CN1901902A

CN1901902A - Thiophene and benzothiophene hydroxamic acid derivatives

Info

Publication number: CN1901902A
Application number: CN 200480036197
Authority: CN
Inventors: T·A·米勒; D·J·韦特; S·贝尔韦德雷
Original assignee: Aton Pharma Inc
Current assignee: Aton Pharma Inc
Priority date: 2003-10-09
Filing date: 2004-10-08
Publication date: 2007-01-24

Abstract

The present invention relates to a novel class of hydroxamic acid derivatives having a benzothiophene or thiophene backbone. The hydroxamic acid compounds can be used to treat cancer. The hydroxamic acid compounds can also inhibit historic deacetylase and are suitable for use in selectively inducing terminal differentiation, and arresting cell growth and/or apoptosis of neoplastic cells, thereby inhibiting proliferation of such cells. Thus, the compounds of the present invention are useful in treating a patient having a tumor characterized by proliferation of neoplastic cells. The compounds of the invention are also useful in the prevention and treatment of TRX-mediated diseases, such as autoimmune, allergic and inflammatory diseases, and in the prevention and/or treatment of diseases of the central nervous system (CNS), such as neurodegenerative diseases, The present invention further provides pharmaceutical compositions comprising the hydroxamic acid derivatives and safe dosing regimens of these pharmaceutical compositions, which are easy to follow, and which result in a therapeutically effective amount of the hydroxamic acid derivatives in vivo.

Description

Thiophene and benzothiophene hydroxamic acid derivatives

Invention field

The present invention relates to a kind of novel hydroxamic acid derivs with benzothiophene or thiophene skeleton.Described hydroxamic acid compound can be used for treating cancer.But described hydroxamic acid compound is inhibition of histone deacetylase and be applicable to the eventually end differentiation of selective induction tumor sexual cell, cell growth retardation and/or apoptosis also, thereby suppresses this class cell proliferation.Therefore, chemical compound of the present invention can be used for treating and suffers from the patient that tumor is characterised in that tumor sexual cell propagation.Chemical compound of the present invention also can be used for the disease of prevention and treatment TRX (thioredoxin)-mediation, for example autoimmune disease, allergia and inflammatory diseases, and be used to prevent and/or treat central nervous system (CNS) disease, for example neurodegenerative disease.

Background of invention

Chemical compound with hydroxamic acid part has demonstrated has useful biological activity.The for example known many Peptidyl compounds that contain the hydroxamic acid part suppress matrix metalloproteinase (MMPs), and it is for containing zinc endopeptidase family.Play an important role during the tissue of MMPs on the physiology and on the pathology is aging.Therefore, can suppress the disease that the active Peptidyl compounds of MMPs can be used for treating or preventing to relate to tissue decay and inflammation.In addition, to small part based on hydroxamic acid group and the bonded characteristic of zinc, the chemical compound that contains hydroxamic acid part has demonstrated inhibition of histone deacetylase (HDACs).

Express but suppress the HDACs repressor gene, comprise the gene expression relevant with tumor suppression.The inhibition of histone deacetylase can cause the transcription repression of tumor suppressor gene to histone deacetylase-mediation.For example, the inhibition of histone deacetylase can provide a kind of treatment cancer, hematologic disease (for example hematopoietic disease) and with the method for the metabolic disease of gene-correlation.More particularly, transcriptional control is the critical event in cell differentiation, propagation and the apoptosis.There are a plurality of evidences to show the transcriptional regulatory (Grunstein, M., Nature, 389:349-52 (1997)) of finishing cell by histone acetyl baseization and deacetylation mechanism.It is believed that these effects take place by the variation of chromatin Structure, this variation realizes the affinity of coiled coil type DNA in the nucleosome by changing histone.5 kinds of histones have been identified.Find histone H2A, H2B, H3 and H4 in nucleosome, H1 is the connector between nucleosome.Except that the H1 that separately exists in the nucleosomal structure outside, each nucleosome contains two kinds of histones wherein in its nuclear.Think that the affinity of histone and phosphoric acid DNA skeleton is bigger when histone hangs down acetylation.This affinity causes DNA and histone to be combined closely, and causes DNA to be difficult to transcription regulatory element and device.

Regulate the acetylation state by the active balance between acetylation of histone transferring enzyme (HAT) and two kinds of multienzyme complexs of histone deacetylase (HDAC).Think that low acetylation state suppresses relative dna and transcribes.Should low big polyprotein (large multiprotein) the complex catalysis of acetylation state by comprising the HDAC enzyme.Especially confirmed that HDACs catalysis removes the acetyl group on the chromatin nucleohistone.

Several examples show that the activity that upsets HAT or HDAC relates to the malignant phenotype and grows.For example, as if in acute promyelocytic leukemia, PML and α RAR merge the oncoprotein that produces and transcribe (Lin, R.J. etc., Nature391:811-14 (1998)) by raising HDACs inhibition specific gene.The tumor sexual cell can not be finished differentiation in such a way, and causing the leukaemia is hyper-proliferative.

United States Patent (USP) 5,369,108,5,932,616,5,700,811,6,087,367 and 6,511,990 disclose the hydroxamic acid derivs that can be used for the end differentiation eventually of selective induction tumor sexual cell, cell growth retardation or apoptosis, and these documents are combined in herein by reference.Except its biological activity as antitumor drug, think that recently these hydroxamic acid derivs can be used for the disease and the symptom for the treatment of or preventing various thioredoxins (TRX)-mediation, for example inflammatory diseases, allergic disease, autoimmune disease, with the oxidative stress diseases associated be characterized as the disease (U.S. Patent application the 10/369th of cell hyperproliferation, No. 094, on February 15th, 2003 submitted to, and the document is quoted by integral body and is attached to herein).In addition, think that these hydroxamic acid derivs can be used for treating central nervous system (CNS) disease such as neurodegenerative disease and are used for the treatment of the brain cancer (referring to U.S. Patent application the 10/273rd, No. 401, on October 16th, 2002 submitted to, and the document is quoted by integral body and is attached to herein).

Think and studies confirm that through the x-ray crystal analysis method, suppress HDAC with the chemical compound Vorinostat (SAHA) that contains hydroxamic acid and carry out (Finnin by catalytic site direct interaction with enzyme, M.S. etc., Nature 401:188-193 (1999)).Think that the result who suppresses HDAC does not have the universality effect to genome, but only influence genomic smaller subset (Van Lint, C. etc., Gene Expression 5:245-53 (1996)).The evidence that the little ordering of DNA (microarrays) that is with the malignant cell of cultivating with hdac inhibitor provides shows the gene of the limited quantity (1-2%) that its product change is arranged.For example, in culture medium, handle the inhibitors of kinases p21 (Archer, S.Shufen, M.Shei, A., Hodin, R. (1998) PNAS 95:6791-96) that the continuous induction cyclin dependent appears in cell with hdac inhibitor.This albumen plays an important role in suppressing cell cycle.Think that hdac inhibitor increases the p21 transcription rate by the high acetylation state that spreads histone in the p21 gene region, thereby make the gene can transcriptional machinery.It is expressed the gene that not influenced by hdac inhibitor and do not change (Dressel, U. etc., Anticancer Research20 (2A): 1017-22 (2000)) in the acetylation of zone association histone.

In addition, hydroxamic acid derivs for example SAHA can inducing tumor cell growth stop, differentiation and/or apoptosis (Richon etc., Proc.Natl.Acad.Sci.USA, 93:5705-5708 (1996)).These targeting compounds become the inherent mechanism of malignant cell ability, because they toxicity (Cohen, L.A. etc., Anticancer Research 19:4999-5006 (1999)) do not occur under the dosage that effectively suppresses the animal tumor growth.

Consider that the chemical compound that contains the hydroxamic acid part has application widely, therefore is starved of the hydroxamic acid derivs with improvement performance of development of new, the bioavailability of for example improved usefulness or increase.

Summary of the invention

The present invention relates to a kind of novel hydroxamic acid derivs with benzothiophene or thiophene skeleton.This hydroxamic acid compound can be used for treating cancer.But this hydroxamic acid compound is the inhibition of histone deacetylase also, and is applicable to the end differentiation eventually of selective induction tumor sexual cell, cell growth retardation and/or apoptosis, thereby suppresses this class cell proliferation.Therefore, chemical compound of the present invention can be used for treating the patient that the tumor of suffering from is characterised in that tumor sexual cell propagation.Chemical compound of the present invention also can be used for preventing and treats the disease of TRX-mediation, for example autoimmune disease, allergia and inflammatory diseases, and be used to prevent and/or treat central nervous system (CNS) disease, for example neurodegenerative disease.The present invention also provides the pharmaceutical composition that comprises described hydroxamic acid derivs and has easily comply with and made the safe dose scheme (dosing regimen) of the amount of proper interior hydroxamic acid derivs for these pharmaceutical compositions of treatment effective dose.

Be surprised to find that some hydroxamic acid derivs with thiophene or benzothiophene skeleton shows the activity of increase as histone deacetylase (HDAC) inhibitor.

Therefore, chemical compound that the formula I of the present invention relates to represents and pharmaceutically acceptable salt thereof, solvate and hydrate, this point as this paper in detail as described in.

By the apparent above-mentioned purpose of the present invention of the description of the following preferred embodiment of the invention more specifically, feature and advantage and other purposes, feature and advantage.

Detailed Description Of The Invention

The present invention relates to a kind of novel hydroxamic acid derivs with benzothiophene or thiophene skeleton.In one embodiment, but this hydroxamic acid derivs inhibition of histone deacetylase, and be applicable to the end differentiation eventually of selective induction tumor sexual cell, cell growth retardation and/or apoptosis, thus suppress this class cell proliferation.Therefore, chemical compound of the present invention can be used for treating the cancer that the patient suffers from.Chemical compound of the present invention also can be used for preventing and treats the disease of TRX-mediation, for example autoimmune disease, allergia and inflammatory diseases, and be used to prevent and/or treat central nervous system (CNS) disease, for example neurodegenerative disease.

Unexpectedly and be surprised to find some hydroxamic acid derivs and show the activity of increase as histone deacetylase (HDAC) inhibitor with thiophene or benzothiophene skeleton.

Chemical compound

The chemical compound that the formula I of the present invention relates to represents (being benzothiophene hydroxamic acid derivatives) and/or its stereoisomer (comprising enantiomer), racemic modification, pharmaceutically acceptable salt, solvate, hydrate or polymorphic.

Wherein A is alkyl, aryl or the group that is selected from following formula:

R wherein ₁-R ₁₆Separate separately is hydrogen or alkyl, thiazolinyl, aryl, cycloalkyl, heterocyclic radical, alkylaryl (alkylaryl), alkyl-cycloalkyl (alkylcycloalkyl) or alkyl heterocyclic (alkylheterocyclyl) for not replacing or replace; Or one or more R ₁And R ₂, R ₆And R ₇And R ₁₁And R ₁₂Connected nitrogen-atoms forms nitrogenous heterocycle together;

M, p and q are separate separately to be 0,1 or 2;

Or its stereoisomer, enantiomer, racemic modification, pharmaceutically acceptable salt, solvate, hydrate or polymorphic.

The chemical compound that the formula I of the invention still further relates to represents (being benzothiophene hydroxamic acid derivatives) and/or its stereoisomer (comprising enantiomer), racemic modification, pharmaceutically acceptable salt, solvate, hydrate or polymorphic.

Wherein A is alkyl, aryl or the group that is selected from following formula:

R wherein ₁-R ₁₆Separate separately is hydrogen or alkyl, thiazolinyl, aryl, cycloalkyl, heterocyclic radical, alkylaryl, alkyl-cycloalkyl or alkyl heterocyclic for not replacing or replace; Or one or more R ₁And R ₂, R ₆And R ₇And R ₁₁And R ₁₂Connected nitrogen-atoms forms nitrogenous heterocycle together;

M, p and q are separate separately to be 0,1 or 2;

The chemical compound that the formula I of the invention still further relates to represents, wherein A is selected from:

In a special embodiment, the chemical compound of formula I shows with following structural table:

The chemical compound that the formula II of the invention still further relates to represents (being thiophene hydroxamic acid derivatives) and/or its stereoisomer (comprising enantiomer), racemic modification, pharmaceutically acceptable salt, solvate, hydrate or polymorphic.

Wherein

A is alkyl, aryl or the group that is selected from following formula:

R wherein ₁-R ₁₇Separate separately is hydrogen or alkyl, thiazolinyl, aryl, assorted alkyl (heteroalkyl), cycloalkyl, heterocyclic radical, alkylaryl, cycloalkyl aryl, alkyl-cycloalkyl, acyl group, sulfonyl or alkyl heterocyclic for not replacing or replacing; Or one or more R ₁And R ₂, R ₆And R ₇And R ₁₁And R ₁₂Connected nitrogen-atoms forms nitrogenous heterocycle together;

B is

N is 0 or 1;

M and p are separate separately to be 0,1 or 2;

Wherein

A is alkyl, aryl or the group that is selected from following formula:

B is

N is 0 or 1;

M, p and q are separate separately to be 0,1 or 2;

In the embodiment of formula I or formula II, A is

R wherein ₁And R ₂As mentioned above.In a special embodiment, R ₁And R ₂In at least one be phenyl, naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.

In another embodiment of formula I or formula II, A is

R wherein ₃And R ₄As mentioned above.In a special embodiment, R ₃And R ₄In at least one be phenyl, naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.

In another embodiment of formula I or formula II, A is

R wherein ₅As mentioned above.In a special embodiment, R ₅For phenyl, naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.

In another embodiment of formula I or formula II, A is

R wherein ₆And R ₇As mentioned above.In a special embodiment, R ₆And R ₇In at least one be phenyl, naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.

In another embodiment of formula I or formula II, A is

R wherein ₈As mentioned above.In a special embodiment, R ₈For phenyl, naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.

In another embodiment of formula I or formula II, A is

R wherein ₉As mentioned above.In a special embodiment, R ₉For phenyl, naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.

In another embodiment of formula I or formula II, A is

R wherein ₁₀As mentioned above.In a special embodiment, R ₁₀For phenyl, naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.

In another embodiment of formula I or formula II, A is

R wherein ₁₁And R ₁₂As mentioned above.In a special embodiment, R ₁₁And R ₁₂In at least one be phenyl, naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.

In another embodiment of formula I or formula II, A is

In another embodiment of formula I or formula II, A is

In another embodiment of formula I or formula II, A is

In another embodiment of formula I or formula II, A is

Wherein p, R ₁₃And R ₁₄As mentioned above.In a special embodiment, R ₁₃And R ₁₄In at least one be phenyl, naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.In a special embodiment, p is 0.In another special embodiment, p is 1.In another special embodiment, p is 2.

In another embodiment of formula I or formula II, A is

Wherein q, R ₁₅And R ₁₆As mentioned above.In a special embodiment, R ₁₅And R ₁₆In at least one be phenyl, naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.In a special embodiment, q is 0.In another special embodiment, q is 1.In another special embodiment, q is 2.

In the embodiment of formula I or formula II, R ₁And R ₂, R ₆And R ₇And R ₁₁And R ₁₂Connected nitrogen-atoms forms nitrogenous heterocycle together.Described heterocycle can be monocycle or can be condensed bicyclo-or three rings.In addition, except nitrogen, described heterocycle also can comprise one or more hetero atoms, for example O, S, N and P.

In addition, in the special embodiment of formula II, B is:

In another special embodiment of formula II, B is:

-CH ₂-CH ₂-

In another special embodiment of formula II, B is:

The see below table 1 of experimental section of the specific embodiments of the limiting examples of the benzothiophene hydroxamic acid derivatives of formula I.The see below table 2 of experimental section of the specific embodiments of the limiting examples of the thiophene hydroxamic acid derivatives of formula II.

The chemistry definition

" alkyl " used herein comprises the side chain with specific carbon number and the radical of saturated aliphatic alkyl of straight chain.For example, " C ₁-C ₁₀Alkyl " in C ₁-C ₁₀Be defined as the carbon atom of 1,2,3,4,5,6,7,8,9 or 10 linear or branched arrangement.For example, " C ₁-C ₁₀Alkyl " specifically comprise methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, isobutyl group, amyl group, hexyl, heptyl, octyl group, nonyl, decyl etc.Term " cycloalkyl " is meant the monocycle radical of saturated aliphatic alkyl with specific carbon number.For example, " cycloalkyl " comprises cyclopropyl, methyl-cyclopropyl, 2,2-dimethyl-cyclobutyl, 2-ethyl-cyclopenta, cyclohexyl etc.In certain embodiments of the invention, term " cycloalkyl " comprises above-mentioned group and comprises monocycle unsaturated aliphatic alkyl.For example, Ding Yi " cycloalkyl " comprises cyclopropyl, methyl-cyclopropyl, 2 in these embodiments, 2-dimethyl-cyclobutyl, 2-ethyl-cyclopenta, cyclohexyl, cyclopentenyl, cyclobutane base etc.In one embodiment, if there is not the concrete regulation carbon number, then " alkyl " is meant C ₁-C ₁₂Alkyl, and in another embodiment, " alkyl " is meant C ₁-C ₆Alkyl.In one embodiment, if there is not the concrete regulation carbon number, then " cycloalkyl " is meant C ₃-C ₁₀Cycloalkyl, and in another embodiment, " cycloalkyl " is meant C ₃-C ₇Cycloalkyl.In one embodiment, the example of " alkyl " has methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group and isobutyl group.

