31(s，2H)，3.82(s，3H)，1.25(s，12H)。

Embodiment 31

N-(4 '-ethanoyl-4-amino-biphenyl-3-yl)-4-methoxyl group-benzamide (117) step 1.N-(4 '-ethanoyl-4-amino-biphenyl-3-yl)-4-methoxyl group-benzamide (117)

In pressurized vessel, add N-[2-amino-5-(4,4,5,5-tetramethyl--[1,3,2] dioxaborolan-2-yl)-phenyl]-(170 milligrams of 4-methoxyl group-benzamide (116), 0.462 mmole), 1-(4-bromophenyl) ethyl ketone (184 milligrams, 0.923 mmole) (or any aryl bromide in the following table), DME (4.6 milliliters/every mole 116) and H ₂O (2.15 milliliters/every mole 116).Remove air by vacuum then, use nitrogen purging container then.Add Pd (PPh then ₃) ₄(27 milligrams, 0.023 mmole, 0.05 equivalent) and Na ₂CO ₃(147 milligrams, 1.38 mmoles, 3.0 equivalents), and at each back removal oxygen that adds.Spend the night 75 ℃ of stirrings with sealing for pressure vessels and with mixture.Mixture is at room temperature cooled off, add entry, and mixture is extracted with EtOAc.With the organic layer salt water rinse that merges, through MgSO ₄Dry and concentrated, the titled reference compound 117 of generation 42 milligrams (25%). ¹H NMR(DMSO-d ₆)δ(ppm)：9.61(s，1H)，7.96(dd，J＝12.8，8.8Hz，4H)，7.70(d，J＝8.8Hz，2H)，7.60(d，J＝2.1Hz，1H)，7.42(dd，J＝8.4，2.3Hz，1H)，7.04(d，J＝8.8Hz，2H)，6.86(d，J＝8.2Hz，1H)，5.26(s，2H)，3.84(s，3H)，2.58(s，3H)。MS(m/z)：360.41(calc)361.1(MH ⁺)(found)。

Table 3a

Embodiment 32

4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-amino-5-(benzene sulphur-2-base sulfenyl) phenyl) benzamide (122)

Scheme 22

Step 1.5-fluoro-2-nitrophenyl t-butyl carbamate (119)

In flame-dried pressurized vessel, pack into 5-fluoro-2-nitrobenzoic acid 118 (5.00 gram, 27.0 mmoles) and anhydrous tertiary butanol (50 milliliters).In this solution, add N successively, N-di-isopropyl-N-ethamine (5 milliliters) and diphenylphosphine acid azide (6.42 milliliters, 29.7 mmoles).Container is sealed with the tetrafluoroethylene lid, and mixture was heated 2 hours at 90 ℃.Make it through being cooled to room temperature in 16 hours then.Remove solvent in a vacuum, and make resistates at EtOAc and H ₂Layering between the O.With new EtOAc aqueous layer extracted, and with the organic layer HCl 1N that merges, saturated NaHCO ₃, the salt water washing, through MgSO ₄Drying is filtered and is concentrated.On silica gel, use EtOAc/ hexane (10: 90) to make eluent the gained yellow oil and purify, obtain the titled reference compound 119 (6.03 grams, 87% yield) of pale yellow crystals shape by flash chromatography.LRMS：(m/z)：279.3(M+Na ⁺)。

Step 2.2-nitro-5-(benzene sulphur-2-base sulfenyl) phenylcarbamic acid tert-butyl ester (120)

Thiophene-2-mercaptan (236 milligrams, 2.03 mmoles) and THF (4 milliliters) pack in pressurized vessel.In this solution, add sodium hydride (60% suspension in mineral oil) (86 milligrams, 2.15 mmoles) and compound 119 (500 milligrams, 1.95 mmoles) successively.Container with tetrafluoroethylene lid sealing, and ℃ is reached mixture heating up to 90 at 2 hours.Make it be cooled to room temperature; And use H ₂O makes the reaction quenching, removes THF then in a vacuum.Make resistates at EtOAc and H ₂Layering between the O.With new EtOAc aqueous layer extracted, and with the organic layer HCl 1N that merges, saturated NaHCO ₃, the salt water washing, through MgSO ₄Drying is filtered and is concentrated.Make resistates crystallization from the mixture of EtOAc/ hexane through 72 hours, obtain titled reference compound 120 (610 milligrams, 88% yield). ¹H NMR：(400MHz，Acetone-d ₆)δ(ppm)：9.67(s，1H)，8.32(d，J＝2.2Hz，1H)，8.13(d，J＝8.8Hz，1H)，7.90(dd，J＝5.3，1.2Hz，1H)，7.50(dd，J＝3.5，1.2Hz，1H)，7.28(dd，J＝5.3，3.5Hz，1H)，6.81(dd，J＝8.8，2.0Hz，1H)，1.53(s，9H)。

Step 3.2-nitro-5-(benzene sulphur-2-base sulfenyl) aniline (121, the R=2-thienyl)

According to embodiment 27, identical program in the step 3 (scheme 20) replaces to compound 120 (550 milligrams, 1.56 mmoles) with compound 111, obtains titled reference compound 121 (271 milligrams, 69% yield). ¹H NMR：(400MHz，acetone-d ₆)δ(ppm)：7.97(d，J＝9.0Hz，1H)，7.87(dd，J＝5.3，1.2Hz，1H)，7.44(dd，J＝3.5，1.2Hz，1H)，7.25(dd，J＝5.5，3.7Hz，1H)，7.11(bs，2H)，6.66(d，J＝2.0Hz，1H)，6.42(dd，J＝9.0，2.0Hz，1H)。LRMS：(m/z)：253.1(MH ⁺)。

Step 4 and 5.4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-amino-5-(benzene sulphur-2-base sulfenyl) phenyl) benzamide (122)

According to embodiment 21, identical program in the step 3 and 4 (scheme 18), but compound 97 is replaced to compound 121 obtains titled reference compound 122 (through 2 steps) with 6% yield. ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：9.57(s，1H)，7.87(d，J＝8.4Hz，2H)，7.57(dd，J＝5.3，1.2Hz，1H)，7.44(d，J＝8.4Hz，2H)，7.27(d，J＝2.0Hz，1H)，7.19(dd，J＝3.5，1.2Hz，1H)，7.05(dd，J＝8.2，2.2Hz，1H)，7.01(dd，J＝5.3，3.5Hz，1H)，6.72(d，J＝8.2Hz，1H)，6.63(d，J＝8.6Hz，1H)，6.30(d，J＝2.5Hz，1H)，5.97(dd，J＝8.4，2.5Hz，1H)，5.96(d，J＝6.5Hz，1H)，5.20(s，2H)，4.28(d，J＝6.3Hz，2H)，3.65(s，3H)，3.58(s，3H)。LRMS：(m/z)：492.5(MH ⁺)。

Embodiment 33

4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-amino-5-(propyl group sulfenyl) phenyl) benzamide (123):

According to embodiment 21, identical program in the step 3 and 4 (scheme 18), but compound 97 is replaced to commercially available 2-nitro-5-(propyl group sulfenyl) aniline (121, the R=n-propyl) (222 milligram, 1.04 mmole), obtain the titled reference compound (123) (102 milligrams is 22% for 2 step yields) of light yellow oily. ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：9.57(s，1H)，7.89(d，J＝8.2Hz，2H)，7.45(d，J＝8.0Hz，2H)，7.23(d，J＝0.4Hz，1H)，7.01(dd，J＝8.4，2.2Hz，1H)，6.71(d，J＝8.4Hz，1H)，6.63(d，J＝8.6Hz，1H)，6.31(d，J＝2.3Hz，1H)，5.98(dd，J＝8.2，2.5Hz，1H)，5.97(d，J＝5.9Hz，1H)，5.04(s，2H)，4.29(d，J＝5.9Hz，2H)，3.65(s，3H)，3.58(s，3H)，2.71(t，J＝7.0Hz，2H)，1.50(sext，J＝7.0Hz，2H)，0.93(t，J＝7.2Hz，3H)。LRMS：(m/z)：452.5(MH ⁺)。

Embodiment 34

4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-amino-5-(2-phenylacetylene base) phenyl) benzamide (125)

Scheme 23

Step 1.2-nitro-5-(2-phenylacetylene base) aniline (124)

In flame-dried flask, pack into 5-bromo-2-N-methyl-p-nitroaniline (2,300 milligrams, 1.38 mmoles) (scheme 1, embodiment 1), phenylacetylene (155 milligrams, 1.52 mmoles) and ethyl acetate (13.8 milliliters).Solution is outgased under vacuum and place N ₂Under the atmosphere.Then, add dichloro two (triphenyl phosphine) palladium (48 milligrams, 0.069 mmole) and cupric iodide (26 milligrams, 0.138 mmole).This yellow solution is outgased once more (3 times), add N, N-Diisopropylamine (231 microlitres, 1.68 mmoles), the rapid deepening of solution.Outgas twice again, and at N ₂At room temperature stirred under the atmosphere 16 hours.Make it pass through C salt then and filtrate is used weak ammonia (NH successively ₄OH), saturated NaHCO ₃, saturated NH ₄Cl, salt water washing are through MgSO ₄Drying is filtered and is concentrated.The EtOAc/ hexane that uses polarity to increase progressively (10: 90 to 15: 85) on silica gel is made eluent and by flash chromatography the dark-coloured solid of gained is purified, and obtains the titled reference compound 124 (242 milligrams, 74% yield) of deep yellow solid state. ¹H NMR：(400MHz，CD ₃OD)δ(ppm)：8.04(dd，J＝8.8，0.4Hz，1H)，7.54-7.51(m，2H)，7.40-7.37(m，3H)，7.11(dd，J＝1.8，0.4Hz，1H)，6.73(dd，J＝8.8，1.8Hz，1H)。LRMS：(m/z)：239.3(MH ⁺)。

Step 2 and 3.4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-amino-5-(2-phenylacetylene base) phenyl) benzamide (125)

According to embodiment 21, identical program in the step 3 and 4 (scheme 18), but compound 97 is replaced to compound 124 (240 milligrams, 1.01 mmoles), synthetic compound 125 (136 milligrams is 31% for 2 step yields). ¹H NMR：(400MHz，CD ₃OD)δ(ppm)：7.93(d，J＝8.4Hz，2H)，7.52(d，J＝8.2Hz，2H)，7.44(dd，J＝8.2，1.8Hz，2H)，7.35-7.29(m，4H)，7.21(dd，J＝8.2，2.0Hz，1H)，6.85(d，J＝8.4Hz，1H)，6.71(d，J＝8.4Hz，1H)，6.36(d，J＝2.7Hz，1H)，6.13(dd，J＝8.4，2.5Hz，1H)，4.39(s，2H)，3.75(s，3H)，3.71(s，3H)。LRMS：(m/z)：478.5(MH ⁺)。

Embodiment 34-1

4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-amino-5-styryl phenyl) benzamide (127)

Embodiment 35

4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-amino-5-styroyl phenyl) benzamide (178) and

Embodiment 36

N-(2-amino-5-styroyl-phenyl)-4-methyl-benzamide (129)

Scheme 24

Step 1.2-nitro-5-styryl aniline (126)

According to embodiment 1, identical program in the step 2 (scheme 1), but the 2-thienyl boric acid replaced to trans-2-phenylethyl boric acid (245 milligrams, 1.66 mmoles), thereby preparation titled reference compound 126 (230 milligrams, 69% yield). ¹H NMR：(400MHz，acetone-d ₆)δ(ppm)：7.89(d，J＝8.8Hz，1H)，7.49(d，J＝7.0Hz，2H)，7.27-7.18(m，3H)，7.19(d，J＝16.2Hz，1H)，7.05(d，J＝15.3Hz，1H)，7.02(s，1H)，6.93(bs，2H)，6.87(dd，J＝9.0，1.6Hz，1H)。LRMS：(m/z)：241.3(MH ⁺)。

Step 2 and 3.4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-amino-5-styryl phenyl) benzamide (127)

According to embodiment 21, identical program in the step 3 and 4 (scheme 18), but compound 97 is replaced to compound 126 (230 milligrams, 0.957 mmole), thereby preparation titled reference compound 127 (159 milligrams is 35% for 2 step yields). ¹H NMR：(400MHz，Acetone-d ₆)δ(ppm)：9.07(s，1H)，8.01(d，J＝8.2Hz，2H)，7.55(d，J＝8.2Hz，2H)，7.55-7.52(m，3H)，7.32(t，J＝7.4Hz，2H)，7.28(dd，J＝8.2，2.2Hz，1H)，7.19(t，J＝7.2Hz，1H)，7.13(d，J＝16.4Hz，1H)，7.0(d，J＝16.2Hz，1H)，6.89(d，J＝8.2Hz，1H)，6.70(d，J＝8.4Hz，1H)，6.41(d，J＝2.7Hz，1H)，6.12(dd，J＝8.6，2.7Hz，1H)，5.33(bs，1H)，4.85(bs，2H)，4.43(s，2H)，3.72(s，3H)，3.67(s，3H)。LRMS：(m/z)：480.5(MH ⁺)。

Step 4.4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-amino-5-styroyl phenyl) benzamide and N-(2-amino-5-styroyl phenyl)-4-methyl benzamide (129)

In the de-gassed solution of compound 127 (100 milligrams, 0.209 mmole) in the mixture of methyl alcohol and ethyl acetate (1: 1), add 10% year palladium charcoal of catalytic amount, and mixture is placed H ₂Atmosphere (1 normal atmosphere) is descended and was stirred 1 hour, filters through C salt, and filtrate is concentrated in a vacuum.The EtOAc/ hexane that uses polarity to increase progressively (40: 60 to 60: 40) on silica gel is made eluent by the flash chromatography separating mixture.The minimum compound 129 of polarity is as (31 milligrams of white solids, 31% yield) separates, the compound that polarity is the highest is further purified by crystallization from the mixture of ethyl acetate and hexane, thereby obtains the compound 128 (18 milligrams, 18% yield) of oldlace lenticular.

Compound 128: ¹H NMR:(400MHz, acetone-d ₆) δ (ppm): 9.07 (s, 1H), 7.99 (d, J=8.2Hz, 2H), 7.53 (d, J=8.6Hz, 2H), and 7.27-7.22 (m, 5H), 7.19-7.14 (m, 1H), 6.87 (dd, J=8.0,2.0Hz, 1H), 6.79 (d, J=8.0Hz, 1H), 6.70 (d, J=8.4Hz, 1H), 6.40 (d, J=2.8Hz, 1H), 6.11 (dd, J=8.4,2.5Hz, 1H), 5.33 (bs, 1H), 4.51 (bs, 2H), 4.42 (s, 2H), 3.72 (s, 3H), 3.67 (s, 3H).LRMS：(m/z)：482.2(MH ⁺)。

Compound 129: ¹H NMR:(400MHz, acetone-d ₆) δ (ppm): 9.03 (bs, 1H), 7.94 (d, J=8.0Hz, 2H), 7.33 (d, J=7.8Hz, 2H), 7.28-7.23 (m, 5H), 7.18-7.13 (m, 1H), 6.87 (dd, J=8.0,2.0Hz, 1H), 6.79 (d, J=8.2Hz, 1H), 4.48 (bs, 2H), 2.90-2.86 (m, 2H), 2.83-2.78 (m, 2H), 2.42 (s, 3H).LRMS：(m/z)：331.1(MH)。

Embodiment 37

4-((6-(2-(dimethylamino) oxyethyl group)-5-fluoro-1H-benzo [d] imidazoles-2-base sulfenyl) methyl)-N-(2-amino-5-(benzene sulphur-2-yl) phenyl) benzamide (131)

Scheme 25

According to embodiment 1, identical program in the step 3 and 4 (scheme 1), but compound 4 is replaced to (300 milligrams of compounds 130,0.559 mmole, in patent application WO03/024448, describe to some extent), thereby preparation titled reference compound 131 (7 milligrams is 3.7% through two step yields). ¹H NMR：(400MHz，acetone-d ₆)δ(ppm)：9.16(bs，1H)，7.97(d，J＝8.4Hz，2H)，7.62(d，J＝2.9Hz，1H)，7.61(d，J＝8.4Hz，2H)，7.32(dd，J＝8.2，2.2Hz，1H)，7.28(bs，0.5H)，7.27(dd，J＝5.1，1.0Hz，1H)，7.26(bs，0.5H)，7.22(dd，J＝3.5，1.0Hz，1H)，7.21(bs，1H)，7.03(dd，J＝5.1，3.5Hz，1H)，6.89(d，J＝8.2Hz，1H)，4.87(bs，2H)，4.65(s，2H)，4.16(t，J＝5.7Hz，2H)，2.73(t，J＝5.9Hz，2H)，2.30(s，6H)。LRMS：(m/z)：562.3(MH ⁺)。

Embodiment 38

4-acetylaminohydroxyphenylarsonic acid N-(2-amino-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan-2-yl) phenyl) benzamide (134)

Scheme 26

Step 1.5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan-2-yl)-2-nitrobenzamide (132)

According to J.Org.Chem.1995,60, the program described in the 7508-7510 prepares compound 132.Be starting raw material and use diox to synthesize with 2-nitro-5-bromaniline (2,300 milligrams, 1.38 mmoles) (scheme 1, embodiment 1) as solvent.The amount that makes compound 132 is 191 milligrams (52% yields). ¹H NMR：(400MHz，acetone-d ₆)δ(ppm)：8.02(d，J＝8.6Hz，1H)，7.46(d，J＝1.0Hz，1H)，6.99(s，2H)，6.97(dd，J＝8.4，1.2Hz，1H)，1.37(s，12H)。

Step 2.4-acetylamino-N-[2-nitro-5-(4,4,5,5-tetramethyl--[1,3,2] dioxaborolan-2-yl)-phenyl]-benzamide (133)

(18 milligrams of compounds 132,0.689 add (150 milligrams of 4-kharophen Benzoyl chlorides in pyridine mmole) (2.8 milliliters) solution, 0.758 mmole) and 4-(dimethylamino) pyridine (8 milligrams, 0.07 mmole), and with this mixture at room temperature stirred 16 hours.Then, make it at EtOAc and H ₂Layering between the O.With new EtOAc aqueous layer extracted, and with the organic layer salt water washing that merges, through MgSO ₄Drying is filtered and is concentrated in a vacuum.Using methyl alcohol/EtOAc (5: 95) to make eluent on silica gel the gained raw oil purifies by flash chromatography, obtain the titled reference compound 133 (47 milligrams, 16% yield) that exists as 1: 1 mixture with 4-acetylamino benzoic acid (starting material of hydrolysis). ¹H NMR：(Acetone-d ₆)δ(ppm)：10.76(bs，1H)，9.52(bs，1H)，9.00(d，J＝1.0Hz，1H)，8.20(d，J＝7.2Hz，1H)，7.99(d，J＝8.6Hz，2H)，7.85(d，J＝8.6Hz，2H)，7.64(dd，J＝8.2，1.2Hz，1H)，2.15(s，3H)，1.40(s，12H)。

Step 3.4-acetylaminohydroxyphenylarsonic acid N-(2-amino-5-(4,4,5,5-tetramethyl--1,3,2-dioxaborolan-2-yl) phenyl) benzamide (134)

According to embodiment 19, identical program in the step 4 (scheme 17), but compound 92 is replaced to compound 133 (75 milligrams, 0.176 mmole), thus obtain titled reference compound 134 (11 milligrams, 31% yield). ¹H NMR：(acetone-d ₆)δ(ppm)：9.42(bs，1H)，9.03(bs，1H)，8.03(d，J＝8.8Hz，2H)，7.77(d，J＝8.8Hz，2H)，7.60(d，J＝1.6Hz，1H)，7.39(dd，J＝8.0，1.6Hz，1H)，6.84(d，J＝7.8Hz，1H)，5.01(bs，2H)，2.13(s，3H)，1.31(s，12H)。LRMS：(m/z)：396.1(MH ⁺)。

Embodiment 39

N-(2-amino-5-(thiophene-2-carbonyl)-phenyl)-4-methoxy benzamide (136)

Scheme 27

Step 1.N-(2-amino-5-(thiophene-2-carbonyl)-phenyl)-4-methoxy benzamide (136)

According to embodiment 24, identical program in the step 1 (scheme 20), but compound 106 is replaced to 3,4-diaminobenzene thiophthene ketone dihydrochloride (135,200 milligrams, 0.687 mmole), thereby prepare orange foamed titled reference compound 136 (102 milligrams, 42% yield). ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：9.61(s，1H)，8.02(d，J＝6.3Hz，1H)，8.01(d，J＝8.6Hz，2H)，7.83(d，J＝2.0Hz，1H)，7.75(d，J＝3.2Hz，1H)，7.63(dd，J＝8.4，2.0Hz，1H)，7.29(dd，J＝4.9，3.2Hz，1H)，7.08(d，J＝8.8Hz，2H)，6.87(d，J＝8.6Hz，1H)，6.01(s，2H)，3.88(s，3H)。LRMS：(m/z)：353.1(MH ⁺)。

Embodiment 40

N-(2-amino-5-benzene sulphur-2-base phenyl)-4-(2-(N, N-dimethylamino) kharophen) benzamide (140)

Scheme 28

Step 1.4-(N, N-dimethylamino) acetylamino benzoic acid (139)

At N, add powdery sodium bicarbonate (11.9 grams, 141 mmoles) in acetonitrile (300 milliliters) solution of N-dimethylamino acetyl chloride hydrochloride (137,10.1 grams, 64.2 mmoles), add 4-benzaminic acid (138,9.68 grams, 70.6 mmoles) then.With this mixture vigorous stirring 16 hours at room temperature, and with the acetonitrile decantation.To remain natural gum with methyl alcohol development and filtration, obtain titled reference compound 139 (10.9 grams, 76% yield). ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：10.21(s，1H)，7.84(d，J＝8.4Hz，2H)，7.76(d，J＝8.6Hz，2H)，4.17(bs，2H)，2.27(s，6H)。LRMS：(m/z)：223.3(MH ⁺)。

Step 2 and 3.N-(2-amino-5-benzene sulphur-2-base phenyl)-4-(2-(N, N-dimethylamino) kharophen) benzamide (140)

According to embodiment 1, identical program in the step 3 and 4 (scheme 1), but compound 4 is replaced to compound 139[798 milligram (37% purity), 1.24 mmoles], thereby preparation titled reference compound 140 (7.4 milligrams is 1.5% through two step yields). ¹H NMR：(400MHz，CD ₃OD)δ(ppm)：7.99(d，J＝8.8Hz，2H)，7.77(d，J＝8.8Hz，2H)，7.48(d，J＝2.2Hz，1H)，7.35(dd，J＝8.2，2.2Hz，1H)，7.22(dd，J＝5.1，1.2Hz，1H)，7.20(td，J＝3.5，1.2Hz，1H)，7.01(dd，J＝5.1，3.7Hz，1H)，6.90(d，J＝8.6Hz，1H)，3.24(s，2H)，2.43(s，6H)。LRMS：(m/z)：395.1(MH ⁺)。

Embodiment 41a

4-(2-amino-5-(benzene sulphur-2-yl) phenyl amino formyl radical) benzylamino formic acid (pyridin-3-yl) methyl esters

Scheme 29

Step 1 and 2.4-(2-amino-5-(benzene sulphur-2-yl) phenyl amino formyl radical) benzylamino formic acid (pyridin-3-yl) methyl esters (143a)

(US 6,174,905B1) add compound 3 (424 milligrams, 1.93 mmoles), embodiment (scheme 1) in (533 milligrams, 1.75 mmoles) suspension in pyridine (5 milliliters) at compound 141a.Gained solution was at room temperature stirred 4 hours and concentrated in a vacuum.Crude compound 142a (855 milligrams, 1.75 mmoles) is dissolved in 1: 1 mixture of THF and methyl alcohol (14 milliliters) and adds two hydration tin chlorides (II) (1.97 grams, 8.75 mmoles).This mixture was stirred 3 hours and removed in a vacuum solvent.Resistates is suspended in the methyl alcohol, is adsorbing on the silica gel and on silica gel, using ethanol/methylene (10: 90) to make eluent and purify by flash chromatography.Gained natural gum is dissolved in methyl alcohol and makes its crystallization.Add ethyl acetate and the remainder of this compound is gone out by in ultra sonic bath, rotating.Filter the titled reference compound 143a (63 milligrams is 8% through 2 step yields) that produces white solid. ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：9.69(bs，1H)，8.58(s，1H)，8.53-8.51(m，1H)，7.98-7.96(m，1H)，7.94(d，J＝7.8Hz，2H)，7.78-7.76(m，1H)，7.46(s，1H)，7.40-7.38(m，1H)，7.37(d，J＝8.4Hz，2H)，7.29(d，J＝8.8Hz，1H)，7.24-7.23(m，1H)，7.05-7.03(m，1H)，6.80(d，J＝8.4Hz，1H)，5.15(bs，2H)，5.10(s，2H)，4.29(d，J＝6.1Hz，2H)。LRMS：(m/z)：459.2(MH ⁺)。

Embodiment 41b

N-(2-amino-5-benzene sulphur-2-base-phenyl)-4-fluoro-benzamide (143b)

With 4-fluorobenzoyl chloride (141b) is that starting raw material similarly obtains compound 143b (embodiment 41b) according to scheme 29 with compound 143a (embodiment 41a) via nitro intermediate 142b.Yield 44% (through two steps).

Embodiment 41c

N-(2-amino-5-benzene sulphur-2-base-phenyl)-4-trifluoromethyl sulfane base-benzamide (143c)

With 4-(trifluoromethyl sulfenyl) Benzoyl chloride (141c) is that starting raw material similarly obtains compound 143c (embodiment 41c) according to scheme 29 with compound 143a (embodiment 41a) via nitro intermediate 142c.Yield 1.4% (through two steps).

Embodiment 41d

N-(2-amino-5-benzene sulphur-2-base-phenyl)-3-chloro-4-fluoro-benzamide (143d)

With 3-chloro-4-fluorobenzoyl chloride (141d) is that starting raw material similarly obtains compound 143d (embodiment 41d) according to scheme 29 with compound 143a (embodiment 41a) via nitro intermediate 142d.Yield 30% (through two steps).

Embodiment 42

(E)-N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-3-(4-(tosyl group amino) phenyl) acrylamide (146)

Scheme 30

Step 1 and 2.N-(2-amino-5-(benzene sulphur-2-yl) phenyl) acrylamide (144)

In flame-dried round-bottomed flask, pack into compound 3 (100 milligrams, 0.453 mmole) and place N ₂Under the atmosphere.Add trace p methoxy phenol (to prevent polymerization), add acrylate chloride (74 microlitres, 0.906 mmole) then.This mixture was stirred 1 hour, and under high vacuum, placed 1 hour.Then, add THF (500 microlitre), add two hydration tin chlorides (II) (510 milligrams, 2.27 mmoles) then.With solution stirring 1 hour, and make eluent at the EtOAc/ hexane that increases progressively (50: 50 to 90: 10) on the silica gel with polarity and purify by flash chromatography (adding the trace p methoxy phenol to avoid polymerization before concentrating), produce titled reference compound 144 (70 milligrams is 63% for 2 step yields). ¹H NMR：(400MHz，acetone-d ₆)δ(ppm)：8.37(d，J＝1.8Hz，1H)，7.59(dd，J＝8.2，1.9Hz，1H)，7.51(d，J＝1.6Hz，1H)，7.50(dd，J＝2.5，1.2Hz，1H)，7.23(d，J＝8.2Hz，1H)，7.15(dd，J＝4.9，3.7Hz，1H)，6.75(d，J＝0.8Hz，1H)，6.52(dd，J＝16.8，10.0Hz，1H)，6.38(d，J＝16.8，1.8Hz，1H)，5.80(dd，J＝10.2，2.0Hz，1H)。LRMS：(m/z)：245.1(MH ⁺)。

Step 3. (E)-N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-3-(4-(tosyl group amino) phenyl) acrylamide (146)

In pressurized vessel, pack into compound 144 (70 milligrams, 0.287 mmole), DMF (800 microlitre) and compound 145 (WO 02/069947) (89 milligrams, 0.239 mmole).Solution is outgased under vacuum and place N ₂Under the atmosphere (3 times).Then, add three (dibenzalacetones), two palladiums (7 milligrams, 0.007 mmole), and this red solution outgased once more (3 times).Add three-adjacent toluene phosphine (4 milligrams, 0.014 mmole), the rapid deepening of solution.Add triethylamine (100 microlitres, 0.717 mmole), and it is outgased twice again, and make it at N ₂Stirred 3 hours at 90 ℃ under the atmosphere.Make it pass through C salt and filtrate is concentrated in a vacuum then.On silica gel, use EtOAc to make eluent and it is purified, use methyl alcohol/chloroform (5: 95) to make eluent then and purify again by flash chromatography.Make cut crystallization from this solvent mixture (methyl alcohol/chloroform 5: 95) of merging, produce titled reference compound 146 (3.8 milligrams, 3% yield). ¹H NMR：(400MHz，Acetone-d ₆)δ(ppm)：9.20(bs，1H)，8.84(bs，1H)，7.72(d，J＝8.0Hz，3H)，7.58(d，J＝15.7Hz，1H)，7.54(d，J＝8.4Hz，2H)，7.34(d，J＝8.6Hz，2H)，7.29-7.27(m，4H)，7.22(d，J＝3.5Hz，1H)，7.04(t，J＝4.9Hz，1H)，6.88(d，J＝8.4Hz，1H)，6.86(d，J＝15.3Hz，1H)，4.84(bs，2H)，2.38(s，3H)。LRMS：(m/z)：490.1(MH ⁺)。

Embodiment 43

N-(2-amino-5-(thiazolamine-4-yl) phenyl)-4-methoxy benzamide (153)

Scheme 31

Step 1.4-(4-nitrophenyl) thiazole-2-amine (148)

With 2-bromo-4 '-nitro-acetophenone 147 be starting raw material according to J.HeterocyclicChem.1970,7, the program of describing among the 1137-1141 prepares titled reference compound 148 with 96% yield. ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：8.21(d，J＝8.8Hz，2H)，8.02(d，J＝8.8Hz，2H)，7.40(s，1H)，7.22(s，2H)。LRMS(m/z)：222.1(MH ⁺)。

Step 2.2-(N, N-di-t-butyl formamyl)-4-(4-nitrophenyl) thiazole (149)

In THF (20 milliliters) solution of compound 148 (1.00 grams, 4.52 mmoles), add tert-Butyl dicarbonate (1.16 grams, 9.94 mmoles) and 4-(dimethylamino) pyridine (55 milligrams, 0.45 mmole), and this mixture was at room temperature stirred 4 days.To remain that yellow solid leaches and filtrate will be concentrated in a vacuum.Make resistates at EtOAc and H ₂Layering between the O.With organic layer salt water washing, through MgSO ₄Drying is filtered and is concentrated.Crystallization from EtOAc/ hexane (twice) obtains the titled reference compound 149 (1.23 gram, 65% yield) of beige crystals shape. ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：8.26(d，J＝9.0Hz，1H)，8.21(s，1H)，8.09(d，J＝9.0Hz，1H)，1.53(s，18H)。LRMS：(m/z)：422.2(MH ⁺)。

Step 3.4-(3-amino-4-nitrophenyl) thiazol-2-yl t-butyl carbamate (150)

With compound 149 be starting raw material according to J.Chem.Soc.Perkin Trans.1999, the program described in the 1437-1444 prepares compound 150 with 62% yield. ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：11.68(s，1H)，7.97(d，J＝9.0Hz，1H)，7.71(s，1H)，7.54(s，2H)，7.45(d，J＝2.0Hz，1H)，7.07(dd，J＝9.0，2.0Hz，1H)，1.50(s，9H)。LRMS：(m/z)：337.2(MH ⁺)。

Step 4.4-(3-(4-methoxybenzoyl amino)-4-nitrophenyl) thiazol-2-yl t-butyl carbamate (151)

In the pyridine solution of compound 150 (390 milligrams, 1.28 mmoles), add 4-methoxy benzoyl chloride (181 milligrams, 1.06 mmoles) and 4-(N, N-dimethylamino) pyridine (13 milligrams, 0.11 mmole).With this mixture stirring 16 hours and at EtOAc and H ₂Layering between the O.Organic layer is collected some compounds with salt water washing and filtration.With filtrate through MgSO ₄Drying is filtered also and is concentrated crystallization from the mixture of EtOAc/ hexane then in a vacuum.With two batches of merging, obtain titled reference compound 151 (358 milligrams, 72% yield). ¹H NMR：(400MHz，CD ₃OD)δ(ppm)：11.73(s，1H)，10.71(s，1H)，8.36(d，J＝2.0Hz，1H)，8.08(d，J＝8.6Hz，1H)，7.95(d，J＝9.0Hz，2H)，7.86(d，J＝0.8Hz，1H)，7.83(dd，J＝8.6，2.0Hz，1H)，7.10(d，J＝9.0Hz，2H)，3.85(s，3H)，1.50(s，9H)。

Step 5:4-(3-(4-methoxybenzoyl amino)-4-aminophenyl) thiazol-2-yl t-butyl carbamate (152)

According to embodiment 19, identical program in the step 4 (scheme 17), but compound 92 is replaced to compound 151 prepares titled reference compound 152 with 62% yield. ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：8.06(d，J＝8.6Hz，2H)，7.83(d，J＝2.2Hz，1H)，7.55(d，J＝8.2，2.0Hz，1H)，7.12(s，1H)，7.05(d，J＝9.0Hz，2H)，6.88(d，J＝8.2Hz，1H)，3.90(s，3H)，1.55(s，9H)。LRMS：(m/z)：441.4(MH ⁺)。

Step 6:N-[2-amino-5-(thiazolamine-4-yl) phenyl]-4-methoxy benzamide (153)

According to embodiment 27, identical program in the step 3 (scheme 20), but compound 111 is replaced to compound 152 (201 milligrams, 0.457 mmole) obtains titled reference compound 153 (63 milligrams, 100% yield). ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：9.55(s，1H)，7.96(d，J＝9.0Hz，2H)，7.60(d，J＝2.2Hz，1H)，7.39(dd，J＝8.2，2.0Hz，1H)，7.02(d，J＝9.0Hz，2H)，6.90(s，2H)，6.73(d，J＝8.4Hz，1H)，6.63(s，1H)，4.98(s，2H)，3.83(s，3H)。LRMS：(m/z)：341.2(MH ⁺)。

Embodiment 44

N-(2-amino-5-(4-amino-3-pyridyl) phenyl)-4-methoxy benzamide (157)

Scheme 32

The step 1.5-bromopyridine-2-aminocarbamic acid tert-butyl ester (155)

According to embodiment 43, identical program in the step 2 (scheme 31), but compound 148 is replaced to 5-bromo-pyridine-2-base-amine (154,972 milligrams, 5.62 mmoles), preparation titled reference compound 155 (313 milligrams, 20% yield). ¹H NMR：(400MHz，CD ₃OD)δ(ppm)：8.55(dd，J＝2.5，0.8Hz，1H)，8.06(dd，J＝8.6，2.5Hz，1H)，7.45(dd，J＝8.4，0.6Hz，1H)，1.43(s，9H)。LRMS：(m/z)：273.1/275.1(M ⁺/M+2)。

Step 2.N-(2-amino-5-(4-tertiary butyl formamyl-3-pyridyl) phenyl)-4-methoxy benzamide (156)

According to embodiment 31, identical program in the step 2 (scheme 21), but compound 148 is replaced to compound 155 (135 milligrams, 0.494 mmole) obtains titled reference compound 156 (36 milligrams, 25% yield). ¹H NMR：(400MHz，CD ₃OD)δ(ppm)：8.41(d，J＝2.2Hz，1H)，7.98(d，J＝9.0Hz，2H)，7.92(dd，J＝8.8，2.3Hz，1H)，7.85(d，J＝8.4Hz，1H)，7.45(s，1H)，7.34(dd，J＝8.4，2.0Hz，1H)，7.04(d，J＝8.8Hz，2H)，6.98(d，J＝8.4Hz，1H)，3.88(s，3H)，1.55(s，9H)。LRMS：(m/z)：435.2(MH ⁺)。

Step 3.N-(2-amino-5-(4-amino-3-pyridyl) phenyl)-4-methoxy benzamide (157)

According to embodiment 27, identical program in the step 3 (scheme 20), but compound 111 is replaced to compound 156 (36 milligrams, 0.083 mmole) obtains titled reference compound 157 (7 milligrams, 25% yield). ¹H NMR：(400MHz，acetone-d ₆)δ(ppm)：8.94(bs，1H)，8.03(d，J＝1.8Hz，1H)，7.88(d，J＝8.8Hz，1H)，7.47(dd，J＝8.9，2.5Hz，1H)，7.36(d，J＝2.3Hz，1H)，7.07(dd，J＝8.2，2.3Hz，1H)，6.89(d，J＝8.8Hz，2H)，6.77(d，J＝8.2Hz，1H)，6.45(dd，J＝8.4，0.6Hz，1H)，5.29(bs，2H)，3.74(s，3H)。LRMS：(m/z)：335.1(MH ⁺)。

Embodiment 44a

N-(4,4 '-diamino-3 '-fluoro-biphenyl-3-yl)-4-methoxyl group-benzamide (157a)

Using 4-bromo-2-fluoroaniline to make starting material replaces 5-bromo-pyridine-2-base-amine (154) to prepare N-(4,4 '-diamino-3 '-fluoro-biphenyl-3-yl)-4-methoxyl group-benzamide (157a) similarly according to scheme 32 and compound 157 (embodiment 44).