Term " alkylidene " is meant the bivalent hydrocarbon radical with specific carbon number.For example, " alkylidene " comprises-CH ₂-,-CH ₂CH ₂-etc.In one embodiment, if there is not the concrete regulation carbon number, then " alkylidene " is meant C ₁-C ₁₂Alkylidene, and in another embodiment, " alkylidene " is meant C ₁-C ₆Alkylidene.

In the time of in being used in phrase " alkylaryl ", " alkyl-cycloalkyl " and " alkyl heterocyclic ", term " alkyl " is meant the moieties of this group, and does not describe the atomic number of the aryl and the heteroaryl moieties of this group.In one embodiment, if there is not the concrete regulation carbon number, then " alkyl " of " alkylaryl ", " alkyl-cycloalkyl " and " alkyl heterocyclic " is meant C ₁-C ₁₂Alkyl, and in another embodiment, the alkyl in " aralkyl (aralkyl) " is meant C ₁-C ₆Alkyl.

If concrete regulation carbon number not, then term " thiazolinyl " is meant straight chain, side chain or the cyclic non-aromatic hydrocarbyl that comprises 2-10 carbon atom and at least one carbon-carbon double bond.Preferred there is a carbon-carbon double bond, and can exists and be up to four non-aromatics carbon-carbon double bonds.Therefore " C ₂-C ₆Thiazolinyl " be meant thiazolinyl with 2-6 carbon atom.Thiazolinyl comprises vinyl, acrylic, cyclobutenyl, 2-methyl butene base and cyclohexenyl group.The straight chain of described thiazolinyl, side chain and annulus can comprise two keys, and if refer to the thiazolinyl of replacement, then the straight chain of described thiazolinyl, side chain and annulus can be substituted.

Term " alkynyl " is meant and comprises 2-10 carbon atom and the triple-linked straight chain of at least one carbon carbon, side chain or cyclic alkyl.Can exist and be up to three carbon carbon triple bonds.Therefore, " C ₂-C ₆Alkynyl " be meant alkynyl with 2-6 carbon atom.Alkynyl comprises acetenyl, propinyl, butynyl, 3-methyl butynyl etc.The straight chain of described alkynyl, side chain or annulus can comprise triple bond, and if refer to the alkynyl of replacement, then the straight chain of described alkynyl, side chain or annulus can be substituted.

In some cases, the defined carbon atom scope of substituent group can comprise 0, for example (C ₀-C ₆) alkylidene-aryl.If aryl is a phenyl, then this scope comprise phenyl itself and-CH ₂Ph ,-CH ₂CH ₂Ph, CH (CH ₃) CH ₂CH (CH ₃) Ph etc.

In one embodiment, " aryl " used herein is meant that the atomic number of each ring is up to 7 any stable monocycle or bicyclic carbocyclic ring, and wherein at least one ring is aromatic ring.The example of this class aryl comprises phenyl, naphthyl, tetralyl, indanyl and xenyl.At described aryl substituent is that dicyclo and a ring are under the situation of non-aromatic ring, should be understood that by aromatic ring to connect.

In another embodiment, " aryl " is the aromatic ring of 5-14 carbon atom, and comprises Cycloalkylfused isocyclic aryl, for example indane with 5-or 6-unit.The example of isocyclic aryl includes but not limited to phenyl; Naphthyl, for example 1-naphthyl and 2-naphthyl; Anthryl, for example 1-anthryl, 2-anthryl; Phenanthryl; Fluorenone base, for example 9-Fluorenone base; Indanyl etc.Isocyclic aryl is optional to be replaced by the substituent group that specifies number as described below.

The atomic number of each ring of term used herein " heteroaryl " expression is up to 7 stable monocycle or bicyclo-, and wherein at least one ring is aromatic ring and comprises 1-4 hetero atom that is selected from O, N and S.In another embodiment, term " heteroaryl " is meant the monocyclic, bicyclic or tricyclic aromatic ring of 5-14 the annular atoms of being made up of carbon atom and the individual hetero atom that is selected from O, N or S of 1-4.Heteroaryl in this range of definition includes but not limited to following group: acridinyl, carbazyl, cinnolinyl, quinoxalinyl, pyrazolyl, indyl, benzotriazole base, furyl, thienyl, benzothienyl, benzofuranyl, quinolyl, isoquinolyl,  azoles base, different  azoles base, indyl, pyrazinyl, pyridazinyl, pyridine radicals, pyrimidine radicals, pyrrole radicals, tetrahydric quinoline group.To heterocyclic definition, it should also be understood that " heteroaryl " comprises the nitrogen oxide derivant of any nitrogenous heteroaryl according to following.In described heteroaryl substituent group is that dicyclo and a ring are non-aromatic ring or do not contain under the heteroatomic situation, should be understood that respectively by aromatic ring or contain heteroatomic ring to connect.

In another embodiment, the monocyclic, bicyclic or tricyclic aromatic ring of " heteroaryl " 5-14 annular atoms forming for the hetero atom that is selected from O, N or S by carbon atom and 1-4.The example of heteroaryl includes but not limited to pyridine radicals, for example 2-pyridine radicals (being also referred to as α-pyridine radicals), 3-pyridine radicals (being also referred to as β-pyridine radicals) and 4-pyridine radicals (being also referred to as the DB3 base); Thienyl, for example 2-thienyl and 3-thienyl; Furyl, for example 2-furyl and 3-furyl; Pyrimidine radicals, for example 2-pyrimidine radicals and 4-pyrimidine radicals; Imidazole radicals, for example 2-imidazole radicals; Pyranose, for example 2-pyranose and 3-pyranose; Pyrazolyl, for example 4-pyrazolyl and 5-pyrazolyl; Thiazolyl, for example 2-thiazolyl, 4-thiazolyl and 5-thiazolyl; Thiadiazolyl group; Isothiazolyl;  azoles base, for example 2- azoles base, 4- azoles base and 5- azoles base; Different  azoles base; Pyrrole radicals; Pyridazinyl; Pyrazinyl etc.Heterocyclic aromatic group (or heteroaryl) can be chosen the described substituent group replacement that is used for aromatic group of designated number wantonly as defined above.

In one embodiment, " heteroaryl " also can comprise " condensed polyaromatic ", and it is the heterocyclic fused heteroaryl with one or more other heteroaryls or non-aromatics.The example comprises quinolyl and isoquinolyl, for example 2-quinolyl, 3-quinolyl, 4-quinolyl, 5-quinolyl, 6-quinolyl, 7-quinolyl and 8-quinolyl, 1-isoquinolyl, 3-quinolyl, 4-isoquinolyl, 5-isoquinolyl, 6-isoquinolyl, 7-isoquinolyl and 8-isoquinolyl; Benzofuranyl, for example 2-benzofuranyl and 3-benzofuranyl; Dibenzofuran group, for example 2, the 3-dihydro benzo furyl; The dibenzothiophenes base; Benzothienyl, for example 2-benzothienyl and 3-benzothienyl; Indyl, for example 2-indyl and 3-indyl; Benzothiazolyl, for example 2-[4-morpholinodithio base; Benzoxazol base, for example 2-benzoxazol base; Benzimidazolyl, for example 2-benzimidazolyl; Isoindolyl, for example 1-isoindolyl and 3-isoindolyl; The benzotriazole base; Purine radicals; Thianaphthenyl, pyrazinyl etc.The substituent group as herein described that condensed polycyclic aromatic member ring systems can be chosen designated number wantonly replaces.

Term used herein " heterocycle " or " heterocyclic radical " are meant and comprise 1-4 heteroatomic 3 to 10 yuan of aromatics or the non-aromatic heterocyclics that are selected from O, N and S, and comprise bicyclic groups.Therefore " heterocyclic radical " comprises above-mentioned heteroaryl and dihydro and tetrahydrochysene analog.Other examples of " heterocyclic radical " include but not limited to following group: azetidinyl; benzimidazolyl; benzofuranyl; benzo furazan base; the benzopyrazoles base; the benzotriazole base; benzothienyl; the benzoxazol base; carbazyl; carbolinyl; cinnolinyl; furyl; imidazole radicals; indolinyl; indyl; indolazinyl; indazolyl; isobenzofuran-base; isoindolyl; isoquinolyl; isothiazolyl; different  azoles base; naphthyridinyl; the  di azoly;  azoles base;  azoles quinoline base; different  azoles quinoline base; oxetanyl; pyranose; pyrazinyl; pyrazolyl; pyridazinyl; the pyridopyridine base; pyridazinyl; pyridine radicals; pyrimidine radicals; pyrrole radicals; quinazolyl; quinolyl; quinoxalinyl; THP trtrahydropyranyl; tetrahydro thiapyran base; tetrahydro isoquinolyl; tetrazole radical; the tetrazolo pyridine radicals; thiadiazolyl group; thiazolyl; thienyl; triazolyl; azetidinyl; 1; 4-two  alkyl; six hydrogen azepine  bases; piperazinyl; piperidyl; the pyridin-2-ones base; pyrrolidinyl; morpholinyl; thio-morpholinyl; the dihydrobenzo imidazole radicals; dihydro benzo furyl; the dihydrobenzo thienyl; dihydrobenzo  azoles base; the dihydrofuran base; the glyoxalidine base; indolinyl; the different  azoles of dihydro base; the dihydro isothiazolyl; dihydro  diazole, dihydro  azoles base; the dihydro pyrazinyl; the pyrazoline base; the dihydropyridine base; the dihydro-pyrimidin base; the pyrrolin base; the dihydroquinoline base; the dihydro tetrazole radical; the thiodiazoline base; dihydro-thiazolyl; the dihydro-thiophene base; the dihydro triazolyl; the dihydro azetidinyl; the methylenedioxyphenyl formoxyl; tetrahydrofuran base and tetrahydro-thienyl and nitrogen oxide thereof.The heterocyclic radical substituent group can connect by carbon atom or by hetero atom.

In one embodiment, the monocyclic, bicyclic or tricyclic saturated or unsaturated ring of " heterocycle " (being also referred to as " heterocyclic radical " herein) for forming by 5-14 ring carbon atom and the individual hetero atom that is selected from O, N, S or P of 1-4.Heterocyclic example includes but not limited to: pyrrolidinyl, piperidyl, morpholinyl, thio-morpholinyl, piperazinyl, dihydrofuran base, tetrahydrofuran base, dihydro pyranyl, THP trtrahydropyranyl (tetrahydrodropyranyl), dihydroquinoline base, tetrahydric quinoline group, dihydro-isoquinoline base, tetrahydro isoquinolyl, dihydro pyrazinyl, tetrahydrochysene pyrazinyl, dihydropyridine base, tetrahydro pyridyl etc.

" alkylaryl " (aralkyl) is by the alkyl of aryl, preferred phenyl replacement.Preferred alkylaryl is a benzyl.The aryl that is fit to is as described herein, and the alkyl that is fit to is as described herein.The substituent group of the alkylaryl that is fit to is as described herein.

" alkyl heterocyclic " alkyl for being replaced by heterocyclic radical.The heterocyclic radical that is fit to is as described herein, and the alkyl that is fit to is as described herein.The substituent group of the alkyl heterocyclic that is fit to is as described herein.

" alkyl-cycloalkyl " alkyl for being substituted by cycloalkyl.The cycloalkyl that is fit to is as described herein, and the alkyl that is fit to is as described herein.The substituent group of the alkyl-cycloalkyl that is fit to is as described herein.

" aryloxy group " is the aryl (for example phenoxy group) that is connected with chemical compound by oxygen.

" alkoxyl " used herein (alkyl oxy) is the C of the straight or branched that is connected with chemical compound by oxygen atom ₁-C ₁₂Or cyclic C ₃-C ₁₂Alkyl.The example of alkoxyl includes but not limited to methoxyl group, ethyoxyl and propoxyl group.

" alkoxy aryl " (aryl alkyl oxygen base) is the aryl alkyl (for example phenyl methoxyl group) that is connected with chemical compound by the oxygen that is connected with the moieties of aryl alkyl.

" arylamino " used herein is the aryl that is connected with chemical compound by nitrogen.

" aryl-alkyl amino " used herein is the aryl alkyl that is connected with chemical compound by the nitrogen that is connected with the moieties of aryl alkyl.

A plurality of part used herein or group are known as " replacement or unsubstituted ".When claiming that certain part is substituted, be meant and on any the position of substitution of well known to a person skilled in the art of this part, replace.In one embodiment, " choose wantonly and replaced by one or more substituent groups " is meant " 0-5 substituent group ", is meant a substituent group, two substituent groups, three substituent groups, four substituent groups or five substituent groups in other embodiments.For example, can be by the metathetical hydrogen atom of the group outside the dehydrogenation (being substituent group) by substituted group.A plurality of substituent groups can be arranged.When a plurality of substituent group, each substituent group can be identical or different, and can replace in any commutable position.This means be substituted by well known in the art.Substituent example includes but not limited to: alkyl (also can further be replaced by one or more substituent groups), alkoxyl (can be substituted), halogen or halogen (F, Cl, Br, I), hydroxyl, nitro, oxo,-CN,-COH,-COOH, amino, azido, N-alkyl amino or N, N-dialkyl amido (alkyl wherein also can further be substituted), N-arylamino or N, N-ammonia diaryl base (aryl wherein also can further be substituted), ester group (C (O)-OR, wherein R can be for example alkyl, aryl etc., these groups can be substituted), aryl (can be substituted), cycloalkyl (can be substituted), alkylaryl (can be substituted), alkyl heterocyclic (can be substituted), alkyl-cycloalkyl (can be substituted) and aryloxy group.

Spatial chemistry

Many organic compound existence have the optically-active form of the plane rotatory power that makes linearly polarized light.When describing optically active compounds, represent molecule absolute configuration about its chiral centre with prefix D and L or R and S.Make the symbol of linearly polarized light rotation with prefix d and l or (+) and (-) representation compound, with (-) or represent that this chemical compound is left-handed.Chemical compound with prefix (+) or d is dextral.For the chemical constitution of determining, except that they were each other non-stack mirror image, these chemical compounds that are known as stereoisomer were identical.A kind of special stereoisomer can be described as enantiomer again, and this type of mixture of isomers is commonly referred to mixture of enantiomers.50: 50 mixture of enantiomers is called racemic mixture.Described herein multiple chemical compound can have one or more chiral centres, therefore can have different enantiomer.Available if desired asterisk (*) expression chiral carbon.When in formula of the present invention, when the key that connects chiral carbon plots straight line, be interpreted as (R) of chiral carbon and (S) two kinds of configurations, so this formula comprise enantiomer and composition thereof both.Identical with this area usage, when needs are specified the absolute configuration of chiral carbon, a key of chiral carbon can be plotted wedge shape (being connected), and another can plot the wedge shape (being connected with the atom below the plane) of dotted line or short parallel lines with the atom more than the plane.Available Cahn-Inglod-Prelog system represents (R) of chiral carbon or (S) configuration.

When hdac inhibitor of the present invention contained a chiral centre, there were two kinds of enantiomeric forms in these chemical compounds, and the present invention includes the mixture of enantiomer and enantiomer, for example were called 50: 50 special mixture of racemic mixture.Can for example pass through to form separable diastereoisomeric salt by method known to those skilled in the art: for example by crystallization (referring to CRC Handbook of Optical Resolutions via Diastereomeric SaltFormation by David Kozma (CRC Press, 2001)); Form separable non-enantiomer derivative or complex, for example by crystallization, gas phase-liquid phase or liquid chromatograph; Make for example enzymatic esterification of a kind of enantiomer and the selective reaction of enantiomer specific reagent; Or in chiral environment, carry out gas phase-liquid phase or liquid chromatograph, for example in chiral support for example on the silica gel of bonded chiral part, or in the presence of chiral solvent, split these enantiomer.Those skilled in the art will recognize that, when the enantiomer of needs being converted into another kind of chemical entities, need further disengage the step that needs enantiomer by one of above-mentioned separation method.Perhaps, available optical activity reagent, substrate, catalyst or solvent by asymmetric synthesis or by asymmetric conversion, are converted into another kind of enantiomer with a kind of enantiomer, synthetic concrete enantiomer.

The symbol of the concrete absolute configuration of The compounds of this invention chiral carbon is interpreted as representing that the appointment enantiomeric form of this chemical compound is enantiomeric excess (ee), or in other words is substantially free of another kind of enantiomer.For example, being substantially free of " R " formalization compound in the serpentine formula chemical compound, is serpentine formula enantiomeric excess therefore.On the contrary, being substantially free of serpentine formula chemical compound in " R " formalization compound, is " R " form enantiomeric excess therefore.Enantiomeric excess used herein is that certain enantiomer exists greater than 50%.For example, enantiomeric excess can be about 60% or more, and for example about 70% or more, for example about 80% or more, for example about 90% or more.In a special embodiment, when indicating specific absolute configuration, the enantiomeric excess of described chemical compound is at least about 90%.In a more specific embodiment, the enantiomeric excess of chemical compound is at least about 95%, for example at least about 97.5%, and at least 99% enantiomeric excess for example.

When The compounds of this invention had two or more chiral carbon, it can have the optical isomer greater than two, and has diastereomer.For example, when two chiral carbon, chemical compound can have be up to 4 optical isomers and the two pairs of enantiomer ((S, S)/(R, R) and (R, S)/(S, R)).Enantiomer is to (for example (S, S)/(R, R)) mirror-image stereo isomer each other.Be not mirror image stereoisomer (for example (and S, S) and (R, S)) be diastereomer.Diastereomer is to can be by method known to those skilled in the art for example chromatograph or Crystallization Separation, and each enantiomer of every centering can separate as stated above.The present invention includes each diastereomer of this compounds and composition thereof.