Embodiment 45

N-(4-amino-4 '-xenol-3-yl)-4-methoxy benzamide (160)

Scheme 33

Step 1. (3-bromine phenoxy group) (tertiary butyl) dimethylsilane (159)

According to embodiment 19, identical program in the step 2 (scheme 17), but compound 90 is replaced to 3-bromophenol 158 (200 milligrams, 0.501 mmole) obtains titled reference compound 159 (14 milligrams, 5% yield). ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：7.21(t，J＝8.0Hz，1H)，7.14(d，J＝7.8Hz，1H)，7.01(s，1H)，6.86(d，J＝8.0Hz，1H)，0.95(d，J＝1.0Hz，9H)，0.20(d，J＝1.2Hz，6H)。

Step 2.N-(4-amino-4 '-xenol-3-yl)-4-methoxy benzamide (160)

According to embodiment 31, identical program in the step 1 (scheme 21), but 1-(4-bromophenyl) ethyl ketone is replaced to compound 159 (312 milligrams, 1.09 mmoles) obtains titled reference compound 160 (79 milligrams, 44% yield). ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：9.58(s，1H)，9.35(s，1H)，7.97(d，J＝8.4Hz，2H)，7.43(s，1H)，7.23(dd，J＝8.2，1.4Hz，1H)，7.16(t，J＝7.6Hz，1H)，7.04(d，J＝8.4Hz，2H)，6.95(d，J＝7.6Hz，1H)，6.91(s，1H)，6.82(d，J＝8.4Hz，1H)，6.62(dt，J＝8.0，1.0Hz，1H)，5.05(s，2H)，3.84(s，3H)。LRMS：(m/z)：335.2(MH ⁺)。

Embodiment 46

N-(4-((2-amino-5-(benzene sulphur-2-yl) phenyl) formamyl) phenyl)-4-methylpiperazine-1-carboxylic acid amides (164)

Scheme 34

Step 1.4-(1-methylpiperazine-4-amide group) ethyl benzoate (162)

THF (10 milliliters) solution of N methyl piperazine (0.61 milliliter, 5.49 mmoles) and 4-ethyl isocyanato-benzoic ether 161 (1.00 grams, 5.23 mmoles) was at room temperature stirred 16 hours.Throw out filtered and with the ether rinsing to produce 1.40 titled reference compounds 162 that restrain (92%) white powder. ¹H NMR：(400MHz，DMSO)δ(ppm)：8.87(s，1H)，7.81(d，J＝8.4Hz，2H)，7.59(d，J＝8.4Hz，2H)，7.25(q，J＝6.8Hz，2H)，3.45(d，J＝4.9Hz，4H)，2.31(t，J＝4.9Hz，4H)，2.19(s，3H)，1.30(t，J＝6.8Hz，3H)。

Step 2.4-(1-methylpiperazine-4-amide group) phenylformic acid (163)

162 (1.39 grams, 4.77 mmoles) and LiOH.H ₂O (300 milligrams, 7.16 mmoles) is 1: 1THF: the solution in the water (8 milliliters) at room temperature stirred 24 hours.Add 1MHCl to reach pH=5 and with solvent evaporation.By preparation HPLC (Aquasil C18, anti-phase, eluent: MeOH/ water) titled reference compound is purified, produce the titled reference compound 163 of 979 milligrams of (78%) white powder. ¹H NMR：(400MHz，DMSO)δ(ppm)：8.81(s，1H)，7.78(dt，J＝8.6，1.8Hz，2H)，7.53(dt，J＝8.8，2.0Hz，2H)，3.44(t，J＝4.9Hz，4H)，2.31(t，J＝5.0Hz，4H)，2.19(s，3H)。

Step 3 and 4.4-methyl-piperazine-1-carboxylic acid [4-(2-nitro-5-benzene sulphur-2-base-phenyl amino formyl radical)-phenyl]-acid amides (164)

According to embodiment 1, identical program in the step 3 and 4 (scheme 1), but compound 4 is replaced to compound 163 obtains titled reference compound 164 (through two steps) with 8.4% yield. ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：9.57(s，1H)，8.80(s，1H)，7.89(d，J＝8.8Hz，2H)，7.59(d，J＝8.8Hz，2H)，7.44(d，J＝2.2Hz，1H)，7.34(dd，J＝5.1，1.0Hz，1H)，7.27(dd，J＝8.2，2.2Hz，1H)，7.23(dd，J＝3.5，1.2Hz，1H)，7.03(dd，J＝5.1，3.5Hz，1H)，6.79(d，J＝8.4Hz，1H)，5.12(sb，2H)，3.46(t，J＝4.8Hz，4H)，2.33(t，J＝4.9Hz，4H)。MS：(calc.)435.2；(obt.)436.4(MH) ⁺。

Embodiment 47

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-1-Methyl-1H-indole-6-carboxylic acid amides (41)

Scheme 35

Step 1:1-Methyl-1H-indole-6-carboxylate methyl ester (166)

Make 1H-Indole-6-carboxylic acid 37 (0.20 gram, 1.24 mmoles) be dissolved in dimethyl formamide (10 milliliters) and be cooled to 0 ℃ with by part adding a sodium hydride (0.20 gram, 4.96 mmoles).After adding fully, make reaction mixture be warming up to room temperature and stirred 1 hour, in reaction mixture, add methyl-iodide (0.15 milliliter, 2.48 mmoles) then.The water quenching, rotary evaporation to be to produce rough resistates then, and it is water-soluble, and uses ethyl acetate extraction.Through dried over mgso, filtering and evaporating provides rough 166 (they are used for next step with rough form) with organic phase.MS：189.08(calc)，190.1(obs)。

Step 2:1-Methyl-1H-indole-6-carboxylic acid (167)

With 1-Methyl-1H-indole-6-carboxylate methyl ester 166 (1.24 mmole) and sodium hydroxide (0.59 gram, 14.88 mmole) in 2: 2: 1 mixtures (7.5 milliliters) of methyl alcohol/THF/ water, at room temperature stir 36 hours to form throw out, also freeze-drying is collected in its filtration spends the night to produce titled reference compound 167 (0.54 gram, 99% yield).MS：175.06(calc)，176.1(obs)。

Step 3 and 4:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-1-Methyl-1H-indole-6-carboxylic acid amides (168)

According to embodiment 1, identical program in the step 3 and 4 (scheme 1), but compound 4 is replaced to compound 167 obtains titled reference compound 168 (through two steps) with 0.5% yield. ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：9.72(s，1H)，8.19(s，1H)，7.67(abq，J＝29.4，7.6Hz，2H)，7.52(d，J＝7.6Hz，2H)，7.36(s，1H)，7.31(d，J＝6.5Hz，1H)，7.26(s，1H)，7.06(s，1H)，6.83(d，J＝8.0Hz，1H)，6.52(s，1H)，5.16(s，2H)，3.90(s，3H)。MS：347.11(calc)，348.1(obs)。

Embodiment 48

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-(1H-tetrazolium-5-yl) benzamide (172)

Scheme 36

Step 1.4-cyano group-N-(2-nitro-5-benzene sulphur-2-base-phenyl)-benzamide (170)

According to embodiment 1, identical program in the step 3 (scheme 1), but compound 4 is replaced to compound 169 obtains titled reference compound 170 with 51% yield. ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)δ(ppm)：8.15(d，J＝8.0Hz，2H)，8.10(d，J＝2.0Hz，1H)，7.93(d，J＝8.0Hz，2H)，7.85(d，J＝8.6Hz，1H)，7.67(dd，J＝4.9，1.0Hz，1H)，7.64(dd，J＝3.7，1.7Hz，1H)，7.45(dd，J＝8.4，1.4Hz，1H)，7.20-7.17(m，1H)。MS：349.05(calc)，348.0(obs)。

Step 2.N-(2-nitro-5-(benzene sulphur-2-yl) phenyl)-4-(1H-tetrazolium-5-yl) benzamide (171)

(0.06 milliliter of azide tributyl tin in having toluene (2 milliliters), 0.21 under situation mmole), with (60.5 milligrams of nitro-cyano compounds 170, reach 24 hours 0.17 mmole) be heated to 95 ℃, then with solvent evaporation and by flash chromatography (1: 1 ethyl acetate: hexane) resistates is purified so that tetrazolium 171 (51.4 milligrams, 76% yield) to be provided. ¹H NMR：(DMSO)δ(ppm)：10.85(s，1H)，8.17(d，J＝14.9Hz，2H)，8.13(s，1H)，8.08(d，J＝8.4Hz，1H)，7.99(d，J＝7.4Hz，2H)，7.74(m，3H)，7.23(d，J＝3.7Hz，1H)。MS：392.07(calc)，393.1(obs)。

Step 3:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-(1H-tetrazolium-5-yl) benzamide (172)

In existing in methyl alcohol (1 milliliter) 10% year the palladium charcoal (catalytic amount) situation under, with nitro-compound 171 (20 milligrams, 0.05 mmole) hydrogenations at room temperature (1 normal atmosphere) 2-3 hour.Reaction mixture is filtered by C salt _ pad, the filtrate evaporation to produce crude product, is made it be suspended in the methylene dichloride and at room temperature stirs and spend the night, filtration provides titled reference compound 172 (6.3 milligrams, 27% yield) then. ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：9.71(s，1H)，8.07(d，J＝8.2Hz，2H)，8.00(d，J＝8.2Hz，2H)，7.48(s，1H)，7.34(d，J＝5.1Hz，1H)，7.28(dd，J＝8.2，2.0Hz，1H)，7.24(d，J＝3.5Hz，1H)，7.03(t，J＝3.7Hz，1H)，6.79(d，J＝8.4Hz，1H)，5.17(s，2H)。MS：362.09(calc)，363.1(obs)。

Embodiment 49

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-cyano group benzamide (173)

Step 1:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-cyano group benzamide (173)

According to embodiment 1, identical program in the step 4 (scheme 1), but compound 4 is replaced to compound 170 obtains titled reference compound 173 with 56% yield. ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：9.92(s，1H)，8.14(d，J＝8.4Hz，2H)，8.00(d，J＝8.4Hz，2H)，7.44(d，J＝2.0Hz，1H)，7.34(dd，J＝5.1，0.98Hz，1H)，7.30(dd，J＝8.2，2.2Hz，1H)，7.23(d，J＝3.5Hz，1H)，7.03(dd，J＝5.1，3.5Hz，1H)，6.79(d，J＝8.4Hz，1H)，5.24(s，2H)。MS：319.08(calc)，320.1(obs)。

Embodiment 50

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-(4,5-dihydro-1H-imidazoles-2-yl) benzamide (174)

Step 1:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-(4,5-dihydro-1H-imidazoles-2-yl) benzamide (174)

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-cyano group benzamide 173 (30 milligrams, 0.1 mmole), quadrol (0.126 milliliter, 1.9 mmoles) and dithiocarbonic anhydride (catalyzer) stirred in DMF at 50 ℃ spend the night.Then reaction mixture is evaporated to driedly, is dissolved in methyl alcohol and filters, produce the titled reference compound 174 (16.3 milligrams, 48%) of yellow solid shape. ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：9.78(s，1H)，8.02(d，J＝8.0Hz，2H)，7.92(d，J＝8.0Hz，2H)，7.45(s，1H)，7.33(d，J＝5.1Hz，1H)，7.28(d，J＝8.2Hz，1H)，7.22(d，J＝3.3Hz，1H)，7.03(t，J＝3.9Hz，1H)，6.79(d，J＝8.2Hz，1H)，5.18(s，2H)，3.63(s，4H)。MS：362.12(calc)，363.1(obs)。

Embodiment 51

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-3-methoxy benzamide (181)

Scheme 37

Step 1:4-bromo-2-nitrophenyl t-butyl carbamate (175)

In dimethyl formamide (55 milliliters) solution of 0 ℃ 4-bromo-2-N-methyl-p-nitroaniline 13 (5.00 grams, 23.07 mmoles), add a sodium hydride (1.02 grams, 25.38 mmoles, 1.1 equivalents) by part.H ₂After shedding fully, slowly add in the reaction mixture by sleeve pipe with 30 minutes dimethyl formamide (20 milliliters) solution with Boc acid anhydride (5.04 grams, 23.07 mmoles, 1 equivalent).Make reaction be warming up to room temperature, stir then and spend the night.Water quenching then, and remove DMF in a vacuum.Resistates is water-soluble and use ethyl acetate extraction.Through dried over sodium sulfate, filtration and evaporation are to provide 175 (3.72 grams, 51%) with organic phase. ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：9.67(s，1H)，8.10(d，J＝2.3Hz，1H)，7.84(dd，J＝8.6，2.3Hz，1H)，7.56(d，J＝8.8Hz，1H)，1.44(s，9H)。MS：(calc.)316.01；(obt.)217.1(M-Boc) ⁺。

Step 2:2-nitro-4-(benzene sulphur-2-yl) phenylcarbamic acid tert-butyl ester (177)

With 4-bromo-2-nitrophenyl t-butyl carbamate 175 (3.97 grams, 12.5 mmoles), 2-thienyl boric acid 176 (1.68 grams, 13.4 mmoles), yellow soda ash (3.98 grams, 37.56 mmoles) and Pd (PPh ₃) ₄The solution of (0.94 gram, 0.814 mmole) stirs in 100 ℃ of mixtures at DME and water (2: 1,70 milliliters) and spends the night.To doing, dilute with water is also used ethyl acetate extraction with solution evaporation.With organic phase salt water washing, through dried over sodium sulfate, filtration and evaporation with this purification of products, provide titled reference compound 177 (2.14 grams, 53% yield) by flash chromatography (hexane solution of 10% ethyl acetate) so that crude product to be provided. ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：9.63(s，1H)，8.12(d，J＝2.3Hz，1H)，7.92(dd，J＝8.4，2.2Hz，1H)，7.66(d，J＝8.4Hz，1H)，7.61(q，J＝2.2Hz，2H)，7.15(dd，J＝5.1，3.7Hz，1H)，1.46(s，9H)。MS：(calc.)320.08；(obt.)343.1(M+Na)。

Step 3:2-amino-4-(benzene sulphur-2-yl) phenylcarbamic acid tert-butyl ester (178)

According to embodiment 48, identical program in the step 3 (scheme 36), but compound 171 is replaced to compound 177 obtains titled reference compound 178 (68% yield). ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：8.34(s，1H)，7.43(dd，J＝5.1，1.2Hz，1H)，7.27(dd，J＝3.5，1.2Hz，1H)，7.24(d，J＝8.0Hz，1H)，7.06(dd，J＝5.1，3.7Hz，1H)，6.95(d，J＝2.2Hz，1H)，6.82(dd，J＝8.2，2.2Hz，1H)，5.00(s，2H)，1.47(s，9H)。MS：(calc.)290.11；(obt.)291.1(MH) ⁺。

Step 4:2-(3-methoxybenzoyl amino)-4-(benzene sulphur-2-yl) the phenylcarbamic acid tert-butyl ester (180)

With 3-methoxy benzoyl chloride 179 (0.20 gram, 1.17 mmole) and 178 (0.34 the gram, 1.17 mmole) in pyridine (15 milliliters), at room temperature stirred 4 hours, remove pyridine by rotary evaporation then, and rough material is purified so that titled reference compound 180 (0.44 gram, 89% yield) to be provided by column chromatography (hexane solution of 25% ethyl acetate). ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：9.88(s，1H)，8.72(s，1H)，7.80(s，1H)，7.60(d，J＝8.4Hz，1H)，7.43-7.55(m，6H)，7.17(dd，J＝7.6，1.8Hz，1H)，7.11(dd，J＝4.9，3.5Hz，1H)，3.84(s，3H)，1.46(s，9H)。MS：(calc.)424.15；(obt.)425.1(MH) ⁺。

Step 5: trifluoroacetic acid N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-3-methoxy benzamide (181)

With 2-(3-methoxybenzoyl amino)-4-(benzene sulphur-2-yl) phenylcarbamic acid tert-butyl ester 180 (0.214 gram, 0.504 mmole) at trifluoroacetic acid: dichloromethane solution at room temperature stirred 5 hours in (1: 3,4 milliliters), then with solvent evaporation.Also evaporate several to remove excessive trifluoroacetic acid with the rough resistates of washed with dichloromethane, titled reference compound 181 (0.22 gram, 100%) is provided. ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：9.96(1H，s)，7.59-7.52(3H，m)，7.46-7.41(3H，m)，7.39(1H，d，2.2Hz)，7.33(1H，dd，2.5and 1.0Hz)，7.16(1H，dd，5.7and 1.8Hz)，6.98(1H，d，8.4Hz)，3.84(3H，s)。MS：324.09(calc)，325.1(obs)。

Embodiment 52

Acetate 4-(2-amino-5-(benzene sulphur-2-yl) phenyl amino formyl radical) phenyl ester (184)

Step 1: acetate 4-(2-tert-butoxycarbonyl amino-5-benzene sulphur-2-base-phenyl amino formyl radical)-phenyl ester (183)

With 2-amino-4-(benzene sulphur-2-yl) phenylcarbamic acid tert-butyl ester 178 (0.198 gram, 0.68 phosphofluoric acid benzotriazole-1-base oxygen base-three (dimethylamino) Phosphonium (BOP) (0.302 gram mmole),, 0.68 mmole) and 4-acetoxy-benzoic acid (182) (0.123 the gram, 0.68 mmole) stirring is at room temperature spent the night in pyridine, purify so that 183 (0.11 gram, 36%) to be provided with solvent evaporation and by flash chromatography (hexane solution of 35% ethyl acetate) then. ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：9.91(s，1H)，8.72(s，1H)，8.01(d，J＝8.8Hz，2H)，7.78(d，J＝1.8Hz，1H)，7.63(d，J＝8.4Hz，1H)，7.51(dd，J＝4.9，0.98Hz，2H)，7.44(dd，J＝3.7，0.98Hz，1H)，7.30(d，J＝8.6Hz，1H)，7.11(dd，J＝5.1Hz，1H)，2.32(s，3H)，1.46(s，9H)。MS：(calc.)452.14；(obt.)475(M+Na)。

Step 2: acetate 4-(2-amino-5-(benzene sulphur-2-yl) phenyl amino formyl radical) phenyl ester trifluoro-acetate (184)

According to embodiment 51, identical program in the step 5 (same approach 37), but compound 180 is replaced to compound 183 obtains titled reference compound 184 (16% yield). ¹HNMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：9.73(1H，s)，8.03(2H，d，8.4)，7.45(1H，s)，7.34(1H，d，9.0Hz)，7.30-7.22(4H，m)，7.04(1H，dd，3.5and 1.6Hz)，6.79(1H，d，8.4Hz)，5.18(2H，s)，2.31(3H，s)。MS：352.1(calc)，353.1(obs)。

Embodiment 53

4-(2-(piperidines-1-yl) ethylamino)-N-(2-amino-5-(benzene sulphur-2-yl) phenyl) benzamide (190)

Scheme 38

Step 1:4-(2-(piperidines-1-yl) ethylamino) t-butyl perbenzoate (187)

With the 4-fluorobenzoic acid tert-butyl ester 185 (0.502 gram, 2.55 mmole) and (1.46 milliliters in 2-(piperidines-1-yl) ethamine 186,10.21 mmole) spend the night 120 ℃ of stirrings, dilute with ethyl acetate then, with saturated aqueous solution of sodium bicarbonate (1 *), salt solution (1 *) washing, through dried over mgso, and evaporation is to obtain 187 (0.501 gram, 64%). ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：7.59(d，J＝8.8Hz，2H)，6.55(d，J＝8.8Hz，2H)，6.24(t，J＝5.1Hz，1H)，4.11(m，2H)，3.21-3.13(m，6H)，2.44(t，J＝7.1Hz，2H)，2.37(m，2H)，1.49(s，9H)，1.47to 1.38(m，2H)。MS：304.22(calc)，249.1(M-tBu)。

Step 2:4-(2-(piperidines-1-yl) ethylamino) phenylformic acid trifluoro-acetate (188)

According to embodiment 51, the identical program of step 5 (scheme 37), but compound 187 is replaced to compound 183 obtains titled reference compound 188 (0.37 gram, 90.5%). ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：7.69(d，J＝8.6Hz，2H)，6.62(d，J＝8.8Hz，2H)，6.51(t，J＝6.8Hz，1H)，3.46(d，J＝5.7Hz，2H)，3.33(s，2H)，3.14(d，J＝11.5Hz，4H)，1.72(m，6H)。MS：248.15(calc)，249.2(obs)。

Step 3:4-(2-(piperidines-1-yl) ethylamino)-N-(2-nitro-5-(benzene sulphur-2-yl) phenylbenzamaide (189)

According to embodiment 1, the identical program of step 3 (scheme 1), but with acid 4 replace to acid 188, the acquisition titled reference compound 189 (19% yield).MS：450.17(calc)，451.2(obs)。

Step 4:4-(2-(piperidines-1-yl) ethylamino)-N-(2-amino-5-(benzene sulphur-2-yl) phenyl) benzamide (190)

According to embodiment 51, the identical program of step 3 (scheme 37), but nitro-compound 177 is replaced to nitro-compound 189 obtains titled reference compound 190 (8% yield). ¹HNMR:(DMSO) δ (ppm): 400MHz, (DMSO) d (ppm): 9.34 (1H, s), [8.25 (2H is s) from formate], 7.77 (2H, d, 8.8), 7.44 (1H, d, 2.2Hz), 7.34 (1H, dd, 4.0 and 1.2Hz), 7.26-7.21 (2H, m), 7.03 (1H, dd, 3.5 and 1.4), 6.78 (1H, d, 8.2), 6.62 (1H, d, 8.8Hz), 6.09 (1H, m), 3.25-3.15 (8H, m), 1.53-1.49 (4H, m), 1.39 (2H, m).MS：420.2(calc)，421.3(obs)。

Embodiment 54

4-(2-morpholino oxyethyl group)-N-(2-amino-5-(benzene sulphur-2-yl) phenyl) benzamide 197

Scheme 39

Step 1:4-(2-morpholino oxyethyl group) methyl benzoate (193)

Add salt of wormwood (2.95 grams, 21.3 mmoles) at 4-methyl hydroxybenzoate 191 (1.08 grams, 7.10 mmoles) and 4-(2-chloroethyl) morpholine hydrochloride 192 (1.45 grams, 7.82 mmoles) in the stirred solution in acetonitrile.Reaction mixture is heated to 50 ℃ spends the night, be cooled to room temperature then, and the gained throw out filtered and use methanol wash, thereby 4-(2-morpholino oxyethyl group) methyl benzoate 193 (2.67 restrain 142%) is provided. ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：7.87(s，J＝9.0Hz，2h)，7.03(d，J＝9.0Hz，2H)，4.15(t，J＝5.7Hz，2H)，3.80(s，3H)，3.56(t，J＝4.5Hz，4H)，2.69(t，J＝5.7Hz，4H)，2.47(m，4H)。MS：265.13(calc)，266.1(obs)。

Step 2:4-(2-morpholino oxyethyl group) phenylformic acid (194)

In the solution of 4-(2-morpholino oxyethyl group) methyl benzoate 193 (1.25 grams, 4.7 mmoles) in 1: 1 mixture (20 milliliters) of THF-water, add lithium hydroxide (hydration) (0.59 gram, 14.1 mmoles).Reaction mixture at room temperature stirred spends the night, be acidified to pH 2 with 1N HCl then, with solvent evaporation and with the resistates freeze-drying so that rough 194 (1.66 grams,＞＞100% yields) to be provided. ¹H NMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：7.88(d，J＝8.8Hz，2H)，7.05(d，J＝8.8Hz，2H)，4.53(m，2H)，3.89(m，4H)，3.53(m，2H)，3.26-3.14(m，4H)。MS：251.12(calc)，252.1(obs)。

Step 3:4-(2-morpholino oxyethyl group) Benzoyl chloride (195)

4-(2-morpholino oxyethyl group) phenylformic acid 194 (330 milligrams, 1.31 mmoles) is dissolved in thionyl chloride (4 milliliters) and adds several dimethyl formamides.In sealed tube, reaction mixture was stirred 1.5 hours at 80 ℃, open wide evaporation then and spend the night.Resistates placed in vacuum pump spend the night, and be used for next reaction (0.30 gram, 100%) like this.MS:269.08 (calc, COCl), 265.13 (calc, Me esters), 266.2 (obs, Me esters).

Step 4:4-(2-morpholino oxyethyl group)-N-(2-nitro-5-(benzene sulphur-2-yl) phenyl) benzamide (196)

According to embodiment 51, the identical program of step 4 (scheme 37), but compound 178 is replaced to compound 3, and compound 179 is replaced to compound 195 obtains titled reference compound 196 (3% yield).MS：453.14(calc)，454.2(obs)。

Step 5:4-(2-morpholino oxyethyl group)-N-(2-amino-5-(benzene sulphur-2-yl) phenyl) benzamide (197)

According to embodiment 1, the identical program of step 4 (scheme 1), but nitro-compound 5 is replaced to nitro-compound 196 obtains titled reference compound 197 (3 milligrams, 19%). ¹HNMR：(DMSO)δ(ppm)：400MHz，(DMSO)d(ppm)：9.67(1H，s)，8.01(2H，d，8.8)，7.44(1H，d，2.0Hz)，7.36(1H，dd，4.1 and 1.0Hz)，7.30(1H，dd，6.1 and 2.2Hz)，7.24(1H，dd，2.5 and 1.2)，7.12(2H，d，8.8)，7.04(1H，dd，3.5 and 1.6Hz)，6.82(1H，d，8.4Hz)，4.44(2H，t，4.1)，3.65-3.15(1OH，m)。MS：423.16(calc)，424.2(obs)。

Embodiment 55

4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-amino-5-cyano phenyl) benzamide (199)

Scheme 40

Step 1:4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-amino-5-cyano phenyl) benzamide (199)

According to embodiment 27, identical program described in the step 2 (scheme 20) obtains titled reference compound 199 with 16% yield. ¹H NMR：(DMSO)δ(ppm)：9.56(bs，1H)，7.89(d，J＝8.0Hz，2H)，7.52(bs，1H)，7.45(d，J＝8.4Hz，2H)，6.77(d，J＝8.4Hz，1H)，6.63(d，J＝8.4Hz，1H)，6.30(d，J＝2.4Hz，1H)，5.99-5.95(m，2H)，5.74(bs，1H)，4.92(bs，2H)，3.64(s，3H)，3.32(s，3H)。MS：(calc.)；402.5(obt.)403.4(MH) ⁺。

Embodiment 56

4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-amino-4-fluoro-5-(benzene sulphur-2-yl) phenyl) benzamide (205):

Scheme 41

Step 1:5-chloro-4-fluoro-2-nitrophenyl carboxylamine di tert butyl carbonate (201)

According to embodiment 43, the program described in the step 2 (scheme 31) is used THF as solvent, but compound 108 is replaced to compound 200, obtains titled reference compound 201 with 55% yield.MS：(calc.)390.8；(obt.)413(M+Na) ⁺。

Step 2:4-fluoro-2-nitro-5-(benzene sulphur-2-yl) phenylcarbamic acid di tert butyl carbonate (202)

According to embodiment 1, the described identical program of step 2 (scheme 1), but aryl bromide 2 is replaced to compound 201 obtains titled reference compound 202 (36% yield). ¹H NMR：(CDCl ₃)δ(ppm)：7.85(d，J＝10.4Hz，1H)，7.56-7.54(m，1H)，7.49(d，J＝6.8Hz，1H)，7.44(dd，J＝1.2，5.2Hz，1H)，7.10(dd，J＝0.8，5.2Hz，1H)，1.36(bs，18H)。MS：(calc.)438.4；(obt.)239.1(MH-2tert-Boc) ⁺。

Step 3:4-fluoro-2-nitro-5-(benzene sulphur-2-yl) aniline (203)

According to embodiment 27, the described identical program of step 3 (scheme 20), but compound 111 is replaced to compound 202 obtains titled reference compound 203 (32% yield). ¹H NMR：(CD3OD)δ(ppm)：7.86(d，J＝12.0Hz，1H)，7.63-7.60(m，2H)，7.31(d，J＝6.8Hz，1H)，7.17(t，J＝4.4Hz，1H)。MS：(calc.)238.3；(obt.)239.1(MH) ⁺。

Step 4:4-((3,4-Dimethoxyphenyl amino) methyl)-N-(4-fluoro-2-nitro-5-(benzene sulphur-2-yl) phenyl) benzamide (204):

According to embodiment 1, the described identical program of step 3 (scheme 1), but compound 3 is replaced to compound 203 obtains titled reference compound 204 (89% yield). ¹H NMR：(DMSO)δ(ppm)：10.70(bs，1H)，8.17(d，J＝7.2z，1H)，8.10(d，J＝10.8Hz，1H)，7.90(d，J＝8.8Hz，2H)，7.85(dd，J＝5.2；1.2Hz，1H)，7.73(d，J＝4.0Hz，1H)，7.52(d，J＝8.8Hz，2H)，7.62(dt，J＝5.2；1.2Hz，1H)，6.40(d，J＝8.8Hz，1H)，6.31(d，J＝2.4Hz，1H)，6.01-5.96(m，2H)，4.31(d，J＝6.6Hz，2H)，3.65(s，3H)，3.58(s，3H)。MS：(calc.)507.5；(obt.)508.3(MH) ⁺。

Step 5:4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-amino-4-fluoro-5-(benzene sulphur-2-yl) phenyl) benzamide (205):

According to embodiment 1, the described identical program of step 4 (scheme 1), but compound 5 is replaced to compound 204, and reacting in room temperature obtains titled reference compound 205 (41% yield). ¹H NMR：(DMSO)δ(ppm)：9.65(s，1H)，7.96(d，J＝8.0Hz，2H)，7.48-7.51(m，4H)，7.31(d，J＝4.0Hz，1H)，7.11(d，J＝4.0Hz，1H)，6.80(d，J＝8.8Hz，1H)，6.50(d，J＝13.6Hz，1H)，6.35(d，J＝2.8Hz，1H)，6.03-6.01(m，2H)，5.50(bs，2H)，4.34(d，J＝6.0Hz，2H)，3.70(s，3H)，3.62(s，3H)。MS：(calc.)477.6；(obt.)478.4(MH) ⁺。

Embodiment 57a

N-(5-(1-methyl isophthalic acid H-imidazoles-2-base sulfenyl)-2-amino-4-fluorophenyl)-4-((3,4-Dimethoxyphenyl amino) methyl) benzamide (209a)

Scheme 42

Step 1:5-(1-methyl isophthalic acid H-imidazoles-2-base sulfenyl)-4-fluoro-2-N-methyl-p-nitroaniline (208a):

In the DMF (20 milliliters) of 206 (500 milligrams, 2.8 mmoles) stirred solution, add 1-methyl isophthalic acid H-imidazoles-2-mercaptan (207a, 2.8 mmoles, 328 milligrams) and salt of wormwood (1.58 grams, 11.49 mmoles).Reaction mixture was stirred 5 hours at 60 ℃.Add ethyl acetate and filter removal K ₂CO ₃Filtrate is concentrated, reduction vaporization, and on silica gel, by flash chromatography (eluent hexane-EtOAc (1: 2), EtOAc (100%) then) resistates is purified to produce 208a (751 milligrams, 98% yield).MS：(calc.)268.3；(obt.)269.1(MH) ⁺。

Step 2-3:N-(5-(1-methyl isophthalic acid H-imidazoles-2-base sulfenyl)-2-amino-4-fluorophenyl)-4-((3,4-Dimethoxyphenyl amino) methyl) benzamide (209a)

According to embodiment 1, the program described in the step 3 and 4 (scheme 1), but compound 3 is replaced to compound 208a, obtain titled reference compound 209a with 28% yield. ¹H NMR：(DMSO)δ(ppm)：9.5(s，1H)，7.86(d，J＝8.4Hz，2H)，7.43(d，J＝8.4Hz，2H)，7.2(s，1H)，7.10(d，J＝8.4Hz，1H)，6.90(s，1H)，6.6(d，J＝8.8Hz，1H)，6.56(d，J＝11.6Hz，1H)，6.29(d，J＝2.4Hz，1H)，5.95(dd，J＝2.4，8.8Hz，2H)，5.52(bs，2H)，4.28(bs，2H)，3.64(s，6H)，3.57(s，3H)。MS：(calc.)507.6；(obt.)508.4(MH) ⁺。

Embodiment 57b

4-((3,4-Dimethoxyphenyl amino) methyl)-N-(5-(4-(1H-imidazoles-1-yl) phenoxy group)-2-amino-4-fluorophenyl) benzamide (209b)

Step 1:5-(4-(1H-imidazoles-1-yl) phenoxy group)-4-fluoro-2-N-methyl-p-nitroaniline (208b)

According to embodiment 57a, identical program described in the step 1 (scheme 42), but imidazoles 207a is replaced to 4-(1H-imidazoles-1-yl) phenol (207b) obtains compound 208b with 23% yield.MS：(calc.)314.6；(obt.)315.1(MH) ⁺。

Step 2-3:4-((3,4-Dimethoxyphenyl amino) methyl)-N-(5-(4-(1H-imidazoles-1-yl) phenoxy group)-2-amino-4-fluorophenyl) benzamide (209b)

According to embodiment 1, the program described in the step 3 and 4 (scheme 1), but compound 2 is replaced to compound 208b, obtain titled reference compound 209b with 65% yield. ¹H NMR：(DMSO)δ(ppm)：7.87(d，J＝8.4Hz，2H)，7.75(bs，1H)，7.60(d，J＝8.0Hz，2H)，7.44(d，J＝8.4Hz，2H)，7.26(bs，1H)，7.14(d，J＝8.0Hz，1H)，7.03(d，J＝8.0Hz，2H)，6.723(d，J＝13.2Hz，1H)，6.62(d，J＝8.4Hz，1H)，6.29(d，J＝2.4Hz，1H)，5.96(dd，J＝2.4，8.8Hz，2H)，4.28(bs，2H)，3.64(s，3H)，3.57(s，3H)。MS：(calc.)553.6；(obt.)554.5(MH) ⁺。

Embodiment 58

4-acetylaminohydroxyphenylarsonic acid N-(2-amino-4-fluoro-5-(1H-pyrroles-1-yl) phenyl) benzamide (213) step 1:4-fluoro-2-nitro-5-(1H-pyrroles-1-yl) aniline (211):

In 206 (500 milligrams, 2.87 mmoles) and pyrroles's's (210,239 microlitres, 3.44 mmoles) DMF (10 milliliters) stirred solution, add NaH (207 milligrams, 5.17 mmoles).Reaction mixture was stirred 18 hours at 50 ℃, and water (100 milliliters) quenching is also used DCM (2 * 50 milliliters) extraction.With organic phase with dried over mgso and concentrating under reduced pressure.On silica gel, resistates is purified to produce titled reference compound 211 (145 milligrams, 25% yield) by flash chromatography (eluent hexane-EtOAc 4: 1, hexane-EtOAc is 1: 1 then). ¹HNMR：(DMSO)δ：7.94(d，J＝12.0Hz，1H)，7.12(q，J＝2.4，4.4Hz，2H)，7.02(d，J＝6.8Hz，1H)，6.32(t，J＝2.4，4.8Hz，2H)。MS：(calc.)221.8；(obt.)222.1(MH) ⁺。

Step 2-3:4-acetylaminohydroxyphenylarsonic acid N-(2-amino-4-fluoro-5-(1H-pyrroles-1-yl) phenyl) benzamide (213)

According to embodiment 1, the program described in the step 3 and 4 (scheme 1), but amine 3 is replaced to compound 211, and acid 4 is replaced to 4-acetylamino benzoic acid (212), obtain titled reference compound 213 with 40% yield. ¹H NMR：(DMSO)δ(ppm)：10.11(s，1H)，9.48(s，1H)，7.83(d，J＝8.4Hz，2H)，7.56(d，J＝8.8Hz，2H)，7.20(d，J＝8.4Hz，1H)，6.86(dd，J＝2.0，4.0Hz，2H)，6.62(d，J＝12.8Hz，1H)，6.10(2H，dd，J＝2.0，4.0Hz，2H)，5.28(bs，2H)，2.09(s，3H)。MS：(calc.)352.36；(obt.)353.2(MH) ⁺。

Embodiment 59

4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-amino-4-fluoro-5-indoles-5-nitrile) benzamide (218)

Scheme 43

Step 1:4,5-two fluoro-2-nitrophenyl carboxylamine di tert butyl carbonates (214)

According to embodiment 43, the program described in the step 2 (scheme 31), but compound 148 is replaced to compound 206, obtain titled reference compound 214 with 89% yield. ¹H NMR：(CDCl ₃)δ(ppm)：7.99(dd，J＝7.6，9.6Hz，1H)，7.18(dd，J＝7.2，9.6Hz，1H)，1.42(bs，18H)。MS：(calc.)374.3；(obt.)397.2(MNa) ⁺。

Step 2:5-(5-cyano-1 H-indol--1-yl)-4-fluoro-2-nitrophenyl carboxylamine di tert butyl carbonate (216):

According to embodiment 57, the program described in the step 1, but DMF replaced to DMSO and 1-methyl isophthalic acid H-imidazoles-2-mercaptan (207a) replaced to 1H-indoles-5-nitrile (215) thus obtain titled reference compound 216 with 28% yield. ¹H NMR：(CDCl ₃)δ(ppm)：9.71(bs，1H)，8.88(d，J＝3.2Hz，1H)，8.21(d，J＝10.8Hz，1H)，8.02(s，1H)，7.55(bs，1H)，7.43(dd，J＝2.4，6.0Hz，1H)，6.83(d，J＝3.6Hz，1H)，1.55(s，18H)。MS：(calc.)496.5；(obt.)436.3(M+K) ⁺。

Step 3:1-(5-amino-2-fluoro-4-nitrophenyl)-1H-indoles-5-nitrile (217)

According to embodiment 27, the program described in the step 3 (scheme 20), but compound 111 is replaced to compound 216, obtain titled reference compound 217 with 99% yield.MS：(calc.)296.3；(obt.)297.2(MH) ⁺。

Step 4-5:4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-amino-4-fluoro-5-indoles-5-nitrile) benzamide (218)

According to embodiment 1, the program described in the step 3 and 4, but compound 3 is replaced to compound 217, obtain titled reference compound 218 with 41% yield. ¹H NMR：(DMSO)δ(ppm)：8.08(bs，1H)，7.96(d，J＝8.0Hz，2H)，7.54(d，J＝8.0Hz，2H)，7.41-7.50(m，2H)，7.40(d，J＝8.0Hz，1H)，7.35(d，J＝7.6Hz，1H)，6.83(d，J＝8.0Hz，1H)，6.80(d，J＝2.4Hz，1H)，6.72(d，J＝8.8Hz，1H)，6.38(d，J＝2.4Hz，1H)，6.15(dd，J＝2.4，8.8Hz，1H)，4.41(bs，2H)，3.76(s，3H)，3.73(s，3H)。MS：(calc.)535.5；(obt.)536.3(MH) ⁺。

Embodiment 60

4-acetylaminohydroxyphenylarsonic acid N-(2-amino-4-(thiazol-2-yl) phenyl) benzamide (223) and

Embodiment 61a

4-acetylaminohydroxyphenylarsonic acid N-(2-amino-5-(thiazol-2-yl) phenyl) benzamide (224a)

Scheme 44

Step 1:4-amino-3-nitrobenzoyl thioamides (220)

Pyridine (15 milliliters) and Et at 219 (1.96 grams, 12.02 mmoles) ₃In N (6 milliliters) stirred solution, blasted hydrogen sulfide 40 minutes.When reaction is finished, blasted nitrogen again 40 minutes.Resistates is diluted in DCM and water, HCl 10% and salt water washing.Collect organic phase,, obtain titled reference compound 220 (2.11 grams, 89% yield) through dried over sodium sulfate and concentrating under reduced pressure. ¹H NMR：(DMSO)δ(ppm)：9.04(bs，1H)，8.31(d，J＝9.2Hz，1H)，7.28(d，J＝8.8Hz，1H)。MS：(calc.)197.2；(obt.)198.1(MH) ⁺。

Step 2:2-nitro-4-(thiazol-2-yl) aniline (221a)

In ethanol (15 milliliters) stirred solution of 220 (500 milligrams, 2.53 mmoles), add monochloroacetaldehyde (50% aqueous solution, 0.796 milliliter, 5.0 mmoles).80 ℃ of heating 18 hours, reduction vaporization also was dissolved in DCM with resistates, use the salt water washing with this mixture, with dried over sodium sulfate and concentrated.On silica gel, rough material is purified, obtain titled reference compound 221a (104 milligrams, 19% yield) by flash chromatography (eluent hexane-EtOAc (4: 1), EtOAc (100%) then). ¹H NMR：(CD ₃OD)δ(ppm)：8.62(d，J＝2.0Hz，1H)，7.91(dd，J＝2.4，8.8Hz，1H)，7.78(d，J＝3.2Hz，1H)，7.51(d，J＝3.2Hz，1H)，7.07(d，J＝8.8Hz，1H)。MS：(calc.)221.2；(obt.)222.1(MH) ⁺。

Step 3:4-(thiazol-2-yl) benzene-1,2-diamines (222a)

According to embodiment 1, the program described in the step 4 (scheme 1), but replace to compound 221a, acquisition titled reference compound 222a (53% yield) with 5. ¹H NMR：(CD ₃OD)δ(ppm)：7.68(d，J＝3.2Hz，1H)，7.38(d，J＝3.6Hz，1H)，7.26(d，J＝2.0Hz，1H)，7.19(dd，J＝2.0，8.0Hz，1H)，6.70(d，J＝8.0Hz，1H)。MS：(calc.)191.2；(obs.)192.3(MH) ⁺。

Step 4:4-acetylaminohydroxyphenylarsonic acid N-(2-amino-4-(thiazol-2-yl) phenyl) benzamide (223) and 4-acetylaminohydroxyphenylarsonic acid N-(2-amino-5-(thiazol-2-yl) phenyl) benzamide (224a)

With acetonitrile (1 milliliter) solution that in the acetonitrile (10 milliliters) of 222a (47 milligrams, 0.25 mmole) and pyridine (20 microlitre) stirred solution, added 0 ℃ 2-kharophen Benzoyl chloride (49 milligrams, 0.25 mmole) in 15 minutes.Reaction mixture is warming up to room temperature and stirred concentrating under reduced pressure 4 hours.With rough thing with DCM dilution and use NaHCO ₃With the salt water washing.With organic layer through Na ₂SO ₄Dry also evaporation.On silica gel, resistates is purified, obtain titled reference compound 223 (3 milligrams, 4% yield) and 224a (5 milligrams, 5% yield) by flash chromatography (eluent hexane-EtOAc (1: 3), EtOAc (100%) then).

223： ¹H NMR：(CD ₃OD)δ(ppm)：7.95(d，J＝8.8Hz，2H)，7.60(d，J＝3.2Hz，1H)，7.73-7.71(m，2H)，7.56(d，J＝3.2Hz，1H)，7.48(bs，1H)，7.32(bs，2H)，2.17(s，3H)。MS：(calc.)352.4；(obt.)353.2(MH) ⁺。

224a： ¹H NMR：(DMSO)δ(ppm)：10.18(s，1H)，9.64(s，1H)，8.00-7.94(m，5H)，7.84(d，J＝2.0Hz，1H)，7.68(dd，J＝1.6，7.2Hz，2H)，7.61(dd，J＝2.0，8.4Hz，1H)，7.42(dt，J＝1.6，7.2Hz，2H)，7.32(d，J＝1.6，7.2Hz，1H)，6.84(d，J＝8.4Hz，1H)，5.52(bs，2H)，2.09(s，3H)。MS：(calc.)428.5；(obt.)429.1(MH) ⁺。

Embodiment 61b

4-acetylaminohydroxyphenylarsonic acid N-(2-amino-5-(4-phenyl thiazole-2-yl) phenyl) benzamide (224b)

According to embodiment 61a, identical program described in the step 1-4 (scheme 44), but the monochloroacetaldehyde in second step is replaced to 2-chloro-1-phenyl ethyl ketone obtains title 224b with 24% total recovery.

Embodiment 61c

4-acetylaminohydroxyphenylarsonic acid N-(2-amino-5-(4,5-dimethylthiazole-2-yl) phenyl) benzamide (224c)

According to embodiment 61a, identical program described in the step 1-4 (scheme 44), but the monochloroacetaldehyde in second step is replaced to 3-neoprene-2-ketone obtains title 224c with 3% total recovery.

Scheme 45

Embodiment 62

4-acetylaminohydroxyphenylarsonic acid N-(2-amino-5-(benzo [d] oxazole-2-yl) phenyl) benzamide (228)

Step 1:3-nitro-4-aniline imidoether (imidate) (225)

At 0 ℃, in 5 minutes process, hydrogenchloride is blasted in the reaction flask that contains dehydrated alcohol (10 milliliters).In this solution, add compound 219 (2.00 grams, 12.26 mmoles).Mixture was at room temperature stirred 18 hours, concentrating under reduced pressure and with solid residue with ethyl acetate development titled reference compound 225 (2.72 grams, 79% yield) to produce the yellow solid shape. ¹H NMR：(DMSO)δ(ppm)：8.40(d，J＝2.0Hz，1H)，8.05(bs，2H)，7.65(dd，J＝2.0，8.8Hz，1H)，7.06(d，J＝8.8Hz，1H)。MS：(calc.)209.2；(obt.)210.1(MH) ⁺。

Step 2:4-(benzo [d] oxazole-2-yl)-2-N-methyl-p-nitroaniline (226):

To and in sealed flask, heat 5 hours in the imidoether 225 in the dehydrated alcohol (25 milliliters) (500 milligrams, 1.77 mmoles) usefulness Ortho-Aminophenol (232 milligrams, 2.1 mmoles) processing at 95 ℃.With solvent removed under reduced pressure, and with resistates with ethyl acetate development to produce titled reference compound 226 (517 milligrams, quantitative yield). ¹H NMR：(DMSO)δ(ppm)：8.45(d，J＝2.0Hz，1H)，8.14(dd，J＝2.0，8.8Hz，1H)，8.06(bs，2h)，7.79-7.75(M，2H)，7.41-7.39(m，2h)，7.20(d，J＝1.6Hz，1H)。MS：(calc.)255.2；(obt.)256.0(MH) ⁺。

Step 3:4-(benzo [d] oxazole-2-yl) benzene-1,2-diamines (227):

In methyl alcohol (20 milliliters) stirred solution of 226 (517 milligrams, 1.77 mmoles), add and carry palladium charcoal (10%, 188 milligram).To be reflected under the nitrogen atmosphere and stir 18 hours, filter through C salt pad; With filtrate evaporated under reduced pressure to produce titled reference compound 227 (350 milligrams, 87% yield). ¹H NMR：(DMSO)δ7.673-7.641(m，2H)，7.39(d，J＝2.0Hz，1H)，7.32-7.30(m，3H)，6.64(d，J＝8.0Hz，1H)。MS：(calc.)225.2；(obt.)226.1(MH) ⁺。

Step 4.4-acetylaminohydroxyphenylarsonic acid N-(2-amino-5-(benzo [d] oxazole-2-yl) phenyl) benzamide (228):

Acetonitrile (5 milliliters) solution that in the stirred suspension of 227 (350 milligrams, 1.55 mmoles) in acetonitrile (20 milliliters) and pyridine (2 milliliters), adds 0 ℃ 4-kharophen Benzoyl chloride (307 milligrams, 1.55 mmoles).This solution is warming up to room temperature and stirred 4 hours.Resistates is purified by flash chromatography (eluent hexane-EtOAc (1: 3), EtOAc (100%) then) with the reaction mixture concentrating under reduced pressure and on silica gel, obtain 228 (5 milligrams, 1% yield) of beige solid shape. ¹H NMR：(DMSO)δ(ppm)：10.22(s，1H)，9.62(s，1H)，8.05(d，J＝2.4Hz，1H)，7.89(d，J＝8.4Hz，2H)，7.80(1H，dd，J＝2.0，8.4Hz，1H)，7.68-7.73(m，4H)，7.33-7.35(m，2H)，6.91(d，J＝8.4Hz，1H)，5.86(bs，2H)，2.12(s，3H)。MS：(calc.)386.41；(obt.)387.1(MH) ⁺。

Embodiment 63

(E)-3-(4-((3-chloro-phenyl-amino) methyl) phenyl)-N-(2-amino-5-(benzene sulphur-2-yl) phenyl) acrylamide (232)

Scheme 46

Step 1. (E)-3-(4-((3-chloro-phenyl-amino) methyl) phenyl) vinylformic acid (231)

At (E)-3-(4-formyl radical phenyl) vinylformic acid 229 (1 gram; 5.67 mmole) and 3-chloroaniline 230 (596 microlitres; 5.67 dropwise add phenyl silane (697 microlitres, 5.67 mmoles) in THF mmole) (8 milliliters), dichloride dibutyl tin (173 milligrams, the 0.57 mmole) solution.Under nitrogen atmosphere, the gained mixture at room temperature stirred and spend the night, with MeOH dilution and concentrating under reduced pressure.Solid residue is developed to produce titled reference compound 231 (1.24 grams, 76% yield) with DCM. ¹H NMR：(DMSO)δ(ppm)：7.61(d，J＝8.0Hz，2H)，7.53(d，J＝16.0Hz，1H)，7.34(d，J＝8.4Hz，2H)，7.00(t，J＝8.0Hz，1H)，6.53(t，J＝2.0Hz，1H)，6.49-6.48(m，2H)，6.46(d，J＝16.0Hz，1H)，4.28(bs，2H)。MS：(calc.)287.7；(obt.)288.1(MH) ⁺。

Step 2-3. (E)-3-(4-((3-chloro-phenyl-amino) methyl) phenyl)-N-(2-amino-5-(benzene sulphur-2-yl) phenyl) acrylamide (232)

According to embodiment 1, the program described in the step 3-4 (scheme 1), but acid 4 is replaced to acid 231, obtain titled reference compound 232 with 60% yield. ¹H NMR：(DMSO)δ(ppm)：9.42(bs，1H)，7.66-7.32(m，7H)，7.22-7.14(m，2H)，7.10-7.00(m，2H)，6.87-6.74(m，1H)，6.62-6.50(m，4H)，5.19(bs，1H)，4.29(d，J＝5.6Hz，2H)。MS：(calc.)459.2；(obt.)460.3(MH) ⁺。

Embodiment 64

6-acetylaminohydroxyphenylarsonic acid N-(2-amino-5-(benzene sulphur-2-yl) phenyl) pyridine-3-carboxylic acid amides (235)

Scheme 47

Step 1:6-kharophen pyridine-3-carboxylic acid (234)

In pyridine (60 milliliters) stirred solution of 233 (2 grams, 14.48 mmoles), add diacetyl oxide (1.62 milliliters, 15.93 mmoles).Reaction mixture is heated to 130 ℃ in sealed vessel, stirred 16 hours, be evaporated to 30 milliliters and be cooled to 0 ℃.The gained throw out is filtered, with cold pyridine and water washing, and dry.This produces 234 (1.85 grams, 71% yields) of white solid. ¹H-NMR：(DMSO)δ：10.82(s，1H)，8.77(dd，J＝2.2，0.8Hz，1H)，8.20(dd，J＝8.7，2.2Hz，1H)，8.14(d，J＝8.7Hz，1H)，2.12(s，3H)。

Step 2-3:6-acetylaminohydroxyphenylarsonic acid N-(2-amino-5-(benzene sulphur-2-yl) phenyl) pyridine-3-carboxylic acid amides (235)

According to embodiment 1, the program described in the step 3 and 4 (making solubility promoter) with DMF, but acid 4 is replaced to acid 234, obtain the titled reference compound 235 (20 milligrams, 9% yield) of yellow solid shape. ¹H NMR：(DMSO)δ10.79(br s，1H)，9.75(br s，1H)，8.90(s，1H)，8.31(d，J＝9.4Hz，1H)，8.15(d，J＝8.5Hz，1H)，7.42(s，1H)，7.33(m，1H)，7.28(d，J＝8.5Hz，1H)，7.22(s，1H)，7.02(m，1H)，6.78(d，J＝8.0Hz，1H)，5.20(br s，2H)，2.13(s，3H)。

Embodiment 65a

N-(2-amino-5-(benzene sulphur-2-yl) phenyl) quinoxaline-6-carboxylic acid amides (238a)

Scheme 48

Step 1: quinoxaline-6-carboxylate methyl ester (237a)

3, add in Virahol (50 milliliters) stirred solution of 4-diamino-methyl benzoate (236,2 gram, 12.03 mmoles) oxalic dialdehyde 40% aqueous solution (13.23 mmoles, 1.52 milliliters).80 ℃ of heating 2 hours, decompression was removed solvent and with resistates dry 237a (2.09 grams, 93% yield) to produce the yellow solid shape under vacuum with reaction mixture. ¹H NMR：(DMSO)δ9.01(s，2H)，8.54(d，J＝1.6Hz，1H)，8.23(dd，J＝8.6，2.0Hz，1H)，8.14(dd，J＝8.6，0.6Hz，1H)，3.35(s，3H)。

Step 2-4:N-(2-amino-5-(benzene sulphur-2-yl) phenyl) quinoxaline-6-carboxylic acid amides (238a)

According to the identical program of embodiment 4 steps 3, then according to embodiment 1, the program described in the step 3 and 4 (making solubility promoter with DMF) obtains the titled reference compound 238a (through 3 steps) of orange solids shape with 26% yield. ¹H NMR：(DMSO)δ10.09(br s，1H)，9.04(dd，J＝6.7，1.8Hz，2H)，8.79(d，J＝1.8Hz，1H)，8.37(dd，J＝8.9，2.0Hz，1H)，8.20(d，J＝8.6Hz，1H)，7.51(d，J＝2.2Hz，1H)，7.34(dd，J＝4.9，1.0Hz，1H)，7.30(dd，J＝2.1，8.1Hz，1H)，7.24(dd，J＝3.5，1.2Hz，1H)，7.04(dd，J＝4.9，3.5Hz，1H)，6.81(d，J＝8.2Hz，1H)，5.28(br s，2H)。

Embodiment 65b

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-2,3-two (furans-2-yl) quinoxaline-6-carboxylic acid amides (238b)

Step 1-4:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-2,3-two (furans-2-yl) quinoxaline-6-carboxylic acid amides (238b)

According to identical program described in the embodiment 65a, but the oxalic dialdehyde in the step 1 is replaced to 1,2-two (furans-2-yl) ethane-1, the 2-diketone obtains the titled reference compound 238b (through four steps) of yellow solid shape with 28% yield. ¹H NMR：(CD ₃OD)δ8.56(s，1H)，8.21(d，J＝8.6Hz，1H)，8.03(d，J＝8.8Hz，1H)，7.63(s，2H)，7.45(d，J＝1.7Hz，1H)，7.27(d，J＝8.4Hz，1H)，7.13-7.12(m，2H)，6.90(t，J＝4.1Hz，1H)，6.83(d，J＝8.4Hz，1H)，6.69(t，J＝3.9Hz，2H)，6.55-6.56(m，2H)。

Embodiment 65c

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-2,3-two (benzene sulphur-2-yl) quinoxaline-6-carboxylic acid amides (238c)

Step 1-4:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-2,3-two (benzene sulphur-2-yl) quinoxaline-6-carboxylic acid amides (238c)

According to identical program described in the embodiment 65a, but the oxalic dialdehyde in the step 1 is replaced to 1,2-two (benzene sulphur-2-yl) ethane-1, the 2-diketone obtains the titled reference compound 65c (through four steps) of yellow solid shape with 25% yield. ¹H NMR：(DMSO)δ10.09(s，1H)，8.75(d，J＝1.8Hz，1H)，8.32(dd，J＝8.6，2.0Hz，1H)，8.12(d，J＝8.6Hz，1H)，7.84-7.82(m，2H)，7.52(d，J＝2.0Hz，1H)，7.35-7.24(m，5H)，7.14-7.11(m，2H)，7.03(dd，J＝5.0，3.5Hz，1H)，6.81(d，J＝8.4Hz，1H)，5.29(s，2H)。

Embodiment 66

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-(morpholino methyl) benzamide (242)

Scheme 49

Step 1:4-(morpholino methyl) phenylformic acid (240)

In THF (15 milliliters) stirred solution of 4-brooethyl-phenylformic acid (239,1.5 grams, 6.78 mmoles), add morpholine (0.61 milliliter, 6.78 mmoles).Reaction mixture was stirred 10 minutes, then the gained white depositions is leached and throw aside.With filtrate evaporated under reduced pressure and with remaining solid dry titled reference compound 240 (1.15 grams, 75% yield) under vacuum to produce white solid. ¹H NMR：(DMSO)δ：7.89-7.86(m，2H)，7.52(d，J＝8.4Hz，1H)，7.41(d，J＝8.0Hz，1H)，4.12(s，2H)，3.75-3.72(m，1H)，3.56-3.58(m，4H)，3.10-3.07(m，1H)，2.45-2.35(m，2H)。

Step 2:4-(morpholino methyl)-N-(2-nitro-5-(benzene sulphur-2-yl) phenyl) benzamide (241)

In the DCM (10 milliliters) of 240 (221 milligrams, 1.0 mmoles) stirred solution, add oxalyl chloride (2M, 0.5 milliliter, 1.0 mmoles) and DMF (1).With gained solution stirring 20 minutes.Decompression is removed DCM and is added pyridine (10 milliliters), adds 2-nitro-5-benzene sulphur-2-base-aniline (3,220 milligrams, 1.0 mmoles) and NaH (160 milligrams, 4.0 mmoles) then.Reaction mixture was stirred 1 hour, use acetate (2.0 milliliters) quenching then.Pyridine is removed in decompression, and by flash chromatography (eluent EtOAc-hexane (4: 1)) resistates is purified on silica gel, produces the titled reference compound 241 (75 milligrams, 18% yield) of orange solids shape.

Step 3:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-(morpholino methyl) benzamide (242)

According to embodiment 1, identical program described in the step 4,59% yield obtains the titled reference compound 242 of orange solids shape. ¹H NMR：(CDCl ₃)δ8.61-8.59(m，1H)，8.02(br s，1H)，7.86(d，J＝8.0Hz，2H)，7.53(br s，1H)，7.44(d，J＝8.0Hz，2H)，7.33(dd，J＝8.2，2.2Hz，1H)，7.30-7.26(m，1H)，7.17(dd，J＝5.1，1.2Hz，1H)，7.15-7.14(m，1H)，7.01(dd，J＝5.1，3.5Hz，1H)，6.82(d，J＝8.2Hz，1H)，3.73(t，J＝4.7Hz，4H)，3.57(s，2H)，2.47(t，J＝4.3Hz，4H)。

Embodiment 67a

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-5-bromobenzene and furans-2-carboxylic acid amides (245a)

Scheme 50

Step 1:5-bromobenzene and furans-2-carboxylate methyl ester (244a)

In DMF (20 milliliters) stirred solution of 5-bromo-2-hydroxy benzaldehyde (14a, 1.5 grams, 7.46 mmoles), add methyl bromoacetate (8.21 gram mmoles, 0.78 milliliter) and salt of wormwood (4.12 grams, 29.84 mmoles).Reaction mixture is heated and stirred 15 hours at 80 ℃, and water (100 milliliters) quenching is also used ethyl acetate (2 * 50 milliliters).Organic phase through dried over sodium sulfate, is concentrated and by flash chromatography (eluent hexane-EtOAc (9: 1)) resistates purified on silica gel.This produces the 244a (650 milligrams, 35% yield) of white solid. ¹H NMR：(DMSO)δ8.01-8.00(m，1H)，7.73-7.70(m，2H)，7.66-7.63(m，1H)，3.89(s，3H)。

Step 2-4:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-5-bromobenzene and furans-2-carboxylic acid amides (245a)

According to the program described in embodiment 4 steps 3,, obtain the titled reference compound 245a of orange solids shape with 13% yield then according to the program (making solubility promoter) described in embodiment 66 steps 2 and embodiment 1 step 3 and 4 with DMF. ¹H NMR：(DMSO)δ10.01(s，1H)，8.05(d，J＝1.6Hz，1H)，7.69-7.67(m，2H)，7.61(dd，J＝8.8，2.0Hz，1H)，7.44(d，J＝2.2Hz，1H)，7.34(dd，J＝5.1，1.2Hz，1H)，7.30(dd，J＝8.4，2.2Hz，1H)，7.23(dd，J＝3.6，1.2Hz，1H)，7.02(dd，J＝4.9，3.6Hz，1H)，6.79(d，J＝8.4Hz，1H)，5.24(s，2H)。

Embodiment 67b

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-5,6-dimethoxy benzo furans-2-carboxylic acid amides (245b) step 1:2-hydroxyl-4,5-dimethoxy benzaldehyde (243b)

At 2-(benzyloxy)-4, add 10% year palladium charcoal (250 milligrams) in ethyl acetate (100 milliliters) stirred solution of 5-dimethoxy benzaldehyde (246,5.05 grams, 18.6 mmoles).With the flask hydrogen purge, then reaction mixture was stirred 15 hours down in nitrogen atmosphere (1 normal atmosphere), filter through C salt pad, with filtrate evaporated under reduced pressure, and with gained solid dry 243b (3.3 grams, 98% yield) to produce white solid under vacuum. ¹H NMR：(DMSO)δ11.39(s，1H)，9.68(s，1H)，6.90(d，J＝2.5Hz，1H)，6.47(s，1H)，3.94(s，3H)，3.89(s，3H)。

Step 2-5:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-5,6-dimethoxy benzo furans-2-carboxylic acid amides (245b)

According to identical program described in the embodiment 67, but with 2-hydroxyl-4,5-dimethoxy benzaldehyde (243b) replaces 243a, obtains the titled reference compound 245b of light yellow solid shape with 9.1% yield via intermediate 244b. ¹H NMR：(DMSO)δ9.77(s，1H)，7.64(s，1H)，7.51(d，J＝2.1Hz，1H)，7.37(dd，J＝5.1，1.2Hz，1H)，7.33(d，J＝2.2Hz，1H)，7.31-7.30(m，2H)，7.26(dd，J＝3.7，1.2Hz，1H)，7.06(dd，J＝5.1，3.5Hz，1H)，6.83(d，J＝8.5Hz，1H)，5.22(s，2H)，3.88(s，3H)，3.85(s，3H)。

Embodiment 67c

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-5-fluorobenzene and furans-2-carboxylic acid amides (245c) step 1-4:N-(2-amino-5-(benzene sulphur-2-yl) phenyl-5-fluorobenzene and furans-2-carboxylic acid amides (245c)

According to identical program described in the embodiment 67, but replace 243a with 5-fluoro-2-hydroxy benzaldehyde (243c), obtain the titled reference compound 245c of light yellow solid shape with 5.6% yield via intermediate 244c. ¹H NMR：(DMSO)δ9.98(s，1H)，7.75-7.71(m，2H)，7.63(dd，J＝9.0，2.8Hz，1H)，7.44(d，J＝2.0Hz，1H)，7.36-7.29(m，3H)，7.23(dd，J＝3.5，1.1Hz，1H)，7.03(dd，J＝5.1，3.7Hz，1H)，6.79(d，J＝8.4Hz，1H)，5.24(s，2H)。

Embodiment 67d

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4,6-dichloro cumarone-2-carboxylic acid amides (245d) step 1-4:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4,6-dichloro cumarone-2-carboxylic acid amides (245d)

According to identical program described in the embodiment 67, but with 2,4-two chloro-6-hydroxy benzaldehydes (243d) replace 243a, obtain the titled reference compound 245b of light yellow solid shape with 5.9% yield (through four steps) via intermediate 244d. ¹H NMR：(DMSO)δ10.04(s，1H)，7.95(dd，J＝1.6，1.0Hz，1H)，7.85(s，1H)，7.63(d，J＝1.6Hz，1H)，7.43(d，J＝2.2Hz，1H)，7.34(dd，J＝5.1，1.2Hz，1H)，7.30(dd，J＝8.4，2.3Hz，1H)，7.23(dd，J＝3.5，1.2Hz，1H)，7.03(dd，J＝5.1，3.5Hz，1H)，6.78(d，J＝8.3Hz，1H)，5.28(s，2H)。

Embodiment 67e

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4,6-dimethoxy benzo furans-2-carboxylic acid amides (245e) step 1-4:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4,6-dimethoxy benzo furans-2-carboxylic acid amides (245e)

According to identical program described in the embodiment 67, but with 2-hydroxyl-4,6-dimethoxy benzaldehyde (243e) replaces 243a, obtains the titled reference compound 245b of light yellow solid shape with 4.8% yield (through four steps) via intermediate 244e. ¹H NMR：(DMSO)δ9.68(s，1H)，7.64(s，1H)，7.46(d，J＝2.0Hz，1H)，7.32(d，J＝1.0Hz，1H)，7.27(dd，J＝8.2，2.1Hz，1H)，7.22(dd，J＝3.5，1.0Hz，1H)，7.02(dd，J＝4.9，3.5Hz，1H)，6.84(s，1H)，6.78(d，J＝8.4Hz，1H)，6.47(d，J＝1.7Hz，1H)，5.20(s，2H)，3.90(s，3H)，3.83(s，3H)。

Embodiment 67f

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-6-(diethylamino) cumarone-2-carboxylic acid amides (245f)

Step 1-4:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-6-(diethylamino) cumarone-2-carboxylic acid amides (245f)

According to identical program described in the embodiment 67, but replace 243a with 4-(diethylamino)-2-hydroxy benzaldehyde (243f), obtain the titled reference compound 245f of light yellow solid shape with 18.1% yield (through four steps) via intermediate 244f. ¹H NMR：(DMSO)δ9.60(s，1H)，7.51-7.49(m，3H)，7.33(dd，J＝5.1，1.2Hz，1H)，7.27(dd，J＝8.2，2.1Hz，1H)，7.22(dd，J＝3.5，1.2Hz，1H)，7.02(dd，J＝5.0，3.5Hz，1H)，6.80-6.76(m，3H)，5.17(s，2H)，3.40(q，J＝6.8Hz，4H)，1.13(t，J＝7.0Hz，6H)。

Embodiment 68

2-acetylaminohydroxyphenylarsonic acid N-(2-amino-5-(benzene sulphur-2-yl) phenyl) pyrimidine-5-carboxylic acid amides (250)

Scheme 51

Step 1:N-(5-iodine pyrimidine-2-yl) ethanamide (248)

With 5-iodo-pyrimidine-2-base amine (17,1.1 gram, 4.98 mmoles) with diacetyl oxide (14.94 mmoles, 1.41 milliliters) is dissolved in pyridine (20 milliliters) and 110 ℃ of stirrings 48 hours.With reaction mixture cooling and water (50 milliliters) quenching.Add ethyl acetate (100 milliliters) and filter collection gained white depositions, produce the titled reference compound 248 (300 milligrams, 23% yield) of white solid. ¹H NMR：(DMSO)δ10.67(s，1H)，8.85(s，2H)，2.18(s，3H)。

Step 2:2-acetylaminohydroxyphenylarsonic acid N-(2-nitro-5-(benzene sulphur-2-yl) phenyl) pyrimidine-5-carboxylic acid amides (249)

At 248 (265 milligrams, 1.01 mmoles) and Pd (PPh ₃) ₂Cl ₂Add 2-nitro-5-benzene sulphur-2-base-aniline (3,288 milligrams, 1.3 mmoles) and triethylamine (1.5 mmoles, 0.2 milliliter) in DMF (4 milliliters) stirred solution of (35 milligrams, 0.05 mmole).Solution is purged with carbon monoxide and be forced into 65psi,, stirred simultaneously 15 hours then 65 ℃ of heating.Dilute with the solution cooling and with ethyl acetate (20 milliliters).Filter and collect the gained yellow mercury oxide, produce 249 (145 milligrams, 40%) of yellow solid shape. ¹H NMR：(DMSO)δ11.02(s，1H)，10.97(s，1H)，9.15(s，2H)，8.10(d，J＝8.6Hz，1H)，8.03(d，J＝2.0Hz，1H)，7.80-7.76(m，3H)，7.26(dd，J＝4.9，3.7Hz，1H)，2.28(s，3H)。

Step 3:2-acetylaminohydroxyphenylarsonic acid N-(2-amino-5-(benzene sulphur-2-yl) phenyl) pyrimidine-5-carboxylic acid amides (250)

According to embodiment 1, identical program (making solubility promoter with DMF) described in the step 4 obtains titled reference compound 250 with 32% yield. ¹H NMR：(DMSO)δ10.90(s，1H)，9.87(s，1H)，9.16(s，2H)，7.47(d，J＝2.2Hz，1H)，7.36(dd，J＝5.1，1.2Hz，1H)，7.32(dd，J＝8.4，2.2Hz，1H)，7.25(dd，J＝3.5，1.1Hz，1H)，7.05(dd，J＝5.1，3.7Hz，1H)，6.81(d，J＝8.4Hz，1H)，5.33(br s，2H)，2.26(s，3H)。

Embodiment 69a

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-(3,5-dimethyl-1H-pyrazol-1-yl) benzamide (253a)

Scheme 52

Step 1:4-(3,5-dimethyl-1H-pyrazol-1-yl) phenylformic acid (252a)

With 4-hydrazino-benzoic acid (251a, 2 grams, 13.2 mmoles) and 2,4-diacetylmethane (1.35 milliliters, 13.2 mmoles) is dissolved in Virahol (40 milliliters) and refluxed 15 hours.The 252a (2.85 grams, 99% yield) of solvent to produce white solid removed in decompression. ¹H NMR：(DMSO)δ8.04(d，J＝8.6Hz，2H)，7.66(d，J＝8.8Hz，2H)，6.14(s，1H)，2.39(s，3H)，2.22(s，3H)。

Step 2-3:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-(3,5-dimethyl-1H-pyrazol-1-yl) benzamide (253a)

With sour 252a be starting raw material and according to identical program described in embodiment 66 steps 2 and embodiment 1 step 4, (making solubility promoter with DMF) obtains the titled reference compound 253a of white solid with 14% yield (through two steps). ¹H NMR：(DMSO)δ9.81(s，1H)，8.09(d，J＝8.4Hz，2H)，7.64(d，J＝8.6Hz，2H)，7.46(d，J＝2.0Hz，1H)，7.33(dd，J＝5.1，1.2Hz，1H)，7.28(dd，J＝8.2，2.2Hz，1H)，7.23(dd，J＝3.5，1.0Hz，1H)，7.03(dd，J＝5.1，3.5Hz，1H)，6.80(d，J＝8.3Hz，1H)，6.12(s，1H)，5.19(s，2H)，2.38(s，3H)，2.20(s，3H)。

Embodiment 69b

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-(2,5-dimethyl-1H-pyrazol-1-yl) benzamide (253b)

Step 1:4-(3,5-dimethyl-1H-pyrazol-1-yl) phenylformic acid (252b)

With 4-benzaminic acid (251b, 1.5 grams, 10.9 mmoles) and 2,5-hexanedione (1.28 milliliters, 10.9 mmoles) is dissolved in Virahol (40 milliliters) and refluxed 15 hours.Solvent is removed in decompression, produces the 252b (2.35 grams, 99% yield) of white solid. ¹H NMR：(DMSO)δ8.02(d，J＝8.6Hz，2H)，7.36(d，J＝8.6Hz，2H)，5.81(s，2H)，1.98(s，6H)。

Step 2-3:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-(2,5-dimethyl-1H-pyrazol-1-yl) benzamide (253b)

With sour 252b be starting raw material and according to identical program described in embodiment 66 steps 2 and embodiment 1 step 4, (making solubility promoter with DMF) is to obtain the titled reference compound 253b of beige solid shapes through two step 28% yields. ¹H NMR：(DMSO)δ9.85(s，1H)，8.14(d，J＝8.4Hz，2H)，7.49(d，J＝2.0Hz，1H)，7.44(d，J＝8.4Hz，2H)，7.37(dd，J＝5.1，1.2Hz，1H)，7.32(dd，J＝8.5，2.4Hz，1H)，7.26(dd，J＝3.6，1.0Hz，1H)，7.07(dd，J＝5.1，3.5Hz，1H)，6.83(d，J＝8.4Hz，1H)，5.86(s，2H)，5.24(s，2H)，2.05(s，6H)。

Embodiment 70a

N-(2-amino-5-(benzene sulphur-2-yl) phenyl) benzo [d] [1,3] dioxole-5-carboxylic acid amides (256a)

Scheme 53

Step 1: benzo [d] [1,3] dioxole-5-carboxylic acid (255a)

At benzo [d] [1,3] dioxole-5-formaldehyde (254a, 2 grams, 13.3 mmoles), Na ₂H ₂PO ₄Add Textone (7.19 grams, 79.9 mmoles) in (6.38 grams, 53.2 mmoles) and the stirred solution of 2-methyl-2-butene (9.85 milliliters, 93.1 mmoles) in t-BuOH (41 milliliters) and water (17 milliliters).The gained reaction mixture was at room temperature stirred 2 hours.Add entry (100 milliliters) and 1M HCl (25 milliliters) and extract this mixture with EtOAc (2 * 50 milliliters).Organic phase is separated,, with dried over sodium sulfate and reduction vaporization.With the gained solid titled reference compound 255a (1.9 grams, 86% yield) of EtOAc (20 milliliters) development to produce white solid. ¹H NMR：(DMSO)δ12.72(br s，1H)，7.53-7.50(m，1H)，7.34-7.32(m，1H)，6.99-6.95(m，1H)，6.10(s，2H)。

Step 2-3:N-(2-amino-5-(benzene sulphur-2-yl) phenyl) benzo [d] [1,3] dioxole-5-carboxylic acid amides (256a)

According to embodiment 1, step 3 and program (making solubility promoter with DMF) identical described in 4 obtain the titled reference compound 256a of light orange solid state with 22% yield (through two steps). ¹H NMR：(DMSO)δ9.59(s，1H)，7.60(dd，J＝8.0，1.6Hz，1H)，7.55(d，J＝1.6Hz，1H)，7.43(d，J＝2.2Hz，1H)，7.35(dd，J＝4.9，0.6Hz，1H)，7.29(dd，J＝8.2，2.2Hz，1H)，7.24(dd，J＝3.7，1.0Hz，1H)，7.06-7.04(m，2H)，6.79(d，J＝8.2Hz，1H)，6.13(s，2H)，5.15(br s，2H)。

Embodiment 70b

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-2,3-dihydrobenzo [b] [1,4] dioxine-6-carboxylic acid amides (256b)

Step 1-3:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-2,3-dihydrobenzo [b] [1,4] dioxine-6-carboxylic acid amides (256b)

According to embodiment 70a step 1 and embodiment 1, step 3 and program (making solubility promoter with DMF) identical described in 4 obtain the titled reference compound 256b of orange solids shape with 38% yield (through three steps). ¹H NMR：(DMSO)δ9.57(s，1H)，7.54(d，J＝2.1Hz，1H)，7.51(dd，J＝8.4，2.1Hz，1H)，7.42(d，J＝2.1Hz，1H)，7.33(dd，J＝5.1，1.2Hz，1H)，7.26(dd，J＝8.4，2.3Hz，1H)，7.22(dd，J＝3.5，1.2Hz，1H)，7.02(dd，J＝5.1，3.5Hz，1H)，6.95(d，J＝8.2Hz，1H)，6.79(d，J＝8.4Hz，1H)，5.11(s，2H)，4.31-4.28(m，4H)。

Embodiment 70c

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-7-methoxyl group benzo [d] [1,3] dioxole-5-carboxylic acid amides (256c)

Step 1-3:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-7-methoxyl group benzo [d] [1,3] dioxole-5-carboxylic acid amides (256c)

According to embodiment 70a step 1 and embodiment 1, step 3 and program (making solubility promoter with DMF) identical described in 4 obtain the titled reference compound 256c of orange solids shape with 20% yield (through three steps). ¹H NMR：(DMSO)δ9.60(s，1H)，7.41(d，J＝2.2Hz，1H)，7.36(d，J＝1.4Hz，1H)，7.34(dd，J＝5.2，1.2Hz，1H)，7.30-7.26(m，2H)，7.23(dd，J＝3.6，1.2Hz，1H)，7.04(dd，J＝4.9，3.5Hz，1H)，6.79(d，J＝8.4Hz，1H)，6.10(s，2H)，5.14(br s，2H)，3.91(s，3H)。

Embodiment 71a

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-3,4-dimethoxy benzamide (258a)

Scheme 54

Step 1-2:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-3,4-dimethoxy benzamide (258a)

According to embodiment 1, step 3 and program (making solubility promoter with DMF) identical described in 4, but compound 4 is replaced to compound 257a obtain the titled reference compound 258a of beige solid shape with 56% yield. ¹H NMR：(DMSO)δ9.64(s，1H)，7.63(dd，J＝8.2，2.0Hz，1H)，7.57(d，J＝2.2Hz，1H)，7.42(d，J＝2.2Hz，1H)，7.33(dd，J＝5.1，1.2Hz，1H)，7.28(dd，J＝8.3，2.3Hz，1H)，7.23(dd，J＝3.5，1.2Hz，1H)，7.05(d，J＝8.6Hz，1H)，7.02(dd，J＝5.1，3.6Hz，1H)，6.79(d，J＝8.3Hz，1H)，5.12(br s，2H)，3.83(s，3H)，3.82(s，3H)。

Embodiment 71b

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-1H-benzo [d] [1,2,3] triazole-5-carboxylic acid amides (258b) step 1-2:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-1H-benzo [d] [1,2,3] triazole-5-carboxylic acid amides (28b)

According to embodiment 1, step 3 and program (making solubility promoter with DMF) identical described in 4, but compound 4 is replaced to compound 257b obtain the titled reference compound 258b of orange solids shape with 16% yield (through two steps). ¹H NMR：(DMSO)δ9.90(s，1H)，8.66(s，1H)，8.05(d，J＝9.8Hz，1H)，7.96(d，J＝8.6Hz，1H)，7.49(d，J＝2.0Hz，1H)，7.33(dd，J＝5.1，1.2Hz，1H)，7.30(dd，J＝8.2，2.2Hz，1H)，7.23(dd，J＝3.5，1.1Hz，1H)，7.03(dd，J＝5.0，3.7Hz，1H)，6.81(d，J＝8.4Hz，1H)，5.23(br s，2H)。

Embodiment 71c

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-2-(pyridin-4-yl) thiazole-4-carboxylic acid amides (258c) step 1-2:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-2-(pyridin-4-yl) thiazole-4-carboxylic acid amides (258c)

According to embodiment 1, step 3 and program (making solubility promoter with DMF) identical described in 4, but compound 4 is replaced to compound 257c obtain the titled reference compound 258c of pale solid shape with 28% yield (through two steps). ¹H NMR：(DMSO)δ9.94(s，1H)，8.78(m，3H)，8.11(dd，J＝4.3，1.6Hz，2H)，7.64(d，J＝2.2Hz，1H)，7.38(dd，J＝5.1，1.0Hz，1H)，7.33(dd，J＝8.2，2.1Hz，1H)，7.28(dd，J＝3.7，1.2Hz，1H)，7.07(dd，J＝5.1，3.7Hz，1H)，6.86(d，J＝8.4Hz，1H)，5.23(s，2H)。

Embodiment 71d

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-1H-benzo [d] imidazoles-5-carboxylic acid amides (28d) step 1-2:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-1H-benzo [d] imidazoles-5-carboxylic acid amides (258d)

According to embodiment 1, step 3 and program (making solubility promoter with DMF) identical described in 4, but compound 4 is replaced to compound 257d obtain the titled reference compound 258d of white solid with 29% yield (through two steps). ¹H NMR：(DMSO)δ9.72(s，1H)，8.34(s，2H)，7.87-7.85(m，2H)，7.48(d，J＝1.8Hz，1H)，7.34(dd，J＝5.1，1.0Hz，1H)，7.28(dd，J＝8.1，5.2Hz，1H)，7.23(dd，J＝3.5，1.2Hz，1H)，7.03(dd，J＝5.1，3.6Hz，1H)，6.80(d，J＝8.4Hz，1H)，5.15(s，2H)。

Embodiment 71e

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-2-naphthoamide (258e) step 1-2:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-2-naphthoamide (258e)

According to embodiment 1, step 3 and program (making solubility promoter with DMF) identical described in 4, but compound 4 is replaced to compound 257e obtain the titled reference compound 258e of yellow solid shape with 15% yield (through two steps). ¹H NMR：(DMSO)δ9.90(s，1H)，8.62(s，1H)，8.07-7.98(m，4H)，7.63-7.60(m，2H)，7.51(d，J＝2.1Hz，1H)，7.34(dd，J＝5.1，1.2Hz，1H)，7.30(dd，J＝8.4，2.2Hz，1H)，7.24(dd，J＝3.5，1.2Hz，1H)，7.04(dd，J＝5.1，3.7Hz，1H)，6.81(d，J＝8.4Hz，1H)，5.21(s，2H)。

Embodiment 71f

N-(2-amino-5-(benzene sulphur-2-yl) phenyl) benzo [b] thiophene-2-carboxylic acid amides (258f) step 1-2:N-(2-amino-5-(benzene sulphur-2-yl) phenyl) benzo [b] thiophene-2-carboxylic acid amides (258f)

According to embodiment 1, step 3 and program (making solubility promoter with DMF) identical described in 4, but compound 4 is replaced to compound 257f obtain the titled reference compound 258f of brown solid shape with 12% yield (through two steps). ¹H NMR：(DMSO)δ9.99(s，1H)，8.32(s，1H)，8.03(dd，J＝8.4，2.0Hz，1H)，7.97(dd，J＝6.6，2.7Hz，1H)，7.49-7.43(m，3H)，7.33(dd，J＝5.0，1.1Hz，1H)，7.30(dd，J＝8.2，2.2Hz，1H)，7.24(dd，J＝3.6，1.0Hz，1H)，7.03(dd，J＝5.2，3.7Hz，1H)，6.80(d，J＝8.4Hz，1H)，5.24(s，2H)。

Embodiment 71g

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-3,4-dihydro-2H-benzo [b] [1,4] dioxepine-7-carboxylic acid amides (258g)

Step 1-2:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-3,4-dihydro-2H-benzo [b] [1,4] dioxepine-7-carboxylic acid amides (258g)

According to embodiment 1, step 3 and program (making solubility promoter with DMF) identical described in 4, but compound 4 is replaced to compound 257g obtain the titled reference compound 258g of orange solids shape with 15% yield (through two steps). ¹H NMR：(DMSO)δ9.61(s，1H)，7.63(d，J＝2.2Hz，1H)，7.59(dd，J＝8.4，2.2Hz，1H)，7.41(d，J＝2.0Hz，1H)，7.33(d，J＝5.1Hz，1H)，7.27(dd，J＝8.2，2.2Hz，1H)，7.22(dd，J＝3.5，1.0Hz，1H)，7.06-7.01(m，2H)，6.78(d，J＝8.4Hz，1H)，5.12(br s，2H)，4.22-4.17(m，4H)，2.16(quintet，J＝5.5Hz，2H)。

Embodiment 72a

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-5-bromobenzene is [b] thiophene-2-carboxylic acid amides (261a) also

Scheme 55

Step 1:5-bromobenzene is [b] thiophene-2-carboxylic acid methyl esters (260a) also

In DMF (20 milliliters) stirred solution of 259a (2 grams, 9.90 mmoles), add thioglycolic acid methyl esters (10.9 mmoles, 0.97 milliliter) and salt of wormwood (5.47 grams, 39.6 mmoles).The gained mixture was stirred 15 hours at 60 ℃.DMF is removed in decompression, adds entry (50 milliliters) and extracts mixture with ethyl acetate (2 * 40 milliliters).Separate organic phase and through dried over sodium sulfate, it is also dry under vacuum with the gained solid that solvent is removed in decompression.This produces the 260a (1.3 grams, 49% yield) of white solid. ¹H NMR：(DMSO)δ8.22(d，J＝2.0Hz，2H)，8.11(s，1H)，8.00(d，J＝8.0Hz，1H)，7.62(dd，J＝8.6，2.0Hz，1H)，3.88(s，3H)。

Step 2-4:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-5-bromobenzene is [b] thiophene-2-carboxylic acid amides (261a) also

According to identical program described in embodiment 4 steps 3, then according to the program (making solubility promoter) described in embodiment 66 steps 2 and embodiment 1 step 4, obtain titled reference compound 261a with 32% yield (through three steps) with DMF. ¹H NMR：(DMSO)δ10.08(s，1H)，8.27(s，1H)，8.23(d，J＝1.8Hz，1H)，8.02(d，J＝8.6Hz，1H)，7.60(dd，J＝8.6，2.0Hz，1H)，7.43(d，J＝2.3Hz，1H)，7.34(dd，J＝5.0，1.2Hz，1H)，7.30(dd，J＝8.2，2.2Hz，1H)，7.24(dd，J＝3.5，1.2Hz，1H)，7.03(dd，J＝5.1，3.5Hz，1H)，6.79(d，J＝8.2Hz，1H)，5.25(s，2H)。

Embodiment 72b

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-5,6-dimethoxy benzo [b] thiophene-2-carboxylic acid amides (261b)

Step 1-4:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-5,6-dimethoxy benzo [b] thiophene-2-carboxylic acid amides (261b)

According to identical program described in the embodiment 72a step 1, but compound 259a is replaced to compound 259b, according to the program (making solubility promoter) described in embodiment 4 steps 3 and embodiment 1 step 3 and 4, obtain the titled reference compound 261b of yellow solid shape with 20% yield (through four steps) then with DMF. ¹H NMR：(DMSO)δ9.87(s，1H)，8.14(s，1H)，7.58(s，1H)，7.44(d，J＝2.2Hz，1H)，7.41(s，1H)，7.34(dd，J＝5.1，1.1Hz，1H)，7.29(dd，J＝8.4，2.3Hz，1H)，7.03(dd，J＝4.9，3.5Hz，1H)，6.80(d，J＝8.4Hz，1H)，5.20(s，2H)，3.85(s，3H)，3.84(s，3H)。

Embodiment 73

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-5-(pyridin-3-yl) benzo [b] thiophene-2-carboxylic acid amides (262)

Scheme 56

Step 1:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-5-(pyridin-3-yl) benzo [b] thiophene-2-carboxylic acid amides (262)

Add Pd (PPh in the stirred solution at 261a (120 milligrams, 0.26 mmole) and pyridin-3-yl-3-boric acid (123 milligrams, 0.34 mmole) in 2: 1 mixtures (9 milliliters) at DME-water ₃) ₄(22 milligrams, 0.018 mmole), three adjacent toluene phosphines (6 milligrams, 0.018 mmole) and salt of wormwood (109 milligrams, 0.79 mmole).With this solution N ₂Outgased 5 minutes, then 80 ℃ of heating 15 hours.Add entry (50 milliliters) and extract mixture with ethyl acetate (2 * 40 milliliters).Separate organic layer, with dried over mgso and reduction vaporization.On silica gel, resistates is purified by flash chromatography (eluent ethyl acetate).With DCM development 15 minutes, produce 262 (80 milligrams, 67% yield) of white solid subsequently. ¹H NMR：(DMSO)δ10.09(s，1H)，8.99(dd，J＝2.3，0.8Hz，1H)，8.58(dd，J＝4.7，1.6Hz，1H)，8.38(s，1H)，8.33(d，J＝1.4Hz，1H)，8.17(ddd，J＝9.6，3.9，1.8Hz，1H)，7.83(dd，J＝8.5，1.8Hz，1H)，7.53-7.50(m，2H)，7.46(d，J＝2.2Hz，1H)，7.34(dd，J＝5.1，1.2Hz，1H)，7.31(dd，J＝8.2，2.2Hz，1H)，7.25(dd，J＝3.5，1.2Hz，1H)，7.03(dd，J＝5.1，3.7Hz，1H)，6.81(d，J＝8.4Hz，1H)，5.74(s，2H)。

Embodiment 74

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4H-benzo [d] [1,3] dioxine-6-carboxylic acid amides (264)

Scheme 57

Step 1.4H-benzo [1,3] dioxine-6-carboxylate methyl ester (263)

According to Monatsh.Chem., 102; 1971; Program described in the 946-950 is that starting raw material prepares compound 263 with the 4-methyl hydroxybenzoate.