Except that this paper had clearly regulation in addition, expression-form used herein and definite article " were somebody's turn to do " and comprise odd number and plural indicant.Therefore, for example " active medicine " or " pharmacologically active medicine " comprises the combination of the active medicine that a kind of active medicine is different with two or more, and " carrier " comprises the mixture of two or more carriers and a kind of carrier etc.

The present invention also comprises the prodrug of hydroxamic acid derivs disclosed herein.The available materia medica technology of knowing prepares any prodrug of this compounds.

Divided by on outside the chemical compound enumerated, the present invention also comprises the homologue of this compounds and the purposes of analog.In this article, homologue is the molecule that has basically with the above-claimed cpd structural similarity, and analog is to have the molecule of biological similarity basically, and no matter whether structure is similar.

Pharmaceutically acceptable salt

As mentioned above, hydroxamic acid derivs as herein described can be prepared into the form of its pharmaceutically acceptable salt.Pharmaceutically acceptable salt is the salt that has kept the required biological activity of parent compound and do not had deleterious toxic action.The acid-addition salts of the organic and mineral acid of the example of this salt, for example described acid is hydrochloric acid, sulphuric acid, methanesulfonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid, phosphoric acid etc.Pharmaceutically acceptable salt also can obtain by handling with inorganic base and organic base, inorganic base for example is sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide or hydrated ferric oxide., and organic base is 2-aminopropane., trimethylamine, 2-ethyl amido alcohol, histidine, procaine etc. for example.Pharmaceutically acceptable salt also can be the anion that is formed by element (as chlorine, bromine and iodine).

As mentioned above, disclosed reactive compound also can be prepared into its hydrate forms.Term " hydrate " includes but not limited to semihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate etc.

As mentioned above, disclosed reactive compound also can be prepared into the solvate with any organic or inorganic solvent, for example alcohol (as methanol, ethanol, propanol and isopropyl alcohol), ketone (as acetone), arsol etc.

Disclosed reactive compound also can be prepared into any solid or liquid profile, and for example described chemical compound can be crystal habit, amorphous form, and can be any particle diameter.This compound particle can maybe can be become any other form of bulk, graininess, Powdered, oily, oily suspension or little solid or liquid by micronization.

Also there is polymorphism in chemical compound of the present invention.The present invention also comprises the different polymorphic of The compounds of this invention.Term " polymorphic " is meant the specific crystalline state of material, and this crystalline state has specific physical characteristic for example X-ray diffraction, IR spectrum, fusing point etc.

Except that this paper had clearly regulation in addition, expression-form used herein and definite article " were somebody's turn to do " and comprise odd number and plural indicant.Therefore, for example " active medicine " or " pharmacologically active medicine " comprises the combination of a kind of active medicine active medicine different with two or more, and " carrier " comprises the mixture of two or more carriers and a kind of carrier etc.

Therapeutic Method

The invention still further relates to the method for using hydroxamic acid derivs as herein described.Prove that as this paper hydroxamic acid derivs of the present invention can be used for treating cancer.In addition, find that this hydroxamic acid derivs also can be used for multiple other diseases.Non-limiting instance is the disease and central nervous system as herein described (CNS) disease of sulfur oxygen cyclase protein as herein described (TRX)-mediation.

1. treatment cancer

Prove that as this paper hydroxamic acid derivs of the present invention can be used for treating cancer.Therefore, in one embodiment, the present invention relates to treatment needs curee's method for cancer, this method to comprise to give the described hydroxamic acid derivs that described curee treats effective dose herein.

Term " cancer " is meant any cancer that is caused by tumor sexual cell propagation, for example solid tumor, tumor, cancer, sarcoma, leukemia, lymphoma etc.For example, cancer includes but not limited to: leukemia, comprise acute leukemia and chronic leukemia, for example acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), chronic lymphocytic leukemia (CML) and hairy cell leukemia; Lymphoma, for example skin T-cell lymphoma (CTCL), non-skin Peripheral T-cell lymphoma, the lymphoma relevant such as Adult T-cell leukemia/lymphoma (ATLL), Hodgkin and non-Hodgkin lymphoma, large celllymphoma, the big B-cell lymphoma of dispersivity (DLBCL) with human T lymphotrophic virus (HTLV); Burkitt lymphoma; Constitutional central nervous system (CNS) lymphoma; Multiple myeloma; Child's solid tumor is for example head and neck cancer (for example mouthful, the larynx and the esophageal carcinoma), urogenital cancer (for example prostate, bladder, kidney, uterus, ovary, testis, rectum and colon cancer), pulmonary carcinoma, breast carcinoma, cancer of pancreas, melanoma and other skin carcinomas, gastric cancer, cerebroma, hepatocarcinoma and thyroid carcinoma of cerebroma, neuroblastoma, retinoblastoma, wilms' tumor, osteoma and soft tissue sarcoma, the common solid tumor of adult for example.

2. treat the disease of sulfur oxygen cyclase protein (TRX)-mediation

In another embodiment, described hydroxamic acid derivs is used for the treatment of in curee's sulfur oxygen cyclase protein (the TRX)-disease of mediation or the method for disease of needs treatments, and described method comprises and gives one or more hydroxamic acid compounds as herein described that the curee treats effective dose.

The example of the disease of TRX-mediation include but not limited to acute and chronic inflammatory disease, autoimmune disease, allergic disease, with oxidative stress diseases associated and the disease that is characterized as cell hyperproliferation.

Non-limiting example has arthritis to comprise rheumatoid arthritis (RA) and psoriasis arthropathica; Inflammatory bowel is Crohn disease and ulcerative colitis for example; Ridge awl arthrosis; Scleroderma; Psoriasis (comprising the psoriasis that T is cell-mediated) and inflammatory dermatosis be dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria for example; Vasculitis (for example gangrenosum acne, skin and allergic angiitis); Acidophilia's myositis, eosinophilic fasciitis; Comprise cerebral ischemia (for example brain injury, epilepsy, hemorrhage or apoplexy due to the wound, wherein every kind of situation can cause neural degeneration) with cancer, the ischemic injury of skin or organ leukocyte infiltration; HIV, heart failure; Chronic, acute or pernicious hepatopathy, autoimmune thyroiditis; Systemic lupus erythematosus, Si Yegelun (Sjorgren ' s) syndrome, pneumonopathy (for example ARDS); Acute pancreatitis; Amyotrophic lateral sclerosis (ALS); Presenile dementia; Cachexia/apositia; Asthma; Atherosclerosis; Chronic fatigue syndrome, fever; Diabetes (for example insulin diabetes or juvenile diabetes); Glomerulonephritis; Graft repels (for example in transplant operation) to the host; Hemorrhagic shock; Hyperpathia; Inflammatory bowel; Multiple sclerosis; Myopathy (for example myogen metabolism is especially in sepsis); Osteoporosis; Parkinson disease; Pain; Premature labor; Psoriasis; Reperfusion injury; The toxicity that cytokine causes (for example septic shock, interior toxicogenic shock); The mandibular bone arthrosis of caused by radiation side effect, temporo, neoplasm metastasis; Or strain, sprain, cartilage injury, wound for example burn, orthomorphia, infection or other diseases process cause inflammation.Allergic disease and disease include but not limited to breathe for example asthma of allergic disease, allergic rhinitis, anaphylaxis pneumonopathy, hypersensitivity pneumonitis, acidophilia's pneumonia (Lv Fule (Loeffler ' s) syndrome for example, the chronic eosinophilic pneumonia), delayed hypersensitivity, interstitial lung disease (ILD) (for example idiopathic pulmonary fibrosis or and rheumatoid arthritis, systemic lupus erythematosus, ankylosing spondylitis, Sjogren's syndrome disease, xerodermosteosis, the ILD that polymyositis or dermatomyositis are relevant); Systemic anaphylaxis or allergy, drug allergy (for example to penicillin, cephalosporins), sting allergy etc.

3. treat central nervous system disease (CNS)

In another embodiment, described hydroxamic acid derivs can be used for treating in curee's the method for central nervous system disease of needs treatment, and described method comprises and gives one or more hydroxamic acid compounds as herein described that the curee treats effective dose.

In a special embodiment, described CNS disease is a neurodegenerative disease.In another embodiment, described neurodegenerative disease is the heritability neurodegenerative disease, for example is polyglutamyl amine expansion disease.Usually neurodegenerative disease can be divided into following disease:

I. be characterised in that the disease of the progressive dementia that does not have other remarkable neurological's signs, for example presenile dementia; Alzheimer type alzheimer disease and pik (Pick ' s) sick (circumscribed atrophy of brain).

II. the syndrome that merges progressive dementia and other obvious dysautonomias, for example: the A) syndrome that mainly in the adult, occurs (for example multiple system atrophy that paralysis (Steel-Richardson-Olszewski), dispersivity thunder dimension corpusculum disease and cortex dentate nucleus (corticodentatonigral) degeneration show on Huntington Chorea, merging dementia and movement disorder and/or parkinson disease, the carrying out property nuclear); And B) mainly appears at syndrome (for example Ha-Shi (Hallervorden-Spatz) disease and progressive familial myoclonic epilepsy) among child or the young adult.

III. figure and the syndrome that undergoes an unusual development gradually of motion, for example paralysis, torsion dysmyotonia (torsional spasm on shaking palsy (parkinson disease), striatonigral degeneration, the carrying out property nuclear; Dystonia musculorum deformans), spasmodic torticollis and other dyskinesia, familial tremor and tourette (Gilles de la Tourette) syndrome.

IV. carrying out property ataxic syndrome, for example cerebellum degeneration (for example cortex of cerebellum degeneration and olivopontocerebellar atrophy (OPCA)); And spinocerebellar degeneration (that Freed relies is uncommon (Friedreich ' s) ataxia and related disorders is arranged).

V. maincenter autonomic nervous system exhaustion syndrome (Xia-De Leige (Shy-Drager) syndrome).

VI. the myasthenia that changes of numbness and syndrome (for example amyotrophic lateral sclerosis of motor neuron disease, Duchenne-Arandisease (for example werdnig-Hoffmann disease (Werdnig-Hoffman), JSMA (Wohlfart-Kugelberg-Welander) and other forms of familial spinal muscular atrophy), primary lateral sclerosis and the hereditary spastic paraplegia of becoming thin.

VII. be associated with sensation myasthenia that changes and the syndrome (charcot-Marie-Tooth atrophy of becoming thin; Chronic familial polyneuropathy), matter polyneuropathy (Dejerine-Sottas) and various forms of chronic progressive external neuropathy between for example peroneal atrophy (Charcot-Marie-Tooth), hypertrophy.

VIII. the syndrome of the carrying out property blindness, for example retinitis pigmentosa (retinitis pigmentosa) and hereditary optic atrophy (Le Baier (Leber ' s) disease).

Definition:

The various grammatical forms of the term relevant with the present invention " treatment " are meant prevention (being chemoprophylaxis), cure, reverse, alleviate, alleviate, minimize, suppress or stop morbid state, the illeffects of disease progression, disease pathogen (for example antibacterial or virus) or other unusual diseases.For example, treatment can relate to and alleviates disease symptoms (promptly not necessarily symptomatology) or slow down disease progression.Because some the inventive method relates to the physical removal pathogen, the technical staff will appreciate that, before being exposed to pathogen or after giving The compounds of this invention (prophylactic treatment) simultaneously and being exposed to pathogen (even after rehabilitation) give in the situation of The compounds of this invention, they are effective on an equal basis.

Treatment of cancer used herein be meant partially or completely suppress, process that delay or prophylaxis of cancer comprise cancerometastasis; Suppress, postpone or prevent to comprise the recurrence of the cancer of cancerometastasis; Or for example people's cancer outbreak or development of prevention (chemoprophylaxis) mammal.

Term used herein " treatment effective dose " will comprise any amount that can obtain needs treatment or biological respinse.Therapeutic effect depends on disease to be treated or disease or required therapeutic effect.Therefore, therapeutical effect can be the related symptoms that alleviates described disease or disease and/or the deterioration of inhibition (partially or completely) disease.Cause that the required amount of therapeutic response depends on curee's age, health, stature and sex.Can determine best consumption by the therapeutic response that detects the curee.

In the present invention, be used for the treatment of or during prophylaxis of cancer, required biological respinse is for partially or completely suppressing, postpones or preventing the cancer deterioration of mammal (for example people) to comprise cancer metastasis when described chemical compound; The cancer return of inhibition, delay or prevention mammal (for example people) comprises cancer metastasis; Perhaps stop cancer outbreak or the development (chemoprophylaxis) of mammal (for example people).

In addition, in the present invention, when described chemical compound is used for the treatment of and/or prevent the disease of sulfur oxygen cyclase protein (TRX)-mediation and disease, the treatment effective dose for the intravital TRX horizontal adjustment of curee (for example increase, reduce or keep) that will need to treat on the physiology proper level to produce the required amount of required therapeutic effect.Described therapeutic effect depends on the disease or the disease of concrete TRX-mediation to be treated.Therefore, therapeutical effect can be the related indication seriousness that alleviates described disease or disease and/or the deterioration or the disease of inhibition (partially or completely) disease.

In addition, in the present invention, when described chemical compound was used for the treatment of and/or prevent central nervous system disease or disease (CNS), the treatment effective dose depended on concrete disease to be treated or disease.Therefore, therapeutical effect can be the related symptoms that alleviates described disease or disease and/or the deterioration or the disease of inhibition (partially or completely) disease.

In addition, the treatment effective dose can be the amount of inhibition of histone deacetylase.

In addition, the treatment effective dose can be the amount of the end differentiation eventually of selective induction tumor sexual cell, cell growth retardation and/or apoptosis, perhaps is the inducing tumor cell amount of end differentiation eventually.

Method of the present invention is used for the treatment of or chemoprophylaxis suffers from the patient of cancer.But described method also can be used for the treatment of other curee curees' cancer effectively." curee " as herein described curee is meant animal, includes but not limited to primate (for example people), cow, sheep, goat, horse, pig, Canis familiaris L., cat, rabbit, guinea pig, rat, mice or other bovines, sheep class, horse class, dog class, cat class, Rodents or Muridae class as mammal.

Histone deacetylase and histone deacetylase inhibitor

As described herein, hydroxamic acid derivs of the present invention has the activity of improvement as histone deacetylase (HDAC) inhibitor.In one embodiment, chemical compound is lower than 1000nm to 50% inhibition concentration (IC50) of histone deacetylase.In another embodiment, chemical compound is 500-1000nm to 50% inhibition concentration (IC50) of histone deacetylase.In another embodiment, chemical compound is 100-500nm to 50% inhibition concentration (IC50) of histone deacetylase.In another embodiment, chemical compound is lower than 100nm to 50% inhibition concentration (IC50) of histone deacetylase.In another embodiment, chemical compound is 10-100nm to 50% inhibition concentration (IC50) of histone deacetylase.In another embodiment, chemical compound is lower than 50nm to 50% inhibition concentration (IC50) of histone deacetylase.In another embodiment, chemical compound is 10-50nm to 50% inhibition concentration (IC50) of histone deacetylase.In another embodiment, chemical compound is lower than 10nm to 50% inhibition concentration (IC50) of histone deacetylase.In another embodiment, chemical compound is 1-10nm to 50% inhibition concentration (IC50) of histone deacetylase.In another embodiment, chemical compound is lower than 1nm to 50% inhibition concentration (IC50) of histone deacetylase.In another embodiment, chemical compound is 0.1-1nm to 50% inhibition concentration (IC50) of histone deacetylase.

As described herein, hydroxamic acid derivs of the present invention has the activity of improvement as histone deacetylase (HDAC) inhibitor.Therefore, in one embodiment, the present invention relates to the active method of a kind of inhibition of histone deacetylase, described method comprises histone deacetylase is contacted with one or more hydroxamic acid compounds as herein described of effective dose.

In one embodiment, described hydroxamic acid derivs is effective inhibitor of I group histone deacetylase (Class I HDACs).Class I HDACs comprises histone deacetylase 1 (HDAC-1), histone deacetylase 2 (HDAC-2), histone deacetylase 3 (HDAC-3) and histone deacetylase 8 (HDAC-8).In a special embodiment, described hydroxamic acid derivs is effective inhibitor of histone deacetylase I (HDAC-1).In another embodiment, described hydroxamic acid derivs is effective inhibitor of II group histone deacetylase (Class II HDACs).Class II HDACs comprises histone deacetylase 4 (HDAC-4), histone deacetylase 5 (HDAC-8), histone deacetylase 6 (HDAC-6), histone deacetylase 7 (HDAC-7) and histone deacetylase 9 (HDAC-9).

Term histone deacetylase used herein (HDACs) is the enzyme that the acetyl group in the lysine residue on the amino end of nucleosome nucleohistone is removed in catalysis.Therefore, HDACs regulates the acetylation state of histone with acetylation of histone transferring enzyme (HATs).Acetylation of histone influences gene expression, and the HDACs inhibitor suppresses tumor growth for example based on the external evoked transformed cell growth stagnation of hydridization polar compound Vorinostat (SAHA), differentiation and/or the apoptosis of hydroxamic acid in the body.According to structural homology, HDACs can be divided three classes.I class HDACs (HDACs 1,2,3 and 8) has yeast RPD3 protein similar, is positioned at nucleus, finds in the complex relevant with transcribing corpresor.II class HDACs (HDACs 4,5,6,7 and 9) and yeast HDA1 protein similar, and have nuclear and cytoplasm subgroup celluar localization.Based on the hdac inhibitor of hydroxamic acid for example SAHA suppress I and II class HDACs.III class HDACs forms structure source far away class NAD dependent enzyme, and they are relevant with yeast SIR2 albumen, are not subjected to the inhibition based on the hdac inhibitor of hydroxamic acid.