Step 2-4:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4H-benzo [d] [1,3] dioxine-6-carboxylic acid amides (264)

According to identical program described in embodiment 4 steps 3, but compound 21 is replaced to compound 263, according to embodiment 1, the program described in the step 3 and 4 (making solubility promoter with DMF) is with the titled reference compound 264 of 37% yield (through three steps) acquisition pale solid shape then. ¹H NMR：(DMSO)δ9.60(s，1H)，7.82(dd，J＝8.6，2.2Hz，1H)，7.74(d，J＝2.1Hz，1H)，7.41(d，J＝2.1Hz，1H)，7.33(dd，J＝5.1，1.2Hz，1H)，7.26(dd，J＝8.4，2.3Hz，1H)，7.21(dd，J＝3.5，1.2Hz，1H)，7.02(dd，J＝5.1，3.8Hz，1H)，6.94(d，J＝8.6Hz，1H)，6.77(d，J＝8.4Hz，1H)，5.32(s，2H)，5.11(s，2H)，4.94(s，2H)。

Embodiment 75

6-(2-morpholino oxyethyl group)-N-(2-amino-5-(benzene sulphur-2-yl) phenyl) cumarone-2-carboxylic acid amides (269)

Scheme 58

Step 1:6-(benzyloxy) cumarone-2-carboxylate methyl ester (266)

According to identical program described in the embodiment 67a step 1, but compound 243a is replaced to compound 265, obtain the titled reference compound 266 of white solid with 49% yield. ¹HNMR：(DMSO)δ7.68-7.64(m，2H)，7.49-7.45(m，2H)，7.42-7.31(m，4H)，7.07-7.04(m，1H)，5.18(s，2H)，3.85(s，2H)。

Step 2:6-hydroxyl benzofuran-2-carboxylate methyl ester (267)

In methyl alcohol (20 milliliters) stirred solution of 266 (1.2 grams, 4.26 mmoles), add 10% year palladium charcoal (250 milligrams).Flask is used hydrogen purge 1 minute, will be reflected at then under the nitrogen atmosphere and stir 15 hours.Palladium is filtered through C salt pad, reduction vaporization filtrate, and the gained solid is dry under vacuum, 267 (700 milligrams, 86%) of generation white solid. ¹H NMR：(DMSO)δ10.07(s，1H)，7.63(s，1H)，7.56(d，J＝8.0Hz，1H)，6.98(s，1H)，6.84(d，J＝9.0Hz，1H)，3.84(s，3H)。

Step 3:6-(2-morpholino oxyethyl group) cumarone-2-carboxylate methyl ester (268)

In the stirred solution of (20 milliliters) in 267 (650 milligrams, 3.39 mmoles) 1: 1 mixture, add 4-(2-chloroethyl) morpholine (630 milligrams, 3.39 mmoles) and salt of wormwood (937 milligrams, 6.78 mmoles) at DMF-acetone.Reaction mixture was stirred 72 hours at 60 ℃.Decompression is removed solvent and add entry (50 milliliters) in resistates.Add 2M sodium carbonate solution (20 milliliters) and use ethyl acetate (2 * 40 milliliters) to extract gained solution.Separate organic phase, remove solvent through dried over sodium sulfate and decompression.On silica gel, (with 1: 1 ethyl acetate-hexane of certain gradient, use ethyl acetate then, use 9: 1 ethyl acetate-methanol-eluted fractions then by flash chromatography.This produces clarification buttery 268 (760 milligrams, 73% yield). ¹H NMR：(DMSO)δ7.67-7.63(m，2H)，7.32(s，1H)，6.98(d，J＝8.5Hz，1H)，4.14-4.16(m，2H)，3.85(s，3H)，3.57-3.55(m，4H)，2.88-2.86(m，2H)，2.72-2.70(m，4H)。

Step 4-6:6-(2-morpholino oxyethyl group)-N-(2-amino-5-(benzene sulphur-2-yl) phenyl) cumarone-2-carboxylic acid amides (269)

According to identical program described in embodiment 4 steps 3, but compound 21 is replaced to compound 268, according to embodiment 1, the program described in the step 3 and 4 is with the titled reference compound 269 of 1.3% yield (through three steps) acquisition pale solid shape then. ¹H NMR：(DMSO)δ7.21(d，1H)，7.14(d，2H)，6.95(d，1H)，6.84-6.79(m，3H)，6.62-6.57(m，2H)，6.49(d，1H)，3.80(m，2H)，3.30(m，4H)，2.46(m，2H)，2.21(m，4H)。

Embodiment 76

N-(2-amino-5-(3H-1,2,3-triazole-4-yl) phenyl)-4-methoxy benzamide (273)

Scheme 59

Step 1:5-(2-(trimethyl silyl) ethynyl)-2-N-methyl-p-nitroaniline (270)

According to embodiment 15, the program described in the step 1 (scheme 13), but at 80 ℃ but not at room temperature react, obtain titled reference compound 270 with 68% yield. ¹H NMR：(400.2MHz，CDCl ₃)δ(ppm)：8.06(d，J＝8.8Hz，1H)；6.92(d，J＝1.6Hz；1H)；6.76(dd，J＝1.6，8.8Hz；1H)；5.70(bs，2H)，0.29(s，9H)。MS：calc：234.3；found：235.1(M+H)。

Step 2:2-nitro-5-(3H-1,2,3-triazole-4-yl) aniline (271)

Use and embodiment 4, identical program described in the step 3 (scheme 3), but compound 21 is replaced to compound 270, thus make the trimethyl silyl cracking.According to embodiment 48, the program described in the step 2 (scheme 26), but be to use m-xylene to replace toluene as solvent, thus this crude product is used for next cycloaddition step to obtain titled reference compound 271 (at two step 9% yields).MS：calc：205.2；found：206.1(M+H)。Step 3:4-methoxyl group-N-(2-nitro-5-(3H-1,2,3-triazole-4-yl) phenyl) benzamide (272)

According to embodiment 43, identical program in the step 4 (scheme 31), but compound 150 is replaced to compound 271 obtains oily titled reference compound 272 and promptly is used for next step without further purification.

Step 4:N-(2-amino-5-(3H-1,2,3-triazole-4-yl) phenyl)-4-methoxy benzamide (273)

According to embodiment 48, identical program in the step 3 (scheme 36), but compound 171 replaced to compound 272 and use ethyl acetate to replace methyl alcohol to make solvent obtains titled reference compound 273 with 25% yield (through two steps). ¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.62(s，1H)；8.08(bs，2H)；7.97(d，J＝8.5Hz；2H)；7.62(s，1H)；7.45(d，J＝8.2Hz；1H)；7.03(d，J＝8.5Hz；2H)；6.82(d，J＝8.2Hz；1H)；5.11(bs，2H)；3.83(s，3H)。MS：calc：309.3；found：310.1(M+H)。

Embodiment 77

N-(2-amino-5-(1H-tetrazolium-5-yl) phenyl)-4-methoxy benzamide 277

Scheme 60

Step 1:3-amino-4-nitrobenzonitrile (274)

In the dark, under nitrogen and room temperature, with (801 milligrams of aryl bromides 2; 3.7 mmole) and (570 milligrams of zinc cyanides; 4.85 mmole; 1.3 equivalent) suspension in degassing dimethyl formamide (15 milliliters) stirred 45 minutes, used four (triphenyl phosphine) palladium (0) (310 milligrams, 1.6 mmoles) to handle then.This mixture was stirred 18 hours at 90 ℃; Filter through C salt pad, concentrating under reduced pressure is also purified to produce titled reference compound 274 (380 milligrams, 63% yield) by flash chromatography (eluent EtOAc-hexane (1: 1)) on silica gel. ¹H NMR：(400.2MHz，CDCl ₃)δ(ppm)：8.22(d，J＝8.6Hz，1H)；7.19(d，J＝1.8Hz；1H)；6.95(dd，J＝1.8，8.6Hz；1H)；6.27(bs，2H)。MS：calc：163.1；found：164.1(M+H)。

Step 2:2-nitro-5-(1H-tetrazolium-5-yl) aniline (275)

According to embodiment 48, the program described in the step 2 (scheme 35), but be to use m-xylene to replace toluene to make solvent, obtain titled reference compound 275 with 79% yield. ¹H NMR：(400.2MHz，CDCl ₃)δ(ppm)：8.21(d，J＝9.0Hz，1H)；7.74(d，J＝1.6Hz；1H)；7.50(dd，J＝1.6，9.0Hz；1H)；6.29(bs，2H)。MS：calc：206.2；found：207.1(M+H)。

Step 3:4-methoxyl group-N-(2-nitro-5-(1H-tetrazolium-5-yl) phenyl) benzamide (276)

According to embodiment 43, identical program in the step 4 (scheme 31), but compound 150 is replaced to compound 275 obtains oily titled reference compound 276 and is used for next step without further purifying.

Step 4:N-(2-amino-5-(1H-tetrazolium-5-yl) phenyl)-4-methoxy benzamide (277)

According to embodiment 48, identical program described in the step 3 (scheme 36), but compound 171 is replaced to compound 276 obtains titled reference compound 277 with 14% yield (through two steps). ¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.63(s，1H)；7.98(d，J＝8.8Hz；2H)；7.81(d，J＝2.0Hz；1H)；7.61(dd；J＝2.0，8.4Hz；1H)；7.04(d，J＝8.8Hz；2H)；6.85(d，J＝8.4Hz；1H)；3.85(s，3H)。MS：calc：310.3；found：311.1(M+H)。

Embodiment 78

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-1-methyl isophthalic acid H-benzo [d] imidazoles-5-carboxylic acid amides (283)

Scheme 61

Step 1:4-(methylamino-)-3-nitrobenzoic acid (279)

At room temperature, (11 milliliters of 40% aqueous solution that in the stirred suspension of 4-fluoro-3-nitrobenzoic acid (278,6.1 gram, 32.9 mmoles) in DMF (20 milliliters), slowly add methylamine; 128 mmoles) (with any other primary amine).After finishing interpolation, mixture was stirred 60 minutes under identical temperature; Concentrate in a vacuum, and be suspended in 5% KHSO ₄In (final pH=2).This suspension stirring is spent the night; Filter the collecting precipitation thing, wash with water, then with the ether washing, dry to obtain titled reference compound 279 (6.5 grams; 100% yield). ¹H NMR：(400.2MHz，DMSO)δ(ppm)：12.8(bs；1H)，8.59(d，J＝2.0Hz；1H)；8.55(q，J＝5.0Hz；1H)；7.96(dd，J＝2.0，9.1Hz；1H)；7.04(d，J＝9.1Hz；1H)；3.00(d，J＝5.0Hz；3H)。MS：calc：196.2；found：197.1(M+H)。

P341

Step 2:3-amino-4-(methylamino-) phenylformic acid (280)

According to embodiment 48, identical program in the step 3 (scheme 36), but compound 171 is replaced to compound 279 obtains titled reference compound with 81% yield. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：7.48(d，J＝8.6Hz；1H)；7.42(s；1H)；7.54(d，J＝8.6Hz；1H)；3.57(bs；＞4H)；2.80(s；3H)。MS：calc：166.1；found：167.1(M+H)。

Step 3:1-methyl isophthalic acid H-benzo [d] imidazole-5-carboxylic acid (281)

At 85 ℃, with (678 milligrams of diamino compounds 280; 4.1 mmole) (or Ortho-Aminophenol) is at 50% HCO in water (if use ortho ester, then be anhydrous solvent) ₂Stirred 13 hours among the H (with any other carboxylic acid and ortho ester), concentrate, water-soluble again and freeze-drying is to provide titled reference compound 281 (712 milligrams, 99% yield) with resistates. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：12.9(bs；1H)；8.80(s；1H)；8.26(d，J＝1.6Hz；1H)；7.96(dd，J＝1.6，8.6Hz；1H)；7.79(d，J＝8.6Hz；1H)；3.95(s，3H)。MS：calc：176.2；found：177.1(M+H)。

Step 4:1-methyl-N-(2-nitro-5-(benzene sulphur-2-yl) phenyl)-1H-benzo [d] imidazoles-5-carboxylic acid amides (282)

According to embodiment 1, identical program described in the step 3 (scheme 1), but compound 4 is replaced to compound 281 obtains titled reference compound 282 with 56% yield. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：10.9(bs，1H)；8.35(bs，2H)，8.24(d，J＝2.1Hz，1H)，8.01(d，J＝8.6Hz，1H)，7.91(dd；J＝1.6，8.4Hz；1H)；7.75(m，3H)，7.70(dd；J＝2.1，8.6Hz；1H)；7.23(dd；J＝3.7，4.9Hz；1H)；3.91(s，3H)。MS：calc：378.4；found：379.1(M+H)。

Step 5:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-1-methyl isophthalic acid H-benzo [d] imidazoles-5-carboxylic acid amides (283)

According to embodiment 1, identical program described in the step 4 (scheme 1), but compound 5 is replaced to compound 282 obtains titled reference compound 283 with 99% yield. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.75(s，1H)，8.38(d，J＝1.0Hz，1H)，8.34(s，1H)，7.95(dd；J＝1.4，8.4Hz；1H)；7.68(d，J＝8.4Hz，1H)，7.50(d；J＝2.2Hz；1H)；7.34(dd；J＝1.0，5.0Hz；1H)；7.28(dd；J＝2.2，8.4Hz；1H)；7.24(dd；J＝1.4，3.6Hz；1H)；7.04(dd；J＝3.6，5.0Hz；1H)；6.81(d；J＝8.4Hz；1H)；3.90(s，3H)。MS：calc：348.4；found：349.1(M+H)。

Embodiment 79

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-1-methyl isophthalic acid H-benzo [d] [1,2,3] triazole-5-carboxylic acid amides (286)

Scheme 62

Step 1:1-methyl isophthalic acid H-benzo [d] [1,2,3] triazole-5-carboxylic acid (284)

At 0 ℃ diamines 280 (1.08 grams; 6.48 mmole) in (with any other adjacent arylene diamines) stirred suspension in water (25 milliliters), dropwise add dense HCl (5.4 milliliters), slowly add NaNO then ₂(643 milligrams; 9.3 water mmole) (10 milliliters) solution.Reaction mixture was stirred 2 hours at 0 ℃, be warming up to 10 ℃ through 4 hours then; Water (30 milliliters) solution neutralization (final pH=6) with KOH (5.6 gram); Concentrate and purify (post aquasil C-18, elutriant 5% to the 95% MeOH aqueous solution) with rp mode, so that (211 milligrams of titled reference compounds 284 to be provided by preparation HPLC; 18% yield). ¹H NMR：(400.2MHz，DMSO)δ(ppm)：8.35(s；1H)；8.08(dd，J＝1.4，8.6Hz；1H)；7.75(d，J＝1.4Hz；1H)；4.03(s，3H)。MS：calc：177.1；found：178.1(M+H)。

Step 2:1-methyl-N-(2-nitro-5-(benzene sulphur-2-yl) phenyl)-1H-benzo [d] [1,2,3] triazole-5-carboxylic acid amides (285)

According to embodiment 1, identical program described in the step 3 (scheme 1), but compound 4 is replaced to compound 284 obtains titled reference compound 285 with 56% yield. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：11.0(bs，1H)；8.72(bs，1H)，8.12(m，2H)，8.07(d，J＝8.7Hz，1H)，8.01(d，J＝8.7Hz，1H)，7.73(m，3H)，7.23(t；J＝4.7Hz；1H)；4.38(s，3H)。MS：calc：379.4；found：380.0(M+H)。

Step 3:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-1-methyl isophthalic acid H-benzo [d] [1,2,3] triazole-5-carboxylic acid amides (286)

According to embodiment 1, identical program described in the step 4 (scheme 1), but compound 5 is replaced to compound 285 obtains titled reference compound 286 with 99% yield. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.88(s，1H)；8.75(s，1H)，8.15(dd；J＝1.0，8.6Hz；1H)；7.95(dd，J＝1.0，8.6Hz，1H)，7.49(d，J＝2.0Hz，1H)，7.34(dd；J＝1.2，5.1Hz；1H)；7.30(dd；J＝2.0，8.3Hz；1H)；7.24(dd；J＝1.2，3.5Hz；1H)；7.04(dd；J＝3.5，5.1Hz；1H)；6.81(d；J＝8.3Hz；1H)；5.24(bs，2H)；4.37(s，3H)。MS：calc：349.4；found：350.1(M+H)。

Embodiment 80

N-(2-amino-5-(benzene sulphur-2-yl) phenyl) H-imidazo [1,2-a] pyridine-6-carboxylic acid amides (291)

Scheme 63

Step 1:H-imidazo [1,2-a] pyridine-6-carboxylate methyl ester (288)

With 2-(brooethyl)-1, the THF (3 milliliters) of 3-dioxolane (0.18 milliliter, 1.67 mmoles) and water (0.2 milliliter) solution are handled with dense HCl (3) and were stirred 50 minutes at 88 ℃.Solution is cooled to 0 ℃ and transfer to and contain (287,204 milligrams of 2-amino-5-methoxycarbonyl pyridine; 1.34 Bu mmole), ₂SnCl ₂(134 milligrams; 0.40 mmole) and NaHCO ₃In the phial of (410 milligrams), and at room temperature stirred 2 days.Reaction mixture is washed with ethyl acetate (60 milliliters) dilution and with saturated sodium-chloride water solution.With organic layer drying (MgSO ₄), filter and concentrate.After using preparation TLC (dichloromethane solution of eluent 50% ethyl acetate) that the resistates chromatogram is purified on the silica gel, obtain titled reference compound 288 (74 milligrams, 31% yield). ¹H NMR：(500.7MHz，CDCl ₃)δ(ppm)：9.00(s，1H)；7.80(m，4H)；4.00(s，3H)。MS：calc：176.1；found：177.1(M+H)。

Step 2:H-imidazo [1,2-a] pyridine-6-carboxylic acid (289)

According to embodiment 46, identical program described in the step 2 (scheme 34), but compound 162 is replaced to compound 288 obtains titled reference compound 289 with 99% yield.MS：calc：162.1；found：163.1(M+H)。

Step 3:N-(2-nitro-5-(benzene sulphur-2-yl) phenyl) H-imidazo [1,2-a] pyridine-6-carboxylic acid amides (290)

According to embodiment 1, identical program described in the step 3 (scheme 1), but compound 4 is replaced to compound 289 obtains titled reference compound 290 with 22% yield.MS：calc：364.2；found：365.2(M+H)。

Step 4:N-(2-amino-5-(benzene sulphur-2-yl) phenyl) H-imidazo [1,2-a] pyridine-6-carboxylic acid amides (291)

According to embodiment 1, identical program described in the step 4 (scheme 1), but compound 5 is replaced to compound 290 obtains titled reference compound 291 with 45% yield. ¹H NMR(400.2MHz，DMSO)δ(ppm)：9.19(s，1H)；7.99(s，1H)；7.86(d；J＝8.5Hz；1H)；7.67(s，1H)；7.64(d；J＝8.5Hz；1H)；7.50(s，1H)；7.37(d；J＝8.5Hz；1H)；7.22(d；J＝4.9Hz；1H)；7.21(m，1H)；7.01(t；J＝4.9Hz；1H)；6.91(d；J＝8.5Hz；1H)。MS：calc：334.4；found：335.1(M+H)。

Embodiment 81

N-(2-amino-5-(benzene sulphur-2-yl) phenyl) H-imidazo [1,2-a] pyridine-2-carboxylic acid amides (296)

Scheme 64

Step 1:H-imidazo [1,2-a] pyridine-6-carboxylic acid, ethyl ester (293)

At 2-aminopyridine (292,1.1022 grams, 11.71 mmoles) and Bu ₂SnCl ₂(431 milligrams; 1.3 in DME mmole) (20 milliliters) solution, add (1.56 milliliters of 3-ethyl bromide acetones; 11.16 mmole) to produce yellow mercury oxide immediately.This suspension was at room temperature stirred 2 hours, add solid K then ₂CO ₃(2.6 grams; 18.8 mmole), and with mixture restir 20 hours under identical temperature.Then reaction mixture is washed with ethyl acetate (200 milliliters) dilution and with saturated sodium-chloride water solution.With organic layer drying (MgSO ₄), filter and concentrate.On silica gel, resistates is purified, obtain the titled reference compound 293 (1.31 grams, 59% yield) of white crystals thing shape by flash chromatography (dichloromethane solution of eluent 50% ethyl acetate). ¹H NMR(400.2MHz，DMSO)δ(ppm)：8.54(m，1H)；8.53(d；J＝0.9Hz；1H)；7.59(ddd；J＝1.3，2.0，9.2Hz；1H)；7.33(ddd；J＝1.3，6.7，9.2Hz；1H)；6.98(dt；J＝0.9，7.8Hz；1H)；4.30(q；J＝7.0Hz；2H)；1.32(t；J＝7.0Hz；3H)。MS：calc：190.0；found：191.1(M+H)。

Step 2:H-imidazo [1,2-a] pyridine-2-carboxylic acids (294)

According to embodiment 46, identical program described in the step 2 (scheme 34), but compound 162 is replaced to compound 293 obtains titled reference compound 294 with 99% yield. ¹HNMR(400.2MHz，DMSO)δ(ppm)：8.63(dt，J＝1.2，6.7Hz；1H)；8.55(d；J＝0.8Hz；1H)；7.63(m；1H)；7.42(ddd；J＝1.2，6.7，7.8Hz；1H)；7.06(dt；J＝1.2，7.8Hz；1H)；MS：calc：162.1；found：163.1(M+H)。

Step 3:N-(2-nitro-5-(benzene sulphur-2-yl) phenyl) H-imidazo [1,2-a] pyridine-2-carboxylic acid amides (295)

According to embodiment 1, identical program described in the step 3 (scheme 1), but compound 4 is replaced to compound 294 obtains titled reference compound 295 with 95% yield. ¹H NMR(400.2MHz，DMSO)δ(ppm)：11.9(s，1H)；9.07(d，J＝1.8Hz；1H)；8.63(m；2H)；8.25(d，J＝8.8Hz；1H)；7.77(ddd；J＝1.0，5.0，12.3Hz；1H)；7.71(dd；J＝1.0，9.2Hz；1H)；7.66(dd；J＝1.8，8.8Hz；1H)；7.41(ddd；J＝1.2，6.7，9.2Hz；1H)；7.25(dd；J＝3.7，5.0Hz；1H)；7.05(dt；J＝1.2，12.3Hz；1H)。MS：calc：364.2；found：365.1(M+H)。

Step 4:N-(2-amino-5-(benzene sulphur-2-yl) phenyl) H-imidazo [1,2-a] pyridine-2-carboxylic acid amides (296)

According to embodiment 1, identical program described in the step 4 (scheme 1), but compound 5 is replaced to compound 223 obtains titled reference compound 296 with 85% yield. ¹H NMR(400.2MHz，DMSO)δ(ppm)：9.73(s，1H)，8.62(dt，J＝1.2；6.8Hz，1H)，8.50(d，J＝0.7Hz；1H)；7.76(d；J＝2.2Hz；1H)；7.66(d，J＝0.7Hz，1H)，7.39(dd；J＝1.6，6.8Hz；1H)；7.36(dt；J＝1.6，4.9Hz；1H)；7.26(dd；J＝2.2，8.2Hz；1H)；7.24(dd；J＝1.2，3.6Hz；1H)；7.05(m；1H)；7.01(dd；J＝1.2，6.8Hz；1H)；6.84(d；J＝8.2Hz；1H)；5.13(bs，2H)。MS：calc：334.4；found：335.1(M+H)。

Embodiment 82

4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-hydroxyl-5-(benzene sulphur-2-yl) phenyl) benzamide (301)

Scheme 65

Step 1:2-nitro-4-(benzene sulphur-2-yl) phenol (298)

According to embodiment 1, identical program described in the step 2 (scheme 1), but compound 2 is replaced to compound 297 obtains titled reference compound 298 with 18% yield. ¹H NMR：(499.7MHz，DMSO)δ(ppm)：8.09(s，1H)；7.82(d，J＝9.0Hz；1H)；7.54(d，J＝3.5Hz；1H)；7.50(s，1H)；7.18(d，J＝9.0Hz；1H)；7.13(m，1H)。MS：calc：221.0；found：219.9(M-H)。

Step 2:(2-nitro-4-(benzene sulphur-2-yl) phenoxy group) (tertiary butyl) dimethylsilane (299)

According to embodiment 19, identical program described in the step 2 (scheme 17), but compound 90 replaced to compound 298 and use methylene dichloride to replace DMF to make solvent obtains titled reference compound 299, it is used for next step without further purifying.

Step 3:(2-amino-4-(benzene sulphur-2-yl) phenoxy group) (tertiary butyl) dimethylsilane (300)

According to embodiment 48, the described identical program of step 3 (scheme 36), but compound 171 replaced to compound 299 and use ethyl acetate and triethylamine replaces methyl alcohol to make solvent obtains titled reference compound 300 with the yield through two steps 41%.MS：calc：305.5；found：306.1(M+H)。

Step 4:4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-hydroxyl-5-(benzene sulphur-2-yl) phenyl) benzamide (301)

According to embodiment 1, identical program described in the step 3 (embodiment 1), but compound 3 is replaced to compound 300 and do not use NaH as alkali obtains titled reference compound 301 (rate of recovery of starting material 228 is 10%) with 17% yield. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：10.1(s，1H)；9.52(s，1H)；8.00(s，1H)；7.92(d，J＝7.0，2H)；7.49(d，J＝7.0，2H)；7.42(m，1H)；7.33(d，J＝8.0，1H)；7.29(s，1H)；7.07(s，1H)；6.93(d，J＝8.0，1H)；6.65(d，J＝8.5，1H)；6.32(s，1H)；5.98(m，2H)；4.30(s，2H)；3.65(s，3H)；3.58(s，3H)。MS：calc：460.5；found：461.1(M+H)。

Embodiment 83

N-(2-amino-5-(5-methylbenzene sulphur-2-yl) phenyl)-4-methoxy benzamide (302)

Scheme 66

According to embodiment 48, the described identical program of step 3 (scheme 36), but compound 171 replaced to compound 94dd and use ethyl acetate to replace methyl alcohol to make solvent obtains titled reference compound 302 with 26% yield. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.60(s，1H)，7.96(d，J＝8.0Hz，2H)；7.36(d，J＝2.1Hz，1H)；7.20(dd，J＝2.1，8.3Hz，1H)；7.03(d，J＝8.0Hz，2H)；7.00(d，J＝3.5Hz，1H)；6.78(d，J＝8.3Hz，1H)，6.70(dd，J＝1.1，3.5Hz，1H)；3.83(s，3H)；2.42(d，J＝1.1Hz，3H)。MS：calc：338.4；found：338.4(M+H)。

Embodiment 84

2-(5-((2-amino-5-(benzene sulphur-2-yl) phenyl) formamyl)-2-methyl isophthalic acid H-benzo [d] imidazoles-1-yl) ethylhexoate (308)

Scheme 67

Step 1:4-(2-hydroxyethylamino)-3-nitrobenzoic acid (303)

According to embodiment 78, the described identical program of step 1 (scheme 61), but be to use thanomin to replace the first ammonium and use Virahol to replace DMF to make solvent obtains titled reference compound 303 with 99% yield.MS：calc：226.2；found：225.1(M-H)。

Step 2:4-(2-hydroxyethylamino)-3-benzaminic acid (304)

According to embodiment 78, the described identical program of step 2 (scheme 61) obtains titled reference compound 304 with 100% yield.MS：calc：196.2；found：197.1(M+H)。

Step 3:1-(2-hydroxyethyl)-2-methyl isophthalic acid H-benzo [d] imidazole-5-carboxylic acid (305) and 1-(2-(1-vinyl ethyl ether oxygen base) ethyl)-2-methyl isophthalic acid H-benzo [d] imidazole-5-carboxylic acid (306)

At room temperature, with diamines 304 (1.18 grams; 6.01 mmole) (20 milliliters of triethyl ortoacetate; 109 mmoles; 18 equivalents) stirred suspension in is handled with trifluoroacetic acid (1.10 milliliters).After 5 minutes, mixture becomes amber solution, and it was stirred 4 hours under uniform temp; Concentrate and purify with (701 milligrams of generation oxygen acid 305 by preparation HPLC (C-18 aquasil post is with 5% to 95% MeOH aqueous solution wash-out); 53% yield) with as (373 milligrams of the ketene diacetal 306 of by product; 21% yield).

Compound 305: ¹H NMR:(499.7MHz, DMSO) δ (ppm): 13.1 (bs; 1H); 8.21 (s; 1H); 7.9 (d, J=8.0Hz; 1H); 7.84 (d, J=8.0Hz; 1H); 5.1 (bs; 1H); 4.42 (s; 2H); 3.75 (s; 2H); 2.75 (s; 3H); MS:calc:220.2; Found:221.1 (M+H).

Compound 306: ¹H NMR:(400.2MHz, DMSO) δ (ppm): 8.17 (m; 2H); 8.08 (d, J=9.2Hz; 1H); 5.03 (d, J=3.9Hz; 1H); 4.84 (d, J=3.9Hz; 1H); 4.63 (t, J=4.5Hz; 2H); 4.22 (q, J=7.0Hz; 2H); 3.84 (t, J=4.5Hz; 2H); 2.92 (s; 3H); 1.39 (t; J=7.0Hz; 3H).MS：calc：290.3；found：291.1(M+H)。

Step 4:2-(5-(2-nitro-5-(benzene sulphur-2-yl) phenyl amino formyl radical)-2-methyl isophthalic acid H-benzo [d] imidazoles-1-yl) ethyl acetate (307)

According to embodiment 1, identical program described in the step 3 (scheme 1), but compound 4 is replaced to compound 306 obtains titled reference compound 307 with 6% yield.MS：calc：464.49；found 465.2(M+H)。

Step 5:2-(5-((2-amino-5-(benzene sulphur-2-yl) phenyl) formamyl)-2-methyl isophthalic acid H-benzo [d] imidazoles-1-yl) ethylhexoate (308)

According to embodiment 48, identical program described in the step 3 (scheme 36), but compound 171 replaced to compound 307 and use ethyl acetate to replace methyl alcohol to make solvent obtains titled reference compound 308 with 96% yield. ¹H NMR：(DMSO)δ(ppm)：9.70(s，1H)，8.23(s，1H)，7.87(dd；J＝1.0，8.4Hz；1H)；7.62(d，J＝8.4Hz，1H)，7.48(d；J＝2.0Hz；1H)；7.34(dd；J＝0.8，4.8Hz；1H)；7.28(dd；J＝2.0，8.0Hz；1H)；7.23(dd；J＝0.8，3.6Hz；1H)；7.03(dd；J＝1.2，4.8Hz；1H)；6.81(d；J＝8.0Hz；1H)；5.15(bs，2H)；4.52(t；J＝4.8Hz；2H)；4.35(t；J＝4.8Hz；2H)；2.60(s，3H)；1.91(s，3H)。MS：calc：434.5；found：435.2(M+H)。

Embodiment 85

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-1-(2-hydroxyethyl)-2-methyl isophthalic acid H-benzo [d] imidazoles-5-carboxylic acid amides (309)

With (18 milligrams of acetic ester 308; 41 micromoles) and the solution of triethylamine (0.5 milliliter) in anhydrous methanol (2.0 milliliters) at room temperature stirred 16 hours, concentrate in a vacuum then, thereby obtain titled reference compound 309 with quantitative yield. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.70(s，1H)，8.22(s，1H)，7.84(dd；J＝1.4，8.2Hz；1H)；7.57(d，J＝8.4Hz，1H)，7.49(d；J＝2.2Hz；1H)；7.34(dd；J＝1.4，5.1Hz；1H)；7.28(dd；J＝2.2，8.2Hz；1H)；7.23(dd；J＝1.0，3.5Hz；1H)；7.04(dd；J＝3.5，5.1Hz；1H)；6.80(d；J＝8.4Hz；1H)；5.14(bs，2H)；5.00(bs，1H)；4.28(t；J＝5.4Hz；2H)；3.72(t；J＝5.4Hz；2H)；2.59(s，3H)。MS：calc：392.5；found：393.2(M+H)。

Embodiment 86

4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-hydroxyl-5-(phenyl) phenyl) benzamide (312)

Scheme 68

Step 1.4-(tertiary butyl-dimethyl-silanyloxy base)-biphenyl-3-base amine (311)

THF (20 milliliters) solution at 2-amino-4-phenylphenol (310,2.05 grams, 11.06 mmoles) and triethylamine (3.08 milliliters, 22.12 mmoles) adds among the TBDMSCI (2.00 grams, 13.28 mmoles).Gained solution was at room temperature stirred 4 days, use saturated NaCl solution (25 milliliters) dilution then, and use ethyl acetate extraction.With organic layer through Na ₂SO ₄Drying is filtered and is concentrated.After flash chromatography (hexane solution of eluent 0-50%EtOAc) purification, obtain the titled reference compound 311 (2.51 grams, 77% yield) of reddish-brown solid state. ¹H NMR：(DMSO)δ(ppm)：0.05(s，6H)，1.05(s，9H)，6.49-6.57(m，2H)，6.72(d，J＝8.1Hz，1H)，7.25(m，1H)，7.29-7.38(m，2H)，7.50(d，J＝7.9Hz，2H)。MS：(calc.)299.5；(obt.)300.2(MH) ⁺。

Step 2.4-((3,4-Dimethoxyphenyl amino) methyl)-N-(2-hydroxyl-5-(phenyl) phenyl) benzamide (312)

In DMF (3 milliliters) solution of acid 4 (schemes 1) (125 milligrams, 0.439 mmole), add BOP (293 milligrams, 0.662 mmole).This solution stirring after 10 minutes, is added aniline 311 (197 milligrams, 0.659 mmole) together with triethylamine (0.31 milliliter, 2.22 mmoles).Gained solution was at room temperature stirred 16 hours, remove solvent then, and make resistates be dissolved in THF (5 milliliters).The THF solution (1.0M, 0.66 milliliter, 0.659 mmole) that adds TBAF then, and reaction mixture at room temperature stirred 5 minutes, with saturated NaCl solution (10 milliliters) dilution, and use ethyl acetate extraction.With organic layer through Na ₂SO ₄Drying is filtered and is concentrated.After flash chromatography (hexane solution of eluent 0-80%EtOAc) purification, obtain the titled reference compound 312 (82 milligrams, 41% yield) of light yellow solid shape. ¹H NMR：(DMSO)δ(ppm)：3.62(s，3H)，3.69(s，3H)，4.34(d，J＝5.7Hz，2H)，6.03(m，2H)，6.35(d，J＝2.2Hz，1H)，6.68(d，J＝8.4Hz，1H)，7.03(d，J＝8.4Hz，1H)，7.32(t，J＝7.2Hz，1H)，7.37(dd，J＝10.4，1.6Hz，1H)，7.45(t，J＝7.6Hz，2H)，7.52(d，J＝8.0Hz，2H)，7.59(d，J＝7.6Hz，2H)，7.95(d，J＝8.0Hz，2H)，8.03(br s，1H)，9.58(br s，1H)，10.00(br s，1H)。MS：(calc.)454.5；(obt.)455.4(MH) ⁺。

Embodiment 87

(E)-3-(4-((3,4,5-trimethoxyphenyl amino) methyl)-phenyl)-N-(2-hydroxyl-5-(phenyl) phenyl) acrylamide (313)

According to identical program described in the embodiment 86, but acid 4 is replaced to acid 66 (schemes 10), with the compound 313 of 22% yield acquisition light yellow solid shape. ¹H NMR：(DMSO)δ(ppm)：3.54(s，3H)，3.68(s，3H)，4.30(d，J＝5.9Hz，2H)，5.92(s，2H)，6.13(t，J＝6.3Hz，1H)，7.01(d，J＝8.2Hz，1H)，7.21(d，J＝15.7Hz，1H)，7.29(dd，J＝8.4，2.3Hz，1H)，7.33(d，J＝7.2Hz，1H)，7.42-7.50(m，4H)，7.54-7.64(m，4H)，8.34(s，1H)，9.55(br s，1H)，10.21(br s，1H)。MS：(calc.)510.6；(obt.)511.2(MH) ⁺。

Embodiment 88

2,3-dihydro-N-(2-hydroxyl-5-(phenyl) phenyl) benzo [b] [1,4] dioxine-6-carboxylic acid amides (314)

According to identical program described in the embodiment 86, but acid 4 is replaced to sour 255a (scheme 53), with the compound 314 of 22% yield acquisition light yellow solid shape. ¹H NMR：(DMSO)δ(ppm)：4.30(d，J＝5.9Hz，2H)，6.98(d，J＝8.3Hz，1H)，7.26-7.36(m，2H)，7.42(t，J＝7.3Hz，2H)，7.50-7.60(m，2H)，7.97(br s，1H)，9.47(br s，1H)，9.93(br s，1H)。MS：(calc.)347.4；(obt.)348.1(MH) ⁺。

Embodiment 89

N ¹-(2-hydroxyl-5-(phenyl) phenyl)-N ⁸-(3-(phenyl) phenyl) octane diamines (317)

Scheme 69

Step 1.7-(3-(phenyl) phenyl amino formyl radical) enanthic acid (316)

In THF/ pyridine (2: 1, the 6 milliliters) solution of 3-amino-biphenyl (315,536 milligrams, 3.17 mmoles), add 7-(chloroformyl) Methylheptanoate (0.49 milliliter, 3.48 mmoles), and gained solution was at room temperature stirred 16 hours.With saturated NaCl solution (15 milliliters) dilution and with behind the ethyl acetate extraction, with organic layer through Na ₂SO ₄Drying is filtered and is concentrated.Then resistates is dissolved in THF/ methyl alcohol/H ₂O (1: 1: 2,8 milliliters) uses LiOH.H then ₂O (665 milligrams, 15.85 mmoles) handles.Reaction mixture was at room temperature stirred 1 hour, acidifying then (pH=1), and use ethyl acetate extraction.With organic layer through Na ₂SO ₄Drying is filtered and is concentrated.After flash chromatography (hexane solution of eluent 0-100EtOAc) purification, obtain the titled reference compound 316 (889 milligrams, 86% yield) of white solid. ¹H NMR：(DMSO)δ(ppm)：1.30-1.40(m，4H)，1.50-1.59(m，2H)，1.60-1.68(m，2H)，2.24(t，J＝7.4Hz，2H)，2.37(t，J＝7.4Hz，2H)，7.32(dt，J＝7.8，1.6Hz，1H)，7.36-7.42(m，2H)，7.46-7.52(m，2H)，7.58-7.64(m，3H)，7.96(s，1H)，10.07(br s，1H)。MS：(calc.)325.4；(obt.)326.1(MH) ⁺。

Step 2.N ¹-(2-hydroxyl-5-(phenyl) phenyl)-N ⁸-(3-(phenyl) phenyl) octane diamines (317)

According to embodiment 86, identical program described in the step 2 (scheme 68), but acid 4 is replaced to acid 316 is with the compound 317 of 31% yield acquisition light brown solid state. ¹HNMR：(DMSO)δ(ppm)：1.34-1.46(m，4H)，1.60-1.74(m，4H)，2.38(t，J＝6.8Hz，2H)，2.47(t，J＝7.0Hz，2H)，6.98(d，J＝8.2Hz，1H)，7.20-7.70(m，15H)，7.96(s，1H)，8.10(s，1H)，9.34(br s，1H)，10.00(br s，1H)。MS：(calc.)492.6；(obt.)493.5(MH) ⁺。

Embodiment 90

2-[4-(naphthalene-2-alkylsulfonyl)-piperazine-1-yl]-pyrimidine-5-carboxylic acid's (2-amino-5-benzene sulphur-2-base-phenyl)-acid amides (320)

Scheme 70

Step 1:[2-(2-[4-(naphthalene-2-alkylsulfonyl)-piperazine-1-yl]-pyrimidine-5-carbonyl }-amino)-4-benzene sulphur-2-base-phenyl]-t-butyl carbamate (319)

According to embodiment 52, the described identical program of step 1 (scheme 37), but compound 182 is replaced to 2-[4-(naphthalene-2-alkylsulfonyl)-piperazine-1-yl]-pyrimidine-5-carboxylic acid (318, WO03/076422), obtain titled reference compound 319 with 75% yield. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.7(bs，1H)；8.81(s，2H)；8.60(bs，1H)；8.44(s，1H)；8.20(d，J＝7.6Hz，1H)；8.15(d，J＝8.6Hz，1H)；8.05(d，J＝6.9Hz，1H)；7.75(dd；J＝1.8，8.6Hz；1H)；7.71(dd；J＝1.3，6.9Hz；1H)；7.68(m，2H)；7.63(d，J＝8.6Hz，1H)；7.47(m，2H)；7.40(dd；J＝1.3，3.5Hz；1H)；7.09(dd；J＝3.5，5.1Hz；1H)；3.97(t，J＝4.1Hz，4H)；3.07(t，J＝4.1Hz，4H)；1.41(s，9H)。MS：calc：670.8；found：671.3(M+H)。

Step 2:2-[4-(naphthalene-2-alkylsulfonyl)-piperazine-1-yl]-pyrimidine-5-carboxylic acid's (2-amino-5-benzene sulphur-2-base-phenyl)-acid amides (320)

According to embodiment 52, the described identical program of step 2 (scheme 37), but compound 183 is replaced to compound 319 obtains titled reference compound 320 with 99% yield. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.52(bs，1H)；8.83(s，2H)；8.44(s，1H)；8.20(d，J＝7.6Hz，1H)；8.15(d，J＝8.6Hz，1H)；8.05(d，J＝8.0Hz，1H)；7.75(dd；J＝1.8，8.6Hz；1H)；7.69(m，2H)；7.37(d，J＝1.8Hz，1H)；7.31(dd；J＝1.2，5.1Hz；1H)；7.25(dd；J＝2.2，8.4Hz；1H)；7.19(dd；J＝1.2，3.5Hz；1H)；7.01(dd；J＝3.5，5.1Hz；1H)；6.74(d，J＝8.2Hz，1H)；5.16(bs，2H)；3.96(t，J＝4.3Hz，4H)；3.07(t，J＝4.3Hz，4H)；MS：calc：570.7；found：571.3(M+H)。

Embodiment 91

2-[4-(biphenyl-4-base formamyl)-piperazine-1-yl]-pyrimidine-5-carboxylic acid's (2-amino-5-benzene sulphur-2-base-phenyl)-acid amides (323)

Scheme 71

Step 1:[2-(2-[4-(biphenyl-4-base formamyl)-piperazine-1-yl]-pyrimidine-5-carbonyl }-amino)-4-benzene sulphur-2-base-phenyl]-t-butyl carbamate (322)

According to embodiment 52; the described identical program of step 1 (scheme 37); but compound 182 is replaced to 2-[4-(biphenyl-4-base formamyl)-piperazine-1-yl]-pyrimidine-5-carboxylic acid's sodium salt (321, WO 03/076421), obtain titled reference compound 322 with 29% yield. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.78(bs，1H)；8.93(s，2H)；8.75(bs，1H)；8.67(bs，1H)；7.76(d，J＝2.0Hz，1H)；7.67(d，J＝8.4Hz，1H)；7.63(d，J＝1.2Hz，1H)；7.61(m，1H)；7.57(m，4H)；7.50(m，2H)；7.42(m，3H)；7.29(m，1H)；7.11(dd；J＝3.5，5.1Hz；1H)；3.94(t，J＝4.5Hz，4H)；3.60(t，J＝4.5Hz，4H)；1.47(s，9H)。MS：calc：675.8；found：698.5(M+Na)。

Step 2:2-[4-(biphenyl-4-base formamyl)-piperazine-1-yl]-pyrimidine-5-carboxylic acid's (2-amino-5-benzene sulphur-2-base-phenyl)-acid amides (323)

According to embodiment 52, the described identical program of step 2 (scheme 37), but compound 183 is replaced to compound 322 obtains titled reference compound 323 with 99% yield. ¹H NMR：(400.2MHz，DMSO)δ(ppm)：9.59(bs，1H)；8.93(s，2H)；8.75(bs，1H)；7.63(d，J＝1.2Hz，1H)；7.61(m，1H)；7.57(m，4H)；7.41(m，3H)；7.33(dd；J＝1.2，5.1Hz；1H)；7.29(m，2H)；7.23(dd；J＝1.2，2.5Hz；1H)；7.03(dd；J＝3.7，5.1Hz；1H)；6.78(d，J＝8.2Hz，1H)；5.22(bs，2H)；3.93(t，J＝3.9Hz，4H)；3.60(t，J＝3.9Hz，4H)。MS：calc：575.7；found：576.3(M+H)。

Embodiment 92

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-(pyridin-3-yl) benzamide (327)

Scheme 72

Step 1.2-(4-bromobenzene formamido group)-4-(benzene sulphur-2-yl) the phenylcarbamic acid tert-butyl ester (325)

According to embodiment 52, identical program in the step 1 (scheme 37), but compound 182 is replaced to compound 324 obtains titled reference compound 325 with 47% yield. ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：9.94(s，1H)，8.72(s，1H)，7.91(d，J＝8.6Hz，2H)，7.76(d，J＝8.2，2H)，7.75(d，J＝2.2Hz，1H)，7.62(d，J＝8.9Hz，1H)，7.51(dd，J＝4.9，1.2Hz，1H)，7.50(dd，J＝8.6，2.2Hz，7.44(d，J＝3.7，1.2Hz，1H)，7.11(dd，J＝5.1，3.5Hz，1H)，1.45(s，9H)。LRMS：(m/z)：495.1/497.1((M/M+2)+23)。

Step 2 and 3.N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-(pyridin-3-yl) benzamide (327)

According to embodiment 29, identical program in the step 1 (scheme 21), but bromide 114 is replaced to bromide 325 and use 3-pyridine boric acid, obtain compound 326 and be used for next step without purification as coupling component (partner) (Suzuki coupling).

According to embodiment 52, identical program in the step 2 (scheme 37), but compound 183 is replaced to compound 326 obtains titled reference compound 327 (is 14% through two step yields). ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：9.80(s，1H)，8.98(d，J＝2.2Hz，1H)，8.60(dd，J＝4.7，1.6Hz，1H)，8.17(d，J＝8.6Hz，1H)，8.12(d，J＝8.0Hz，2H)，7.90(d，J＝8.6Hz，2H)，7.52(dd，J＝7.2，4.1Hz，1H)，7.48(s，1H)，7.35(d，J＝4.1Hz，1H)，7.29(dd，J＝8.4，2.3Hz，1H)，7.24(d，J＝3.3Hz，1H)，7.04(dd，J＝5.1，1.4，1H)，6.80(d，J＝8.2Hz，1H)，5.19(s，2H)。LRMS：(m/z)：372.3(MH ⁺)。

Embodiment 93

4-(2-hydroxyl-5-(benzene sulphur-2-yl) phenyl amino formyl radical) benzylamino formic acid (pyridin-3-yl) methyl esters (333)

Scheme 73

Step 1. acetate 4-bromo-2-nitro phenyl ester (328)

Diacetyl oxide (10 milliliters) solution with 4-bromo-2-nitrophenols (297,1.00 grams, 4.59 mmoles) (scheme 65) in pressurized vessel heated 16 hours at 130-140 ℃.Evaporate most solvents in a vacuum, and gained oil was preserved in refrigerator 3 days.Crystallization takes place when melting.Make white crystal be suspended in EtOAc/ hexane (9: the 1) mixture and the filtration collection, titled reference compound 328 (1.03 grams, 87% yield) is provided. ¹H NMR：(400MHz，DMSO-d ₆)δ(ppm)：8.33(d，J＝2.3Hz，1H)，8.02(dd，J＝8.6，2.3Hz，1H)，7.45(d，J＝8.6Hz，1H)，2.33(s，3H)。LRMS：(m/z)：282.0/284.0((M ⁺/M+2)+23)。

Step 2.2-nitro-4-(benzene sulphur-2-yl) phenol (298)

According to embodiment 44, identical program in the step 2 (scheme 32), but bromide 155 is replaced to bromide 328 (1.00 grams, 3.85 mmole) and with borate 116 replace to (517 milligrams of 2-thienyl boric acid, 4.04 mmole), and, obtain titled reference compound 298 (270 milligrams, 32% yield) 120 ℃ of heating. ¹H NMR：(DMSO-d ₆)δ(ppm)：11.21(bs，1H)，8.07(d，J＝2.3Hz，1H)，7.80(dd，J＝8.6，2.3Hz，1H)，7.49(dd，J＝3.5，1.2Hz，1H)，7.16(d，J＝8.6Hz，1H)，7.11(dd，J＝5.1，3.5Hz，1H)，7.07(d，J＝8.8Hz，1H)。

Step 3.2-amino-4-(benzene sulphur-2-yl) phenol (329)

According to embodiment 51, identical program in the step 3 (scheme 37), but compound 177 is replaced to compound 298 (270 milligrams, 1.22 mmoles) obtains titled reference compound 329 (233 milligrams, 100% yield). ¹H NMR：(DMSO-d ₆)δ(ppm)：9.21(bs，1H)，7.33(dd，J＝5.1，1.0Hz，1H)，7.14(dd，J＝3.5，1.2Hz，1H)，7.01(dd，J＝5.1，3.5Hz，1H)，6.85(d，J＝2.2Hz，1H)，6.63(d，J＝8.0Hz，1H)，6.53(d，J＝8.2Hz，1H)，4.65(bs，2H)。LRMS：(m/z)：192.1(MH ⁺)。

Step 4. o-tert-butyl dimetylsilyl-2-amino-4-(benzene sulphur-2-yl) phenol (330)

According to embodiment 19, identical program in the step 2 (scheme 17), but compound 90 is replaced to compound 329 (233 milligrams, 1.22 mmoles) obtains titled reference compound 330 (211 milligrams, 57% yield). ¹H NMR：(DMSO-d ₆)δ(ppm)：7.75(dd，J＝5.1，1.2Hz，1H)，7.66(dd，J＝3.5，1.2Hz，1H)，7.50(d，J＝2.2Hz，1H)，7.47(dd，J＝5.3，3.7Hz，1H)，7.28(dd，J＝8.2，2.2Hz，1H)，7.21(d，J＝8.2Hz，1H)，4.88(bs，2H)，1.50(s，9H)，0.73(s，6H)。LRMS：(m/z)：306.3(MH ⁺)。

Step 5 and 6:4-(2-hydroxyl-5-(benzene sulphur-2-yl) phenyl amino formyl radical) benzylamino formic acid (pyridin-3-yl) methyl esters (333)

(US 6,174, add Et in DMF 905B1) (6 milliliters) solution at acid 331 (383 milligrams, 0.691 mmole) ₃N (194 microlitres, 1.39 mmoles) and BOP (954 milligrams, 2.08 mmoles).Mixture was stirred 15 minutes, and add DMF (4 milliliters) solution of compound 330 (211 milligrams, 0.691 mmole), add Et then ₃N (510 microlitres, 3.66 mmoles).Mixture was at room temperature stirred 16 hours, concentrate in a vacuum at 80 ℃ then.Make resistates at EtOAc and H ₂Layering between the O, with organic phase HCl 1N extracting twice, and with the saturated NaHCO of acid extract thing that merges ₃Neutralization.The throw out that generates is extracted with EtOAc; With extract salt water washing, through MgSO ₄Drying is filtered and is concentrated.The mixture M eOH/DCM that uses polarity to increase progressively (7: 93 to 10: 90) purifies the gained material by flash chromatography as eluent, obtains intermediate compound 332 (99 milligrams, 20% yield). ¹H NMR：(DMSO-d ₆)δ(ppm)：10.11(s，1H)，8.56(bs，2H)，8.51(bs，2H)，8.02(d，J＝7.8Hz，2H)，7.92-7.90(m，2H)，7.79(d，J＝8.2Hz，2H)，7.76-7.74(m，2H)，7.61(d，J＝7.4Hz，1H)，7.57(d，J＝5.1Hz，1H)，7.53(d，J＝3.5Hz，1H)，7.41(d，J＝8.2Hz，2H)，7.38(d，J＝7.8Hz，2H)，7.29(d，J＝8.2Hz，1H)，7.27(d，J＝5.9Hz，1H)，7.16(dd，J＝5.1，3.7Hz，1H)，5.08(s，2H)，5.07(s，2H)，4.28(d，J＝7.2Hz，2H)，7.23(d，J＝5.5Hz，2H)。LRMS：(m/z)：728.3(MH ⁺)。

(500 microlitres are by being dissolved in 1 milliliter of H with a pill to add excessive NaOH in the THF (500 microlitre) of compound 332 (10 milligrams, 0.0137 mmole) solution ₂The solution that O makes).Also use HCl 1N extracted organic phase with the EtOAc aqueous layer extracted.With the saturated NaHCO of acid extract thing ₃Neutralization extracts this throw out to generate precipitation with EtOAc; With extract salt water washing, through MgSO ₄Drying is filtered and is concentrated.Use MeOH/DCM (7:93) the gained material to be purified, obtain titled reference compound 333 (2.9 milligrams, 46% yield) by preparation TLC. ¹H NMR：(Acetone-d ₆)δ(ppm)：9.37(bs，1H)，9.35(bs，1H)，8.47(d，J＝1.2Hz，8.38(d，J＝3.9Hz，1H)，7.97(s，1H)，7.87(d，J＝8.4Hz，2H)，7.64(d，J＝7.4Hz，1H)，7.35(d，J＝8.2Hz，2H)，7.25(dd，J＝8.4，2.3Hz，1H)，7.22(dd，J＝5.1，1.2Hz，1H)，7.16(dd，J＝3.7，1.2Hz，1H)，6.93(d，J＝8.1Hz，1H)，6.93(d，J＝1.6Hz，1H)，6.86(d，J＝8.4Hz，1H)，5.01(s，2H)，4.31(d，J＝6.3Hz，2H)。LRMS：(m/z)：460.2(MH ⁺)。

Embodiment 94

2-(4-(4-cyano group benzyl) piperazine-1-yl)-N-(2-amino-5-(benzene sulphur-2-yl) phenyl) thiazole-5-carboxylic acid amides (341)

Scheme 74

Step 1:4-(4-cyano group benzyl) piperazine-1-carboxylic acid tert-butyl ester (336)

With piperazine-1-carboxylic acid tert-butyl ester (334,1 grams, 5.37 mmoles), 3-(brooethyl) benzonitrile (335,1.26 grams, 6.45 mmoles) and K ₂CO ₃(1.48 grams, 10.74 mmoles) solution in EtOH (20 milliliters) refluxed 4 hours.Then reaction mixture is concentrated, dilute and wash (20 milliliters) with water with EtOAc (20 milliliters).Separate organic phase, use Na ₂SO ₄Drying is filtered and is concentrated.The hexane solution of use gradient 10%-25% EtOAc is made eluent and by flash chromatography crude product is purified to obtain titled reference compound 336 (1.374 grams, 85%).MS：calc：301.3；found：302.1(M+H)。

Step 2:4-(4-cyano group benzyl) piperazine-1-thioformamide (337)

The DCM (5 milliliters) and TFA (5 milliliters) solution of 4-(4-cyano group benzyl) piperazine-1-carboxylic acid tert-butyl ester (336,1.374 grams, 4.56 mmoles) were at room temperature stirred 1 hour.Reaction mixture concentrated and at N ₂Down, in 0 ℃ of anhydrous DCM (20 milliliters) solution that resistates is added thio-carbonyldiimidazole (1.21 grams, 6.84 mmoles, 1.5 equivalents).Blasted ammonia 10 minutes, and flask was added a cover and stirred two days at 80 ℃.Reaction mixture is concentrated and uses the hexane solution of 60% EtOAc make eluent and purify, to obtain titled reference compound 337 (593 milligrams, 50% yield) by flash chromatography.MS：calc：260.1；found：261.2(M+H)。

Step 3:2-(4-(4-cyano group benzyl) piperazine-1-yl) thiazole-5-carboxylic acid methyl esters (338)

(290 milligrams, 280 milliliters, the solution in 1: 1 mixture (4 milliliters) of 2.51 mmole) Zai diox/water was handled and is stirred 1 hour with NBS (507 milligrams, 2.85 mmoles) at 0 ℃ with 3-methoxy acrylic acid (E)-methyl esters.At room temperature mixture is transferred in the flask that contains sulfo-acid amides 337 (593 milligrams, 2.28 mmoles) and and refluxed 1.5 hours the gained mixture.With its cooling, add saturated NH ₄Cl solution (5 milliliters) quenching also concentrates.Make the layering between EtOAc and water of gained material.With organic phase Na ₂SO ₄Drying is filtered and is concentrated.The hexane solution of use 60%EtOAc is made eluent and by flash chromatography crude product is purified to obtain titled reference compound 338 (602 milligrams, 77% yield).MS：calc：342.1；found：343.1(M+H)。

Step 4:2-(4-(4-cyano group benzyl) piperazine-1-yl) thiazole-5-carboxylic acid (339)

1: 1: 1 solution of THF/ water/MeOH (9 milliliters) of ester 338 (602 milligrams, 1.76 mmoles) and KOH (600 milligrams, 10.71 mmoles, 6 equivalents) was at room temperature stirred 1 hour.Then reaction mixture is concentrated and layering between ether and water.Collect water layer and be acidified to pH=3 also with EtOAc (3 * 5 milliliters) extraction with 1M HCl solution.With organic phase Na ₂SO ₄Drying is filtered and is concentrated.Crude product 339 (WO 03/092686) is directly used in next step.MS：calc：328.1；found：329.1(M+H)。

Step 5:(2-(4-(4-cyano group benzyl) piperazine-1-yl)-thiazole-5-amide group)-4-(benzene sulphur-2-yl) the phenylcarbamic acid tert-butyl ester (340)

Pyridine (2 milliliters) solution of acid 339 (113 milligrams, 0.34 mmole) amine 178 (100 milligrams, 0.34 mmole) and BOP (152 milligrams, 0.34 mmole) at room temperature stirred spend the night.Reaction mixture is concentrated, and use the hexane solution of gradient elution agent 50%-75%EtOAc to purify to obtain titled reference compound 340 (96 milligrams, 47% yield) by flash chromatography.MS：calc：600.1；found：601.3(M+H)。

Step 6:2-(4-(4-cyano group benzyl) piperazine-1-yl)-N-(2-amino-5-(benzene sulphur-2-yl) phenyl) thiazole-5-carboxylic acid amides (341)

With 1 of compound 340 (96 milligrams, 0.16 mmole): 1DCM/TFA (6 milliliters) solution at room temperature stirred 1 hour.Concentrate and use EtOAc to make eluent in mixture and purify, obtain titled reference compound 341 (47 milligrams, 59% yield) by flash chromatography. ¹H NMR：(400.2MHz，CD ₃OD)δ(ppm)：7.95(br.s，1H)，7.75(m，1H)，7.68(m，2H)，7.53(t，1H，J＝7.6Hz)，7.42(s，1H)，7.33(d，1H，J＝8.2Hz)，7.20(m，2H)，7.00(m，1H)，6.87(d，1H，J＝8.3Hz)，3.72(s，2H)，3.60(m，4H)，2.68(m，4H)。MS：calc：500.1；found：501.2(M+H)。

Embodiment 95

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-(4-benzyl diethylenediamine-1-yl) benzamide (344)

Scheme 75

Step 1:2-(4-(4-benzyl diethylenediamine-1-yl) benzamido)-4-(benzene sulphur-2-yl) the phenylcarbamic acid tert-butyl ester (343)

According to embodiment 94, program described in the step 5 (scheme 74), but 2-(4-(4-cyano group benzyl) piperazine-1-yl) thiazole-5-carboxylic acid (339 WO 03/092686) is replaced to 4-(4-benzyl diethylenediamine-1-yl) phenylformic acid (342, WO 03/087057), obtain titled reference compound 343 with 18% yield.MS：calc：568.2；found：569.3(M+H)。

Step 2:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-(4-benzyl diethylenediamine-1-yl) benzamide (344)

With compound 343 (36 milligrams, 0.06 mmole) 1: the solution among the 1DCM/TFA (6 milliliters) at room temperature stirred 1 hour.Mixture is concentrated and layering between water and EtOAc.With organic phase NaHCO ₃Solution washing is used Na ₂SO ₄Drying is filtered and is concentrated to produce titled reference compound 344 (5 milligrams, 17% yield). ¹H NMR：(400.2MHz，CDCl ₃)δ(ppm)：2.625(t，J＝5Hz，4H)，3.35(t，J＝5Hz，4H)，3.59(s，2H)，4.00(s，2H)，6.84(d，J＝8Hz，1H)，6.90(d，J＝9Hz，2H)，7.01(m，1H)，7.16(m，2H)，7.25(m，6H)，7.50(s，1H)，7.75(s，1H)，7.81(d，J＝9Hz，2H)。MS：calc：468.0；found：469.0(M+H)。

Embodiment 96

N1-(2-amino-5-(benzene sulphur-2-yl) phenyl)-N8-phenyl octane diamines (347)

Scheme 76

Step 1:2-(N1-phenyl octane diamido)-4-(benzene sulphur-2-yl) the phenylcarbamic acid tert-butyl ester (346)

Solution in THF/ water/MeOH (1: 1: 1,9 milliliters) at room temperature stirred 1 hour with 7-(phenyl amino formyl radical) Methylheptanoate (345, United States Patent (USP) 5,369,108) (124 milligrams, 0.46 mmole) and KOH (100 milligrams, 1.77 mmoles).Then reaction mixture is concentrated and layering between ether and water.Collect water layer and be acidified to pH=3 also with EtOAc (3 * 5 milliliters) extraction with 1M HCl solution.With the organic phase Na that merges ₂SO ₄Drying is filtered and is concentrated.Crude acid was also at room temperature stirred 20 minutes with thionyl chloride (3 milliliters) and DMF (1) dilution.Reaction mixture is concentrated in a vacuum, dilute and be cooled to 0 ℃ with THF (3 milliliters).It is used Et ₃N (62 milligrams, 86 microlitres, 0.61 mmole) and amine 178 (120 milligrams, 0.41 mmole) are handled, and stir 30 minutes at 0 ℃.Add saturated NH ₄Cl solution is the reaction mixture quenching, and extracts with EtOAc (3 * 3 milliliters).With the organic phase Na that merges ₂SO ₄Drying is filtered and is concentrated.Using the hexane solution of 50% EtOAc to make eluent purifies crude product to obtain titled reference compound 346 (111 milligrams, 52% yield) by flash chromatography.MS：calc：521.2；found：522.3(M+H)。

Step 2:N1-(2-amino-5-(benzene sulphur-2-yl) phenyl)-N8-phenyl octane diamines (347)

The solution of compound 346 (111 milligrams, 0.06 mmole) in 2: 1 DCM/TFA (3 milliliters) was at room temperature stirred 1 hour.Add saturated NaHCO ₃Solution makes the mixture quenching, and extracts with DCM.With organic phase Na ₂SO ₄Drying is filtered and is concentrated.Using EtOAc to make eluent purifies crude product to obtain titled reference compound 347 (20 milligrams, 22% yield) by flash chromatography. ¹H NMR：(400.2MHz，CD ₃OD)δ(ppm)：7.51(br.s，2H)，7.38(s，1H)，7.16-7.27(m，5H)，6.9-7.1(m，2H)，6.84(m，1H)，2.42(m，4H)，1.76(m，4H)，1.49(m，4H)。MS：calc：421.2；found：422.2(M+H)。

Embodiment 97

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-((1,2-dihydro-2,4-dioxo quinazoline-3 (4H)-yl) methyl) benzamide (349)

Scheme 77

Step 1 and 2:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-4-((1,2-dihydro-2,4-dioxo quinazoline-3 (4H)-yl) methyl) benzamide (349)

According to embodiment 52, identical program described in the step 1 and 2 (scheme 37), but acid 182 is replaced to 4-((1,2-dihydro-2,4-dioxo quinazoline-3 (4H) methyl) phenylformic acid 348 (WO 03/024448 and JP 2003137866A); Obtain titled reference compound 349 with 55% yield. ¹H NMR(DMSO-d ₆)δ(ppm)：11.57(s，1H)，9.81(s，1H)，7.95-7.92(m，3H)，7.68(td，J＝7.2，1.4Hz，1H)，7.48(d，J＝1.8Hz，1H)，7.42(d，J＝8.2Hz，2H)，7.38(d，J＝5.1Hz，1H)，7.34(dd，J＝8.2，2.0Hz，1H)，7.27(d，J＝3.3Hz，1H)，7.24-7.20(m，2H)，7.05(dd，J＝4.9，3.5Hz，1H)，6.89(d，J＝8.4Hz，1H)，5.17(s，2H)。(do not see NH ₂Group, itself and H ₂O overlaps).MS(m/z)：468.53(calc)469.2(MH+)(found)。

Embodiment 98

4-(5-(2-amino-5-(benzene sulphur-2-yl) phenyl amino formyl radical) benzene sulphur-2-yl) piperidines-1-carboxylic acid tert-butyl ester (355)

Scheme 78

Step 1:1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-base trifluoromethayl sulfonic acid ester (351)

Butyllithium (14.96 mmoles, 1.4M, 2.09 milliliters) and Isopropylamine (14.96 mmoles, 10.68 milliliters) added among-78 ℃ the anhydrous THF to produce LDA solution.THF (10 milliliters) solution that in this LDA solution, adds 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (350,2.71 grams, 13.6 mmoles).The gained mixture is warming up to room temperature and restir 30 minutes, is cooled to-78 ℃ again, and add the THF solution of N-phenyl trifluoromethanesulfonate sulfonyl methane imines (5.1 grams, 14.3 mmoles) by syringe.Make the reaction mixture of merging be warming up to room temperature and restir 3 hours, water (50 milliliters) quenching and with ethyl acetate (2 * 50 milliliters) extraction.With extract through dried over sodium sulfate, evaporation and with resistates on silica gel by flash chromatography (7: 1 mixture hexane-ethyl acetate of eluent), to produce light yellow oily titled reference compound 351 (2.55 grams, 57% yield). ¹H NMR：(DMSO)δ：6.00(s，1H)，3.97-3.96(m，2H)，3.53(t，J＝5.7Hz，2H)，2.41-2.40(m，2H)，1.41(s，9H)。

Step 2:5-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridine-4-yl) thiophene-2-carboxylic acid (353)

In 351 (1.1 grams, 3.32 mmoles) and the stirred solution of 352 (571 milligrams, 3.32 mmoles) in 2: 1 mixtures (30 milliliters) of DME-water, add Pd (PPh ₃) ₄(268 milligrams, 0.232 mmole), three adjacent toluene phosphines (71 milligrams, 0.232 mmole) and salt of wormwood (1.38 grams, 9.96 mmoles).Reaction mixture was stirred 15 hours with the nitrogen degassing 5 minutes and at 80 ℃, cooling, water (50 milliliters) is handled and is extracted with ethyl acetate (2 * 40 milliliters).Separate organic layer, to form resistates, it is purified by flash chromatography (use from 2: 1 hexane-ethyl acetate to 1: the gradient solvent system wash-out of 1 hexane-ethyl acetate) with dried over sodium sulfate and reduction vaporization.Develop 15 minutes to produce 353 (330 milligrams, 33% yield) of beige solid shape with the hexane solution of 10% ethyl acetate subsequently. ¹H NMR：(DMSO)δ：7.60(d，J＝2.2Hz，1H)，7.14(d，J＝3.7Hz，1H)，6.28-6.29(m，1H)，4.00-3.99(m，2H)，3.52(t，J＝5.9Hz，2H)，2.45-2.46(m，2H)，1.42(s，9H)。

Step 3:4-(5-(2-nitro-5-(benzene sulphur-2-yl) phenyl amino formyl radical) benzene sulphur-2-yl)-5,6-dihydropyridine-1 (2H)-carboxylic acid tert-butyl ester (354)

Compound 353 (270 milligrams, 0,87 mmole), 2-nitro-5-(benzene sulphur-2-yl) aniline (3,193 milligrams, 0.87 mmole) and BOP (386 milligrams, 0.87 mmole) are dissolved in anhydrous pyridine (10 milliliters).Add sodium hydride (140 milligrams, 3.50 mmoles), and gained solution was at room temperature stirred 2 hours, with Glacial acetic acid (1 milliliter) quenching, and pyridine is removed in decompression.Add entry (50 milliliters) and use ethyl acetate (2 * 50 milliliters) to extract in mixture.With sodium sulfate the dry also evaporation of extract is produced resistates, it was developed 15 minutes with ethyl acetate, obtain the titled reference compound 354 (270 milligrams, 61% yield) of yellow oily. ¹H NMR：(DMSO)δ：10.79(s，1H)，8.06-8.04(m，2H)，7.86(d，J＝3.9Hz，1H)，7.75-7.68(m，3H)，7.25-7.20(m，2H)，6.32(s，1H)，4.04-4.01(m，2H)，3.54(t，J＝5.3Hz，2H)，1.43(s，9H)。

Step 4:4-(5-(2-amino-5-(benzene sulphur-2-yl) phenyl amino formyl radical) benzene sulphur-2-yl) piperidines-1-carboxylic acid tert-butyl ester (355)

In methyl alcohol (25 milliliters) stirred solution of 354 (270 milligrams, 0.53 mmole), add 10% year palladium charcoal (150 milligrams).With gained mixture H ₂Gas purging also stirred 3 days under nitrogen atmosphere, filtered through C salt pad, and evaporation is also passed through flash chromatography (1: 1 hexane-ethyl acetate of eluent) and purified, and obtains the titled reference compound 355 (24 milligrams, 10% yield) of white solid. ¹H NMR：(CD ₃OD)δ7.73(d，J＝3.3Hz，1H)，7.45(d，J＝2.1Hz，1H)，7.34(dd，J＝8.2，2.2Hz，1H)，7.23-7.19(m，2H)，7.01(dd，J＝4.7，3.7Hz，1H)，6.96(d，J＝3.9Hz，1H)，6.88(d，J＝8.1Hz，1H)，4.17(d，J＝13.1Hz，2H)，3.00-2.90(m，2H)，2.04(d，J＝12.1Hz，2H)，1.60-1.54(m，2H)。

Embodiment 99

N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-2-(2-morpholino ethyl)-1,3-dioxoisoindolin-5-carboxylic acid amides (358)

Scheme 79

Step 1:2-(2-morpholino ethyl)-1,3-dioxoisoindolin-5-carboxylic acid (357)

With 1,2,4-benzene tricarbonic acid acid anhydride (356,0.487 grams, 2.53 mmoles) and 4-(2-amino-ethyl) morpholine (0.33 gram, 2.53 mmoles) stirred 2 hours in acetate (10 milliliters) at 130 ℃.Then reaction mixture is cooled to room temperature, and filters the collecting precipitation solid, use H ₂The O washing is also dry under vacuum, produces the titled reference compound 357 (0.63 gram, 82% yield) of white powder. ¹H NMR (DMSO) δ (ppm): 8.26 (dd, J=7.6,1.4Hz, 1H), 8.15 (dd, J=1.4,0.6Hz, 1H), 7.92 (dd, J=7.6,0.6Hz, 1H), 3.73 (t, J=6.5Hz, 2H), 3.50 (t, J=4.5Hz, 4H), 2.59 (t, J=6.5Hz, 2H), 2.47 (overlap with DMSO, 4H).MS：304.3(calc)，305.1(obs)。

Step 2 and 3:N-(2-amino-5-(benzene sulphur-2-yl) phenyl)-2-(2-morpholino ethyl)-1,3-dioxoisoindolin-5-carboxylic acid amides (358)

According to embodiment 71a, identical program described in the step 2 and 3 (scheme 54), but with 3,4-dimethoxybenzoic acid (257a) replaces to compound 357, obtains titled reference compound 358 with 18% yield (through two steps). ¹H NMR：(DMSO)δ(ppm)：10.03(s，1H)，8.45(s，1H)，8.38(d，J＝7.6Hz，1H)，7.99(d，J＝7.6Hz，1H)，7.44(d，J＝2.0Hz，1H)，7.32(dd，J＝11.9，5.1Hz，1H)，7.28(d，J＝2.0Hz，1H)，7.03(d，J＝4.9Hz，1H)，6.78(d，J＝8.2Hz，1H)，5.27(s，2H)，3.73(t，J＝6.3Hz，2H)，3.48(m，4H)，2.54(t，J＝6.5Hz，2H)，2.41(m，4H)。MS：476.15(calc)，477.2(obs)。

Embodiment 100

N-(2-amino-5-(1H-imidazoles-1-yl) phenyl)-4-methoxy benzamide (361)

Scheme 80

Step 1:5-(1H-imidazoles-1-yl)-2-N-methyl-p-nitroaniline (360)

According to embodiment 1, identical program described in the step 1 (scheme 1), but 1-bromo-4-oil of mirbane (1) is replaced to 1-(4-nitrophenyl)-1H-imidazoles (359) obtains titled reference compound 360 with 32% yield.MS：204.06(calc)，205.1(found)。

Step 2 and 3:N-(2-amino-5-(1H-imidazoles-1-yl) phenyl)-4-methoxy benzamide (361)

According to embodiment 19, identical program described in the step 3 and 4 (scheme 17), but compound 91 is replaced to compound 360 obtains titled reference compound 361 with 10.5% yield (through 2 steps). ¹H NMR：(DMSO)δ(ppm)：9.62(s，1H)，7.96(d，J＝9.0Hz，3H)，7.52(m，1H)，7.42(d，J＝2.5Hz，1H)，7.19(dd，J＝8.6，2.5Hz，1H)，7.04(d，J＝8.8Hz，2H)，7.03(s，1H)，6.85(d，J＝8.4Hz，1H)，5.11(s，2H)，3.83(s，3H)。MS：308.13(calc)，309.2(obs)。

Pharmacy composite

In second aspect, the invention provides the pharmacy composite that contains with good grounds histone deacetylase inhibitors of the present invention and pharmaceutically acceptable carrier, vehicle or thinner.Compound of the present invention can be by any method preparation well known in the art, and can be prepared as by any administration, includes but not limited to, enteron aisle is outer, oral, the hypogloeeis, in skin, part, nose, in the tracheae or internal rectum.In some preferred implementation, compound of the present invention in medical treatment device through intravenously administrable.In some other preferred implementation, the preferred by oral route of administration is carried out.

The feature of carrier depends on route of administration.Term used herein " pharmacy is acceptable " is meant the non-toxic material that biological activity compatible with the biosystem of cell, cell culture, tissue or organism and so on and can the interferon activity composition is renderd a service.Therefore, except inhibitor, composition of the present invention can also contain thinner, weighting agent, salt, buffer reagent, stablizer, solubilizing agent and other material well known in the art.In for example Remington ' s PharmaceuticalSciences, 18 ^ThEdition, ed.A.Gennaro, Mack Publishing Co., Easton, PA has described the preparation of the acceptable preparation of pharmacy in 1990.

Term pharmacologically acceptable salts used herein is meant the required biological activity that keeps above-claimed cpd and shows minimum or do not have the salt of unacceptable toxicological effect fully.The example of these salt comprises, but be not limited to, the acid salt that forms with mineral acid (for example, hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid, nitric acid and analogue), the salt that forms with organic acid (for example acetate, oxalic acid, tartrate, succsinic acid, oxysuccinic acid, xitix, phenylformic acid, tannic acid, pounce on acid, alginic acid, polyglutamic acid, naphthene sulfonic acid, naphthalene disulfonic acid and polygalacturonic acid).These compounds also can be used as the form of the acceptable quaternary salt of pharmacy well known by persons skilled in the art and use, this specifically comprises the quaternary ammonium salt of formula-NR+Z-, wherein R is a hydrogen, alkyl or benzyl, Z is a counterion, comprises muriate, bromide, iodide,-O-alkyl, tosylate, metilsulfate, sulfonate, phosphoric acid salt, or carboxylate salt (benzoate for example, succinate, acetate, glycollate, maleate, malate, Citrate trianion, tartrate, ascorbate salt, benzoate, cinnamate (cinnamoate), mandelate (mandeloate), benzyloate, with diphenyl acetic acid salt).Term used herein " salt " also will comprise mixture, for example with the mixture of basic metal or alkaline-earth metal.

The content of active compound in pharmaceutically acceptable carrier or thinner should be enough to the treatment effective dose is sent in the patient body, can not cause serious toxic effect to the patient who is treated simultaneously.For all above-mentioned symptoms, the preferred dose of active compound is about 0.01 to 300 mg/kg, and preferred 0.1 to 100 mg/kg/day is more typically 0.5 to about 25 mg/kg person's body weight/day that is subjected to the medicine.Typical local dose in suitable carrier is 0.01-3% wt/wt.Can calculate the effective dosage ranges of pharmacy acceptable derivates based on parent compound weight to be passed.If itself shows activity derivative, can use the weight of derivative as above to estimate effective dose, or by alternate manner estimation well known by persons skilled in the art.

The inhibition of histone deacetylase

In the third aspect, the invention provides a kind of in cell the method for inhibition of histone deacetylase, comprise the cell that needs the inhibition of histone deacetylase is contacted with histone deacetylase inhibitors of the present invention.Because compound of the present invention has suppressed histone deacetylase, they are useful tool for the in vitro study of histone deacetylase and the effect in bioprocess thereof.In addition, compound selective of the present invention ground has suppressed some isomer of HDAC.

The measurement of the enzymic activity of histone deacetylase can use currently known methods to carry out.For example, Yoshida etc., J.Biol.Chem., 265:17174-17179 (1990) have described by detecting the enzymic activity that acetylated histones is evaluated histone deacetylase in the cell of handling at trichostatin A.Taunton etc., Science, 272:408-411 (1996) have described the method endogenous and reorganization HDAC-1 measurement histone deacetylase enzymic activity of using similarly.

In some preferred implementations, all histone deacetylases in histone deacetylase inhibitors and the cell interact and reduce its activity.In according to these some other preferred implementations on the one hand of the present invention, non-whole histone deacetylases interaction and reduce its activity in histone deacetylase inhibitors and the cell.In some preferred implementation; inhibitor and a kind of histone deacetylase (for example HDAC-1) interact and reduce its activity, but do not have not interact with other histone deacetylase (for example HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7 and HDAC-8) or reduce its activity.As described below, some particularly preferred histone deacetylase inhibitors is, and participates in the inhibitor that histone deacetylase that tumour forms interacts and reduces its enzymic activity.Some other preferred histone deacetylase inhibitors interacts with the fungi histone deacetylase and reduces its enzymic activity.

Preferably, suppressed the cell proliferation of exposing cell according to the method for a third aspect of the present invention.Term " inhibition cell proliferation " is used in reference to the cell that does not contact to be compared, the retardance ability of the histone deacetylase inhibitors pair cell that contacts with this inhibitor growth.Can use Coulter Cell Counter (Coulter, Miami, FL) or hematimeter calculate the contact and the quantity of exposing cell not, thereby evaluation cell proliferation.When cellular entities growth (for example, solid tumor (solid tumor) or organ), can measure growth and with the growth size of exposing cell and comparing of exposing cell not with calipers, thereby evaluate cell proliferation.