Term histone deacetylase inhibitor used herein or hdac inhibitor be body interior, external or both can the deacetylated chemical compound of inhibition of histone.Therefore, hdac inhibitor suppresses the activity of at least a histone deacetylase.Owing to suppress at least a histone deacetylation, occur that acetylated histones increases and acetylated histones to accumulate be to estimate the active suitable biomarker of hdac inhibitor.Therefore, can measure the HDAC that method that acetylated histones accumulates can be used for measuring the purpose chemical compound and suppress active.Also can combine but should understand the active chemical compound of inhibition of histone deacetylase, and therefore can suppress for example enzyme of other biological bioactive molecule with other substrates.Will also be understood that The compounds of this invention can suppress above any histone deacetylase or any other histone deacetylase of setting forth.

For example, in accepting the patient of hdac inhibitor, the acetylated histones of available suitable blank determination in peripheral mononuclear cells of handling with hdac inhibitor and tissue accumulated.

The available HDAC of the enzyme test external test particular compound that suppresses at least a histone deacetylase that for example shows suppresses active.In addition, be determined at the HDAC that can measure chemical compound and suppress active with accumulating of acetylated histones in the cell of concrete compositions-treated.

The method that the mensuration acetylated histones is accumulated is known in the literature.Referring to, Marks for example, P.A. etc., J.Natl.Cancer Inst., 92:1210-1215,2000; Butler, L.M. etc., Cancer Res.60:5165-5170 (2000); Richon, V.M. etc., Proc.Natl.Acad.Sci., USA, 95:3003-3007,1998 and Yoshida, M. etc., J.Biol.Chem., 265:17174-17179,1990.

For example, the enzymatic determination of measuring the hdac inhibitor compound activity can carry out as follows.Briefly, can be by on ice, no substrate exists down, and with about 20 minutes of the inhibitor compound incubation of enzyme preparation and set amount, mensuration hdac inhibitor chemical compound was to the influence of the people of purification epitope tagged (flag form) HDAC1 affinity.Can add substrate ([ ³H] histone that is derived from MELC of acetyl group labelling), can be under 37 ℃ with sample, incubation is 20 minutes in cumulative volume 30 μ L.But cessation reaction can extract the acetas that discharges then, measures the exit dose that discharges by scinticounting.The assay method that another kind is used to measure the hdac inhibitor compound activity is BIOMOL Research Laboratories, Inc., PlymouthMeeting, PA provide " the HDAC fluorescence activity is measured; Drug discovery test kit (DrugDiscovery Kit)-AK-500 ".

Can followingly carry out research in the body.For example inject the hdac inhibitor chemical compound in the mouse peritoneum can for animal.After the administration, can separate for example brain, spleen, the liver etc. organized of selection at the fixed time.Can be from basically with Yoshida etc., J.Biol.Chem.265:17174-17179, discrete group albumen in the 1990 described tissues.Can carry out equivalent histone (about 1 μ g) electrophoresis in the 15%SDS-polyacrylamide gel, be transferred to Hybond-P filter (deriving from Amersham) then.Filter can block with 3% breast, and (Upstate Biotechnology Inc.) surveys for anti-acetylated histones H4 antibody of available rabbit purification polyclone (α Ac-H4) and anti-acetylated histones H3 antibody (α Ac-H3).Available yoke closes the goat anti-rabbit antibodies (1: 5000) and SuperSignal chemical luminous substrate (Pierce) the visual inspection acetylated histones level of horseradish peroxidase.As the load sample contrast of histone, can carry out parallel gel electrophoresis, use Coomassie blue (CB) dyeing then.

In addition, shown that the hdac inhibitor based on hydroxamic acid raises p21 ^WAF1Gene expression.With standard method multiple transformant is cultivated with hdac inhibitor, induced p21 in 2 hours ^WAF1Albumen.P21 ^WAF1Gene inducedly accumulate relevant with acetylated histones in the chromatin zone of this gene.Therefore, can think p21 ^WAF1Induce and relate to that the G1 cell cycle stops in the transformant that is caused by hdac inhibitor.

Usually, hdac inhibitor roughly is divided into 5 classes: 1) hydroxamic acid derivs; 2) short-chain fatty acid (SCFAs); 3) cyclic tetrapeptide; 4) Benzoylamide; With 5) electrophilicity ketone.The example of these hdac inhibitors is as follows:

A. hydroxamic acid derivs, for example Vorinostat (SAHA) (Richon etc., Proc.Natl.Acad.Sci.USA 95,3003-3007 (1998)); Between o-carboxy cinnamic acid dihydroxy amide (CBHA) (Richon etc., the same); Pyroxamide; The trichostatin analog is Trichostatin A (TSA) and trichostatin C (1998.Biochem.Pharmacol.56:1359-1364 such as Koghe) for example; Salicyl hydroxamic acid (Andrews etc., Intemational J.Parasitology 30,761-768 (2000)); Suberoyl two hydroxamic acid (SBHA) (U.S. Patent number 5,608,108); Hydroxamic acid in the ninth of the ten Heavenly Stems two (ABHA) (Andrews etc., the same); Azelaic Acid-1-Hydroxamates-9-anilide (AAHA) (Qiu etc., Mol.Biol.Cell11,2069-2083 (2000)); 6-(3-chlorphenyl urea groups) own hydroxamic acid (3C1-UCHA); Oxamflatin[(2E)-and the 5-[3-[(benzenesulfonyl) aminophenyl]-penta-2-alkene-4-alkynes acyl hydroxamic acid (ynohydroxamic acid)] (Oncogene such as Kim, 18:2461 2470 (1999)); A-161906, Scriptaid (2000Cancer Research such as Su, 60:3137-3142); PXD-101 (Prolifix); LAQ-824; CHAP; MW2796 (Andrews etc., the same); MW2996 (Andrews etc., the same); Or disclosed any hydroxamic acid in the United States Patent (USP) 5,369,108,5,932,616,5,700,811,6,087,367 and 6,511,990.

B. cyclic tetrapeptide, trapoxin A (TPX)-cyclic tetrapeptide (ring-(L-phenylalanyl-L-phenylalanyl-D-(2-methyl) piperidyl-L-2-amino-8-oxo-9 for example, 10-epoxy capryl)) (Kijima etc., J Biol.Chem.268,22429-22435 (1993)); FR901228 (FK228, ester peptide) (Nakajima etc., Ex.Cell Res.241,126-133 (1998)); FR225497 cyclic tetrapeptide (H.Mori etc., PCT applies for WO 00/08048 (on February 17th, 2000)); Apicidin cyclic tetrapeptide [ring (N-O-methyl-L-tryptophanyl-L-isoleucyl--D-(2-methyl) piperidyl-L-2-amino-8-oxo capryl)] (Darkin-Rattray etc., Proc.Natl.Acad.Sci.USA 93,1314313147 (1996)); Apicidin Ia, apicidin Ib, apicidin Ic, apicidinIIa and apicidin IIb (P.Dulski etc. ask WO 97/11366 among the PCT); CHAP, HC-toxin cyclic tetrapeptide (Bosch etc., Plant Cell 7,1941-1950 (1995)); WF27082 cyclic tetrapeptide (PCT applies for WO 98/48825); And chlamydocin (Bosch etc., the same).

C. short-chain fatty acid (SCFA) derivant, for example sodium butyrate (Cousens etc., J.Biol.Chem.254,1716-1723 (1979)); Isovalerate (ester) (McBain etc., Biochem.Pharm.53:1357-1368 (1997)); Valerate (ester) (McBain etc., the same); 4-phenylbutyric acid salt (ester) is (Lea and Tulsyan, Anticancer Research, 15,879-873 (1995)) (4-PBA); Phenylbutyric acid salt (ester) is (Wang etc., Cancer Research, 59,2766-2799 (1999)) (PB); Propionate (ester) (McBain etc., the same); Butyramide (Lea and Tulsyan, the same); Isobutyramide (Lea and Tulsyan, the same); Phenylacetic acid salt (ester) (Lea and Tulsyan, the same); 3-bromo-propionic acid salt (ester) (Lea and Tulsyan, the same); Tributyorin (Guan etc., CancerResearch, 60,749-755 (2000)); Valproic acid, valproate (ester) and Pivanex ^TM

D. heterocyclic carbamate derivatives, for example CI-994; MS-275[N-(2-aminophenyl)-4-[N-(pyridin-3-yl methoxycarbonyl) amino methyl] Benzoylamide] (Saito etc., Proc.Natl.Acad.Sci.USA 96,4592-4597 (1999)); With 3 of MS-275 '-aminoderivative (Saito etc., the same).

E. electrophilicity ketone derivatives, for example trifluoromethyl ketone (Frey etc., Bioorganic ﹠amp; Med.Chem.Lett. (2002), 12,3443-3447; U.S.6,511,990) and alpha-keto amide N-methyl-alpha-keto amide for example

F. other hdac inhibitors, for example natural product, psammaplins and Depudecin (1998.PNAS 95:3356-3361 such as Kwon).

Drug combination

Hydroxamic acid compound of the present invention can give separately or be applicable to the other drug of the disease for the treatment of or disease unite and give.When adopting independently dosage form, described hydroxamic acid compound and other drug be (in the lump) or the time administration (in turn) that staggers respectively substantially simultaneously.Should be understood that drug combination comprises all these situations.These different medications all are suitable for the present invention, as long as at the basic favourable therapeutical effect of realizing described hydroxamic acid compound and other drug simultaneously in patient's body.Preferably when keeping the target haemoconcentration of each active medicine substantially simultaneously, reached described favourable effect.

Described hydroxamic acid derivs can with any or multiple hdac inhibitor, alkylating agent, antibiotic, antimetabolite, hormonal medicaments, plant origin medicine, angiogenesis inhibitor medicine (anti-angiogenic agent), differentiating inducer, cell growth retardation derivant, inducer of apoptosis, cytotoxic agent, biological reagent, genomic medicine or its combination.

Alkylating agent

The for example reaction of the chemical entities on the nucleotide precursor that generates DNA of alkylating agent and nucleophilicity residue.They influence fission process by making these nucleotide alkylations and stoping it to be assembled among the DNA.

The example of alkylating agent includes but not limited to two chlorethamins (chlormethine is chlorambucil, cyclophosphamide, ifosfamide, chlormethine, melphalan, uracil mustard for example), ethylene imine (for example plug is for group), alkyl ketone sulphonic acid ester (for example busulfan), nitroso ureas (for example carmustine, lomustine, streptozocin), atypia alkylating agent (altretamine, dacarbazine and procarbazine), platinum compounds (carboplatin and cisplatin).These chemical compounds and phosphate ester, amino, hydroxyl, sulfydryl (sulfihydryl), carboxyl and imidazole radicals reaction.

Under physiological condition, these medicine ionizations produce the positively charged ion that is connected with protein with responsive nucleic acid, cause cell cycle to suppress and/or cell death.Alkylating agent is cell cycle phase non-specific (cell cycle phase nonspecific) medicine, brings into play their activity because they are independent of the concrete phase of cell cycle.Chlormethine and alkyl ketone sulphonic acid ester are the most effective to G1 or M phase cell.Nitroso ureas, chlormethine and ethylene imine influence are by G1 and the development of S phase to M phase.Chabner and Collins edit (1990) " Cancer Chemotherapy:Principles and Practice ", Philadelphia:JB Lippincott.

Alkylating agent has activity to multiple tumor disease, and treatment leukemia and lymphoma and solid tumor have significant activity.Clinically, this type of medicine is generally used for treating acute and chronic leukemia; Hodgkin; Non-Hodgkin lymphoma; Multiple myeloma; Primary brain tumor; The cancer of mammary gland, ovary, testis, lung, bladder, cervix uteri, head and neck and malignant melanoma.

Antibiotic

Antibiotic (for example cell toxicant antibiotic) works by direct inhibition DNA or RNA are synthetic, thus in whole cell cycle effectively.The example of antibiotic medicine comprises anthracycline (for example doxorubicin, daunorubicin, epirubicin, idarubicin and amerantrone), ametycin, bleomycin, actinomycin D and plicatomycin.The interference cell growth of these antibiotic by the different cell component of targeting.For example, it has been generally acknowledged that anthracycline disturbs the effect of DNA topoisomerase II in the zone of transcriptional activity DNA, cause DNA to unwind.

It has been generally acknowledged that the bleomycin chelated iron, and form activated complex, it combines with the base of DNA then, causes unwinding and cell death.

Antibiotic medicine as multiple tumor treatment of diseases medicine, comprises mammary gland, lung, the thyroid cancer of harmonization of the stomach, lymphoma, myelomatosis, myeloma and sarcoma.

Antimetabolite

Antimetabolite (being antimetabolite) is that a class is disturbed the physiological function of cancerous cell and the medicine of the vital metabolic process of propagation.The active cancerous cell of propagation needs constantly synthetic a large amount of nucleic acid, protein, lipid and other important cell component.

Many antimetabolite suppress purine or pyrimidine nucleoside is synthetic or the enzyme of inhibition dna replication dna.Some antimetabolite also disturbs ribonucleotide and RNA is synthetic and/or amino acid metabolism and protein synthesis.By disturbing important cell component synthetic, antimetabolite can postpone or the anticancer growth.The example of antimetabolite includes but not limited to fluorouracil (5-FU), floxuridine (5-FUdR), methotrexate, folinic acid, hydroxyurea, thioguanine (6-TG), mercaptopurine (6-MP), cytosine arabinoside, pentostatin, fludarabine phosphate, carat Qu Bin (2-CDA), asparaginase and gemcitabine.

Antimetabolite has been widely used in the cancer of the some frequent specieses of treatment, comprises the cancer, malignant melanoma of colon, rectum, mammary gland, liver, harmonization of the stomach pancreas, acute and chronic leukemia, hairy cell.

Hormonal medicaments

Hormonal medicaments is a class medicine of regulating its target organ g and D.Most of hormonal medicaments are sex steroid and derivant and analog, for example estrogen, progestogen, antiestrogen, androgen, antiandrogen and progesterone.These hormonal medicaments can be used as the antagonist of sex steroid receptor, and downward modulation expression of receptor and important gene are transcribed.The example of this type of hormonal medicaments has synthetic estrogen (for example diethylstilbestrol), antiestrogen (for example tamoxifen, toremifene, fluoxymesterol and raloxifene), antiandrogen (bicalutamide, nilutamide, flutamide), aromatase inhibitor (for example aminoglutethimide, Anastrozole and tetrazolium), luteinising hormone-releasing hormo (LHRH) analog, ketoconazole, goserelin acetate, leuproside, megestrol acetate and mifepristone.

Hormonal medicaments is used for the treatment of breast carcinoma, carcinoma of prostate, melanoma and meningioma.Because the main effect of hormone mediates by steroid receptor, so 60% receptor-positive breast carcinoma produces reaction to a line hormone therapy; And produce reaction less than 10% receptor-negative tumor.Progestogen are particularly useful for treating carcinoma of endometrium because these cancers occur in be exposed to progestogen can not the high-level estrogenic women of antagonism in.Antiandrogen is mainly used in the treatment carcinoma of prostate, and it is a hormonal dependent.They are used to reduce testosterone levels, thereby suppress tumor growth.

Hormone therapy breast carcinoma relates to the estrogen level that reduces dependence activation estrogen receptor in the mastadenoma sexual cell.Antiestrogen works by combining and prevent to raise coactivator with estrogen receptor thereby suppressing the estrogen signal.

The LHRH analog is used for the treatment of carcinoma of prostate, thereby reduce testosterone levels tumor growth is reduced.

Aromatase inhibitor works by suppressing the required enzyme of synthetic hormone.In postmenopausal women, estrogenic main source is by virtue enzymatic conversion androstenedione.

The plant origin medicine

The plant origin medicine is to derive from a medicine of plant or a class medicine of modifying on the molecular structure basis of these medicines.They assemble and suppress cellular replication by stoping pair cell to divide vital cell component.

The example of plant origin medicine comprises vinca alkaloids (for example vincristine, vinblastine, vindesine, vinzolidine and vinorelbine), podophyllotoxin (for example etoposide (VP-16) and teniposide (VM-26)), taxanes (for example paclitaxel and docetaxel).These plant origin medicines are usually identical with the effect of anti-mitosis medicine, and they combine with tubulin and suppress mitosis.Think podophyllotoxin for example etoposide cause DNA to unwind and disturb DNA synthetic by interacting with topoisomerase II.

The plant origin medicine is used to treat multiple cancer.For example, vincristine is used for the treatment of leukemia, Huo Qijin and non-Hodgkin lymphoma and pediatric tumor neuroblastoma, rhabdomyosarcoma and wilms' tumor.Vinblastine is used for lymphoma, carcinoma of testis, renal cell carcinoma, mycosis fungoides and Kaposi sarcoma.Confirmed that docetaxel is expected to have anti-advanced breast cancer, the activity of nonsmall-cell lung cancer (NSCLC) and ovarian cancer.

Etoposide has the activity of anti-multiple tumor, and wherein small cell lung cancer, carcinoma of testis and NSCLC are the most responsive.

Biological medicine

Biological medicine is to use separately or unite with chemotherapy and/or radiotherapy to cause the class biomolecule that cancer/tumor disappears and takes off when using.The example of biological medicine comprises immune modulator, for example the monoclonal antibody of cytokine, tumor-resistant antigen, tumor suppressor gene and Theratope.