Preferably, with the growth phase ratio of exposing cell not, the growth of the cell that contacts with inhibitor has been suppressed at least 50%.More preferably, 100% has suppressed cell proliferation (just exposing cell quantitatively can not increase).Most preferably, term " inhibition cell proliferation " comprises that exposing cell compares the reduction of quantity or size with exposing cell not.Therefore, according to the histone deacetylase inhibitors of cell proliferation in the inhibition exposing cell of the present invention, can cause retarded growth, cessation of growth cessation (arrest), program necrocytosis (apoptosis just) or the non-viable non-apoptotic cell death of exposing cell.

The cell inhibitory effect ability of histone deacetylase inhibitors of the present invention can make a group asynchronous growth cell synchronous.For example, histone deacetylase inhibitors of the present invention can be used for making G1 or the G2 phase that is stuck in the cell cycle at a group non-tumor cell of growth in vitro.This passable synchronously, for example, gene and/or gene prod that G1 that identifies in the cell cycle or G2 stage express.This effectiveness that also can be used for testing synchronously new transfection scheme of culturing cell, wherein the specific cells phase of the cycles of not waiting and depend on transfected cell is renderd a service in transfection.Use histone deacetylase inhibitors of the present invention can make the cell colony synchronization, render a service thereby help to detect the enhanced transfection.

Some preferred embodiment in, exposing cell is a tumour cell.Term " tumour cell " is used in reference to the cell that shows abnormal cell growth.Preferably, the abnormal cell growth of tumour cell is the cell growth that increases.Tumour cell can be proliferative cell, external show cell, the innocent tumor cell that can not shift in vivo of the contact inhibition that lacks growth or can shift in vivo and attempt to remove after can the regenerated cancer cells.Term " tumour formation " is used in reference to and brings out cell proliferation, and this causes tumor growth.In some embodiments, histone deacetylase inhibitors brings out the cytodifferentiation in the exposing cell.Thus, tumour cell may be induced differentiation when contacting with histone deacetylase inhibitors, thereby is created on the phylogenetic systematics than the exposing cell non-tumour daughter cell of high-grade more.

In some preferred implementations, in tumour cell, can be by analyzing some suppressor oncogene (p21 for example ^WAF1/Cip1) expression evaluate the antitumour activity of hdac inhibitor.Hdac inhibitor brings out the p21 among the human cancer cell ^WAF1/Cip1Express, this causes the retardance of on cell proliferation.

In some preferred implementations, exposing cell is in animal body.Thus, the invention provides a kind of cell proliferation disorders of animal or method of symptom for the treatment of, comprise histone deacetylase inhibitors of the present invention the animal administering therapeutic significant quantity of this treatment of needs.Preferably, animal is a Mammals, more preferably, is the Mammals of raising and train.Most preferably, this animal is the people.

Term " cell proliferation disorders or symptom " is meant that with abnormal cell growth especially the cell proliferation of supernormal growth is any symptom of feature.The example of this cell proliferation disorders or symptom includes but not limited to, cancer, restenosis and psoriasis.In particularly preferred embodiments, the invention provides a kind of method that suppresses the intravital tumor cell proliferation of animal, comprise there being the histone deacetylase of the present invention of the animal administering therapeutic significant quantity of at least one tumour cell in the body.

Estimate that compounds more of the present invention have the activity of inhibition to the histone deacetylase from the protozoon source.Therefore, the present invention also provides the method for a kind of treatment or prevention protozoan disease or infection, comprises the histone deacetylase inhibitors of the present invention to the animal administering therapeutic significant quantity of this treatment of needs.Preferably, this animal is a Mammals, more preferably is the people.Preferably; histone deacetylase inhibitors according to this embodiment use of the present invention; inhibition degree to the protozoon histone deacetylase is higher than its inhibition degree to the Mammals histone deacetylase, particularly is higher than its inhibition degree to human histone deacetylase.

The present invention further provides a kind of method for the treatment of fungal disease or infection, comprised histone deacetylase inhibitors of the present invention the animal administering therapeutic significant quantity of this treatment of needs.Preferably, this animal is a Mammals, more preferably is the people.Preferably; the histone deacetylase inhibitors that uses according to this embodiment of the present invention is higher than its inhibition degree to the Mammals histone deacetylase to the inhibition degree of fungi histone deacetylase, particularly is higher than its inhibition degree to human histone deacetylase.

Term " treatment significant quantity " is meant is enough to the active dosage of inhibition of histone deacetylase in the object cell, or is enough to the dosage that suppresses cell proliferation or be enough to bring out cytodifferentiation in subject.Can pass through any administration, include but not limited to, enteron aisle is outer, oral, the hypogloeeis, in skin, part, nose, in the tracheae or internal rectum.In some particularly preferred embodiment, compound of the present invention in medical treatment device through intravenously administrable.In some other preferred implementation, the preferred by oral route of administration is carried out.

When the general administration; histone deacetylase inhibitors is preferably to be enough to the making blood concentration of inhibitor reach about 0.01 μ M to about 100 μ M; more preferably about 0.05 μ M is to about 50 μ M; preferably approximately 0.1 μ M is to about 25 μ M again, and still more preferably about 0.5 μ M is to the dosed administration of about 25 μ M.For topical, can be effectively than this much lower concentration, also can allow much higher concentration.One skilled in the art will recognize that the dosage that produces the required histone deacetylase inhibitors of result of treatment can have very big change according to tissue, organ or particular animals to be treated or patient's difference.

In some preferred implementation of a third aspect of the present invention, this method further comprises makes cell contact with the antisense oligonucleotide of inhibition of histone deacetylation expression of enzymes.Nucleic acid level inhibitor (nucleic acid level inhibitor) (for example antisense oligonucleotide) and albumen level inhibitor (protein level inhibitor) are (promptly; the being used in combination histone deacetylase activity inhibitor) produces better inhibition effect; required amount is compared during thus with any inhibitor of independent use, has reduced to obtain the required inhibition dosage of given inhibition effect.According to the regional complementarity of the RNA of this antisense oligonucleotide on the one hand of the present invention and coding HDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7 and/or HDAC-8 or double-stranded DNA (for example, for HDAC-1 referring to GenBank AccessionNumber U50079, for HDAC-2 referring to GenBank Accession NumberU31814, and for HDAC-3 referring to GenBank Accession Number U75697).

For the purposes of the present invention, term " oligonucleotide " comprises two or more dezyribonucleosides, ribonucleoside or 2 '-replacement ribonucleoside residue or its any combination of polymers.Preferably, these oligonucleotide contain about 6 to about 100 nucleosides residues, and more preferably about 8 to about 50 nucleosides residues, and most preferably about 12 to about 30 nucleosides residues.The nucleosides residue can be by many known any internucleotide linkages and interconnection.Bonding includes but not limited between this nucleosides, thiophosphatephosphorothioate, phosphorodithioate, phosphonate ester, alkyl thio-phosphonate, phosphotriester, phosphoramidate, siloxanes, carbonic ether, carboxyl ester, ethanamide ester (acetamidate), carbamate, thioether, bridge joint phosphoramidate, bridge joint phosphonic acids methylene ester, bridge joint thiophosphatephosphorothioate and sulfone internucleotide linkage.In some preferred implementation, bonding can be phosphodiester, phosphotriester, thiophosphatephosphorothioate or phosphoramidic acid ester bond or their combination between these nucleosides.The term oligonucleotide also comprises alkali or sugar that contains chemical modification and/or the polymkeric substance that contains extra substituting group (including but not limited to oleophilic group, intercalating agent, diamines and diamantane).

For the purposes of the present invention, term " 2 '-replace ribonucleoside " comprises following ribonucleoside---wherein, the hydroxyl on 2 ' of the pentose part is substituted to produce the ribonucleoside of 2 '-O-replacement.Preferably; this replacement is to carry out with the low-carbon alkyl that contains the saturated or unsaturated carbon atom of 1-6 or with aryl or the allyl group that contains 2-6 carbon atom; wherein these alkyl, aryl or allyl group can not replace or be substituted, for example by halogen, hydroxyl, trifluoromethyl, cyano group, nitro, acyl group, acyloxy, alkoxyl group, carboxyl, carbalkoxy or amino the replacement.Term " 2 '-replace ribonucleoside " comprises that also wherein 2 '-hydroxyl is by ribonucleoside amino or that replaced by halogen group (preferably fluorine-based).

The particularly preferred antisense oligonucleotide that uses in this one side of the present invention comprises chimeric oligonucleotide and hybrid oligonucleotide.

For the purposes of the present invention, " chimeric oligonucleotide " is meant the oligonucleotide that contains bonding between more than one nucleosides.A preferred example of this chimeric oligonucleotide is to contain thiophosphatephosphorothioate, phosphodiester or phosphorodithioate zone, preferably comprise about 2 to about 12 Nucleotide, with the chimeric oligonucleotide in phosphonate ester or alkyl thio-phosphonate zone (referring to, Pederson etc. for example, United States Patent (USP) the 5th, 635,377 and 5,366, No. 878).Preferably, these chimeric oligonucleotides contain at least three and are selected from bonding between phosphodiester and phosphorothioate bond or the continuous nucleosides of their bonded.

For the purposes of the present invention, " hybrid oligonucleotide " is meant the oligonucleotide that contains more than one nucleosides.A preferred example of this hybrid oligonucleotide comprises the ribonucleoside acid region of ribonucleotide or 2 '-replacement, preferably comprises the Nucleotide and the deoxyribonucleotide zone of about 2 to about 12 2 '-replacement.Preferably, this hybrid oligonucleotide contains at least three successive dezyribonucleosides, also contains the ribonucleoside of ribonucleoside, 2 '-replacement, the ribonucleoside that preferred 2 '-O-replaces, or their combination (referring to, for example, Metelev and Agrawal, United States Patent (USP) the 5th, 652, No. 355).

The definite nucleotide sequence and the chemical structure of the antisense oligonucleotide that uses among the present invention can change, and suppress the ability that relevant group is expressed as long as this oligonucleotide keeps it.Whether this can easily have active next definite by testing specific antisense oligonucleotide.To this available assay method comprise mensuration to the quantity of the mRNA of gene prod coding, be used for western blotting (Western blotting) the analytical test method of gene prod, the activation method that is used for the enzymic activity gene prod or soft agar growth assay method or reporter gene structure assay method or tumor growth in vivo assay method, all these has a detailed description in (1997) Proc.Natl.Acad.Sci.USA 94:684-689 such as this specification sheets or Ramchandani.

The antisense oligonucleotide that uses among the present invention can use known chemical process synthetic on suitable solid carrier easily, combine (just some is recycled H-phosphonic acid ester chemical method, and other is recycled the phosphoramidite chemical method) that comprises H-phosphonic acid ester chemical method, phosphoramidite chemical method or H-phosphonic acid ester chemical method and phosphoramidite chemical method.Suitable solid carrier comprises and is used for any standard solid carrier of solid phase oligonucleotide synthetic, for example controlled pore glass (CPG) (referring to, Pon for example, R.T. (1993) Methods in Molec.Biol.20:465-496).

Particularly preferred oligonucleotide has about 13 nucleotide sequences to about 35 Nucleotide, and it comprises the nucleotide sequence shown in the table 4.Other particularly preferred oligonucleotide has about 15 nucleotide sequences to about 26 Nucleotide of the nucleotide sequence shown in the table 1.

Table 4

Oligo	Target	Registration number	Nucleotide position	Sequence	Intragenic position	Seq ID No.
Oligo	Target	Registration number	Nucleotide position	Sequence	Intragenic position	Seq ID No.	HDAC1 AS1 HDAC1 AS2 HDAC1 MM	Human HDAC1 Human HDAC1 Human HDAC1	U50079 U50079 U50079	1585-1604 1565-1584 1585-1604	5’-GAAACGTGAGGGACTCAGCA-3’ 5’-GGAAGCCAGAGCTGGAGAGG-3’ 5’-GTTAGGTGAGGCACTGAGGA-3’	3’-UTR 3’-UTR 3’-UTR	Seq ID No：1 Seq ID No：2 Seq ID No：3
HDAC2 AS HDAC2 MM	Human HDAC2 Human HDAC2	U31814 U31814	1643-1622 1643-1622	5’-GCTGAGCTGTTCTGATTTGG-3’ 5’-CGTGAGCACTTCTCATTTCC-3’	3’-UTR 3’-UTR	Seq ID No：4 Seq ID No：5	HDAC1 AS1 HDAC1 AS2 HDAC1 MM	Human HDAC1 Human HDAC1 Human HDAC1	U50079 U50079 U50079	1585-1604 1565-1584 1585-1604		3’-UTR 3’-UTR 3’-UTR	Seq ID No：1 Seq ID No：2 Seq ID No：3
HDAC2 AS HDAC2 MM	Human HDAC2 Human HDAC2	U31814 U31814	1643-1622 1643-1622	5’-GCTGAGCTGTTCTGATTTGG-3’ 5’-CGTGAGCACTTCTCATTTCC-3’	3’-UTR 3’-UTR	Seq ID No：4 Seq ID No：5	HDAC3 AS HDAC3 MM	Human HDAC3 Human HDAC3	AF039703 AF039703	1276-1295 1276-1295	5’-CGCTTTCCTTGTCATTGACA-3’ 5’-GCCTTTCCTACTCATTGTGT-3’	3’-UTR 3’-UTR	Seq ID No：6 Seq ID No：7
HDAC4 AS1 HDAC4 MM1 HDAC4 AS2 HDAC4 MM4	Human HDAC4 Human HDAC4 Human HDAC4 Human HDAC4	AB006626 AB006626 AB006626 AB006626	514-33 514-33 7710-29 7710-29	5-GCTGCCTGCCGTGCCCACCC-3’ 5’-CGTGCCTGCGCTGCCCACGG-3’ 5’-TACAGTCCATGCAACCTCCA-3’ 5’-ATCAGTCCAACCAACCTCGT-3’	5’-UTR 5’-UTR 3’-UTR 3’-UTR	Seq ID No：8 Seq ID No：9 Seq ID No：10 Seq ID No：11	HDAC3 AS HDAC3 MM	Human HDAC3 Human HDAC3	AF039703 AF039703	1276-1295 1276-1295	5’-CGCTTTCCTTGTCATTGACA-3’ 5’-GCCTTTCCTACTCATTGTGT-3’	3’-UTR 3’-UTR	Seq ID No：6 Seq ID No：7
HDAC4 AS1 HDAC4 MM1 HDAC4 AS2 HDAC4 MM4	Human HDAC4 Human HDAC4 Human HDAC4 Human HDAC4	AB006626 AB006626 AB006626 AB006626	514-33 514-33 7710-29 7710-29		5’-UTR 5’-UTR 3’-UTR 3’-UTR	Seq ID No：8 Seq ID No：9 Seq ID No：10 Seq ID No：11	HDAC5 AS	Human HDAC5	AF039691	2663-2682	5’-CTTCGGTCTCACCTGCTTGG-3’	3’-UTR	Seq ID No：12
HDAC6 AS HDAC6 MM	Human HDAC6 Human HDAC6	AJ011972 AJ011972	3791-3810 3791-3810	5’-CAGGCTGGAATGAGCTACAG-3’ 5’-GACGCTGCAATCAGGTAGAC-3’	3’-UTR 3’-UTR	Seq ID No：13 Seq ID No：14	HDAC5 AS	Human HDAC5	AF039691	2663-2682	5’-CTTCGGTCTCACCTGCTTGG-3’	3’-UTR	Seq ID No：12
HDAC6 AS HDAC6 MM	Human HDAC6 Human HDAC6	AJ011972 AJ011972	3791-3810 3791-3810	5’-CAGGCTGGAATGAGCTACAG-3’ 5’-GACGCTGCAATCAGGTAGAC-3’	3’-UTR 3’-UTR	Seq ID No：13 Seq ID No：14	HDAC7 AS	Human HDAC7	AF239243	2896-2915	5’-CTTCAGCCAGGATGCCCACA-3’	3’-UTR	Seq ID No：15
HDAC8 AS1 HDAC8 AS2	Human HDAC8 Human HDAC8	AF230097 AF230097	51-70 1328-1347	5’-CTCCGGCTCCTCCATCTTCC-3’ 5’-AGCCAGCTGCCACTTGATGC-3’	5’-UTR 3’-UTR	Seq ID No：16 Seq ID No：17	HDAC7 AS	Human HDAC7	AF239243	2896-2915	5’-CTTCAGCCAGGATGCCCACA-3’	3’-UTR	Seq ID No：15

The following example is used for further illustrating some of the preferred embodiment of the invention, and is not to limit the scope of the invention.

Chemical examination embodiment

Chemical examination embodiment 1

The active inhibition of histone deacetylase enzyme (HDAC-1)

Use follow procedure to chemically examine compound of the present invention.In this assay method, used buffer reagent is 25mM HEPES, and pH 8.0,137mM NaCl, 2.7mM KCl, 1mM MgCl ₂, matrix is Boc-Lys (the Ac)-AMC in 50mM DMSO liquid storage.The enzyme liquid storage is 4.08 mcg/ml in buffer reagent.

Compound is at room temperature used the pre-cultivation of enzyme (20 microlitres, 4.08 mcg/ml) (2 microlitres in DMSO are diluted to 13 microlitres to transfer in the chemical examination plate in buffer reagent) 10 minutes (the pre-culture volume of 35 microlitres).Mixture was at room temperature cultivated 5 minutes in advance.Make temperature reach 37 ℃ and add 16 microlitre matrix, thereby make the reaction beginning.Total reaction volume is 50 liters.Add photographic developer (Fluor-de-Lys photographic developer, Cat.#K1-105) stopped reaction of 50 microlitres after 20 minutes as making as described in the Biomol.Before reading, plate is at room temperature cultivated 10 minutes (λ in the dark _Ex=360 nanometers, λ _Em=470 nanometers, 435 nanometers by filtering).

Table 5: the inhibition of histone deacetylase ^*

Cpd	Title	HDAC-1 (μM)
Cpd	Title	HDAC-1 (μM)	6	N-[2-amino-5-(2-thienyl) phenyl]-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	a
12	N-[2-amino-5-(2-thienyl) phenyl]-4-{[(3-fluoro-4-p-methoxy-phenyl) amino] methyl } benzamide	a	6		a
12		a	23	N-[2-amino-5-(2-thienyl) phenyl]-1-(3,4,5-trimethoxy benzyl) indoline-6-carboxylic acid amides	a
29	N-[2-amino-5-(2-thienyl) phenyl]-5-{[(3,4, the 5-trimethoxyphenyl) amino] methyl }-1-cumarone-2-carboxylic acid amides	a	23		a
29		a	43	N-[2-amino-5-(2-thienyl) phenyl]-4-{[(4-pyridin-3-yl pyrimidine-2-yl) amino] methyl } benzamide	a

Cpd	Title	HDAC-1 (μM)
Cpd	Title	HDAC-1 (μM)	50	N-[2-amino-5-(2-thienyl) phenyl]-4-[({6-[2-(dimethylamino) oxyethyl group]-1H-benzimidazolyl-2 radicals-yl } sulfenyl) methyl] benzamide	a
67	(2E)-trans-N-[2-amino-5-(2-thienyl) phenyl]-3-(4-{[(3,4,5-trimethoxyphenyl) amino] methyl } phenyl) acrylamide	a	50		a
67		a	90	N-[2-amino-5-(3-thienyl) phenyl]-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	a
91	N-[2-amino-5-(3-furyl) phenyl]-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	a	90		a
91		a	92	N-[2-amino-5-(phenyl) phenyl]-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	a
B	N-(2-amino-4,5-difluorophenyl)-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	b	92		a
B		b	5	4-[(3,4-dimethoxy-phenyl amino)-methyl]-N-(2-nitro-5-benzene sulphur-2-base-phenyl)-benzamide	c
15	4-[(3,4-dimethoxy-phenyl amino)-methyl]-N-(2-nitro-4-benzene sulphur-2-base-phenyl)-benzamide	c	5		c
15		c	16	N-[2-amino-4-(2-thienyl) phenyl]-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	b
18	N-(2-amino-4-bromophenyl)-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	b	16		b
18		b	32	4-{[(3, the 4-Dimethoxyphenyl) amino] methyl }-N-[3-(2-thienyl) phenyl] benzamide	c
33	4-{[(3, the 4-Dimethoxyphenyl) amino] methyl }-the N-[3-fluorophenyl] benzamide	a	32		c
33		a	34	N-(3-amino-2-naphthyl)-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	c
35	N-(2-amino-5-chloro-4-fluorophenyl)-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	b	34		c
35		b	36	N-(2-amino-4,5-dichlorophenyl)-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	b

Cpd	Title	HDAC-1 (μM)
Cpd	Title	HDAC-1 (μM)	61	N-(4-amino-5-phenyl-3-thienyl)-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	c
62	N-(3-amino-2,2 '-thiophthene-4-yl)-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	c	61		c
62		c	68	N-(2-amino-5-butyl phenyl)-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	b
69	N-(2-amino-5-butyl phenyl)-4-methyl benzamide	b	68		b
69	N-(2-amino-5-butyl phenyl)-4-methyl benzamide	b	71	N-(2-amino-4-butyl phenyl)-4-methyl benzamide	c
76	N-[2-amino-5-(3-hydroxyl third-1-alkynes-1-yl) phenyl]-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	a	71	N-(2-amino-4-butyl phenyl)-4-methyl benzamide	c
76		a	87	N-(2-amino-5-bromophenyl)-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	b
88	N-{2-amino-5-[(1E)-3-amino-3-oxygen third-1-alkene-1-yl] phenyl }-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	b	87		b
88		b	93	N-[2-amino-5-(trifluoromethyl) phenyl]-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	d
94	N-[2, the 6-diamino-phenyl]-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide	b	93		d

^*The data of thick line top are the data that have the compound (compound just of the present invention) of planar rings structure in the contraposition of anilino amino; The cell that has two symbols is the result from twice measurement.Unless otherwise specified, in all tables of this specification sheets:

a＜1；1≤b＜20；c≥20；d＝9999

Following table 6A and 6b have shown the correlation data of compound of the present invention, and it shows owing to having added the plane substituting group and has produced the HDAC-1 that improves and suppress active.

Table 6A

Table 6B

Chemical examination embodiment 2

Histone deacetylase inhibitors is in vivo to the antitumous effect of human tumour heterogeneity graft

With 2 * 10 ⁶Pre-treatment HCT116 human colon rectum cancer cell, A549 Human Lung Cancer, the SW48 human colon rectum cancer, A431 carcinoma vulvae and the colo205 human colon rectum cancer are to female BCD1 mouse (Taconic Labs in 8 to 10 ages in week, Great Barrington NY) carries out subcutaneous injection in flank portion.The pre-treatment of these cells is finished by carry out minimum three successive tumour transplatations on mutually syngenesious nude mice.Subsequently, excise about 30 milligrams tumor fragment, and Forene anesthesia (Abbott Labs, Geneva, Switzerland) under in left flank portion subcutaneous implantation mouse body.When tumour reaches 100 cubic millimeters average-volume; every day is with the initial dose of 10 mg/kg; through vein, the subcutaneous or histone deacetylase inhibitors solution of peritoneal injection in suitable carrier (for example PBS, DMSO/ water or Tween 80/ water), treat mouse thus.Determine the optimal dose of hdac inhibitor by the dose response experiment according to standard program.Annotate and every other day to calculate gross tumor volume after defeated according to standard method (for example Meyer etc., Int.J.Cancer 43:851-856 (1989)).With hdac inhibitor treatment according to the present invention, compare with the control group of only using carrier (just not having hdac inhibitor) treatment, obviously reduce tumor weight and volume.Histone deacetylase inhibitors compound 6,29,67,258aa and 43 result are presented among Fig. 1-10.

Chemical examination embodiment 3

Histone deacetylase inhibitors and histone deacetylase antisense oligonucleotide in vivo to tumour in conjunction with antitumous effect

The purpose of present embodiment is to show being used in combination of histone deacetylase inhibitors of the present invention and histone deacetylase antisense oligonucleotide, to improve the ability to the inhibition of the intravital tumor growth of Mammals.Preferably, antisense oligonucleotide and hdac inhibitor have suppressed the expression and the activity of identical histone deacetylase.

Every day is with containing the mouse that about 0.1 milligram of salt solution preparation for treating to about 30 milligrams of histone deacetylase antisense oligonucleotide/kg body weight has the HCT116 tumour (100 cubic millimeters of average-volumes) of transplanting.Every day is with containing about 0.01 milligram of second group of mouse of the acceptable preparation for treating of pharmacy to about 5 milligrams of hdac inhibitor/kg body weight.

Some mouse are accepted antisense oligonucleotide and hdac inhibitor simultaneously.In these mouse, one group via the tail vein simultaneously vein accept antisense oligonucleotide and hdac inhibitor.Another group is accepted antisense oligonucleotide via the tail vein, and through the subcutaneous hdac inhibitor of accepting.Another group through subcutaneous antisense oligonucleotide and the hdac inhibitor accepted.Set up following control group similarly: the agent of not receiving treatment (for example only salt solution), only mispairing antisense oligonucleotide, the not active control compound of inhibition of histone deacetylase and mispairing antisense oligonucleotide and control compound arranged.

Measure gross tumor volume with calipers.Add that with antisense oligonucleotide histone deacetylation zymoprotein inhibitor according to the present invention treats, compare with control group and can obviously reduce tumor weight and volume.

Table 6C provide use 3-[4,5-dimethylthiazole-2-base-2,5-phenylbenzene tetrazolium] bromide (MTT) when chemical examination, compound is to the HDAC1 enzyme, to the inhibition data of antiproliferative activity (HCT116 human colon cancer cells), and p21 ^WAF1/Cip1Tumor suppressor gene induce data.

Table 6C

Embodiment	Compound	HD-1 μM	MTT HCT116 μM	P21 (HCT116 ) μM
Embodiment	Compound	HD-1 μM	MTT HCT116 μM	P21 (HCT116 ) μM	41a	143a	a	a	b
41b	143b	a	b	b	41a	143a	a	a	b
41b	143b	a	b	b	41c	143c	a	b	b
42	146	a	a	b	41c	143c	a	b	b
42	146	a	a	b	46	164	a	a	b
46cc	164cc	a	a	b	46	164	a	a	b
46cc	164cc	a	a	b	49	173	a	b	b
51	181	a	a	b	49	173	a	b	b

52	184	a	a	b
52	184	a	a	b	66	242	a	a	b
67e	245e	a	a	b	66	242	a	a	b
67e	245e	a	a	b	70a	256a	a	a	b
70b	256b	a	a	b	70a	256a	a	a	b
70b	256b	a	a	b	70c	256c	a	a	b
71d	258d	a	a	b	70c	256c	a	a	b
71d	258d	a	a	b	71aa	258aa	a	a	b
71cc	258cc	a	a	b	71aa	258aa	a	a	b
71cc	258cc	a	a	b	71hh	258hh	a	a	b
71mm	258mm	a	a	b	71hh	258hh	a	a	b
71mm	258mm	a	a	b	71nn	258nn	a	b	b
71pp	258pp	a	a	b	71nn	258nn	a	b	b
71pp	258pp	a	a	b	71qq	258qq	a	a	b
78	283	a	a	b	71qq	258qq	a	a	b
78	283	a	a	b	79	286	a	b	b
79aa	286aa	a	a	b	79	286	a	b	b
79aa	286aa	a	a	b	97	349	a	a	b

The MTT chemical examination

The compound that adds various concentration in human colon's cancer HCT116 cell in the 96-orifice plate.With cell at 37 ℃ at 5% CO ₂Cultivated 72 hours in the incubator.Ultimate density with 0.5 mg/ml adds MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-phenylbenzene tetrazolium bromide, Sigma) also use cell cultures 4 hours, solubilising buffer reagent (50% N that in culturing cell, adds equal volume then, the N-methylformamide, 20% SDS, pH 4.7).After the overnight incubation, use benchmark, determine the quantity of solubilising dyestuff by the colorimetric reading under 570nM at 630nM.Standard growth curve according to relevant cell system changes into cell count with the OD value.50% o'clock the concentration of cell count being reduced to DMSO-processing cell is confirmed as MTT IC ₅₀

P21 ^WAF1/Cip1Chemical examination

With the report plasmid of the luciferase of coding p21 promoters driven transfection HCT116 cell stably.With shown in the hdac inhibitor of concentration cell was handled 16 hours, collect the plain enzymic activity of cell and analysis of fluorescence then.Specifying the effective concentration (EC) of MS-275 is 1 μ M.Compare hdac inhibitor and MS-275 (T.Suzuki etc., J.Med.Chem., 1999, ability 3001-3003).The low EC of given compound show this compound induce aspect the p21 expression more effective than MS-275.

Sequence table

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<130>MBHB-03-552-C

<160>17

<170>PatentIn version 3.3

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<212>DNA

＜213〉artificial

<220>

＜223〉synthetic oligonucleotide: registration number U50079

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gaaacgtgag ggactcagca 20

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<212>DNA

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<220>

＜223〉synthetic oligonucleotide: registration number U50079

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ggaagccaga gctggagagg 20

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<212>DNA

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<220>

＜223〉synthetic oligonucleotide: registration number U50079

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gttaggtgag gcactgagga 20

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<220>

＜223〉synthetic oligonucleotide: registration number U31814

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gctgagctgt tctgatttgg 20

<210>5

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＜213〉artificial

<220>

＜223〉synthetic oligonucleotide: registration number U31814

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cgtgagcact tctcatttcc 20

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＜223〉synthetic oligonucleotide: registration number AF039703

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cgctttcctt gtcattgaca 20

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gcctttccta ctcattgtgt 20

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＜223〉synthetic oligonucleotide: registration number AB006626

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gctgcctgcc gtgcccaccc 20

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cttcagccag gatgcccaca 20

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agccagctgc cacttgatgc 20

Claims

1. the histone deacetylase inhibitors of formula (1) or its pharmacologically acceptable salts:

Wherein

Ar ²Be saturated or single-or poly--unsaturated C ₅-C ₁₄-single-or condense poly--cyclic hydrocarbon radical, and each ring is chosen wantonly and is contained one, two, three or four one-tenth ring hetero atom, and each ring is optional by one or more C that are selected from ₁-C ₇-alkyl, hydroxyl, C ₁-C ₇-alkoxyl group, halogen and amino group replace, and condition is one and becomes ring O or S not to become ring O or S adjacent with another;

Q is 0 or 1;

Y is any by 1 to 50 acceptable chemical part of the pharmacy that atom is formed; And

Condition is

2. according to the compound of claim 1, R wherein ¹Be phenyl, naphthyl, anthryl or fluorenyl.

3. according to the compound of claim 1, R wherein ¹Be furyl or thienyl.

4. according to the compound of claim 2, R wherein ², R ³And R ⁴Be hydrogen.

5. according to the compound of claim 3, R wherein ², R ³And R ⁴Be hydrogen.

6. according to the compound of claim 1, wherein Y is Cy ²-X ¹-and

Cy ²Be hydrogen, cycloalkyl, aryl, heteroaryl or heterocyclic radical, their optional separately being substituted, and optional separately being fused on one or two aryl or the heteroaryl ring, or be fused on one or two saturated or the undersaturated cycloalkyl of part or heterocyclic ring, and any optional being substituted of aforementioned ring wherein; And

M ¹Be independently selected from each case-O-,-N (R ⁷)-,-S-,-S (O)-, S (O) ₂-,-S (O) ₂N (R ⁷)-,-N (R ⁷)-S (O) ₂-,-C (O)-,-C (O)-NH-,-NH-C (O)-,-NH-C (O)-O-and-O-C (O)-NH-,-NH-C (O)-NH-,

7. according to the compound of claim 6, X wherein ¹Be selected from-N (Z)-C ₀-C ₇-alkyl-,-O-C ₀-C ₇-alkyl-,-C (H)=CH-C ₀-C ₇-alkyl-,-S-C ₀-C ₇-alkyl-or-C ₁-C ₇-alkyl-, wherein Z be-H or optional quilt-OH ,-NH ₂, or halogen replace-C ₁-C ₇-alkyl-.

8. according to the compound of claim 6, X wherein ¹Be selected from methylene radical, amino methyl and sulphomethyl.

9. according to the compound of claim 6, Cy wherein ²Be selected from

Their optional separately being substituted, and optional being fused on one or more aromatic rings.

10. according to the compound of claim 6, Cy wherein ²Be aryl or heteroaryl, their optional separately being substituted.

11. according to the compound of claim 6, wherein Cy ²Be phenyl, pyrimidyl, benzimidazolyl-or benzothiazolyl, their optional separately being substituted.

12. according to the compound of claim 11, wherein Cy ²Contain one to three and be independently selected from C ₁-C ₇-alkoxyl group, halogen, two-C ₁-C ₇-alkylamino-C ₁-C ₇The substituting group of-alkoxyl group and heteroaryl.

13. according to the compound of claim 12, wherein said substituting group is selected from methoxyl group, fluorine, chlorine, pyridyl and dimethylamino-oxyethyl group.

14. according to the compound of claim 13, wherein Cy ²By one to three CH ₃The phenyl that O-replaces.

15. according to the compound of claim 6, wherein Y be (V '-L ⁴) _t-V-L ³-, and

M1 and m2 are 0 or 1 independently;

X ' is-N (R ²¹)-,-C (O) N (R ²¹)-, N (R ²¹) C (O)-,-O-or-S-;

R ²¹Be-H, V "-(C ₁-C ₆-alkyl) a;

L ⁴Be (C ₁-C ₆-alkyl) _a-M-(C ₁-C ₆-alkyl) _b

A and b are 0 or 1 independently;

M is-NH-,-NHC (O)-,-C (O) NH-,-C (O)-,-SO ₂-,-NHSO ₂-or-SO ₂NH-;

T is 0 or 1.

16. according to the compound of claim 15, wherein Y is V-L ³And

L ³Be-NH-CH-or-CH-NH-;

V chooses wantonly to be independently selected from halogen, hydroxyl, C by 1 to 3 ₁-C ₆-alkyl, C ₁-C ₆-alkyl-oxygen base or-phenyl that the part of sulfenyl (particularly methoxyl group or methylthio group) replaces, wherein each hydrocarbyl portion is optional is replaced by one or more parts that are independently selected from halogen, nitroso-group, amino, sulfonamido and cyano group.

17. according to the compound of claim 16, wherein V is the optional loop section that replaces, it is selected from:

18. according to the compound of claim 6, wherein

19. according to the compound of claim 6, wherein Y is selected from:

F) morpholinyl-CH ₂-;

G) the optional aryl that replaces;

J) optional heteroaryl that replaces or the optional heterocyclic radical that replaces;

r)F ₃CC(O)NH-；

20. according to the compound of claim 6, wherein Y is selected from:

21. according to the compound of claim 2, wherein R ²To R ⁴Be independently hydrogen ,-NH ₂, nitro, furyl, chlorine, fluorine, butyl, trifluoromethyl, bromine, thienyl, phenyl ,-CHCHC (O)-NH ₂,-C ≡ CCH ₂-R ⁹, R wherein ⁹Be hydrogen, C ₁-C ₇-alkyl, hydroxyl, amino or C ₁-C ₇-alkoxyl group.

22. according to the compound of claim 3, wherein R ²To R ⁴Be independently hydrogen ,-NH ₂, nitro, furyl, chlorine, fluorine, butyl, trifluoromethyl, bromine, thienyl, phenyl ,-CHCHC (O)-NH ₂,-C ≡ CCH ₂-R ⁹, R wherein ⁹Be hydrogen, C ₁-C ₇-alkyl, hydroxyl, amino or C ₁-C ₇-alkoxyl group.

23. according to the compound of claim 6, wherein q is 0 and X ¹Be independently selected from-NH-CH ₂-,-S-CH ₂-and-CH ₂-.

24. according to the compound of claim 1, wherein Ar ²Has following formula

25. according to the compound of claim 24, wherein Ar ²Has following formula

26. according to the compound of claim 24, wherein Ar ²Be selected from phenylene, benzo furylidene and indolylidene.

27. according to the compound of claim 6, wherein by Cy ²-X ¹The part that forms is selected from:

28. according to the compound of claim 6, it is formula (2):

Or its pharmacologically acceptable salts, wherein

R ²And R ³Be independently selected from hydrogen, trifluoromethyl, butyl ,-(CH ₂) ₃-OH, chlorine, fluorine, amino, phenyl, thienyl, furyl ,-CHCCHC (O) NH ₂,-C ≡ CCH ₂-OH ,-C ≡ CCH ₂-OCH ₃And

29. according to the compound of claim 28, wherein Cy ²Be selected from:

30. according to the compound of claim 28, wherein the A ring is not further replaced.

31. according to the compound of claim 28, wherein R ²And R ³All be-H.

32. the compound according to claim 1 is selected from:

N-[2-amino-5-(2-thienyl) phenyl]-4-{[(3, the 4-Dimethoxyphenyl) amino] methyl } benzamide;

N-[2-amino-5-(2-thienyl) phenyl]-4-{[(4-pyridin-3-yl pyrimidine-2-base) amino] methyl } benzamide;

N-[2-amino-5-(2-thienyl) phenyl]-4-[({6-[2-(dimethylamino) oxyethyl group]-1H-benzimidazolyl-2 radicals-yl } sulfenyl) methyl] benzamide;

N-[2-amino-5-(2-thienyl) phenyl]-amino of 4-{[(5-chloro-6-fluoro-1H-benzimidazolyl-2 radicals-yl)] methyl } benzamide;

N-[2-amino-5-(2-thienyl) phenyl]-5-{[(3,4, the 5-trimethoxyphenyl) amino] methyl }-1-cumarone-2-carboxylic acid amides;

N-[2-amino-5-(2-thienyl) phenyl]-1-(3,4,5-trimethoxy benzyl) indoline-6-carboxylic acid amides;

Trans-N-[2-amino-5-(2-thienyl) phenyl]-3-(4-{[(3,4,5-trimethoxyphenyl) amino] methyl } phenyl) acrylamide;

N-[2-amino-5-(2-thienyl) phenyl]-4-{[(3-fluoro-4-p-methoxy-phenyl) amino] methyl } benzamide;

N-[2-amino-5-(2-thienyl) phenyl]-sulfenyl of 4-{[(6-chloro-5-fluoro-1H-benzimidazolyl-2 radicals-yl)] methyl } benzamide;

With any one or more pharmacologically acceptable salts in the aforesaid compound.

33., be used for the inhibition of histone deacetylase according to the compound of claim 1.

34., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 1.

35. the compound of claim 34, wherein said treatment realizes by the inhibition of histone deacetylase.

36. the compound of claim 34, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

37. the compound of claim 34, wherein said cell proliferation disorders is a cancer.

38. the compound of claim 37, wherein said cancer is a solid tumor cancer.

39. the compound of claim 37, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

40. a pharmacy composite contains compound according to claim 1 and pharmaceutically acceptable carrier.

41. the pharmacy composite of claim 40, it further contains the nucleic acid level inhibitor of histone deacetylase.

42. the pharmacy composite of claim 41, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

43. the pharmacy composite of claim 42, wherein said antisense oligonucleotide are selected from SEQID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

44. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 1 that suppresses significant quantity.

45. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 40 of described individual administering therapeutic significant quantity.

46. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 41 of described individual administering therapeutic significant quantity.

47. the method for claim 45, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

48. the method for claim 45, wherein said cell proliferation disorders is a cancer.

49. the method for claim 48, wherein said cancer is a solid tumor cancer.

50. the method for claim 49, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

51. the method for claim 46, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

52. the method for claim 46, wherein said cell proliferation disorders is a cancer.

53. the method for claim 52, wherein said cancer is a solid tumor cancer.

54. the method for claim 53, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

55. the compound of following formula

Or its pharmacologically acceptable salts or interior hydrolyzable ester of body or acid amides, wherein:

Φ is-NH ₂Or-OH;

M is 0,1,2,3 or 4; R wherein ⁵Value can be identical or different;

R ⁶It is halogen;

N is 0,1 or 2; R wherein ⁶Value can be identical or different; And

R ¹, R ², R ³And R ⁴As defined in claim 1.

56. the compound of claim 55, wherein:

Ring A is a heterocyclic radical;

M is 0,1,2,3 or 4; R wherein ⁵Value identical or different;

R ⁶It is halogen; And

N is 0,1 or 2; R wherein ⁶Value can be identical or different.

57. the compound of claim 56, wherein:

M is 0,1,2,3 or 4; R wherein ⁵Value identical or different;

R ⁶It is fluorine or chlorine; And

N is 0,1 or 2; R wherein ⁶Value identical or different;

58. the compound of claim 57, wherein:

D and F are independently selected from fluorine, methoxy or ethoxy;

M is 0,1 or 2; R wherein ⁵Value identical or different;

R ⁶It is fluorine; And

N is 0 or 1.

59. the compound of claim 55, it is selected from by using

The terminal portions of the table 1-8 of replacement WO03/087057 and 13 compound And the compound of modification, wherein Φ, R ¹, R ², R ³, and R ⁴Such as claim 1 definition.

60., be used for the inhibition of histone deacetylase according to the compound of claim 55.

61., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 55.

62. the compound of claim 61, wherein said treatment realizes by the inhibition of histone deacetylase.

63. the compound of claim 61, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

64. the compound of claim 61, wherein said cell proliferation disorders is a cancer.