Cytokine has extremely strong immunoregulatory activity.Some cytokine is interleukin-2 (IL-2, aldesleukin) and alpha-interferon (IFN-α) confirmation anti-tumor activity for example, and approved is used for the treatment of the patient who suffers from metastatic renal cell cancer and metastatic malignant melanoma.IL-2 is to the very important T cell growth factor of the cell-mediated immunoreation of T.Think that IL-2 is the immunoreactive result that has any different between cell-mediated oneself and the non-oneself to some patient's selectivity antitumor action.

Alpha-interferon comprises having the active relevant hypotype greater than 23 of stack.As if IFN-α confirms to have the activity of anti-multiple solid tumor and hematologic malignancies, and the latter is especially responsive.

The example of interferon comprises alpha-interferon, beta-interferon (fiblaferon) and gamma interferon (fiblaferon).The example of other cytokines comprises erythropoietin (α-erythropoietin), granulocyte-CSF (filgrastim) and granulocyte, macrophage-CSF (Sargramostim).Other acellular factor immunomodulators comprise bacillus calmette-guerin vaccine, levamisole and octreotide, act on the long-acting octapeptide of the hormone somatostatin of similar natural generation.

In addition, anticancer therapy can comprise the treatment of the immunotherapy of the reagent that uses antibody and the use of tumor inoculation vaccine method.Main medicine in this type of therapy is separately or for example carry toxin or chemotherapeutics/cancerous cell is produced the antibody of cytotoxic chemical compound.The monoclonal antibody of tumor-resistant antigen is the antibody that causes the antitumor antigen expressed, preferred tumor specific antigen.For example, propose to resist the human epidermal growth factor receptor 2 (HER2) of overexpression in some breast tumor, comprise metastatic breast cancer with monoclonal antibody HERCEPTIN  (trastuzumab).The HER2 protein overexpression is relatively poor relevant with more aggressive disease and clinical prognosis.HERCEPTIN  is used for the treatment of separately and suffers from the proteic metastatic breast cancer patient of tumor overexpression HER2.

Another example of the monoclonal antibody of tumor-resistant antigen is RITUXAN  (Rituximab), and the CD20 and the selectivity that propose on its lymphoma sexual cell reduce normal and pernicious CD20+ pre B lymphocyte and mature B cell.

RITUXAN be used for the treatment of separately suffer from recurrence or intractable low level or folliculus, the patient of CD20+B cell non-Hodgkin's.MYELOTARG  (Gemtuzumab Ozogamicin) and CAMPATH  (alemtuzumab) are another examples of the monoclonal antibody of spendable tumor-resistant antigen.

Tumor suppressor gene is the gene that act as cell growth inhibiting and division cycle, thereby stops tumour development.The tumor suppressor gene sudden change causes cell to ignore one or more and suppresses the signal network composition, overcomes cell cycle chechpoint, and causes controlling the growth-cancer of cell more speed.The example of tumor suppressor gene comprises Duc-4, NF-1, NF-2, RB, p53, WT1, BRCA1 and BRCA2.

DPC4 relates to cancer of pancreas, and participates in suppressing fissional kytoplasm approach.The NF-1 coding suppresses the albumen of Ras, and it is the kytoplasm Profilin.NF-1 relates to neural neurofibroma and pheochromocytoma and myelomatosis.The NF-2 coding relates to the nucleoprotein of neural meningioma, schwannoma and ependymoma.RB coding pRB albumen, it is the main inhibitor nucleoprotein of cell cycle.RB relates to retinoblastoma and bone, bladder, minicell lung and breast carcinoma.The fissional p53 albumen of P53 coding and regulating, and can induce to transfer and die.Discovery is p53 sudden change and/or inactivation in multiple cancer.WTI relates to the kidney wilms' tumor.BRCA1 relates to mammary gland and ovarian cancer, and BRCA2 relates to breast carcinoma.Tumor suppressor gene can be transferred in the tumor cell that wherein can bring into play its tumor suppression function.

Theratope is to induce health tumor to be produced a class medicine of specific immune response.The most of Theratopes that are in research, exploitation and the clinical trial are tumor associated antigen (TAAs).TAAs is present on the tumor cell, and the structure (being albumen, enzyme or carbohydrate) that does not exist or reduce relatively on normal cell.Because quite unique to tumor cell, TAAs provides target for immune system recognition, and causes their destruction.The example of TAAs comprises the full cell or the part/lysate of antigen (MART-1, gap100, MAGE 1,3 tryrosinase), human papillomavirus E6 and E7 segment, autologous tumor cell and allos tumor cell that ganglioside (GM2), prostate specific antigen (PSA), alpha-fetoglobulin (AFP), carcinoembryonic antigen (CEA) (for example mammary gland, lung, harmonization of the stomach cancer of pancreas produce by colon cancer and other adenocarcinoma), melanoma are relevant.

Other therapies

Except that with traditional cell toxicant and the hormonotherapy treatment cancer, also introduce other therapies of the treatment cancer of newly-developed.

For example, the gene therapy of various ways is being carried out clinical preceding or clinical trial.

In addition, form the method that (blood vessel generation) suppresses in exploitation based on tumor vessel at present.The purpose of this notion is that tumors of nutrients and the oxygen supply that is provided by the new tumor vessel system that forms is provided.

In addition, also attempt by inducing the tumor sexual cell cancer therapy of end differentiation eventually.Suitable differentiation agent is included in disclosed chemical compound in following any one or more lists of references, and the content of these documents is attached to herein by reference.

A) polar compound (Marks etc. (1987); Friend, C., Scher, W., Holland, J.W. and Sato, T. (1971) Proc.Natl.Acad.Sci. (USA) 68:378-382; Tanaka, M., Levy, J., Terada, M., Breslow, R., Rifkind, R.A. and Marks, P.A. (1975) Proc.Natl.Acad.Sci. (USA) 72:1003-1006; Reuben, R.C., Wife, R.L., Breslow, R., Rifkind, R.A. and Marks, P.A. (1976) Proc.Natl.Acad.Sci. (USA) 73:862-866);

B) derivant of vitamin D and retinoic acid (Abe, E., Miyaura, C., Sakagami, H., Takeda, M., Konno, K., Yamazaki, T., Yoshika, S. and Suda, T. (1981) Proc.Natl.Acad.Sci. (USA) 78:4990-4994; Schwartz, E.L., Snoddy, J.R., Kreutter, D., Rasmussen, H., and Sartorelli, A.C. (1983) Proc.Am.Assoc.Cancer Res.24:18; Tanenaga, K., Hozumi, M. and Sakagami, Y. (1980) Cancer Res.40:914-919);

C) steroid hormone (Lotem, J. and Sachs, L. (1975) Int.J.Cancer 15:731-740);

D) somatomedin (Sachs, L. (1978) Nature (Lond.) 274:535, Metcalf, D. (1985) Science, 229:16-22);

E) protease (Scher, W., Scher, B.M. and Waxman, S. (1983) Exp.Hematol.11:490-498; Scher, W., Scher, B.M. and Waxman, S. (1982) Biochem.﹠amp; Biophys.Res.Comm.109:348-354);

F) tumor promotor (Huberman, E. and Callaham, M.F. (1979) Proc.Natl.Acad.Sci. (USA) 76:1293-1297; Lottem, J. and Sachs, L. (1979) Proc.Natl.Acad.Sci. (USA) 76:5158-5162); With

G) DNA or rna synthesis inhibitor (Schwartz, E.L. and Sartorelli, A.C. (1982) Cancer Res.42:2651-2655, Terada, M., Epner, E., Nudel, U., Salmon, J., Fibach, E., Rifkind, R.A. and Marks, P.A. (1978) Proc.Natl.Acad.Sci. (USA) 75:2795-2799; Morin, M.J. and Sartorelli, A.C. (1984) Cancer Res.44:2807-2812; Schwartz, E.L., Brown, B.J., Nierenberg, M., Marsh, J.C. and Sartorelli, A.C. (1983) Cancer Res.43:2725-2730; Sugano, H., Furusawa, M., Kawaguchi, T. and Ikawa, Y. (1973) Bibl.Hematol.39:943-954; Ebert, P.S., Wars, I. and Buell, D.N. (1976) CancerRes.36:1809-1813; Hayashi, M., Okabe, J. and Hozumi, M. (1979) Gann70:235-238),

The purposes that all these methods and hydroxamic acid compound as herein described are united use within the scope of the present invention.

Dosage and dosage

Use the dosage of hydroxamic acid derivs of the present invention to select, comprise kind, species, age, body weight, sex and the cancer types for the treatment of according to multiple factor; The order of severity of the disease for the treatment of (being the stage); Route of administration; Patient's kidney and liver function; With the particular compound or its salt that use.Gengral practitioner or veterinary can determine easily and prescribed treatment for example prevents, suppresses (wholly or in part) or makes this disease progression stop the medicine of required effective dose.

Be used for oral administration, suitable daily dose for example is about 5-4000mg/m ², oral, once-a-day, twice on the one or three times on the one, continuously (every day) take or be interrupted and take (for example all 3-5 days).For example, when being used for the treatment of target disease, the daily dose of described hydroxamic acid can be the about 2000mg of about 2mg-, the about 2000mg of for example about 20mg-, the about 1200mg of for example about 400mg-.For example oral daily dose is about 2, about 20, about 200, about 400, about 800, about 1200, about 1600 or about 2000mg.

For example, the acceptable dosage of patient is about 2mg/ days-Yue 2000mg/ days, for example about 20-2000mg/ days, and for example about 200-about 2000mg/ days, for example about 400mg/ days-Yue 1200mg/ days.Therefore when taking one time every day, suitable final drug can comprise the about 2000mg of about 2mg-, the about 2000mg of for example about 20mg-, the about 1200mg of for example about 200mg-, for example about 400mg/ days-Yue 1200mg/ days.Therefore took twice o'clock every day, suitable final drug comprises half active constituents of medicine of required daily dose.

Once-a-day (QD) gives described hydroxamic acid derivs, or is divided into a plurality of daily doses, for example twice on the one (BID) and three times on the one (TID).When therefore taking one time every day, suitable final drug comprises required whole daily doses.Took every day twice o'clock, suitable final drug comprises the required daily dose of half.When taking three every day, suitable final drug comprises 1/3rd required daily dose.

The daily dose that is fit to is that the accumulated dose of every day is up to 800mg, for example 150mg, 200mg, 300mg, 400mg, 600mg or 800mg, and this accumulated dose is administered once as mentioned above every day, perhaps can be divided into a plurality of daily doses.The preferred oral administration that adopts.Described chemical compound can give separately or give with the form of the pharmaceutical composition that comprises described chemical compound and pharmaceutically acceptable carrier or excipient.

In one embodiment, the dosage by about 200-600mg gives described compositions once a day.In another embodiment, give described compositions twice by dosage every day of about 200-400mg.In another embodiment, give described chemical compound, for example weekly 3 days, 4 days or 5 days by dosage twice interruption every day of about 200-400mg.In another embodiment, give described compositions three times by dosage every day of about 100-250mg.

In one embodiment, daily dose is 200mg, can be once-a-day, give for twice on the one or three times on the one.In one embodiment, daily dose is 300mg, can be once-a-day, give for twice on the one or three times on the one.In one embodiment, daily dose is 400mg, can once-a-day or give for twice on the one.In one embodiment, daily dose is 150mg, can give for twice on the one or three times on the one.

In addition, administration (being every day) or be interrupted and carry out continuously.Term used herein " interruption " is meant with fixed interval or non-fixed interval and stops or beginning administration.For example, be interrupted to give hdac inhibitor and can be administration 1-6 days weekly, perhaps can cycle form administration (for example administration every day is carried out 2-8 week continuously, stops administration then and is up to a week) or administration can represent the next day.

In one embodiment, described therapy scheme comprises once a day, twice of every day or three successive administrations every day (being administration every day), and total daily dose is the about 600mg of about 200mg-.

In another embodiment, described therapy scheme comprises once a day, twice of every day or every day three times 3-5 days intermittent administrations weekly, total daily dose is the about 600mg of about 200mg-.

In a special embodiment, press 400mg dosage once a day or press 200mg dosage twice successive administration every day.

In another special embodiment, press 400mg dosage once a day or press twice of the 200mg dosage every day of 3 days intermittent administrations weekly.

In another special embodiment, press 400mg dosage once a day or press twice of the 200mg dosage every day of 4 days intermittent administrations weekly.

In another special embodiment, press 400mg dosage once a day or press twice of the 200mg dosage every day of 5 days intermittent administrations weekly.

In another special embodiment, press 600mg dosage once a day, twice of 300mg dosage every day or 200mg dosage three successive administrations every day.

In another special embodiment, press 600mg dosage once a day, twice of 300mg dosage every day or 200mg dosage every day three times 3 days intermittent administrations weekly.

In another special embodiment, press 600mg dosage once a day, twice of 300mg dosage every day or 200mg dosage every day three times 4 days intermittent administrations weekly.

In another special embodiment, press 600mg dosage once a day, twice of 300mg dosage every day or 200mg dosage every day three times 5 days intermittent administrations weekly.

In addition, administration can be carried out according to above-mentioned any scheme, continuously several weeks, drug withdrawal a period of time then.For example, described chemical compound or compositions can be carried out 2-8 week according to above-mentioned arbitrary scheme, one week of drug withdrawal then, perhaps press 3-5 days weekly twice of every day of 300mg dosage.In another special embodiment, but described chemical compound or compositions every day gave for two weeks continuously three times, then one week of drug withdrawal.

For intravenous or subcutaneous administration, the amount of the acceptable hdac inhibitor of patient is about 5-4000mg/m every day ², for example, every day about 5,30,60,90,180,300,600,900,1200 or 1500mg/m ²Can the multiple suitable such amount of method afford, for example in one day, divide once or in the long time, give for several times the reactive compound of large volume low concentration.This amount can give one or more continuous skies weekly, be interrupted sky or its combination (7 day cycle).Perhaps give the reactive compound of small size high concentration in the short period of time, for example give one or more continuous skies weekly, be interrupted sky or its combination (7 day cycle).For example, can every day 300mg/m ²Dosage continuously with 5 days, the accumulated dose of each course of treatment is 1500mg/m ²In another dosage regimen, successive medication natural law also can be 5 days, and treatment continued for 2 or 3 weeks, and the accumulated dose of each course of treatment is 3000mg/m ²-4500mg/m ²

Usually, the iv formulation that can prepare comprises concentration and is the about 10mg/mL of about 1.0mg/mL-, the hydroxamic acid derivs of 2.0mg/mL, 3.0mg/mL, 4.0mg/mL, 5.0mg/mL, 6.0mg/mL, 7.0mg/mL, 8.0mg/mL, 9.0mg/mL and 10mg/mL for example, and give with the amount that reaches above-mentioned dosage.In an example, can in one day, give the iv formulation of patient's capacity, make that total daily dose is the about 1500mg/m of about 300- ²

Subcutaneous preparations, preferably according to method well known in the art preparation, pH is about 12 for about 5-, also comprises suitable buffer agent and isotonic agent, and this puts as described below.Can prepare such preparation so that carry the hdac inhibitor of daily dose, for example once a day, secondary or three times by subcutaneous administration once a day or repeatedly.

Described chemical compound can also the intranasal form use suitable intranasal solvent and use to well known to a person skilled in the art that the transdermal patch form gives by transdermal route by the part.In whole dosage regimen, give more continuous with the transdermal delivery system dosage certainly than intermittent administration.

Those skilled in the art it is evident that different modes of administration as described herein, dosage and dosage have only provided specific embodiment, not will be understood that it is restriction to scope of the present invention.The change of any dosage and dosage, variation and compositions include within the scope of the invention.

Pharmaceutical composition

The compounds of this invention and derivant, segment, analog, homologue, pharmaceutically acceptable salt or hydrate can be combined into the Pharmaceutical composition that is applicable to oral administration with pharmaceutically acceptable carrier or excipient.This based composition contains any above chemical compound and the pharmaceutically acceptable carrier for the treatment of effective dose usually.Preferred effective dose is that effective selectivity is induced the end differentiation and less than the amount that causes the patient to poison eventually of suitable tumor sexual cell.

Be commonly used for any inert excipient of carrier or diluent, for example glue, starch, sugar, cellulosic material, acrylate or its mixture can be used for preparation of the present invention.Preferable absorbent is a microcrystalline Cellulose.Compositions also can contain disintegrating agent (as cross-linking sodium carboxymethyl cellulose) and lubricant (as magnesium stearate), in addition, can contain one or more and be selected from following additive: binding agent, buffer agent, protease inhibitor, surfactant, solubilizing agent, plasticizer, emulsifying agent, stabilizing agent, viscosifier, sweeting agent, film former or its any combination.In addition, the present composition can be sustained release form or immediate release formulations.

In one embodiment, therefore the orally give Pharmaceutical composition is mixed with the form that is applicable to oral administration, i.e. solid or liquid preparation.Suitable solid orally ingestible comprises tablet, capsule, pill, granule, micropill etc.Suitable oral liquid comprises solution, suspensoid, dispersion, Emulsion, wet goods.In one embodiment of the invention, compositions is mixed with capsule.By this embodiment, the present composition also contains hard gelatin capsule except that containing hydroxamic acid derivs reactive compound and inert carrier or diluent.

" pharmaceutically acceptable carrier " used herein will comprise and give any of compatibility of drugs and all solvents, disperse medium, coating materials, antibacterium and antifungal, isotonic agent and delay absorbent etc., for example aseptic apirogen water.Among the suitable carriers canonical reference teaching material latest edition Remington ' s Pharmaceutical Sciences in the art description is arranged, it is attached to herein by reference.The example of preferred examples of such carriers or diluent includes but not limited to water, saline, finger ' s solution, glucose solution and 5% human serum albumin.Also can use for example expressed oi of liposome and non-water-soluble matchmaker.Know this type of medium that is used for pharmaceutically active substance and the purposes of reagent in this area.Except that with incompatible any conventional media of reactive compound or reagent, its purposes in compositions can be expected.Also the auxiliary activity chemical compound can be added in the compositions.