65. the compound of claim 64, wherein said cancer is a solid tumor cancer.

66. the compound of claim 64, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

67. a pharmacy composite contains described compound of with good grounds claim 55 and pharmaceutically acceptable carrier.

68. the pharmacy composite of claim 67, it further contains the nucleic acid level inhibitor of histone deacetylase.

69. the pharmacy composite of claim 68, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

70. the pharmacy composite of claim 69, wherein said antisense oligonucleotide are selected from SEQID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

71. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 55 that suppresses significant quantity.

72. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 67 of described individual administering therapeutic significant quantity.

73. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 68 of described individual administering therapeutic significant quantity.

74. the method for claim 72, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

75. the method for claim 72, wherein said cell proliferation disorders is a cancer.

76. the method for claim 75, wherein said cancer is a solid tumor cancer.

77. the method for claim 76, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

78. the method for claim 73, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

79. the method for claim 73, wherein said cell proliferation disorders is a cancer.

80. the method for claim 77, wherein said cancer is a solid tumor cancer.

81. the method for claim 78, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

82. the compound of following formula, its N-oxide form, its pharmacy acceptable addition salt or its stereochemistry heterogeneous forms:

Wherein

Φ is-NH ₂Or-OH;

N is 0,1,2 or 3, wherein when n is 0, is meant direct key;

T is 0,1,2,3 or 4, wherein when t is 0, is meant direct key;

Q, X, Y and Z are N or CH independently;

R ¹Be H or as defined in claim 1;

R ², R ³And R ⁴As defined in claim 1;

Ring A is selected from

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

R ⁵And R⁶Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C_1-6-alkyl; Three halo C_1-6-alkoxyl; C_1-6-alkyl; By aryl and C_3-10The C that-cycloalkyl replaces_1-6-alkyl; C_1-6-alkoxyl; C_1-6-alkoxy C_1-6-alkoxyl; C_1-6-alkyl carbonyl; C_1-6-alkoxyl carbonyl; C_1-6-alkyl sulfonyl base; Cyano group C_1-6-alkyl; Hydroxyl C_1-6-alkyl; Hydroxyl C_1-6-alkoxyl; Hydroxyl C_1-6-alkyl is amino; Amino C_1-6-alkoxyl; Two (C_1-6-alkyl) amino carbonyl; Two (hydroxyl C_1-6-alkyl) amino; (aryl) (C_1-6-alkyl) amino; Two (C_1-6-alkyl) amino C_1-6-alkoxyl; Two (C_1-6-alkyl) amino C_1-6-alkyl is amino; Two (C_1-6-alkyl) amino C_1-6The amino C of-alkyl_1-6-alkyl; Aryl sulfonyl; Arlysulfonylamino; Aryloxy group; Aryloxy group C_1-6-alkyl; Aryl C_2-6-olefin 2 base; Two (C_1-6-alkyl) amino; Two (C_1-6-alkyl) amino C_1-6-alkyl; Two (C_1-6-alkyl) amino (C_1-6-alkyl) amino; Two (C_1-6-alkyl) amino (C_1-6-alkyl) amino C_1-6-alkyl; Two (C_1-6-alkyl) amino C_1-6-alkyl (C_1-6-alkyl) amino; Two (C_1-6-alkyl) amino C_1-6-alkyl (C_1-6-alkyl) amino C_1-6-alkyl; Amino (the C of amino-sulfonyl_1-6-alkyl) amino; Amino (the C of amino-sulfonyl_1-6-alkyl) amino C_1-6-alkyl; Two (C_1-6-alkyl) amino (C of amino-sulfonyl_1-6-alkyl) amino; Two (C_1-6-alkyl) amino (C of amino-sulfonyl_1-6-alkyl) amino C_1-6-alkyl; Cyano group; Thiophenyl; By two (C_1-6-alkyl) amino C_1-6-alkyl (C_1-6-alkyl) amino C_1-6-alkyl replaces, two (C_1-6-alkyl) amino C_1-6-alkyl, C_1-6-alkylpiperazinyl C_1-6-alkyl, hydroxyl C_1-6-alkylpiperazinyl C_1-6-alkyl, hydroxyl C_1-6-alkoxy C_1-6-alkylpiperazinyl C_1-6-alkyl, two (C_1-6-alkyl) amino-sulfonyl piperazinyl C_1-6-alkyl, C_1-6-alkoxyl piperazinyl, C_1-6-alkoxyl piperazinyl C_1-6-alkyl, morpholinyl C_1-6-alkyl, hydroxyl C_1-6-alkyl (C_1-6-alkyl) amino C_1-6-alkyl or two (hydroxyl C_1-6-alkyl) amino C_1-6The thiophenyl that-alkyl replaces; Furyl; By hydroxyl C_1-6The furyl that-alkyl replaces; Benzofuranyl; Imidazole radicals; Oxazolyl; By aryl and C_1-6-alkyl replaces the De oxazolyl; C_1-6-alkyl triazolyl; Tetrazole radical; Pyrrolidinyl; Pyrrole radicals; Piperidyl C_1-6-alkoxyl; Morpholinyl; C_1-6-alkyl morpholine base; Morpholinyl C_1-6-alkoxyl; Morpholinyl C_1-6-alkyl; Morpholinyl C_1-6-alkyl is amino; Morpholinyl C_1-6The amino C of-alkyl_1-6-alkyl; Piperazinyl; C_1-6-alkylpiperazinyl; C_1-6-alkylpiperazinyl C_1-6-alkoxyl; Piperazinyl C_1-6-alkyl; Naphthyl sulfonyl piperazinyl; Naphthyl sulfonyl piperidyl; The naphthyl sulfonyl; C_1-6-alkylpiperazinyl C_1-6-alkyl; C_1-6-alkylpiperazinyl C_1-6-alkyl is amino; C_1-6-alkylpiperazinyl C_1-6The amino C of-alkyl_1-6-alkyl; C_1-6-alkylpiperazinyl sulfonyl; Amino-sulfonyl piperazinyl C_1-6-alkoxyl; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C_1-6-alkyl; Two (C_1-6-alkyl) amino-sulfonyl piperazinyl; Two (C_1-6-alkyl) amino-sulfonyl piperazinyl C_1-6-alkyl; Hydroxyl C_1-6-alkylpiperazinyl; Hydroxyl C_1-6-alkylpiperazinyl C_1-6-alkyl; C_1-6-alkoxyl piperidyl; C_1-6-alkoxyl piperidyl C_1-6-alkyl; The amino C of piperidyl_1-6-alkyl is amino; The amino C of piperidyl_1-6The amino C of-alkyl_1-6-alkyl; (C_1-6-Alkylpiperidine base) (hydroxyl C_1-6-alkyl) amino C_1-6-alkyl is amino; (C_1-6-Alkylpiperidine base) (hydroxyl C_1-6-alkyl) amino C_1-6The amino C of-alkyl_1-6-alkyl; Hydroxyl C_1-6-alkoxy C_1-6-alkylpiperazinyl; Hydroxyl C_1-6-alkoxy C_1-6-alkylpiperazinyl C_1-6-alkyl; (hydroxyl C_1-6-alkyl) (C_1-6-alkyl) amino; (hydroxyl C_1-6-alkyl) (C_1-6-alkyl) amino C_1-6-alkyl; Hydroxyl C_1-6The amino C of-alkyl_1-6-alkyl; Two (hydroxyl C_1-6-alkyl) amino C_1-6-alkyl; Pyrrolidinyl C_1-6-alkyl; Pyrrolidinyl C_1-6-alkoxyl; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two_1-6-alkyl and three halo C_1-6The pyrazolyl that the substituting group of-alkyl replaces; Pyridine radicals; By C_1-6The pyridine radicals that-alkoxyl, aryloxy group or aryl replace; Pyrimidine radicals; The tetrahydro-pyrimidine base piperazinyl; Tetrahydro-pyrimidine base piperazinyl C_1-6-alkyl; Quinolyl; Indyl; Phenyl; By one, two or three are independently selected from the phenyl that the substituting group of following group replaces, these substituting groups are selected from halogen, amino, nitro, C_1-6-alkyl, C_1-6-alkoxyl, hydroxyl C_1-4-alkyl, trifluoromethyl, trifluoro methoxyl group, hydroxyl C_1-4-alkoxyl, C_1-4-alkyl sulfonyl base, C_1-4-alkoxy C_1-4-alkoxyl, C_1-4-alkoxyl carbonyl, amino C_1-4-alkoxyl, two (C_1-4-alkyl) amino C_1-4-alkoxyl, two (C_1-4-alkyl) amino, two (C_1-4-alkyl) amino carbonyl, two (C_1-4-alkyl) amino C_1-4-alkyl, two (C_1-4-alkyl) amino C_1-4The amino C of-alkyl_1-4-alkyl, two (C_1-4-alkyl) amino (C_1-4-alkyl) amino, two (C_1-4-alkyl) amino (C_1-4-alkyl) amino C_1-4-alkyl, two (C_1-4-alkyl) amino C_1-4-alkyl (C_1-4-alkyl) amino, two (C_1-4-alkyl) amino C_1-4-alkyl (C_1-4-alkyl) amino C_1-4-alkyl, the amino (C of amino-sulfonyl_1-4-alkyl) amino, the amino (C of amino-sulfonyl_1-4-alkyl) amino C_1-4-alkyl, two (C_1-4-alkyl) amino (C of amino-sulfonyl_1-4-alkyl) amino, two (C_1-4-alkyl) amino (C of amino-sulfonyl_1-4-alkyl) amino C_1-4-alkyl, cyano group, piperidyl C_1-4-alkoxyl, pyrrolidinyl C_1-4-alkoxyl, amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C_1-4-alkyl, two (C_1-4-alkyl) amino-sulfonyl piperazinyl, two (C_1-4-alkyl) amino-sulfonyl piperazinyl C_1-4-alkyl, hydroxyl C_1-4-alkylpiperazinyl, hydroxyl C_1-4-alkylpiperazinyl C_1-4-alkyl, C_1-4-alkoxyl piperidyl, C_1-4-alkoxyl piperidyl C_1-4-alkyl, hydroxyl C_1-4-alkoxy C_1-4-alkylpiperazinyl, hydroxyl C_1-4-alkoxy C_1-4-alkylpiperazinyl C_1-4-alkyl, (hydroxyl C_1-4-alkyl) (C_1-4-alkyl) amino, (hydroxyl C_1-4-alkyl) (C_1-4-alkyl) amino C_1-4-alkyl, two (hydroxyl C_1-4-alkyl) amino, two (hydroxyl C_1-4-alkyl) amino C_1-4Furyl, pyrrolidinyl C that-alkyl, furyl, quilt-CH=CH-CH=CH-replace_1-4-alkyl, pyrrolidinyl C_1-4-alkoxyl, morpholinyl, morpholinyl C_1-4-alkoxyl, morpholinyl C_1-4-alkyl, morpholinyl C_1-4-alkyl is amino, morpholinyl C_1-4The amino C of-alkyl_1-4-alkyl, piperazinyl, C_1-4-alkylpiperazinyl, C_1-4-alkylpiperazinyl C_1-4-alkoxyl, piperazinyl C_1-4-alkyl, C_1-4-alkylpiperazinyl C_1-4-alkyl, C_1-4-alkylpiperazinyl C_1-4-alkyl is amino, C_1-4-alkylpiperazinyl C_1-4The amino C of-alkyl_1-6-alkyl, tetrahydro-pyrimidine base piperazinyl, tetrahydro-pyrimidine base piperazinyl C_1-4-alkyl, the amino C of piperidyl_1-4-alkyl is amino, the amino C of piperidyl_1-4The amino C of-alkyl_1-4-alkyl, (C_1-4-Alkylpiperidine base) (hydroxyl C_1-4-alkyl) amino C_1-4-alkyl is amino, (C_1-4-Alkylpiperidine base) (hydroxyl C_1-4-alkyl) amino C_1-4The amino C of-alkyl_1-4-alkyl, pyridine radicals C_1-4-alkoxyl, hydroxyl C_1-4-alkyl is amino, hydroxyl C_1-4The amino C of-alkyl_1-4-alkyl, two (C_1-4-alkyl) amino C_1-4-alkyl amino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C_1-4-alkoxyl and thiophenyl C_1-4-alkyl is amino; Core

Each R ⁵And R ⁶Can be positioned on the nitrogen to replace hydrogen;

83. the compound of claim 82, wherein:

N is 1 or 2;

T is 0,1 or 2;

Each Z is a nitrogen;

Each R ¹³Be hydrogen;

Each s is 0,1,2 or 5 independently;

Each R ⁵And R ⁶Be independently selected from hydrogen; Halogen; Nitro; Three halo C _1-6-alkyl; Three halo C _1-6-alkoxyl group; C _1-6-alkyl; C _1-6-alkoxyl group; C _1-6-alkyl sulphonyl; (aryl) (C _1-6-alkyl) amino; Aryl sulfonyl; Aryloxy; Aryl C _2-6-olefin 2 base; Two (C _1-6-alkyl) amino; Thiophenyl; By two (C _1-6-alkyl) amino C _1-6-alkyl (C _1-6-alkyl) amino C _1-6-alkyl, two (C _1-6-alkyl) amino C _1-6-alkyl, C _1-6-alkylpiperazine base C _1-6-alkyl, hydroxyl C _1-6-alkylpiperazine base C _1-6-alkyl, hydroxyl C _1-6-alkoxy C _1-6-alkylpiperazine base C _1-6-alkyl, two (C _1-6-alkyl) amino-sulfonyl piperazinyl C _1-6-alkyl, C _1-6-alkoxyl group piperidyl C _1-6-alkyl, morpholinyl C _1-6-alkyl, hydroxyl C _1-6-alkyl (C _1-6-alkyl) amino C _1-6-alkyl or two (hydroxyl C _1-6-alkyl) amino C _1-6The thiophenyl that-alkyl replaces; Furyl; Oxazolyl; Pyrryl; Pyrazolyl; Pyridyl; By C _1-6The pyridyl that-alkoxyl group replaces; Quinolyl; Indyl; Phenyl; And by one, two or three are independently selected from halogen, amino, C _1-6-alkyl, C _1-6-alkoxyl group, hydroxyl C _1-4-alkyl, trifluoromethyl, trifluoromethoxy, two (C _1-4-alkyl) amino C _1-4-alkoxyl group, two (C _1-4-alkyl) amino, two (C _1-4-alkyl) amino C _1-4-alkyl, two (C _1-4-alkyl) amino C _1-4-alkyl (C _1-4-alkyl) amino, two (C _1-4-alkyl) amino C _1-4-alkyl (C _1-4-alkyl) amino C _1-4-alkyl, hydroxyl C _1-4-alkylpiperazine base C _1-4-alkyl, hydroxyl C _1-4-alkoxy C _1-4-alkylpiperazine base C _1-4-alkyl, two (hydroxyl C _1-4-alkyl) amino C _1-4-alkyl, pyrrolidyl C _1-4-alkyl, pyrrolidyl C _1-4-alkoxyl group, morpholinyl C _1-4-alkoxyl group, morpholinyl C _1-4-alkyl and C _1-4-alkylpiperazine base C _1-4The phenyl that the substituting group of-alkyl replaces, and

Centre portions

Optional with methylene bridge bridging (that is, forming the dicyclo part).

84. the compound of claim 83, wherein:

T is 0 or 2;

R ¹²Be hydrogen;

-L-is direct key;

R ¹⁴Be hydrogen;

The A ring is for being selected from (a-1), (a-9), (a-19), (a-20), (a-21), (a-22), (a-23), (a-49) and group (a-50); And

Each R ⁵And R ⁶Be independently selected from hydrogen; Halogen; Three halo C _1-6-alkyl; Three halo C _1-6-alkoxyl group; C _1-6-alkyl; C _1-6-alkoxyl group; Aryl C _2-6-olefin 2 base; Two (C _1-6-alkyl) amino; Thiophenyl; By two (C _1-6-alkyl) amino C _1-6-alkyl (C _1-6-alkyl) amino C _1-6-alkyl, two (C _1-6-alkyl) amino C _1-6-alkyl, C _1-6-alkylpiperazine base C _1-6-alkyl, hydroxyl C _1-6-alkylpiperazine base C _1-6-alkyl, hydroxyl C _1-6-alkoxy C _1-6-alkylpiperazine base C _1-6-alkyl, C _1-6-alkoxyl group piperidyl C _1-6-alkyl, morpholinyl C _1-6-alkyl, hydroxyl C _1-6-alkyl (C _1-6-alkyl) amino C _1-6-alkyl or two (hydroxyl C _1-6-alkyl) amino C _1-6The thiophenyl that-alkyl replaces; Furyl; Oxazolyl; Pyrazolyl; Pyridyl; By C _1-6The pyridyl that-alkoxyl group replaces; Quinolyl; Indyl; Phenyl; And by one, two or three are independently selected from halogen, amino, C _1-6-alkyl, C _1-6-alkoxyl group, hydroxyl C _1-4-alkyl, trifluoromethyl, trifluoromethoxy, two (C _1-4-alkyl) amino C _1-4-alkoxyl group, two (C _1-4-alkyl) amino, two (C _1-4-alkyl) amino C _1-4-alkyl, two (C _1-4-alkyl) amino C _1-4-alkyl (C _1-4-alkyl) amino C _1-4-alkyl, hydroxyl C _1-4-alkylpiperazine base C _1-4-alkyl, hydroxyl C _1-4-alkoxy C _1-4-alkylpiperazine base C _1-4-alkyl, two (hydroxyl C _1-4-alkyl) amino C _1-4-alkyl, pyrrolidyl C _1-4-alkyl pyrrolidine base C _1-4-alkoxyl group, morpholinyl C _1-4-alkoxyl group, morpholinyl C _1-4-alkyl, C _1-4-alkylpiperazine base C _1-4The phenyl that the substituting group of-alkyl replaces.

85. the compound of claim 83, wherein:

N is 1;

T is 0;

R ¹²Be hydrogen;

-L-is direct key;

R ¹⁴Be hydrogen;

The A ring is to be selected from (a-1) and group (a-20);

Each s is 0 or 1 independently; And

86. the compound of claim 82, wherein L is direct key and R ¹²Be H.

87. the compound of claim 82, wherein:

T is 0;

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

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

R ⁵Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6-alkyl; Three halo C _1-6-alkoxyl group; C _1-6-alkyl; C _1-6-alkoxyl group; C _1-6-alkyl-carbonyl; C _1-6-alkoxy carbonyl; C _1-6-alkyl sulphonyl; Hydroxyl C _1-6-alkyl; Aryloxy; Two (C _1-6-alkyl) amino; Cyano group; Thiophenyl; Furyl; By hydroxyl C _1-6The furyl that-alkyl replaces; Benzofuryl; Imidazolyl; Oxazolyl; By aryl and C _1-6-alkyl replaces the De oxazolyl; C _1-6-alkyl triazolyl; Tetrazyl; Pyrrolidyl; Pyrryl; Morpholinyl; C _1-6-alkyl morpholine base; Piperazinyl; C _1-6-alkylpiperazine base; Hydroxyl C _1-6-alkylpiperazine base; C _1-6-alkoxyl group piperidyl; Pyrazolyl; Be selected from C by one or two _1-6-alkyl and three halo C _1-6The pyrazolyl that the substituting group of-alkyl replaces; Pyridyl; By C _1-6The pyridyl that-alkoxyl group, aryloxy or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; Or be independently selected from halogen, C by one or two _1-6-alkyl, C _1-6The phenyl that the substituting group of-alkoxyl group or trifluoromethyl replaces;

R ⁶Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6-alkyl; Three halo C _1-6-alkoxyl group; C _1-6-alkyl; C _1-6-alkoxyl group; C _1-6-alkyl-carbonyl; C _1-6-alkoxy carbonyl; C _1-6-alkyl sulphonyl; Hydroxyl C _1-6-alkyl; Aryloxy; Two (C _1-6-alkyl) amino; Cyano group; Pyridyl; Phenyl; Or be independently selected from halogen, C by one or two _1-6-alkyl, C _1-6The phenyl that the substituting group of-alkoxyl group and trifluoromethyl replaces, and

Centre portions

Optional with ethylene bridge bridging (that is, forming the dicyclo part).

88. the compound of claim 82, wherein:

R ¹⁴Be hydrogen, hydroxyl, amino, hydroxyl C _1-6-alkyl, C _1-6-alkoxyl group, aryl C _1-6-alkyl, aminocarboxyl, hydroxycarbonyl group, amino C _1-6-alkyl, aminocarboxyl C _1-6-alkyl, hydroxycarbonyl group C _1-6-alkyl, hydroxyl amino carbonyl, C _1-6-alkyl-carbonyl, C _1-6-alkylamino C _1-6-alkyl or two (C _1-6-alkyl) amino C _1-6-alkyl;

Each R ⁵And R ⁶Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6-alkyl; Three halo C _1-6-alkoxyl group; C _1-6-alkyl; C _1-6-alkoxyl group; C _1-6-alkoxy C _1-6-alkoxyl group; C _1-6-alkyl-carbonyl; C _1-6-alkyl sulphonyl; Cyano group C _1-6-alkyl; Hydroxyl C _1-6-alkyl; Hydroxyl C _1-6-alkoxyl group; Hydroxyl C _1-6-alkylamino; Amino C _1-6-alkoxyl group; Two (C _1-6-alkyl) aminocarboxyl; Two (hydroxyl C _1-6-alkyl) amino; Two (C _1-6-alkyl) amino C _1-6-alkoxyl group; Two (C _1-6-alkyl) amino C _1-6-alkylamino; Aryl sulfonyl; Arlysulfonylamino; Aryloxy; Aryl C _2-6-olefin 2 base; Two (C _1-6-alkyl) amino; Cyano group; Thiophenyl; By two (C _1-6-alkyl) amino C _1-6-alkyl (C _1-6-alkyl) amino C _1-6-alkyl, two (C _1-6-alkyl) amino C _1-6-alkyl, C _1-6-alkylpiperazine base C _1-6-alkyl or two (hydroxyl C _1-6-alkyl) amino C _1-6The thiophenyl that-alkyl replaces; Furyl; Imidazolyl; C _1-6-alkyl triazolyl; Tetrazyl; Piperidyl C _1-6-alkoxyl group; Morpholinyl; C _1-6-alkyl morpholine base; Morpholinyl C _1-6-alkoxyl group; Morpholinyl C _1-6-alkyl; C _1-6-alkylpiperazine base C _1-6-alkoxyl group; C _1-6-alkylpiperazine base C _1-6-alkyl; C _1-6-alkylpiperazine base alkylsulfonyl; Amino-sulfonyl piperazinyl C _1-6-alkoxyl group; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C _1-6-alkyl; Two (C _1-6-alkyl) amino-sulfonyl piperazinyl; Two (C _1-6-alkyl) amino-sulfonyl piperazinyl C _1-6-alkyl; Hydroxyl C _1-6-alkylpiperazine base; Hydroxyl C _1-6-alkylpiperazine base C _1-6-alkyl; C _1-6-alkoxyl group piperidyl; C _1-6-alkoxyl group piperidyl C _1-6-alkyl; Hydroxyl C _1-6-alkoxy C _1-6-alkylpiperazine base; Hydroxyl C _1-6-alkoxy C _1-6-alkylpiperazine base C _1-6-alkyl; (hydroxyl C _1-6-alkyl) (C _1-6-alkyl) amino; (hydroxyl C _1-6-alkyl) (C _1-6-alkyl) amino C _1-6-alkyl; Pyrrolidyl C _1-6-alkoxyl group; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two _1-6-alkyl or three halo C _1-6The pyrazolyl that the substituting group of-alkyl replaces; Pyridyl; By C _1-6The pyridyl that-alkoxyl group or aryl replace; Pyrimidyl; Quinolyl; Phenyl; And by one, two or three are independently selected from halogen, amino, C _1-6-alkyl, C _1-6-alkoxyl group, hydroxyl C _1-4-alkyl, trifluoromethyl, trifluoromethoxy, hydroxyl C _1-4-alkoxyl group, C _1-4-alkoxy C _1-4-alkoxyl group, amino C _1-4-alkoxyl group, two (C _1-4-alkyl) amino C _1-4-alkoxyl group, two (C _1-4-alkyl) amino, piperidyl C _1-4-alkoxyl group, pyrrolidyl C _1-4-alkoxyl group, amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C _1-4-alkyl, two (C _1-4-alkyl) amino-sulfonyl piperazinyl, two (C _1-4-alkyl) amino-sulfonyl piperazinyl C _1-4-alkyl, hydroxyl C _1-4-alkylpiperazine base, hydroxyl C _1-4-alkylpiperazine base C _1-4-alkyl, C _1-4-alkoxyl group piperidyl, C _1-4-alkoxyl group piperidyl C _1-4-alkyl, hydroxyl C _1-4-alkoxy C _1-4-alkylpiperazine base, hydroxyl C _1-4-alkoxy C _1-4-alkylpiperazine base C _1-4-alkyl, hydroxyl C _1-4-alkyl) (C _1-4-alkyl) amino, (hydroxyl C _1-4-alkyl) (C _1-4-alkyl) amino C _1-4-alkyl, pyrrolidyl C _1-4-alkoxyl group, morpholinyl C _1-4-alkoxyl group, morpholinyl C _1-4-alkyl, C _1-4-alkylpiperazine base C _1-4-alkoxyl group, C _1-4-alkylpiperazine base C _1-4-alkyl, hydroxyl C _1-4-alkylamino, two (hydroxyl C _1-4-alkyl) amino, two (C _1-4-alkyl) amino C _1-4-alkylamino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C _1-4-alkoxyl group and thiophenyl C _1-4The phenyl that the substituting group of-alkylamino replaces.

89. the compound of claim 82 is selected from one of the 21st and 22 page of WO03/076422 and compound of table F-1, wherein terminal hydroxamic acid part (HO-NH-C (O)-) quilt

Replace,

Wherein Φ, R ¹, R ², R ³And R ⁴As defined in claim 1.

90., be used for the inhibition of histone deacetylase according to the compound of claim 82.

91., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 82.

92. the compound of claim 91, wherein said treatment realizes by the inhibition of histone deacetylase.

93. the compound of claim 91, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

94. the compound of claim 91, wherein said cell proliferation disorders is a cancer.

95. the compound of claim 94, wherein said cancer is a solid tumor cancer.

96. the compound of claim 94, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

97. a pharmacy composite contains 2 described compound and pharmaceutically acceptable carriers according to Claim 8.

98. the pharmacy composite of claim 97, it further contains the nucleic acid level inhibitor of histone deacetylase.

99. the pharmacy composite of claim 98, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

100. the pharmacy composite of claim 99, wherein said antisense oligonucleotide are selected from SEQID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

101. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 82 that suppresses significant quantity.

102. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 97 of described individual administering therapeutic significant quantity.

103. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 98 of described individual administering therapeutic significant quantity.

104. the method for claim 102, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

105. the method for claim 102, wherein said cell proliferation disorders is a cancer.

106. the method for claim 102, wherein said cancer is a solid tumor cancer.

107. the method for claim 106, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

108. the method for claim 103, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

109. the method for claim 103, wherein said cell proliferation disorders is a cancer.

110. the method for claim 109, wherein said cancer is a solid tumor cancer.

111. the method for claim 110, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

112. the compound of following formula or its pharmacologically acceptable salts:

Wherein

Φ is-NH ₂Or-OH;

R ¹Be H or as defined in claim 1;

R ², R ³And R ⁴As defined in claim 1;

N is 0,1,2 or 3, and when n was 0, it was meant direct key;

Q be nitrogen or

X be nitrogen or

Y be nitrogen or

Z be nitrogen or

-C(O)-NH-CH ₂-NR ¹⁰- (a-1)

R wherein ¹⁰Be hydrogen or aryl;

＝CH-CH＝CH-CH＝ (b-1)；

113. the compound of claim 112, wherein:

N is 0 or 1;

Q is

R ¹²Be hydrogen or nitro;

R ¹⁴Be hydrogen;

114. the compound of claim 112, wherein:

N is 1;

Q is

Z is a nitrogen;

R ¹²Be hydrogen;

R ¹⁴Be hydrogen.

115. the compound of claim 112, wherein R ¹²Be H.

116. the compound of claim 112, wherein:

117. the compound of claim 112, wherein,

118. the compound of claim 112, wherein:

N is 0 or 1; Q is

Or-NHC (O) C _1-6Alkane 2 basis SH; R ¹²Be hydrogen or nitro; R ¹³Be C _1-6Alkyl, aryl C _2-6Olefin 2 base, furyl carbonyl, naphthyl carbonyl, C _1-6Alkyl amino-carbonyl, amino-sulfonyl, two (C _1-6Alkyl) the amino C of amino-sulfonyl _1-6Alkyl, two (C _1-6Alkyl) amino C _1-6Alkyl, C _1-12Alkyl sulphonyl, two (C _1-6Alkyl) amino-sulfonyl, three halo C _1-6Alkyl sulphonyl, two (aryl) C _1-6Alkyl-carbonyl, thiophenyl C _1-6Alkyl-carbonyl, pyridyl carbonyl or aryl C _1-6Alkyl-carbonyl; R ¹⁴Be hydrogen; Work as R ¹³And R ¹⁴When being present on the identical carbon atom, R ¹³And R ¹⁴Can form the divalent group of formula (a-1) together, wherein R ¹⁰It is aryl; Or work as R ¹³And R ¹⁴When being present on the adjacent carbon atom, R ¹³And R ¹⁴Can form the divalent group of formula (b-1) together.

119. the compound of claim 112, wherein:

N is 1; Q is

Z is a nitrogen; R ¹²Be hydrogen; R ¹³Be naphthyl carbonyl, C _1-12Alkyl sulphonyl or two (aryl) C _1-6Alkyl-carbonyl; And R ¹⁴Be hydrogen.

120. the compound of claim 112, it is selected from

Wherein terminal hydroxamic acid part (C (O)-NH-OH) quilt

Replace, wherein Φ, R ¹, R ², R ³And R ⁴Define according to claim 1.

121., be used for the inhibition of histone deacetylase according to the compound of claim 112.

122., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 112.

123. the compound of claim 122, wherein said treatment realizes by the inhibition of histone deacetylase.

124. the compound of claim 122, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

125. the compound of claim 122, wherein said cell proliferation disorders is a cancer.

126. the compound of claim 125, wherein said cancer is a solid tumor cancer.

127. the compound of claim 125, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

128. a pharmacy composite contains described compound of with good grounds claim 112 and pharmaceutically acceptable carrier.

129. the pharmacy composite of claim 128, it further contains the nucleic acid level inhibitor of histone deacetylase.

130. the pharmacy composite of claim 129, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

131. the pharmacy composite of claim 130, wherein said antisense oligonucleotide are selected from SEQ ID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

132. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 112 that suppresses significant quantity.

133. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 128 of described individual administering therapeutic significant quantity.

134. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 129 of described individual administering therapeutic significant quantity.

135. the method for claim 133, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

136. the method for claim 133, wherein said cell proliferation disorders is a cancer.

137. the method for claim 136, wherein said cancer is a solid tumor cancer.

138. the method for claim 137, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

139. the method for claim 134, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

140. the method for claim 134, wherein said cell proliferation disorders is a cancer.

141. the method for claim 140, wherein said cancer is a solid tumor cancer.

142. the method for claim 141, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

143. the compound of following formula or its pharmacologically acceptable salts:

Wherein

Φ is-NH ₂Or-OH;

R ¹Be H or as defined in claim 1;

R ², R ³And R ⁴As defined in claim 1;

N is 0,1,2 or 3, and when n was 0, it was meant direct key;

M is 0 or 1, and when m was 0, it was meant direct key;

T is 0,1,2,3 or 4, and when t was 0, it was meant direct key;

Q be nitrogen or

X be nitrogen or

Y be nitrogen or

For being selected from following group

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

Each R ⁶And R ⁷Can be positioned on the nitrogen to replace hydrogen;

144. the compound of claim 143, wherein:

N is 1;

M is 0 or 1;

T is 0,1 or 2;

Q is

R ¹²Be hydrogen or C _1-6Alkyl;

-L-is direct key;

R ¹⁴Be hydrogen;

R ¹⁵Be hydrogen;

Each s is 0,1,2 or 3 independently;

145. the compound of claim 143, wherein:

146. the compound of claim 143, wherein:

t＝0；

m＝0；

R ¹⁵Be hydrogen;

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

147. the compound of claim 143, wherein:

N is 1; M is 0 or 1; T is 0,1 or 2; Q is

R ¹²Be hydrogen;-L-is direct key; R ¹⁴And R ¹⁵Be hydrogen;

148. the compound of claim 143, it is selected from

Wherein terminal hydroxamic acid part (C (O)-NH-OH) quilt

Replace, wherein Φ, R ¹, R ², R ³And R ⁴Define according to claim 1.

149. the compound of claim 143, wherein R ¹, R ², R ³And R ⁴Be H.

150., be used for the inhibition of histone deacetylase according to the compound of claim 143.

151., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 143.

152. the compound of claim 151, wherein said treatment realizes by the inhibition of histone deacetylase.

153. the compound of claim 151, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

154. the compound of claim 151, wherein said cell proliferation disorders is a cancer.

155. the compound of claim 154, wherein said cancer is a solid tumor cancer.

156. the compound of claim 154, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

157. a pharmacy composite contains described compound of with good grounds claim 143 and pharmaceutically acceptable carrier.

158. the pharmacy composite of claim 157, it further contains the nucleic acid level inhibitor of histone deacetylase.

159. the pharmacy composite of claim 158, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

160. the pharmacy composite of claim 159, wherein said antisense oligonucleotide are selected from SEQ ID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

161. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 143 that suppresses significant quantity.

162. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 157 of described individual administering therapeutic significant quantity.

163. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 158 of described individual administering therapeutic significant quantity.

164. the method for claim 162, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

165. the method for claim 162, wherein said cell proliferation disorders is a cancer.

166. the method for claim 165, wherein said cancer is a solid tumor cancer.

167. the method for claim 166, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

168. the method for claim 163, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

169. the method for claim 163, wherein said cell proliferation disorders is a cancer.

170. the method for claim 169, wherein said cancer is a solid tumor cancer.

171. the method for claim 170, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

172. the compound of following formula or its pharmacologically acceptable salts:

Wherein

Φ is-NH ₂Or-OH;

R ¹Be H or as defined in claim 1;

R ², R ³And R ⁴As defined in claim 1;

N is 0,1,2 or 3, and when n was 0, it was meant direct key;

T is 0,1,2,3 or 4, and when t was 0, it was meant direct key;

Q be nitrogen or

X be nitrogen or

Y be nitrogen or

Z be nitrogen or

For being selected from following group

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

Each R⁵And R⁶Be independently selected from hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C_1-6Alkyl; Three halo C_1-6Alkoxyl; C_1-6Alkyl; By aryl and C_3-10The C that cycloalkyl replaces_1-6Alkyl; C_1-6Alkoxyl; C_1-6Alkoxy C_1-6Alkoxyl; C_1-6The alkyl carbonyl; C_1-6The alkoxyl carbonyl; C_1-6The alkyl sulfonyl base; Cyano group C_1-6Alkyl; Hydroxyl C_1-6Alkyl; Hydroxyl C_1-6Alkoxyl; Hydroxyl C_1-6Alkyl is amino; Amino C_1-6Alkoxyl; Two (C_1-6Alkyl) amino carbonyl; Two (hydroxyl C_1-6Alkyl) amino; (aryl) (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkoxyl; Two (C_1-6Alkyl) amino C_1-6Alkyl amino; Two (C_1-6Alkyl) amino C_1-6Alkyl amino C_1-6Alkyl; Aryl sulfonyl; Arlysulfonylamino; Aryloxy group; Aryloxy group C_1-6Alkyl; Aryl C_2-6Olefin 2 base; Two (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino (C_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino; Two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl; Amino (the C of amino-sulfonyl_1-6Alkyl) amino; Amino (the C of amino-sulfonyl_1-6Alkyl) amino C_1-6Alkyl; Two (C_1-6Alkyl) amino (C of amino-sulfonyl_1-6Alkyl) amino; Two (C_1-6Alkyl) amino (C of amino-sulfonyl_1-6Alkyl) amino C_1-6Alkyl; Cyano group; Thiophenyl; By two (C_1-6Alkyl) amino C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl, two (C_1-6Alkyl) amino C_1-6Alkyl, C_1-6Alkylpiperazinyl C_1-6Alkyl, hydroxyl C_1-6Alkylpiperazinyl C_1-6Alkyl, hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl C_1-6Alkyl, two (C_1-6Alkyl) amino-sulfonyl piperazinyl C_1-6Alkyl, C_1-6Alkoxyl piperidyl, C_1-6Alkoxyl piperidyl C_1-6Alkyl, morpholinyl C_1-6Alkyl, hydroxyl C_1-6Alkyl (C_1-6Alkyl) amino C_1-6Alkyl or two (hydroxyl C_1-6Alkyl) amino C_1-6The thiophenyl that alkyl replaces; Furyl; By hydroxyl C_1-6The furyl that-alkyl replaces; Benzofuranyl; Imidazole radicals; Oxazolyl; By aryl and C_1-6Alkyl replaces the De oxazolyl; C_1-6-alkyl triazolyl; Tetrazole radical; Pyrrolidinyl; Pyrrole radicals; Piperidyl C_1-6Alkoxyl; Morpholinyl; C_1-6-alkyl morpholine base; Morpholinyl C_1-6Alkoxyl; Morpholinyl C_1-6Alkyl; Morpholinyl C_1-6Alkyl is amino; Morpholinyl C_1-6The amino C of alkyl_1-6Alkyl; Piperazinyl; C_1-6Alkylpiperazinyl; C_1-6Alkylpiperazinyl C_1-6Alkoxyl; Piperazinyl C_1-6-alkyl; Naphthyl sulfonyl piperazinyl; Naphthyl sulfonyl piperidyl; The naphthyl sulfonyl; C_1-6Alkylpiperazinyl C_1-6Alkyl; C_1-6Alkylpiperazinyl C_1-6Alkyl is amino; C_1-6Alkylpiperazinyl C_1-6The amino C of alkyl_1-6Alkyl; C_1-6The alkylpiperazinyl sulfonyl; Amino-sulfonyl piperazinyl C_1-6Alkoxyl; The amino-sulfonyl piperazinyl; Amino-sulfonyl piperazinyl C_1-6Alkyl; Two (C_1-6Alkyl) amino-sulfonyl piperazinyl; Two (C_1-6-alkyl) amino-sulfonyl piperazinyl C_1-6Alkyl; Hydroxyl C_1-6Alkylpiperazinyl; Hydroxyl C_1-6Alkylpiperazinyl C_1-6Alkyl; C_1-6The alkoxyl piperidyl; C_1-6Alkoxyl piperidyl C_1-6Alkyl; The amino C of piperidyl_1-6Alkyl is amino; The amino C of piperidyl_1-6The amino C of alkyl_1-6Alkyl; (C_1-6The Alkylpiperidine base) (hydroxyl C_1-6Alkyl) amino C_1-6Alkyl is amino; (C_1-6The Alkylpiperidine base) (hydroxyl C_1-6Alkyl) amino C_1-6The amino C of alkyl_1-6Alkyl; Hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl; Hydroxyl C_1-6Alkoxy C_1-6Alkylpiperazinyl C_1-6Alkyl; (hydroxyl C_1-6Alkyl) (C_1-6Alkyl) amino; (hydroxyl C_1-6Alkyl) (C_1-6Alkyl) amino C_1-6Alkyl; Hydroxyl C_1-6The amino C of alkyl_1-6Alkyl; Two (hydroxyl C_1-6Alkyl) amino C_1-6Alkyl; Pyrrolidinyl C_1-6Alkyl; Pyrrolidinyl C_1-6Alkoxyl; Pyrazolyl; The sulfo-pyrazolyl; Be selected from C by two_1-6Alkyl or three halo C_1-6The pyrazolyl that the substituting group of alkyl replaces; Pyridine radicals; By C_1-6The pyridine radicals that alkoxyl, aryloxy group or aryl replace; Pyrimidine radicals; The tetrahydro-pyrimidine base piperazinyl; Tetrahydro-pyrimidine base piperazinyl C_1-6Alkyl; Quinolyl; Indoles; Phenyl; By the phenyl that, two or three substituting groups replace, these substituting groups are independently selected from halogen, amino, nitro, C_1-6Alkyl, C_1-6Alkoxyl, hydroxyl C_1-4Alkyl, trifluoromethyl, trifluoro methoxyl group, hydroxyl C_1-4Alkoxyl, C_1-4Alkyl sulfonyl base, C_1-4Alkoxy C_1-4Alkoxyl, C_1-4Alkoxyl carbonyl, amino C_1-4Alkoxyl, two (C_1-4Alkyl) amino C_1-4Alkoxyl, two (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino carbonyl, two (C_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4The amino C of alkyl_1-4Alkyl, two (C_1-4Alkyl) amino (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino (C_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4Alkyl (C_1-4Alkyl) amino, two (C_1-4Alkyl) amino C_1-4Alkyl (C_1-4Alkyl) amino C_1-4Alkyl, the amino (C of amino-sulfonyl_1-4Alkyl) amino, the amino (C of amino-sulfonyl_1-4Alkyl) amino C_1-4Alkyl, two (C_1-4Alkyl) amino (C of amino-sulfonyl_1-4Alkyl) amino, two (C_1-4Alkyl) amino (C of amino-sulfonyl_1-4Alkyl) amino C_1-6Alkyl, cyano group, piperidyl C_1-4Alkoxyl, pyrrolidinyl C_1-4Alkoxyl, amino-sulfonyl piperazinyl, amino-sulfonyl piperazinyl C_1-4Alkyl, two (C_1-4Alkyl) amino-sulfonyl piperazinyl, two (C_1-4Alkyl) amino-sulfonyl piperazinyl C_1-4Alkyl, hydroxyl C_1-4Alkylpiperazinyl, hydroxyl C_1-4Alkylpiperazinyl C_1-4Alkyl, C_1-4Alkoxyl piperidyl, C_1-4Alkoxyl piperidyl C_1-4Alkyl, hydroxyl C_1-4Alkoxy C_1-4Alkylpiperazinyl, hydroxyl C_1-4Alkoxy C_1-4Alkylpiperazinyl C_1-4Alkyl, (hydroxyl C_1-4Alkyl) (C_1-4Alkyl) amino, (hydroxyl C_1-4Alkyl) (C_1-4Alkyl) amino C_1-4Alkyl, two (hydroxyl C_1-4Alkyl) amino, two (hydroxyl C_1-4Alkyl) amino C_1-4Furyl, pyrrolidinyl C that alkyl, furyl, quilt-CH=CH-CH=CH-replace_1-4Alkyl, pyrrolidinyl C_1-4Alkoxyl, morpholinyl, morpholinyl C_1-4Alkoxyl, morpholinyl C_1-4Alkyl, morpholinyl C_1-4Alkyl is amino, morpholinyl C_1-4The amino C of alkyl_1-4Alkyl, piperazinyl, C_1-4Alkylpiperazinyl, C_1-4Alkylpiperazinyl C_1-4Alkoxyl, piperazinyl C_1-4Alkyl, C_1-4Alkylpiperazinyl C_1-4Alkyl, C_1-4Alkylpiperazinyl C_1-4Alkyl is amino, C_1-4Alkylpiperazinyl C_1-4The amino C of alkyl_1-6Alkyl, tetrahydro-pyrimidine base piperazinyl, tetrahydro-pyrimidine base piperazinyl C_1-4Alkyl, the amino C of piperidyl_1-4Alkyl is amino, the amino C of piperidyl_1-4The amino C of alkyl_1-4Alkyl, (C_1-4The Alkylpiperidine base) (hydroxyl C_1-4Alkyl) amino C_1-4Alkyl is amino, (C_1-4The Alkylpiperidine base) (hydroxyl C_1-4Alkyl) amino C_1-4The amino C of alkyl_1-4Alkyl, piperidyl C_1-4Alkoxyl, hydroxyl C_1-4Alkyl is amino, hydroxyl C_1-4The amino C of alkyl_1-4Alkyl, two (C_1-4Alkyl) amino C_1-4Alkyl amino, amino thiadiazolyl group, amino-sulfonyl piperazinyl C_1-4Alkoxyl or thiophenyl C_1-4Alkyl is amino,

Each R ⁵And R ⁶Can be positioned on the nitrogen to replace hydrogen;

173. the compound of claim 172, wherein R ², R ³And R ⁴Correspond respectively to the R in the claim 172 separately ¹², R ¹³And R ¹⁴, wherein:

N is 1 or 2;

T is 0,1,2 or 4;

Q is

R ²Be hydrogen or nitro;

R ⁴Be hydrogen;

Be to be selected from (a-1), (a-2), (a-3), (a-5), (a-6), (a-11), (a-18), (a-20), (a-21), (a-32), (a-33), (a-47) or group (a-51);

Each s is 0,1,2 or 4 independently;

174. the compound of claim 170, wherein R ², R ³And R ⁴Correspond respectively to the R in the claim 172 separately ¹², R ¹³And R ¹⁴, wherein:

N is 1;

T is 0,1 or 2;

Q is

X is a nitrogen;

Y is a nitrogen;

R ²Be hydrogen;

-L-is direct key;

Each R ³Represent hydrogen atom independently;

R ⁴Be hydrogen;

Be to be selected from (a-6), (a-11), (a-20), (a-47) or group (a-51);

Each s is 0,1 or 4 independently;

175. the compound of claim 172, wherein L is direct key.