Solid carrier/diluent includes but not limited to glue, starch (for example corn starch, pregelatinized Starch), sugar (for example lactose, mannitol, sucrose, glucose), cellulosic material (for example microcrystalline Cellulose), acrylate (for example polymethacrylates), carbonic acid carbon, magnesium oxide, Pulvis Talci or its mixture.

For liquid preparation, pharmaceutically acceptable carrier can be water or non-aqueous solution, suspension, emulsion or oil.Examples of non-aqueous has for example ethyl oleate of propylene glycol, Polyethylene Glycol and injection organic ester.Aqueous carrier comprises water, alcohol/aqueous solution, emulsion or suspension, comprises saline and buffering medium.The example of oil has those oil in oil, animal, plant or synthetic source, for example Oleum Arachidis hypogaeae semen, soybean oil, mineral oil, olive oil, sunflower oil and cod-liver oil.Solution or suspension also can comprise following component: sterile diluent is water for injection, saline solution, expressed oi, Polyethylene Glycol, glycerol, propylene glycol or other synthetics for example; Antibacterial agent is benzyl alcohol or methyl hydroxybenzoate for example; Antioxidant is ascorbic acid or sodium sulfite for example; Chelating agen is ethylenediaminetetraacetic acid (EDTA) for example; Buffer agent is reagent for example sodium chloride or the glucose of acetate, citrate or phosphate and adjusting Zhang Du for example.Usable acid or alkali is hydrochloric acid or sodium hydroxide adjusting pH for example.

In addition, compositions also can contain binding agent (arabic gum for example, corn starch, gelatin, carbomer, ethyl cellulose, guar gum, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, polyvinylpyrrolidone), disintegrating agent (corn starch for example, potato starch, alginic acid, silicon dioxide, cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, guar gum, primojel, carboxymethyl starch sodium (Primogel)), the buffer agent of various pH and ionic strength (tris-HCl for example, acetate, phosphate), the additive of prevention surface adsorption is albumin or gelatin for example, cleaning agent (polysorbas20 for example, Tween 80, Pluronic F68, cholate), protease inhibitor, surfactant (for example sodium lauryl sulphate), penetration enhancer, solubilizing agent (glycerol for example, Polyethylene Glycol), fluidizer (for example silica sol), antioxidant (ascorbic acid for example, sodium pyrosulfite, butylated hydroxyanisol), stabilizing agent (hydroxypropyl cellulose for example, hydroxypropyl emthylcellulose), viscosifier (carbomer for example, silica sol, ethyl cellulose, guar gum), sweeting agent (sucrose for example, aspartame, citric acid), correctives (Herba Menthae for example, methyl salicylate or orange flavor essence), antiseptic (thimerosal for example, benzyl alcohol, Nipagin ester), lubricant (stearic acid for example, magnesium stearate, Polyethylene Glycol, sodium lauryl sulphate), fluidizer (for example silica sol), plasticizer (ethyl phthalate for example, triethyl citrate), emulsifying agent (carbomer for example, hydroxypropyl cellulose, sodium lauryl sulphate), polymer coating agent (for example poloxamer or its ethylene diamine derivative (poloxamines)), coating materials and film former (ethyl cellulose for example, acrylate and polymethacrylates) and/or auxiliary agent.

In one embodiment, make reactive compound and prevent that the carrier that chemical compound is eliminated in vivo fast from preparing together, for example controlled release preparation comprises implant and microcapsule medicine-releasing system.Can use biodegradation, bioavailable polymer, for example ethylene vinyl acetate, polyanhydride, polyglycolic acid, collagen, poe and polylactic acid.The method for preparing this type of preparation is apparent to those skilled in the art.Also can be from Alza Corporation and NovaPharmaceuticals, Inc buys raw material.Also available liposome turbid liquor (comprising the liposome with the monoclonal antibody targeting infection cell of virus antigen) is made pharmaceutically acceptable carrier.These can for example press U.S. Patent number 4,522 by method known to those skilled in the art, the preparation of method described in 811.

It is especially best to prepare the Orally administered composition of being convenient to administration and the uniform dosage unit form of dosage.Dosage unit form used herein is meant the physical separation unit of the unit dose that is applicable to that the curee treats; Per unit contains the pharmaceutical carrier that needs that estimate to produce the scheduled volume reactive compound that needs curative effect and applied in any combination.The specification of dosage unit form of the present invention by specific characteristic, the concrete curative effect of desiring to reach of reactive compound and the inherence that is used for the treatment of individual this type of reactive compound technology of combination limits determine also directly to depend on these factors.

Pharmaceutical composition and medication instruction book can be included in container, packing or the allotter together.

At first day that treats, but intravenous gave The compounds of this invention, second day and date continuous oral administration subsequently.

Can give the purpose that The compounds of this invention is used for the prevent disease development or tumor growth is stagnated.

Understand the preparation of the Pharmaceutical composition that contains active component in the art easily, for example by mixing, granulation or tablet formation method.The active treatment composition usually with pharmaceutically acceptable and with the mixed with excipients of active component compatibility.For example solvent, stabilizing agent or inert diluent mix with the additive that is generally used for this purpose to be used for the active medicine of oral administration, be converted into suitable form of medication by common method, for example above tablet that describes in detail, coated tablet, hard or Gelseal; Water, alcohol or oil solution etc.

The chemical compound amount that gives the patient is less than patient's toxic dose.In certain embodiments, the chemical compound amount that gives the patient is less than causing compound concentration in patient's blood plasma to equal or exceed the amount of this toxicity of compound level.Make preferably that compound concentrations is maintained at about 10nM in patient's blood plasma.In another embodiment, make that compound concentrations is maintained at about 25nM in patient's blood plasma.In another embodiment, make that compound concentrations is maintained at about 50nM in patient's blood plasma.In another embodiment, make that compound concentrations is maintained at about 100nM in patient's blood plasma.In another embodiment, make that compound concentrations is maintained at about 500nM in patient's blood plasma.In another embodiment, make that compound concentrations is maintained at about 1000nM in patient's blood plasma.In another embodiment, make that compound concentrations is maintained at about 2500nM in patient's blood plasma.In another embodiment, make that compound concentrations is maintained at about 5000nM in patient's blood plasma.In the embodiment of this invention, the optimization compound amount that should give the patient depends on the chemical compound of concrete use and the type of the cancer for the treatment of.

In vitro method:

The present invention also provides and has used hydroxamic acid derivs of the present invention to induce the end differentiation eventually of tumor sexual cell, cell growth retardation and/or apoptosis, thereby suppresses the method for such cell proliferation.This method can be in vivo or external carrying out.

In one embodiment, be used for the in vitro method that the end differentiation eventually of selective induction tumor sexual cell, cell growth retardation and/or apoptosis suppress such cell proliferation thereby the invention provides, described method is by contacting described cell with one or more hydroxamic acid derivs as herein described of effective dose.

In a special embodiment, break up the in vitro method that suppresses such cell proliferation in the end eventually thereby the present invention relates to a kind of selective induction tumor sexual cell.Described method comprises under suitable condition described cell is contacted with one or more hydroxamic acid compounds as herein described of effective dose.

In another embodiment, thus the present invention relates to the in vitro method that the growth retardation of a kind of selective induction tumor sexual cell cell suppresses such cell proliferation.Described method comprises under suitable condition described cell is contacted with one or more hydroxamic acid compounds as herein described of effective dose.

In another embodiment, thus the present invention relates to the in vitro method that a kind of selective induction tumor sexual cell apoptosis suppresses such cell proliferation.Described method comprises under suitable condition described cell is contacted with one or more hydroxamic acid compounds as herein described of effective dose.

In another embodiment, the present invention relates to the whole in vitro method of end differentiation of tumor cell in a kind of induced tumor, described method comprises described cell is contacted with one or more hydroxamic acid compounds as herein described of effective dose.

Although method of the present invention can externally be implemented, but think and comprise in vivo and cells contacting, i.e. the curee who has (harboring) tumor sexual cell or tumor cell by described chemical compound being needed treat for the method for the eventually end differentiation of selective induction tumor sexual cell, cell growth retardation and/or apoptosis and the embodiment preferred that suppresses the method for HDAC.

Therefore, thereby the invention provides method in the body that is used for such cell proliferation in the end differentiation eventually of selective induction curee tumor sexual cell, cell growth retardation and/or the apoptosis inhibition curee body, described method is by giving any or multiple hydroxamic acid derivs as herein described of curee's effective dose.

In a special embodiment, thereby the present invention relates to a kind of selective induction tumor sexual cell method of interior such cell proliferation of end differentiation inhibition curee's body eventually.Described method comprises one or more hydroxamic acid derivs as herein described that give curee's effective dose.

In another embodiment, thus the present invention relates to the method that a kind of selective induction tumor sexual cell cell growth retardation suppresses such cell proliferation in curee's body.Described method comprises one or more hydroxamic acid derivs as herein described that give curee's effective dose.

In another embodiment, thus the present invention relates to the method that a kind of selective induction tumor sexual cell apoptosis suppresses such cell proliferation in curee's body.Described method comprises one or more hydroxamic acid derivs as herein described that give curee's effective dose.

In another embodiment, the present invention relates to a kind of treat suffer from the method that tumor is characterised in that the tumor curee of tumor sexual cell propagation.Described method comprises and gives the curee one or more hydroxamic acid derivs as herein described.Thereby the amount of described chemical compound can effective selectivity be induced the end differentiation eventually of tumor sexual cell, inducing cell growth retardation and/or apoptosis-induced its propagation that suppresses.

The present invention further specifies in the embodiment that following experimental section describes in detail.The effect of this part helps to understand the present invention, rather than and not will be understood that it is to limit the present invention who is proposed as in the following claim by any way.

Experimental section describes in detail

Embodiment 1-is synthetic

The synthetic chemical compound of the present invention of the universal method of listing in the synthesis flow below adopting, and details are as follows.

A. benzothiophene

A1. 1 expression of aminobenzene bithiophene flow process is by amide, sulfonamide, urea and the alkylated amines derivant of 5-and the synthetic benzothiophene of 6-aminobenzene bithiophene.

Flow process 1

A2. carboxyl benzothiophene.Flow process 2 expression is by 5 and the amide and the ester derivant of the synthetic benzothiophene of 6-carboxyl benzothiophene.

Flow process 2

A3. by the chemical compound of 5-formoxyl benzothiophene preparation

Flow process 6 expressions use 5-formoxyl benzothiophene to prepare the amino methyl chemical compound of 1 and 2 amine, ether and acyl groupization.

Flow process 6

A4. by the chemical compound of 6-formoxyl benzothiophene preparation.

Flow process 7 expressions use 6-formoxyl benzothiophene to prepare the amino methyl chemical compound of 1 and 2 amine, ether, acyl groupization.

Flow process 7

B. thiophene

B1. phenyl thiophene.Flow process 3 expressions are by the amide and the ester derivant of the synthetic 5-phenyl-thiophene of the 5-aryl thiophene that replaces.

Flow process 3

B2. alkylthrophene and alkenyl thiophene.Flow process 4 expressions are by the amide and the ester derivant of the 5-alkylthrophene that replaces and synthetic 5-alkylthrophene of 5-alkenyl thiophene and 5-alkenyl thiophene.

Flow process 4

B3. aminothiophene.Flow process 5 expressions are by the amide and the ester derivant of 5-aminothiophene synthesizing thiofuran.

Flow process 5

Experiment

Benzothiophene

Preparation 6-aminobenzene bithiophene

6-nitro-benzo [b] thiophene-2-carboxylic acid methyl ester.Toward 2, and the 4-dinitrobenzal-dehyde (6.45g, 32.9mmol) and K ₂CO ₃(5.45g, 39.4mmol) slowly add in the mixture in DMF (60mL) methyl thioglycolate (3.0mL, 32.9mmol).This mixture was at room temperature stirred 1 hour, stirred 2 hours down at 50 ℃ subsequently.With the mixture impouring H that obtains ₂Also stir up to generating precipitation in the O/ ice.Leach solid and grind with hot MeOH.Leach light brown solid. ¹H NMR (DMSO-d ₆) δ 9.13 (s, 1H), 8.33 (s, 1H), 8.30-8.17 (m, 2H), 3.89 (s, 3H) .MS (EI): value of calculation (MH ⁺) 238.01, measured value (MH ⁺) 238.10.

6-amino-benzo [b] thiophene-2-carboxylic acid methyl ester.(3.9g adds 10%Pd/C (700mg, 10% weight) in DMF 15.8mmol) (120mL) solution toward 6-nitro-benzo [b] thiophene-2-carboxylic acid methyl ester that stirs.In reactant, feed hydrogen, the degassing and feed hydrogen again, amount to three times.Under gasbag pressure, room temperature, slurry was stirred 4 days, with filtering removal of solvent under reduced pressure after kieselguhr (Celite) is filled in.Obtain required amine with EtOAc washing solid and filtration. ¹HNMR (CDCl ₃) δ 7.92 (s, 1H), 7.65 (d, J=8.4Hz, 1H), 7.08 (s, 1H), 6.78 (d, J=8.4Hz, 1H), 3.92 (s, 3H) .MS (EI): value of calculation (MH ⁺) 208.04, measured value (MH ⁺) 208.1.

Amide

The universal method of acidylate 6-amino-benzothiophene

6-phenyl acetyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.Toward 6-amino-benzo [b] thiophene-2-carboxylic acid methyl ester (75mg, 0.36mmol) and NMM (51.7 μ L, THF/CH 0.47mmol) ₂Cl ₂(2/1mL) add acyl chlorides (0.434mmol) in the solution.After 24 hours, remove and desolvate.In the gained mixture, add DMA (2mL) and NH ₂OH (50% aqueous solution, 1mL).Stirring gained solution shows up to the LC/MS analysis result and does not contain raw material.Except that after desolvating, add MeOH/H ₂O is up to forming precipitation.Leach solid, obtain required amide. ¹H NMR (DMSO-d ₆) δ 11.38 (br s, 1H), 10.42 (br s, 1H), 9.21 (br s, 1H), 8.38 (s, 1H), 7.90-7.75 (m, 2H), 7.50-7.15 (m, 6H), 3.65 (s, 2H) .MS (EI): value of calculation (MH ⁺) 327.07, measured value (MH ⁺) 327.28.

6-benzoyl-amido-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆) δ 11.37 (br s, 1H), 10.46 (br s, 1H), 9.21 (br s, 1H), 8.53 (s, 1H), 7.99-7.77 (m, 4H), 7.77-7.64 (m, 1H), 7.64-7.45 (m, 3H) .MS (EI): value of calculation (MH ⁺) 313.1, measured value (MH ⁺) 313.3.

6-[(xenyl-4-carbonyl)-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆) δ 11.39 (br s, 1H), 10.50 (br s, 1H), 9.23 (br s, 1H), 8.56 (s, 2H), 8.05 (d, J=7.8Hz, 2H), 8.00-7.60 (m, 7H), 7.60-7.34 (m, 3H) .MS (EI): value of calculation (MH ⁺) 389.1, measured value (MH ⁺) 389.3.

6-(3-phenyl-propiono amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆) δ 11.37 (br s, 1H), 10.13 (br s, 1H), 9.19 (br s, 1H), 8.37 (s, 1H), and 7.85-7.72 (m, 2H), 7.44-7.33 (m, 1H), 7.33-7.08 (m, 6H), and 2.95-2.81 (m, 2H), 2,70-2.59 (m, 2H) .MS (EI): value of calculation (MH ⁺) 341.1, measured value (MH ⁺) 341.3.

6-[(naphthalene-2-carbonyl)-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆) δ 11.39 (br s, 1H), 10.63 (br s, 1H), 9.22 (br s, 1H), 8.57 (s, 2H), 8.15-7.92 (m, 4H), 7.92-7.80 (m, 2H), 7.80-7.70 (m, 1H), 7.70-7.54 (m, 2H) .MS (EI): value of calculation (MH ⁺) 363.1, measured value (MH ⁺) 363.3.

6-isobutyryl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆) δ 11.35 (br s, 1H), 10.05 (br s, 1H), 9.20 (br s, 1H), 8.39 (s, 1H), and 7.85-7.70 (m, 2H), 7.44 (dd, J=8.4,1.4Hz, 1H), and 2.68-2.48 (m, 1H), 1.08 (d, J=7.0Hz, 6H) .MS (EI): value of calculation (MH ⁺) 279.0, measured value (MH ⁺) 279.2.

Quinoline-2-[N-(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-yl)] Methanamide. ¹HNMR (DMSO-d ₆) δ 10.94 (br s, 1H), 10.27 (br s, 1H), 9.22 (br s, 1H), 8.72-8.57 (m, 2H), 8.30-8.18 (m, 2H), 8.10 (d, J=8.4Hz, 1H), 8.04-7.82 (m, 4H), 7.31 (dd, J=7.4,7.4Hz, 1H) .MS (EI): value of calculation (MH ⁺) 364.1, measured value (MH ⁺) 364.3.