176. the compound of claim 172, wherein R ², R ³And R ⁴Correspond respectively to the R in the claim 172 separately ¹², R ¹³And R ¹⁴, wherein:

T is 1,2,3 or 4;

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

R ⁵Be hydrogen; Halogen; Hydroxyl; Amino; Nitro; Three halo C _1-6Alkyl; Three halo C _1-6Alkoxyl group; C _1-6Alkyl; C _1-6Alkoxyl group; C _1-6Alkyl-carbonyl; C _1-6Alkoxy carbonyl; C _1-6Alkyl sulphonyl; Hydroxyl C _1-6Alkyl; Aryloxy; Two (C _1-6Alkyl) amino; Cyano group; Thiophenyl; Furyl; By hydroxyl C _1-6The furyl that alkyl replaces; Benzofuryl; Imidazolyl; Oxazolyl; By aryl and C _1-6Alkyl replaces the De oxazolyl; C _1-6-alkyl triazolyl; Tetrazyl; Pyrrolidyl; Pyrryl; Morpholinyl; C _1-6-alkyl morpholine base; Piperazinyl; C _1-6The alkylpiperazine base; Hydroxyl C _1-6The alkylpiperazine base; C _1-6The alkoxyl group piperidyl; Pyrazolyl; By or two be selected from C _1-6Alkyl or three halo C _1-6The pyrazolyl that alkyl replaces; Pyridyl; By C _1-6The pyridyl that-alkoxyl group, aryloxy or aryl replace; Pyrimidyl; Quinolyl; Indoles; Phenyl; Or be independently selected from halogen, C by one or two _1-6Alkyl, C _1-6The phenyl that the substituting group of alkoxyl group or trifluoromethyl replaces;

177. the compound of claim 172, it is selected from

Wherein terminal hydroxamic acid part (C (O)-NH-OH) quilt

Replace, wherein Φ, R ¹, R ², R ³And R ⁴Define according to claim 1.

178. the compound of claim 172, wherein R ¹, R ², R ³And R ⁴Be H.

179., be used for the inhibition of histone deacetylase according to the compound of claim 172.

180., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 172.

181. the compound of claim 180, wherein said treatment realizes by the inhibition of histone deacetylase.

182. the compound of claim 180, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

183. the compound of claim 180, wherein said cell proliferation disorders is a cancer.

184. the compound of claim 183, wherein said cancer is a solid tumor cancer.

185. the compound of claim 183, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

186. a pharmacy composite contains described compound of with good grounds claim 172 and pharmaceutically acceptable carrier.

187. the pharmacy composite of claim 186, it further contains the nucleic acid level inhibitor of histone deacetylase.

188. the pharmacy composite of claim 187, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

189. the pharmacy composite of claim 188, wherein said antisense oligonucleotide are selected from SEQ ID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

190. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 172 that suppresses significant quantity.

191. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 186 of described individual administering therapeutic significant quantity.

192. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 187 of described individual administering therapeutic significant quantity.

193. the method for claim 191, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

194. the method for claim 191, wherein said cell proliferation disorders is a cancer.

195. the method for claim 194, wherein said cancer is a solid tumor cancer.

196. the method for claim 195, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

197. the method for claim 192, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

198. the method for claim 192, wherein said cell proliferation disorders is a cancer.

199. the method for claim 198, wherein said cancer is a solid tumor cancer.

200. the method for claim 199, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

201. the compound of following formula or its pharmacologically acceptable salts:

Wherein

Φ is-NH ₂Or-OH;

R ¹Be H or as defined in claim 1;

R ², R ³And R ⁴As defined in claim 1;

N is 0,1,2 or 3, and when n was 0, it was meant direct key;

T is 0,1,2,3 or 4, and when t was 0, it was meant direct key;

Q be nitrogen or

X be nitrogen or

Y be nitrogen or

Z be nitrogen or

Each R ¹²Be hydrogen, halogen, hydroxyl, amino, nitro, C _1-6Alkyl, C _1-6Alkoxyl group, trifluoromethyl, two (C _1-6Alkyl) amino, hydroxyl amino or naphthyl alkylsulfonyl pyrazinyl;

For being selected from following group

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

Each R ⁶And R ⁷Can be positioned on the nitrogen to replace hydrogen;

202. the compound of claim 201, wherein R ², R ³, R ⁴And R ⁵Correspond respectively to the R in the claim 201 separately ¹², R ¹³, R ¹⁴And R ¹⁵, wherein:

N is 0,1 or 2;

T is 0,1,2 or 3;

Q is

R ²Be hydrogen, C _1-6Alkyl or naphthyl alkylsulfonyl pyrazinyl;

Each R ³Represent hydrogen atom independently;

R ⁴Be hydrogen, hydroxyl, hydroxyl C _1-6Alkyl or C _1-6Alkoxyl group;

Be to be selected from (a-1), (a-7) or group (a-20);

Each s is 0 or 1 independently;

Each R ⁷Be independently selected from hydrogen.

203. the compound of claim 201, wherein R ², R ³, R ⁴And R ⁵Correspond respectively to the R in the claim 201 separately ¹², R ¹³, R ¹⁴And R ¹⁵, wherein:

N is 1 or 2;

T is 0,1,2 or 3;

Q is

R ²Be hydrogen or C _1-6Alkyl;

Each R ³Represent hydrogen atom independently;

R ⁴Be hydrogen;

R ⁵Be hydrogen or C _1-6Alkoxy C _1-6Alkyl;

Be to be selected from (a-1) or group (a-20);

Each s is 0 or 1 independently;

204. the compound of claim 201, wherein R ¹²Be H.

205. the compound of claim 201, wherein R ², R ³, R ⁴And R ⁵Correspond respectively to the R in the claim 201 separately ¹², R ¹³, R ¹⁴And R ¹⁵, wherein:

T is 0;

R ⁵Be hydrogen;

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

206. the compound of claim 201, wherein R ², R ³, R ⁴And R ⁵Correspond respectively to the R in the claim 201 separately ¹², R ¹³, R ¹⁴And R ¹⁵, wherein:

207. the compound of claim 201, it is selected from

Wherein terminal hydroxamic acid part (C (O)-NH-OH) quilt

Replace, wherein Φ, R ¹, R ², R ³And R ⁴Define according to claim 1.

208., be used for the inhibition of histone deacetylase according to the compound of claim 201.

209., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 201.

210. the compound of claim 209, wherein said treatment realizes by the inhibition of histone deacetylase.

211. the compound of claim 209, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

212. the compound of claim 209, wherein said cell proliferation disorders is a cancer.

213. the compound of claim 212, wherein said cancer is a solid tumor cancer.

214. the compound of claim 212, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

215. a pharmacy composite contains described compound of with good grounds claim 201 and pharmaceutically acceptable carrier.

216. the pharmacy composite of claim 215, it further contains the nucleic acid level inhibitor of histone deacetylase.

217. the pharmacy composite of claim 216, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

218. the pharmacy composite of claim 217, wherein said antisense oligonucleotide are selected from SEQ ID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

219. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 201 that suppresses significant quantity.

220. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 215 of described individual administering therapeutic significant quantity.

221. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 216 of described individual administering therapeutic significant quantity.

222. the method for claim 220, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

223. the method for claim 220, wherein said cell proliferation disorders is a cancer.

224. the method for claim 223, wherein said cancer is a solid tumor cancer.

225. the method for claim 224, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

226. the method for claim 221, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

227. the method for claim 221, wherein said cell proliferation disorders is a cancer.

228. the method for claim 227, wherein said cancer is a solid tumor cancer.

229. the method for claim 228, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

230. the compound of claim 201, wherein R ², R ³And R ⁴Be H.

231. the compound of following formula or its pharmacologically acceptable salts:

Wherein

Φ is-NH ₂Or-OH;

R ¹Be H or as defined in claim 1;

R ², R ³And R ⁴As defined in claim 1;

N is 0,1,2 or 3, and when n was 0, it was meant direct key;

Q be nitrogen or

X be nitrogen or

Y be nitrogen or

Z be nitrogen or

When Z equaled nitrogen ,-L-was direct key;

When Z equals The time ,-L-is-NH-or divalent group-C _1-6Alkane 2 basis NH-;

For being selected from following group

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

Each R ⁵And R ⁶Can be positioned on the nitrogen to replace hydrogen;

232. the compound of claim 231, wherein R ², R ³And R ⁴Correspond respectively to the R in the claim 231 separately ¹², R ¹³And R ¹⁴, wherein:

N is 1;

Q is

R ²Be hydrogen or nitro;

R ³Be hydrogen;

When Z equals The time ,-L-is divalent group-C _1-6Alkane 2 basis NH-;

R ⁴Be hydrogen, C _1-6Alkyl or aryl;

Be to be selected from (a-1) or group (a-21);

Each s is 0,1 or 2 independently;

233. the compound of claim 231, wherein R ², R ³And R ⁴Correspond respectively to the R in the claim 231 separately ¹², R ¹³And R ¹⁴, wherein:

N is 1;

Q is

Each X is a nitrogen;

Each Y is a nitrogen;

R ²Be hydrogen;

R ³Be hydrogen;

When Z equals

The time ,-L-is divalent group-C _1-6Alkane 2 basis NH-;

R ⁴Be hydrogen, C _1-6Alkyl or aryl;

Be group (a-1);

Each s is 0 or 1 independently;

Each R ⁵Be independently selected from hydrogen or phenyl.

234. the compound of claim 231, wherein R ², R ³And R ⁴Correspond respectively to the R in the claim 231 separately ¹², R ¹³And R ¹⁴, wherein:

Each Z is N;

R ⁴Be hydrogen;

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

235. the compound of claim 231, it is selected from

Wherein terminal hydroxamic acid part (C (O)-NH-OH) quilt

Replace, wherein Φ, R ¹, R ², R ³And R ⁴Define according to claim 1.

236. the compound of claim 231, wherein R ¹, R ², R ³And R ⁴Be H.

237., be used for the inhibition of histone deacetylase according to the compound of claim 231.

238., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 231.

239. the compound of claim 238, wherein said treatment realizes by the inhibition of histone deacetylase.

240. the compound of claim 238, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

241. the compound of claim 238, wherein said cell proliferation disorders is a cancer.

242. the compound of claim 241, wherein said cancer is a solid tumor cancer.

243. the compound of claim 241, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

244. a pharmacy composite contains described compound of with good grounds claim 231 and pharmaceutically acceptable carrier.

245. the pharmacy composite of claim 244, it further contains the nucleic acid level inhibitor of histone deacetylase.

246. the pharmacy composite of claim 245, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

247. the pharmacy composite of claim 246, wherein said antisense oligonucleotide are selected from SEQ ID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

248. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 231 that suppresses significant quantity.

249. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 244 of described individual administering therapeutic significant quantity.

250. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 245 of described individual administering therapeutic significant quantity.

251. the method for claim 249, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

252. the method for claim 249, wherein said cell proliferation disorders is a cancer.

253. the method for claim 252, wherein said cancer is a solid tumor cancer.

254. the method for claim 253, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

255. the method for claim 250, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

256. the method for claim 250, wherein said cell proliferation disorders is a cancer.

257. the method for claim 256, wherein said cancer is a solid tumor cancer.

258. the method for claim 257, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

259. the compound of following formula or its pharmacologically acceptable salts:

Wherein

Φ is-NH ₂Or-OH;

R ¹Be H or as defined in claim 1;

R ², R ³And R ⁴As defined in claim 1;

N is 0,1,2 or 3, and when n was 0, it was meant direct key;

M is 0,1,2 or 3, and when m was 0, it was meant direct key;

T is 0 or 1, and when t was 0, it was meant direct key;

Q be nitrogen or

X be nitrogen or

Y be nitrogen or

Z is-CH ₂-or-O-;

For being selected from following group

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

Each R ⁵And R ⁶Can be positioned on the nitrogen to replace hydrogen;

260. the compound of claim 259, wherein R ², R ³And R ⁴Correspond respectively to the R in the claim 259 separately ¹², R ¹³And R ¹⁴, wherein:

N is 0,1 or 2;

M is 0,1 or 2;

Each Q is

Each X is a nitrogen;

R ²Be hydrogen;

Be to be selected from (a-1), (a-20) or group (a-43);

Each s is 0 or 1 independently;

Each R ⁵Be independently selected from hydrogen or phenyl.

261. the compound of claim 259, wherein R ², R ³And R ⁴Correspond respectively to the R in the claim 259 separately ¹², R ¹³And R ¹⁴, wherein:

N is 0,1 or 2;

M is 1 or 2;

Q is

X is a nitrogen;

R ²Be hydrogen;

-L-is the divalent group that is selected from carbonyl or alkylsulfonyl;

Be to be selected from (a-1) or group (a-20);

Each s is 0 or 1 independently;

Each R ⁵Be independently selected from hydrogen or aryl.

262. the compound of claim 259, wherein R ², R ³And R ⁴Correspond respectively to the R in the claim 259 separately ¹², R ¹³And R ¹⁴, wherein:

T is 0;

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

263. the compound of claim 259, it is selected from

Wherein terminal hydroxamic acid part (C (O)-NH-OH) quilt

Replace, wherein Φ, R ¹, R ², R ³And R ⁴Define according to claim 1.

264. the compound of claim 259, wherein R ¹, R ², R ³And R ⁴Be H.

265., be used for the inhibition of histone deacetylase according to the compound of claim 259.

266., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 259.

267. the compound of claim 266, wherein said treatment realizes by the inhibition of histone deacetylase.

268. the compound of claim 266, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

269. the compound of claim 266, wherein said cell proliferation disorders is a cancer.

270. the compound of claim 269, wherein said cancer is a solid tumor cancer.

271. the compound of claim 269, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

272. a pharmacy composite contains described compound of with good grounds claim 259 and pharmaceutically acceptable carrier.

273. the pharmacy composite of claim 272, it further contains the nucleic acid level inhibitor of histone deacetylase.

274. the pharmacy composite of claim 273, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

275. the pharmacy composite of claim 274, wherein said antisense oligonucleotide are selected from SEQ ID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

276. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 259 that suppresses significant quantity.

277. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 272 of described individual administering therapeutic significant quantity.

278. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 273 of described individual administering therapeutic significant quantity.

279. the method for claim 277, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

280. the method for claim 277, wherein said cell proliferation disorders is a cancer.

281. the method for claim 280, wherein said cancer is a solid tumor cancer.

282. the method for claim 281, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

283. the method for claim 278, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

284. the method for claim 278, wherein said cell proliferation disorders is a cancer.

285. the method for claim 284, wherein said cancer is a solid tumor cancer.

286. the method for claim 285, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

287. the compound of following formula or its pharmacologically acceptable salts:

Wherein

Φ is-NH ₂Or-OH;

R ¹Be to define in H or the claim 1;

R ², R ³And R ⁴As defined in claim 1;

T is 0,1,2,3 or 4, and when t was 0, it was meant direct key;

Q be nitrogen or

X be nitrogen or

Y be nitrogen or

Z is-NH-,-O-or-CH ₂-;

For being selected from following group

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

Each R ⁵And R ⁶Can be positioned on the nitrogen to replace hydrogen;

288. the compound of claim 287, wherein R ², R ³And R ⁴Correspond respectively to the R in the claim 287 separately ¹², R ¹³And R ¹⁴, wherein:

T is 0 or 1;

Q is

X is a nitrogen;

R ¹²Be hydrogen, hydroxyl, C _1-6Alkyl or aryl C _1-6Alkyl;

-L-be selected from-NHC (O)-or-NHSO ₂-divalent group;

Be to be selected from (a-1) or group (a-20);

Each s is 0 or 1 independently;

Each R ⁵Be independently selected from hydrogen or phenyl.

289. the compound of claim 287, wherein R ², R ³And R ⁴Correspond respectively to the R in the claim 287 separately ¹², R ¹³And R ¹⁴, wherein:

T is 1;

Q is

X is a nitrogen;

Y is a nitrogen;

Z is-O-or-CH ₂-;

R ¹²Be H;

-L-be selected from-NHC (O)-or-NHSO ₂-divalent group;

Be to be selected from (a-1) or group (a-20);

Each s is 0 or 1 independently;

Each R ⁵Be independently selected from hydrogen or phenyl-

290. the compound of claim 287, wherein R ², R ³And R ⁴Correspond respectively to the R in the claim 287 separately ¹², R ¹³And R ¹⁴, wherein:

T is 0;

-L-be selected from-NHC (O)-or-NHSO ₂-divalent group;

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

291. the compound of claim 287, wherein R ², R ³And R ⁴Correspond respectively to the R in the claim 287 separately ¹², R ¹³And R ¹⁴, wherein:

292. the compound of claim 287, it is selected from

Wherein terminal hydroxamic acid part (C (O)-NH-OH) quilt

Replace, wherein Φ, R ¹, R ², R ³And R ⁴Define according to claim 1.

293. the compound of claim 287, wherein R ¹, R ², R ³And R ⁴Be H.

294., be used for the inhibition of histone deacetylase according to the compound of claim 287.

295., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 287.

296. the compound of claim 295, wherein said treatment realizes by the inhibition of histone deacetylase.

297. the compound of claim 295, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

298. the compound of claim 295, wherein said cell proliferation disorders is a cancer.

299. the compound of claim 298, wherein said cancer is a solid tumor cancer.

300. the compound of claim 298, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

301. a pharmacy composite contains described compound of with good grounds claim 287 and pharmaceutically acceptable carrier.

302. the pharmacy composite of claim 301, it further contains the nucleic acid level inhibitor of histone deacetylase.

303. the pharmacy composite of claim 302, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

304. the pharmacy composite of claim 303, wherein said antisense oligonucleotide are selected from SEQ ID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

305. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 287 that suppresses significant quantity.

306. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 301 of described individual administering therapeutic significant quantity.

307. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 302 of described individual administering therapeutic significant quantity.

308. the method for claim 306, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

309. the method for claim 306, wherein said cell proliferation disorders is a cancer.

310. the method for claim 309, wherein said cancer is a solid tumor cancer.

311. the method for claim 310, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

312. the method for claim 307, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

313. the method for claim 307, wherein said cell proliferation disorders is a cancer.

314. the method for claim 313, wherein said cancer is a solid tumor cancer.

315. the method for claim 314, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

316. the compound of following formula or its pharmacologically acceptable salts:

Wherein

Φ is-NH ₂Or-OH;

R ¹Be H or as defined in claim 1;

R ², R ³And R ⁴As defined in claim 1;

E, E ' and E " be independently selected from-N (R ^a)-,-O-,-C (O) O-,-OC (O)-,-C (O)-,-N (R ^a) C (O)-,-N (R ^a) C (O) N (R ^b)-,-N (R ^a) C (O) O-,-OC (O) N (R ^a)-,-C (O) N (R ^a)-,-S (O) _r-,-SO ₂N (R ^a)-,-N (R ^a) SO ₂-; R wherein ^aAnd Y ^bBe independently selected from hydrogen or the optional C that is replaced by one or more F _1-6Alkyl, and r is 0-2;

M is 0,1,2,3 or 4; R wherein ¹Meaning can be identical or different;

Ring B is selected from following ring

Wherein,

X ¹And X ²Be selected from CH or N, and

R ¹²It is halogen;

N is 0,1 or 2, wherein R ¹²Same meaning or difference.

317. the compound of claim 316, wherein

Or

Ring B is thienyl or pyridyl---wherein, thienyl all links to each other with ring A on the 2-position of thiophene basic ring or pyridyl ring with pyridyl, and links to each other with the amide group of formula (I) on the 5-position of thiophene basic ring or pyridyl ring;

Or

M is 0,1,2,3 or 4; R wherein ¹¹Same meaning or difference;

R ¹²It is halogen;

N is 0,1 or 2; R wherein ¹²And identical or different.

318. the compound of claim 317, wherein

Ring A is pyridin-4-yl, pyridin-3-yl, pyridine-2-base, quinoline-8-base, pyrimidine-6-base, pyrimidine-5-base, pyrimidine-4-base, morpholine-4-base, piperidin-4-yl, piperidines-3-base, piperidines-2-base, piperazine-4-base, pyridazine-5-base, pyrazine-6-base, thiazol-2-yl, thiophene-2-base, thieno-[3,2d] pyrimidyl, thieno-[3,2b] pyrimidyl, thieno-[3,2b] pyridyl, purine-6-base, 1 ', 2 ', 3 ', 6 '-tetrahydropyridine-4-base or triazine-6-base; If wherein ring A contains-the NH-part, then nitrogen can be chosen the group replacement that is selected from G wantonly;

Ring B is thienyl, thiazolyl, pyrimidyl, pyrazinyl, pyridazinyl or pyridyl;

R ¹¹Be halogen, amino, C _1-6-alkyl or C _1-6-alkoxyl group.

319. the compound of claim 317, wherein

Ring B is thienyl or pyridyl;

R ¹¹Be halogen, amino, methyl or methoxy.

320. the compound of claim 317, wherein

321. the compound of claim 317, wherein

Ring A is pyridin-4-yl, pyridin-3-yl, pyridine-2-base or 1,2, the 4-triazolyl.

322. the compound of claim 317, wherein

323. the compound of claim 317, wherein R ¹²It is fluorine.

324. the compound of claim 317, wherein R ¹²Be chlorine.

325. the compound of claim 316, wherein R ², R ³And R ⁴Correspond respectively to the R in the claim 316 separately ¹², R ¹³And R ¹⁴, wherein:

M is 0,1,2, wherein R ¹¹Same meaning or difference;

N is 0,1,2, wherein R ¹²Same meaning or difference;

R ¹²Be F or Cl.

326. the compound of claim 316, wherein R ², R ³And R ⁴Correspond respectively to the R in the claim 316 separately ¹², R ¹³And R ¹⁴, wherein:

Ring A is pyridin-4-yl, pyridin-3-yl, pyridine-2-base or 1,2, the 4-triazolyl;

Ring B is thienyl or pyridyl;

R ¹¹Be halogen, amino, methyl or methoxy;

M is 0,1,2, wherein R ¹¹Same meaning or difference.

N is 0 or 1;

R ¹²Be F.

327. the compound of claim 316, it is

R wherein ¹¹Be selected from:

328. the compound of claim 316, wherein R ², R ³And R ⁴Be H.

329. the compound of claim 316, it is selected from terminal portions-C (the O)-NH-Ay of the compound of WO 03/024448 ¹,-C (O)-NH-Ay ²,-C (O)-NH-Ar ^a-NH ₂, and

The compound that quilt replaces as the lower section:

Wherein Φ, R ¹, R ², R ³And R ⁴Define according to claim.

330., be used for the inhibition of histone deacetylase according to the compound of claim 316.

331., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 316.

332. the compound of claim 331, wherein said treatment realizes by the inhibition of histone deacetylase.

334. the compound of claim 331, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

335. the compound of claim 331, wherein said cell proliferation disorders is a cancer.

336. the compound of claim 335, wherein said cancer is a solid tumor cancer.

337. the compound of claim 335, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

338. a pharmacy composite contains described compound of with good grounds claim 316 and pharmaceutically acceptable carrier.

339. the pharmacy composite of claim 338, it further contains the nucleic acid level inhibitor of histone deacetylase.

340. the pharmacy composite of claim 339, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

341. the pharmacy composite of claim 340, wherein said antisense oligonucleotide are selected from SEQ ID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

342. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 316 that suppresses significant quantity.

343. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 338 of described individual administering therapeutic significant quantity.

344. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 339 of described individual administering therapeutic significant quantity.

345. the method for claim 343, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

346. the method for claim 343, wherein said cell proliferation disorders is a cancer.

347. the method for claim 346, wherein said cancer is a solid tumor cancer.

348. the method for claim 347, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

349. the method for claim 344, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

350. the method for claim 344, wherein said cell proliferation disorders is a cancer.

351. the method for claim 350, wherein said cancer is a solid tumor cancer.

352. the method for claim 351, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

353. the compound of following formula or its pharmacologically acceptable salts:

Wherein

Φ is-NH ₂Or-OH;

R ¹Be H or as defined in claim 1;

R ², R ³And R ⁴As defined in claim 1; And

Ar, A, D, E and G in the JP 2003137866 definition.

354. the compound of claim 353, wherein R ¹, R ², R ³And R ⁴Be H.

355. the compound of claim 353, it is selected from the terminal portions of the compound of JP2003137866:

The compound that quilt replaces as the lower section:

Wherein Φ, R ¹, R ², R ³And R ⁴Define according to claim 1.

356., be used for the inhibition of histone deacetylase according to the compound of claim 353.

357., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 353.

358. the compound of claim 357, wherein said treatment realizes by the inhibition of histone deacetylase.

359. the compound of claim 357, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

360. the compound of claim 357, wherein said cell proliferation disorders is a cancer.

361. the compound of claim 360, wherein said cancer is a solid tumor cancer.

362. the compound of claim 360, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

363. a pharmacy composite contains described compound of with good grounds claim 353 and pharmaceutically acceptable carrier.

364. the pharmacy composite of claim 363, it further contains the nucleic acid level inhibitor of histone deacetylase.

365. the pharmacy composite of claim 364, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

366. the pharmacy composite of claim 365, wherein said antisense oligonucleotide are selected from SEQ ID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

367. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 353 that suppresses significant quantity.

368. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 363 of described individual administering therapeutic significant quantity.

369. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 364 of described individual administering therapeutic significant quantity.

370. the method for claim 368, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

371. the method for claim 368, wherein said cell proliferation disorders is a cancer.

372. the method for claim 371, wherein said cancer is a solid tumor cancer.

373. the method for claim 372, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

374. the method for claim 369, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

375. the method for claim 369, wherein said cell proliferation disorders is a cancer.

376. the method for claim 375, wherein said cancer is a solid tumor cancer.

377. the method for claim 376, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

378. the compound of following formula or its pharmacologically acceptable salts:

Wherein

Φ is-NH ₂Or-OH;

R ¹Be H or as defined in claim 1;

R ², R ³And R ⁴As defined in claim 1;

X, Y and A in the JP 11-269146 (1999) definition; And

R ¹¹R with JP 11-269146 (1999) ¹Identical.

379. the compound of claim 378, wherein R ¹, R ², R ³And R ⁴Be H.

380. the compound of claim 378, it is selected from the terminal portions of the compound 1-50 of JP 11-269146 (1999) table 2-4:

The compound that quilt replaces as the lower section:

Wherein Φ, R ¹, R ², R ³And R ⁴Define according to claim 1.

381., be used for the inhibition of histone deacetylase according to the compound of claim 378.

382., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 378.

383. the compound of claim 382, wherein said treatment realizes by the inhibition of histone deacetylase.

384. the compound of claim 382, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

385. the compound of claim 382, wherein said cell proliferation disorders is a cancer.

386. the compound of claim 385, wherein said cancer is a solid tumor cancer.

387. the compound of claim 385, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

388. a pharmacy composite contains described compound of with good grounds claim 378 and pharmaceutically acceptable carrier.

389. the pharmacy composite of claim 388, it further contains the nucleic acid level inhibitor of histone deacetylase.

390. the pharmacy composite of claim 389, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

391. the pharmacy composite of claim 390, wherein said antisense oligonucleotide are selected from SEQ ID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

392. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 378 that suppresses significant quantity.

393. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 388 of described individual administering therapeutic significant quantity.

394. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 389 of described individual administering therapeutic significant quantity.

395. the method for claim 393, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

396. the method for claim 393, wherein said cell proliferation disorders is a cancer.

397. the method for claim 396, wherein said cancer is a solid tumor cancer.

398. the method for claim 397, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

399. the method for claim 394, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

400. the method for claim 394, wherein said cell proliferation disorders is a cancer.

401. the method for claim 400, wherein said cancer is a solid tumor cancer.

402. the method for claim 401, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

403. the compound of following formula or its pharmacologically acceptable salts:

Wherein

Φ is-NH ₂Or-OH;

R ¹Be H or as defined in claim 1;

R ², R ³And R ⁴As defined in claim 1;

N, X, Q and A in the JP 11-302173 (1999) definition; And

R ¹¹R with JP 11-302173 (1999) ¹Identical.

404. the compound of claim 403, wherein R ¹, R ², R ³And R ⁴Be H.

405. the compound of claim 403, it is selected from the terminal portions of the compound 1-67 of JP 11-302173 (1999):

The compound that quilt replaces as the lower section:

Wherein Φ, R ¹, R ², R ³And R ⁴Define according to claim 1.

406., be used for the inhibition of histone deacetylase according to the compound of claim 403.

407., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 403.

408. the compound of claim 407, wherein said treatment realizes by the inhibition of histone deacetylase.

409. the compound of claim 407, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

410. the compound of claim 407, wherein said cell proliferation disorders is a cancer.

411. the compound of claim 410, wherein said cancer is a solid tumor cancer.

412. the compound of claim 410, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

413. a pharmacy composite contains described compound of with good grounds claim 403 and pharmaceutically acceptable carrier.

414. the pharmacy composite of claim 413, it further contains the nucleic acid level inhibitor of histone deacetylase.

415. the pharmacy composite of claim 414, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

416. the pharmacy composite of claim 415, wherein said antisense oligonucleotide are selected from SEQ ID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

417. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 403 that suppresses significant quantity.

418. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 413 of described individual administering therapeutic significant quantity.

419. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 414 of described individual administering therapeutic significant quantity.

420. the method for claim 418, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

421. the method for claim 418, wherein said cell proliferation disorders is a cancer.

422. the method for claim 421, wherein said cancer is a solid tumor cancer.

423. the method for claim 422, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

424. the method for claim 419, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

425. the method for claim 419, wherein said cell proliferation disorders is a cancer.

426. the method for claim 425, wherein said cancer is a solid tumor cancer.

427. the method for claim 426, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

428. the compound of following formula or its pharmacologically acceptable salts:

Wherein

Φ is-NH ₂Or-OH;

R ¹Be H or as defined in claim 1;

R ², R ³And R ⁴As defined in claim 1;

N, Q and A in the JP 2001131130 definition; And

R ¹¹R with JP 2001131130 ¹Identical.

429. the compound of claim 428, wherein R ¹, R ², R ³And R ⁴Be H.

430. the compound of claim 428, it is selected from the terminal portions of the compound of JP 2001131130

The compound that quilt replaces as the lower section:

Wherein Φ, R ¹, R ², R ³And R ⁴Define according to claim 1.

431., be used for the inhibition of histone deacetylase according to the compound of claim 428.

432., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 428.

433. the compound of claim 432, wherein said treatment realizes by the inhibition of histone deacetylase.

434. the compound of claim 432, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

435. the compound of claim 432, wherein said cell proliferation disorders is a cancer.

436. the compound of claim 435, wherein said cancer is a solid tumor cancer.

437. the compound of claim 435, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

438. a pharmacy composite contains described compound of with good grounds claim 428 and pharmaceutically acceptable carrier.

439. the pharmacy composite of claim 438, it further contains the nucleic acid level inhibitor of histone deacetylase.

440. the pharmacy composite of claim 439, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

441. the pharmacy composite of claim 440, wherein said antisense oligonucleotide are selected from SEQ ID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

442. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 428 that suppresses significant quantity.

443. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 438 of described individual administering therapeutic significant quantity.

444. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 439 of described individual administering therapeutic significant quantity.

445. the method for claim 443, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

446. the method for claim 443, wherein said cell proliferation disorders is a cancer.

447. the method for claim 446, wherein said cancer is a solid tumor cancer.

448. the method for claim 447, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

449. the method for claim 444, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

450. the method for claim 444, wherein said cell proliferation disorders is a cancer.

451. the method for claim 450, wherein said cancer is a solid tumor cancer.

452. the method for claim 451, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

453. the compound of following formula or its pharmacologically acceptable salts:

Wherein

Φ is-NH ₂Or-OH;

R ¹Be H or as defined in claim 1;

R ², R ³And R ⁴As defined in claim 1;

R ¹¹R with JP 10152462, JP 2002332267 and JP 11-302173 ¹Identical.

454. the compound of claim 453, R ¹, R ², R ³And R ⁴Be H.

455. the compound of claim 453, it is selected from the terminal portions of the compound of JP 10152462, JP 2002332267 and JP 11-302173

The compound that quilt replaces as the lower section:

Wherein Φ, R ¹, R ², R ³And R ⁴Define according to claim 1.

456., be used for the inhibition of histone deacetylase according to the compound of claim 453.

457., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 453.

458. the compound of claim 457, wherein said treatment realizes by the inhibition of histone deacetylase.

459. the compound of claim 457, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

460. the compound of claim 457, wherein said cell proliferation disorders is a cancer.

461. the compound of claim 460, wherein said cancer is a solid tumor cancer.

462. the compound of claim 460, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

463. a pharmacy composite contains described compound of with good grounds claim 453 and pharmaceutically acceptable carrier.

464. the pharmacy composite of claim 463, it further contains the nucleic acid level inhibitor of histone deacetylase.

465. the pharmacy composite of claim 464, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

466. the pharmacy composite of claim 465, wherein said antisense oligonucleotide are selected from SEQ ID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

467. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 453 that suppresses significant quantity.

468. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 463 of described individual administering therapeutic significant quantity.

469. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 464 of described individual administering therapeutic significant quantity.

470. the method for claim 468, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

471. the method for claim 468, wherein said cell proliferation disorders is a cancer.

472. the method for claim 471, wherein said cancer is a solid tumor cancer.

473. the method for claim 472, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

474. the method for claim 469, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

475. the method for claim 469, wherein said cell proliferation disorders is a cancer.

476. the method for claim 475, wherein said cancer is a solid tumor cancer.

477. the method for claim 476, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

478. the compound of following formula or its pharmacologically acceptable salts:

Wherein

Φ is-NH ₂Or-OH;

R ¹Be H or as defined in claim 1;

R ², R ³And R ⁴As defined in claim 1;

Define among n, X, Q and A such as the US 6,174,905; And

R ¹¹With US 6,174,905 R ¹Identical.

479. the compound of claim 478, wherein R ¹, R ², R ³And R ⁴Be H.

480. the compound of claim 478, it is selected from US 6,174, and in 905 the compound, US 6,174, the terminal portions of the compound of 905 tables 1:

With US 6,174, the terminal portions of the compound of 905 table 2-4:

The compound that quilt replaces as the lower section:

Wherein Φ, R ¹, R ², R ³And R ⁴Define according to claim 1.

481., be used for the inhibition of histone deacetylase according to the compound of claim 478.

482., be used for the treatment of the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease according to the compound of claim 478.

483. the compound of claim 482, wherein said treatment realizes by the inhibition of histone deacetylase.

484. the compound of claim 482, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

485. the compound of claim 482, wherein said cell proliferation disorders is a cancer.

486. the compound of claim 485, wherein said cancer is a solid tumor cancer.

487. the compound of claim 485, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

488. a pharmacy composite contains described compound of with good grounds claim 478 and pharmaceutically acceptable carrier.

489. the pharmacy composite of claim 488, it further contains the nucleic acid level inhibitor of histone deacetylase.

490. the pharmacy composite of claim 489, wherein said nucleic acid level inhibitor are the coding nucleic acid complementary antisense oligonucleotides with histone deacetylase.

491. the pharmacy composite of claim 490, wherein said antisense oligonucleotide are selected from SEQ ID No:1, SEQ ID No:2, SEQ ID No:3, SEQ ID No:4, SEQ ID No:5, SEQ ID No:6, SEQ ID No:7, SEQ ID No:8, SEQ ID No:9, SEQ ID No:10, SEQ ID No:11, SEQ ID No:12, SEQ ID No:13, SEQ ID No:14, SEQ IDNo:15, SEQ ID No:16 and SEQ ID No:17.

492. the method for an inhibition of histone deacetylase, described method comprise described histone deacetylase is contacted with the compound of the claim 478 that suppresses significant quantity.

493. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 488 of described individual administering therapeutic significant quantity.

494. the method that the individuality of suffering from the disease that is selected from cell proliferation disorders, protozoan disease and fungal disease is treated, described method comprises the pharmacy composite to the claim 489 of described individual administering therapeutic significant quantity.

495. the method for claim 493, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

496. the method for claim 493, wherein said cell proliferation disorders is a cancer.

497. the method for claim 496, wherein said cancer is a solid tumor cancer.

498. the method for claim 497, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

499. the method for claim 494, wherein said cell proliferation disorders are the tumor cell proliferation diseases.

500. the method for claim 494, wherein said cell proliferation disorders is a cancer.

501. the method for claim 500, wherein said cancer is a solid tumor cancer.

502. the method for claim 501, wherein said cancer is selected from lymphoma, lung cancer, colorectal carcinoma, prostate cancer, cancer of the stomach, breast cancer and leukemia.

503. compound and pharmacologically acceptable salts thereof, described compound are selected from the compound of table 1 and table 1a.