N-(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-yl)-nicotiamide. ¹HNMR (DMSO-d ₆) δ 11.40 (m, 1H), 10.66 (br s, 1H), 9.25 (br s, 1H), 9.11 (s, 1H), 8.82-8.70 (m, 1H), 8.54 (s, 1H), 8.30 (d, J=7.5Hz, 1H), 8.00-7.78 (m, 2H), 7.70 (d, J=7.0Hz, 1H), 7.65-7.50 (m, 1H) .MS (EI): value of calculation (MH ⁺) 314.1, measured value (MH ⁺) 314.3.

6-diphenyl acetyl-amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆) δ 11.35 (m, 1H), 10.62 (br s, 1H), 9.19 (br s, 1H), 8.43 (s, 1H), 7.90-7.72 (m, 2H), 7.50-7.15 (m, 11H), 5.17 (s, 1H) .MS (EI): value of calculation (MH ⁺) 403.1, measured value (MH ⁺) 403.3.

6-[(naphthalene-1-carbonyl)-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.(EI): value of calculation (MH ⁺) 363.1, measured value (MH ⁺) 363.3.

6-(3,4-dimethoxy-benzoyl-amido)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆) δ 11.39 (br s, 1H), 10.27 (br s, 1H), 9.22 (br s, 1H), 8.48 (s, 1H), 7.90-7.75 (m, 2H), 7.75-7.55 (m, 2H), 7.52 (s, 1H), 7.08 (d, J=8.0Hz, 1H), 3.82 (s, 3H), 3.81 (s, 3H) .MS (EI): value of calculation (MH ⁺) 373.1, measured value (MH ⁺) 373.2.

6-[2-(3,4-dimethoxy-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆) δ 10.31 (br s, 1H), 8.35 (s, 1H), 7.85-7.72 (m, 2H), 7.42 (dd, J=8.8,1.8Hz, 1H), 6.95-6.75 (m, 3H), 3.69 (s, 3H), 3.67 (s, 3H), 3.54 (s, 2H) .MS (EI): value of calculation (MH ⁺) 387.1, measured value (MH ⁺) 387.2.

6-[2-(4-fluoro-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆) δ 10.39 (br s, 1H), 9.27 (br s, 1H), 8.37 (s, 1H), 7.88-7.72 (m, 2H), 7.50-7.28 (m, 3H), 7.20-7.05 (m, 2H), 3.65 (s, 2H) .MS (EI): value of calculation (MH ⁺) 345.1, measured value (MH ⁺) 345.2.

6-[2-(2,5-dimethoxy-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆) δ 10.25 (br s, 1H), 9.27 (br s, 1H), 8.35 (s, 1H), 7.85-7.69 (m, 2H), 7.45 (dd, J=8.8,1.8Hz, 1H), 6.92-6.68 (m, 3H), 3.66 (s, 3H), 3.65 (s, 3H), 3.60 (s, 2H) .MS (EI): value of calculation (MH ⁺) 387.1, measured value (MH ⁺) 387.2.

6-[2-(3-methoxyl group-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆) δ 10.38 (br s, 1H), 9.27 (br s, 1H), 8.37 (s, 1H), and 7.87-7.73 (m, 2H), 7.45 (dd, J=8.8,1.8Hz, 1H), 7.21 (t, J=8.0,8.0Hz, 1H), and 6.92-6.83 (m, 2H), 6.78 (dd, J=7.0,1.2Hz, 1H), 3.71 (s, 3H), 3.61 (s, 2H) .MS (EI): value of calculation (MH ⁺) 357.1, measured value (MH ⁺) 357.3.

6-[2-(4-chloro-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (CDCl ₃) δ 10.42 (s, 1H), 9.20 (br s, 1H), 8.36 (s, 1H), 7.87-7.71 (m, 2H), 7.49-7.25 (m, 5H), 3.66 (s, 2H) .MS (EI): value of calculation 361.1 (MH ⁺), measured value 361.5 (MH ⁺).

6-[2-(4-methoxyl group-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (CDCl ₃) δ 10.35 (s, 1H), 9.21 (br s, 1H), 8.37 (s, 1H), 7.85-7.70 (m, 2H), 7.51-7.32 (m, 1H), 7.22 (d, 2H, J=8.0Hz), 6.85 (d, 2H, J=8.0Hz), 3.69 (s, 3H), 3.57 (s, 2H) .MS (EI): value of calculation 357.1 (MH ⁺), measured value 357.3 (MH ⁺).

6-(2-phenyl-butyrylamino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (CDCl ₃) δ 11.33 (br s, 1H), 10.31 (s, 1H), 9.19 (br s, 1H), 8.39 (s, 1H), 7.83-7.71 (m, 2H), 7.45-7.15 (m, 6H), 3.56 (t, 1H, 7.2Hz), 2.15-1.90 (m, 1H), and 1.78-1.55 (m, 1H), 0.83 (t, 3H, 7.2Hz) .MS (EI): value of calculation 355.1 (MH ⁺), measured value 355.3 (MH ⁺).

6-(methyl-phenyl acetyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (CDCl ₃) δ 11.48 (br s, 1H), 9.27 (br s, 1H), 8.01-7.85 (m, 3H), 7.33 (d, 1H, J=8.2Hz), 7.35-7.10 (m, 3H), 7.10-6.02 (m, 2H), 3.29 (s, 3H), 3.21 (s, 2H) .MS (EI): value of calculation 341.1 (MH ⁺), measured value 341.2 (MH ⁺).

6-(2-pyridine-2-base-acetyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 328.1 (MH ⁺), measured value 328.2 (MH ⁺).

6-(2-pyridin-3-yl-acetyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (CDCl ₃) δ 10.45 (s, 1H), 9.22 (br s, 1H), 8.51-8.30 (m, 2H), 7.89-7.65 (m, 3H), 7.58 (d, 1H, J=8.0Hz), 7.50-7.22 (m, 2H), 3.71 (s, 2H) .MS (EI): value of calculation 328.1 (MH ⁺), measured value 328.2 (MH ⁺).

6-(2-phenyl-propiono amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (CDCl ₃) δ 10.27 (s, 1H), 9.19 (br s, 1H), 8.38 (s, 1H), 7.83-7.71 (m, 2H), 7.49-7.15 (m, 6H), 3.85 (q, 1H, 7.0Hz), 1.39 (t, 3H, 7.0Hz) .MS (EI): value of calculation 341.1 (MH ⁺), measured value 341.2 (MH ⁺).

6-{[1-(4-chloro-phenyl)-cyclopropane carbonyl]-amino }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 387.1 (MH ⁺), measured value 387.3 (MH ⁺).

6-[(1-phenyl-cyclopropane carbonyl)-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.

MS (EI): value of calculation 353.1 (MH ⁺), measured value 353.2 (MH ⁺).

6-{[1-(4-chloro-phenyl)-Tetramethylene. carbonyl]-amino }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 401.1 (MH ⁺), measured value 401.2 (MN ⁺).

6-[2-(4-chloro-phenyl)-2-methyl-propiono amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 389.1 (MH ⁺), measured value 389.2 (MN ⁺).

6-(2S-phenyl-butyrylamino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 355.1 (MH ⁺), measured value 355.2 (MN ⁺).

6-(2R-phenyl-butyrylamino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 355.1 (MH ⁺), measured value 355.2 (MH ⁺).

Acyl group chemical compound by amino methyl-benzothiophene preparation

6-amino methyl-benzo [b] thiophene-2-carboxylic acid carbethoxy hydrochloride.0 ℃ down toward 6-methylol-benzo [b] thiophene-2-carboxylic acid ethyl ester (2.52g, 10.7mmol) and triethylamine (3.00mL, add in anhydrous THF (80mL) solution 21.5mmol) mesyl chloride (1.24mL, 16.0mmol).The mixture that obtains was stirred 30 minutes down at 0 ℃,, use saturated NaHCO subsequently with EtOAc (400mL) dilution ₃, water and salt water washing.Organic layer is through Na ₂SO ₄Dry.After the filtration, filtrate is concentrated, residue is dissolved in the dry DMF (60mL) subsequently.(1.41g 21.6mmol), heats this mixture 30 minutes down at 50 ℃ to add Hydrazoic acid,sodium salt.After being cooled to room temperature, dilute this mixture with EtOAc (300mL) and water (60mL).Water and salt water washing organic layer once more, and through Na ₂SO ₄Dry.After the filtration, filtrate is concentrated and residue is dissolved in THF (60mL) and the water (6mL).(3.64g 13.9mmol), at room temperature stirs this mixture and to spend the night, and concentrates subsequently to add triphenylphosphine.Residue is dissolved in ether (400mL), drips 4M HCl two  alkane solution (6mL) subsequently.(5 * 30mL) washings are also dry, obtain 6-amino methyl-benzo [b] thiophene-2-carboxylic acid carbethoxy hydrochloride of light solid form with ether for the solid that forms. ¹H?NMR(DMSO-d ₆，200MHz)δ8.66(brs，2H)，8.24-8.10(m，2H)，8.06(d，J＝8.6Hz，1H)，7.62(dd，J＝8.4，1.6Hz，1H)，4.34(q，J＝7.4Hz，2H)，4.13(s，2H)，1.32(t，J＝7.0Hz，3H)。MS (EI): value of calculation 236.1 (MH ⁺), measured value 236.1 (MH ⁺).

6-methylol-benzo [b] thiophene-2-carboxylic acid methyl ester.With 6-methylol-benzo [b] thiophene-2-carboxylic acid ethyl ester (9.45g, 40.0mmol) and DBU (6.00mL, anhydrous MeOH (200mL) solution stirring 40.1mmol) 2 days.After concentrating, residue is dissolved among the EtOAc (800mL) also with 1N HCl, water, saturated NaHCO ₃And salt water washing.Dry organic layer, filtration is also concentrated and dry with filtrate, obtains 6-methylol-benzo [b] thiophene-2-carboxylic acid methyl ester of pale solid form. ¹H?NMR(CDCl ₃，200MHz)δ8.03(d，J＝0.6Hz，1H)，7.90-7.80(m，2H)，7.39(dd，J＝8.0，1.4Hz，1H)，4.83(s，2H)，3.94(s，3H)，1.98(brs，1H)。MS (EI): value of calculation 223.0 (MH ⁺), measured value 223.1 (MH ⁺).

6-amino methyl-benzo [b] thiophene-2-carboxylic acid methyl ester hydrochloride.Prepare this title compound according to being similar to the method for preparing 6-amino methyl-benzo [b] thiophene-2-carboxylic acid carbethoxy hydrochloride by 6-methylol-benzo [b] thiophene-2-carboxylic acid methyl ester. ¹H?NMR(DMSO-d ₆，200MHz)δ8.70(brs，2H)，8.24-8.12(m，2H)，8.05(d，J＝8.4Hz，1H)，7.63(dd，J＝8.0，1.0Hz，1H)，4.20-4.14(m，2H)，3.88(s，3H)。MS (EI): value of calculation 222.0 (MH ⁺), measured value 222.1 (MH ⁺).

6-(benzoyl-amido-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.Toward 6-amino methyl-benzo [b] thiophene-2-carboxylic acid carbethoxy hydrochloride (109mg, 0.40mmol), NMM (132 μ L, 1.20mmol), add in the mixture of DMAP (10mg, 0.08mmol) in anhydrous THF (5mL) Benzenecarbonyl chloride. (55.7 μ L, 0.48mmol) and DMF (2.0mL).After reacting completely, reactant mixture is concentrated.In residue, add MeOH (1mL) and water (10mL).With the solid filtering that forms, wash with water and drying.Be dissolved in this solid residue among the anhydrous MeOH (5mL) and add oxammonium hydrochloride. (106mg, 1.52mmol), add subsequently NaOMe solution (the MeOH solution of 4.37M, 0.70mL, 3.1mmol).Allow this mixture at room temperature stir up to reacting completely.This reactant mixture is concentrated and residue is dissolved in the minimum water.With 2N HCl the solution that obtains is acidified to pH ≈ 8.Filter solid, the washing that forms and pass through the flash column chromatography purification, obtain 6-(benzoyl-amido-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide of white solid. ¹H?NMR(DMSO-d ₆，200MHz)δ11.44(brs，1H)，9.27(brs，1H)，9.13(t，J＝6.2Hz，1H)，8.00-7.78(m，5H)，7.58-7.28(m，4H)，4.60(d，J＝5.8Hz，2H)。MS (EI): value of calculation 327.1 (MH ⁺), measured value 327.1 (MH ⁺).

Employing is similar to the following chemical compound of method preparation for preparing 6-(benzoyl-amido-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.

6-(phenyl acetyl amino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ8.64(t，J＝6.2Hz，1H)，7.94-7.70(m，3H)，7.34-7.14(m，6H)，4.38(d，J＝5.8Hz，2H)，3.49(s，2H)。MS (EI): value of calculation 341.1 (MH ⁺), measured value 341.1 (MH ⁺).

6-{[(naphthalene-1-carbonyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ9.18(t，J＝5.8Hz，1H)，8.24-8.14(m，1H)，8.06-7.84(m，5H)，7.69(dd，J＝7.0，1.0Hz，1H)，7.62-7.42(m，4H)，4.67(d，J＝6.0Hz，2H)。MS (EI): value of calculation 377.1 (MH ⁺), measured value 377.1 (MH ⁺).

6-[(2-methyl-benzoyl-amido)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ11.46(brs，1H)，9.26(brs，1H)，8.87(t，J＝6.2Hz，1H)，7.98-7.82(m，3H)，7.46-7.16(m，5H)，4.55(d，J＝5.8Hz，2H)，2.32(s，3H)。MS (EI): value of calculation 341.1 (MH ⁺), measured value 341.2 (MH ⁺).

6-[(4-methyl-benzoyl-amido)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ11.44(brs，1H)，9.25(brs，1H)，9.03(t，J＝4.6Hz，1H)，7.96-7.72(m，5H)，7.38(d，J＝8.0Hz，2H)，7.27(d，J＝8.2Hz，2H)，4.58(d，J＝6.0Hz，2H)，2.34(s，3H)。MS (EI): value of calculation 341.1 (MH ⁺), measured value 341.2 (MH ⁺).

6-[(3-methoxyl group-benzoyl-amido)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ11.45(brs，1H)，9.25(brs，1H)，9.11(t，J＝6.0Hz，1H)，7.96-7.80(m，3H)，7.54-7.30(m，3H)，7.14-7.04(m，1H)，4.59(d，J＝5.6Hz，2H)，3.79(s，3H)。MS (EI): value of calculation 357.1 (MH ⁺), measured value 357.2 (MH ⁺).

6-[(4-methoxyl group-benzoyl-amido)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ11.44(brs，1H)，9.27(brs，1H)，8.89(t，J＝5.4Hz，1H)，8.00-7.78(m，5H)，7.39(d，J＝8.0Hz，2H)，7.00(d，J＝9.0Hz，2H)，1H)，4.58(d，J＝5.8Hz，2H)，3.80(s，3H)。MS (EI): value of calculation 357.1 (MH ⁺), measured value 357.2 (MH ⁺).

6-[(3,4-dimethoxy-benzoyl-amido)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ11.45(brs，1H)，9.27(brs，1H)，8.99(t，J＝6.0Hz，1H)，7.94-7.80(m，3H)，7.60-7.46(m，2H)，7.38(dd，J＝8.4，1.6Hz，1H)，7.02(d，J＝8.4Hz，1H)，1H)，4.59(d，J＝5.4Hz，2H)，3.80(s，3H)，3.79(s，3H)。MS (EI): value of calculation 387.1 (MH ⁺), measured value 387.2 (MH ⁺).

N-(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-ylmethyl)-nicotiamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 9.32 (t, J=5.6Hz, 1H), 9.06 (d, J=1.4Hz, 1H), 8.71 (dd, J=4.8,2.0Hz, 1H), 8.24 (ddd, J=7.8,2.0,2.0Hz, 1H), 7.96 (s, 1H), 7.92-7.80 (m, 2H), 7.60-7.46 (m, 1H), 7.40 (dd, J=8.4,1.4Hz, 1H), 4.62 (d, J=6.0Hz, 2H) .MS (EI): value of calculation 328.1 (MH ⁺), measured value 328.2 (MH ⁺).

6-(isobutyryl amino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ9.26(brs，1H)，8.34(t，J＝5.6Hz，1H)，7.94-7.74(m，3H)，7.29(d，J＝8.0Hz，1H)，4.36(d，J＝6.0Hz，2H)，2.46-2.30(m，1H)，1.03(d，J＝6.6Hz，6H)。MS (EI): value of calculation 293.1 (MH ⁺), measured value 293.1 (MH ⁺).

6-[(2-methoxyl group-benzoyl-amido)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ9.27(brs，1H)，8.80(t，J＝6.2Hz，1H)，7.98-7.82(m，3H)，7.73(dd，J＝8.0，1.8Hz，1H)，7.54-7.36(m，2H)，7.14(d，J＝8.6Hz，1H)，7.03(t，J＝7.4Hz，1H)，4.61(d，J＝5.8Hz，2H)，3.89(s，3H)。MS (EI): value of calculation 357.1 (MH ⁺), measured value 357.1 (MH ⁺).

6-[(4-chloro-benzoyl-amido)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ9.20(t，J＝5.8Hz，1H)，7.98-7.80(m，5H)，7.55(d，J＝8.4Hz，2H)，7.38(dd，J＝8.4，1.6Hz，1H)，4.59(d，J＝5.8Hz，2H)。MS (EI): value of calculation 361.0 (MH ⁺), measured value 361.1 (MH ⁺).

Sulfonamide

6-phenyl methanesulfonamide acyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.Adopt and prepare 6-phenyl acetyl amino-benzo [b] thiophene-2-(N-hydroxyl) method that Methanamide is identical. ¹HNMR (DMSO-d ₆) δ 11.18 (br s, 1H), 9.99 (br s, 1H), 9.19 (br s, 1H), 7.91-7.60 (m, 3H), 7.42-7.15 (m, 5H), 4.51 (s, 2H) .MS (EI): value of calculation (MH ⁺) 363.04, measured value (MH ⁺) 363.28.

6-benzenesulfonyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆)δ11.38(br?s，1H)，10.47(br?s，1H)，9.22(br?s，1H)，7.90-7.40(m，8H)，7.20-7.03(m，1H)。MS (EI): value of calculation (MH ⁺) 349.0, measured value (MH ⁺) 349.2.

6-(xenyl-4-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆) δ 11.37 (br s, 1H), 10.46 (br s, 1H), 9.21 (br s, 1H), 7.96-7.59 (m, 9H), 7.59-7.30 (m, 3H), 7.30-7.03 (m, 1H) .MS (EI): value of calculation (MH ⁺) 425.1, measured value (MH ⁺) 425.3.

6-(naphthalene-1-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation (MH ⁺) 399.1, measured value (MH ⁺) 399.3.

6-(naphthalene-2-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆) δ 11.32 (br s, 1H), 10.63 (br s, 1H), 9.17 (br s, 1H), 8.45 (s, 1H), 8.25-7.96 (m, 2H), 7.93 (d, J=7.4Hz, 1H), 7.61-7.58 (m, 6H), 7.13 (dd, J=8.6,1.6Hz, 1H) .MS (EI): value of calculation (MH ⁺) 399.1, measured value (MH ⁺) 399.3.

6-(toluene-4-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆)δ11.35(br?s，1H)，10.46(br?s，1H)，9.20(br?s，1H)，7.80-7.57(m，5H)，7.28(d，J＝8.0Hz，2H)，7.14(d，J＝8.4Hz，1H)，5.72(s，1H)，2.27(s，3H)。MS (EI): value of calculation (MH ⁺) 363.0, measured value (MH ⁺) 363.2.

Universal method:

(160 μ L, 0.919mmol) the trickle suspension in the dry DMF of 2.5mL adds in the bottle of the sulfonic acid chloride that contains 0.40mmol with 2-methoxycarbonyl-benzo [b] thiophene-6-ylmethyl-ammonium chloride (100mg, 0.388mmol) and diisopropylethylamine.Mixture is stirred, and mixture becomes transparent after several minutes.With the solution stirring that obtains 1 hour.Slowly add in this intermediate solution azanol 50% aqueous solution (1mL, 16.7mmol).Form post precipitation, the DMF that adds capacity obtains transparent solution.This reactant was at room temperature stirred 2 days.Add entry (4mL) and saline (2mL) precipitated product.Solid collected by filtration is with saturated NaHCO ₃(1mL) and EtOAc (0.5mL) grind together, wash with water subsequently.After the filtration, under fine vacuum, obtain product and be separated into powder.

Data (data)

6-(benzenesulfonyl amino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ8.26(t，J＝6.2Hz，1H)，7.94-7.72(m，5H)，7.64-7.46(m，3H)，7.28(d，J＝8.6Hz，1H)，4.11(d，J＝5.8Hz，2H)。MS (EI): value of calculation 363.0 (MH ⁺), measured value 363.0 (MH ⁺).

6-(phenyl methanesulfonamide acyl amino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.96-7.84(m，3H)，7.42-7.28(m，6H)，4.35(s，2H)，4.21(d，J＝5.8Hz，2H)。MS (EI): value of calculation 377.1 (MH ⁺), measured value 377.0 (MH ⁺).

6-[(naphthalene-1-sulfuryl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ8.76-8.54(m，2H)，8.18-7.96(m，3H)，7.84-7.48(m，6H)，7.16(dd，J＝8.0，1.0Hz，1H)，4.16(d，J＝5.8Hz，2H)。MS (EI): value of calculation 413.1 (MH ⁺), measured value 413.0 (MH ⁺).

6-[(naphthalene-2-sulfuryl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ8.41(d，J＝1.6Hz，1H)，8.16-7.95(m，3H)，7.88-7.56(m，6H)，7.28(d，J＝8.2Hz，1H)，4.14(s，2H)。MS (EI): value of calculation 413.1 (MH ⁺), measured value 413.1 (MH ⁺).

6-[(toluene-4-sulfuryl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) 8.16 (br t, 1H), 7.86 (s, 1H), 7.81 (d, J=8.4Hz, 1H), 7.76 (s, 1H), 7.66 (d, J=8.2Hz, 2H), 7.33 (d, J=8.0Hz, 2H), 7.28 (d, J=8.0Hz, 1H), 4.08 (d, J=4.4Hz, 2H), 2.33 (s, 3H) .MS (ES-): value of calculation 375.05 (M-H ⁺), measured value 375.12 (M-H ⁺).

6-[(2,4,6-trimethyl-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) 8.09 (br t, 1H), 7.83 (s, 1H), 7.76 (d, J=8.4Hz, 1H), 7.64 (s, 1H), 7.24 (d, J=8.0Hz, 2H), 6.90 (s, 2H), 4.10 (d, J=5.2Hz, 2H), 2.51 (s, 6H), 2.16 (s, 3H) .MS (ES+): value of calculation 405.10 (MH ⁺), measured value 405.18 (MH ⁺).

The 6-[(4-tert-butyl group-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) 7.78-7.62 (m, 5H), 7.50 (d, J=8.4Hz, 2H), 7.20 (d, J=8.0Hz, 2H), 4.09 (br s, 2H), 1.25 (s, 9H) .MS (ES-): value of calculation 417.09 (M-H ⁺), measured value 417.19 (M-H ⁺).

6-[(4-fluoro-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) 8.25 (br s, 1H), 7.85-7.77 (m, 5H), 7.40-7.24 (m, 3H), 4.12 (d, J=1.0Hz, 2H) .MS (ES-): value of calculation 379.02 (M-H ⁺), measured value 379.12 (M-H ⁺).

6-[(4-chloro-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) 7.86 (s, 1H), 7.80 (d, J=8.4Hz, 1H), 7.76 (d, J=7.8Hz, 2H), 7.58 (d, J=8.4Hz, 2H), 7.27 (d, J=8.4Hz, 1H), 4.13 (s, 2H) .MS (ES+): value of calculation 397.01 (MH ⁺), measured value 397.09 (MH ⁺).

6-[(3-chloro-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) 7.84-7.66 (m, 5H), 7.66-7.50 (m, 2H), 7.25 (d, J=8.4Hz, 1H), 4.16 (s, 2H) .MS (ES-): value of calculation 394.99 (M-H ⁺), measured value 395.09 (M-H ⁺).

6-[(4-bromo-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) 7.85-7.65 (m, 7H), 7.23 (d, J=8.4Hz, 1H), 4.11 (s, 2H) .MS (ES-): value of calculation 438.94 (M-H ⁺), measured value 439.03 (M-H ⁺).

6-[(3-bromo-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNNR (DMSO-d ₆, 200MHz) 7.85-7.60 (m, 6H), 7.65 (t, J=8.2Hz, 1H), 7.26 (d, J=9.2Hz, 1H), 4.16 (s, 2H) .MS (ES+): value of calculation 440.96 (MH ⁺), measured value 441.03 (MH ⁺).

6-[(3-methoxyl group-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) 8.27 (br s, 1H), 7.85-7.70 (m, 3H), 7.50-7.25 (m, 3H), 7.24 (s, 1H), 7.13 (d, J=8.4Hz, 1H), 4.11 (s, 2H), 3.76 (s, 3H) .MS (ES+): value of calculation 393.06 (MH ⁺), measured value 393.14 (MH ⁺).

6-[(4-nitro-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) 8.28 (d, J=8.8Hz, 1H), 7.96 (d, J=8.8Hz, 1H), 7.80-7.70 (m, 3H), 7.25 (d, J=8.4Hz, 1H), 4.19 (s, 2H) .MS (ES-): value of calculation 406.01 (M-H ⁺), measured value 406.10 (M-H ⁺).

6-[(4-methoxyl group-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NNR (DMSO-d ₆, 200MHz) 7.80-7.65 (m, 5H), 7.23 (d, J=8.6Hz, 1H), 7.05 (d, J=8.8Hz, 2H), 4.04 (s, 2H), 3.79 (s, 3H) .MS (ES-): value of calculation 391.04 (M-H ⁺), measured value 391.17 (M-H ⁺).

6-[(thiophene-2-sulfuryl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) 7.90 (d, J=4.6Hz, 1H), 7.90-7.70 (m, 3H), 7.59 (d, J=3.8Hz, 1H), 7.28 (d, J=8.2Hz, 1H), 7.14 (t, J=3.8Hz, 1H), 4.18 (s, 2H) .MS (ES+): value of calculation 369.01 (MH ⁺), measured value 369.07 (MH ⁺).

6-{[3-(4-methoxyl group-phenoxy group)-propane-1-sulfuryl amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) 7.95-7.70 (m, 4H), 7.36 (d, J=8.4Hz, 1H), 6.90-6.75 (m, 4H), 4.26 (s, 2H), 3.91 (t, J=6.2Hz, 2H), 3.67 (s, 3H), 3.08 (t, J=7.4Hz, 2H), 2.01 (m, 2H) .MS (ES-): value of calculation 449.08 (M-H ⁺), measured value 449.15 (M-H ⁺).

Urea/carbamate

6-(3-benzyl-urea groups)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.Adopt and prepare 6-phenyl acetyl amino-benzo [b] thiophene-2-(N-hydroxyl) method that Methanamide is identical. ¹H(DMSO-d ₆)δ11.28(br?s，1H)，9.19(br?s，1H)，8.82(s，1H)，8.16(s，1H)，7.80-7.62(m，2H)，7.38-7.17(m，5H)，6.68(t，J＝5.8Hz，1H)，4.28(d，J＝5.8Hz，2H)。MS (EI): value of calculation (MH ⁺) 342.08, measured value (MH ⁺) 342.31.

(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-yl)-urethanes. ¹HNNR (DMSO-d ₆) δ 9.86 (br s, 1H), 9.18 (br s, 1H), 8.11 (s, 1H), 7.82-7.70 (m, 2H), 7.38 (dd, J=8.4,1.2Hz, 1H), 4.11 (q, J=6.8Hz, 2H), 1.22 (t, J=6.8Hz, 2H) .MS (EI): value of calculation (MH ⁺) 281.1, measured value (MH ⁺) 281.2.

(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-yl)-benzyq carbamate. ¹HNMR (DMSO-d ₆) δ 11.34 (br s, 1H), 10.02 (br s, 1H), 9.18 (br s, 1H), 8.13 (s, 1H), 7.90-7.70 (m, 2H), 7.49-7.25 (m, 6H), 5.14 (s, 2H) .MS (EI): value of calculation (MH ⁺) 343.1, measured value (MH ⁺) 343.2.

6-(3-phenethyl-urea groups)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆)δ8.74(br?s，1H)，8.16(s，1H)，7.90-7.70(m，2H)，7.40-7.10(m，5H)，6.21(m，1H)，3.40-3.22(m，2H)，2.72(t，J＝7.0Hz，2H)。MS (EI): value of calculation (MH ⁺) 390.1, measured value (MH ⁺) 390.3.

6-(3-benzyl-urea groups methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.94-7.78(m，3H)，7.40-7.16(m，6H)，6.68-6.46(m，2H)，4.34(d，J＝6.0Hz，2H)，4.23(d，J＝6.0Hz，2H)。MS (EI): value of calculation 356.1 (MH ⁺), measured value 356.1 (MH ⁺).

(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-ylmethyl)-benzyq carbamate. ¹HNMR(DMSO-d ₆，200MHz)δ7.98-7.80(m，4H)，7.40-7.26(m，6H)，5.05(s，2H)，4.32(d，J＝6.0Hz，2H)。MS (EI): value of calculation 357.1 (MH ⁺), measured value 357.1 (MH ⁺).

6-[3-(4-isopropyl-phenyl)-urea groups methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) 8.42 (br s, 1H), 7.66 (s, 1H), and 7.68-7.50 (m, 2H), 7.16 (d, J=8.0Hz, 2H), 7.20-7.10 (m, 1H), 6.93 (d, J=8.0Hz, 2H), 6.59 (br s, 1H), 4.23 (br s, 2H), 2.64 (m, 1H), 1.01 (d, J=4.8Hz, 6H) .MS (ES+): value of calculation 384.14 (MH ⁺), measured value 384.19 (MH ⁺).

6-[3-(the 4-tert-butyl group-phenyl)-urea groups methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) 8.38 (br s, 1H), 7.76-7.64 (m, 3H), 7-26-7.02 (m, 5H), 6.53 (t, J=4.8Hz, H), 4.26 (d, J=4.8Hz, H), 1.08 (s, 9H) .MS (ES+): value of calculation 398.15 (MH ⁺), measured value 398.22 (MH ⁺).

6-[3-(3,5-couple-trifluoromethyl-phenyl)-urea groups methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) 9.32 (br s, 1H), 7.96 (s, 2H), 7.75-7.68 (m, 3H), 7.41 (s, 1H), 7.23 (d, J=8.0Hz, 1H), 7.02 (br t, 1H), 4.30 (d, J=6.0Hz, 2H) .MS (ES+): value of calculation 478.07 (MH ⁺), measured value 478.15 (MH ⁺).

6-[3-(3-phenoxy group-phenyl)-urea groups methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) 8.70 (br s, 1H), 7.69 (d, J=5.4Hz, 2H), 7.30-7.80 (m, 9H), 6.67 (br s, 1H), 6.38 (d, J=8.2Hz, 1H), 4.22 (br s, 2H) .MS (ES+): value of calculation 434.12 (MH ⁺), measured value 434.21 (MH ⁺).

Acyl group chemical compound by the preparation of 5-aminobenzene bithiophene

Amide

5-benzoyl-amido-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.In 5-benzoyl-amido-benzo [b] thiophene-2-carboxylic acid ethyl ester (102.9mg, 0.32mmol), add NH ₂OHHCl (76.2mg, 0.97mmol) and the anhydrous MeOH of 5mL.Adding NaOMe solution (the MeOH solution of 4.37M, 0.50mL, 2.18mmol).Allow the mixture that obtains at room temperature stir 2 days.Reactant mixture is concentrated, subsequently residue is dissolved in the minimum water.After 5mL hexane/EtOAc (4: 1) extraction, water layer is acidified to pH ≈ 7 with 2N HCl aqueous solution.Filtration, collection, drying precipitated obtain 5-benzoyl-amido-benzo [b] thiophene-2-(N-hydroxyl) Methanamide of light solid, shaped. ¹H?NMR(DMSO-d ₆，200MHz)δ10.41(s，1H)，8.44(s，1H)，8.10-7.82(m，4H)，7.76(dd，J＝8.7，2.1Hz，1H)，7.68-7.35(m，4H)。MS (EI): value of calculation 313.1 (MH ⁺), measured value 313.2 (MH ⁺).

5-phenyl acetyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ10.36(s，1H)，8.28(s，1H)，7.91(d，J＝8.4Hz，1H)，7.82(s，1H)，7.52(d，J＝8.4Hz，1H)，7.45-7.00(m，5H)，3.67(s，2H)。MS (EI): value of calculation 327.1 (MH ⁺), measured value 327.3 (MH ⁺).

5-(3-phenyl-propiono amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ10.08(s，1H)，8.28(s，1H)，7.90(d，J＝8.8Hz，1H)，7.84(s，1H)，7.48(dd，J＝8.8，1.8Hz，1H)，7.39-6.90(m，5H)，2.93(t，J＝7.2Hz，2H)，2.65(t，J＝7.2Hz，2H)。MS (EI): value of calculation 341.1 (MH ⁺), measured value 341.2 (MH ⁺).

5-(3-phenyl-acryloyl group amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ10.45(s，1H)，8.42(s，1H)，8.10-7.20(m，9H)，6.88(d，J＝15.6Hz，1H)。MS (EI): value of calculation 339.1 (MH ⁺), measured value 339.3 (MH ⁺).

5-[(naphthalene-1-carbonyl)-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 10.74 (s, 1H), 8.54 (s, 1H), 8.28-7.86 (m, 5H), 7.84-7.48 (m, 5H) .MS (EI): value of calculation 363.1 (MH ⁺), measured value 363.3 (MH ⁺).

5-[(naphthalene-2-carbonyl)-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 10.59 (s, 1H), 8.61 (s, 1H), 8.49 (d, J=1.4Hz, 1H), 8.18-7.74 (m, 7H), 7.72-7.50 (m, 2H) .MS (EI): value of calculation 363.1 (MH ⁺), measured value 363.3 (MH ⁺).

Quinoline-2-[N-(2-hydroxyl amino formoxyl-benzo [b] thiophene-5-yl)] Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 11.50 (brs, 1H), 10.92 (s, 1H), 9.30 (brs, 1H), 8.84-8.50 (m, 2H), 8.40-8.20 (m, 2H), 8.20-7.86 (m, 5H), 7.76 (dd, J=7.2,7.2Hz, 1H) .MS (EI): value of calculation 364.1 (MH ⁺), measured value 364.3 (MH ⁺).

N-(2-hydroxyl amino formoxyl-benzo [b] thiophene-5-yl)-nicotiamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 11.47 (brs, 1H), 10.60 (s, 1H), 9.30 (brs, 1H), 9.13 (d, J=1.4Hz, 1H), 8.77 (dd, J=4.6,1.4Hz, 1H), 8.44 (d, J=1.4Hz, 1H), 8.32 (ddd, J=7.8,1.8,1,8Hz, 1H), 8.00 (d, J=8.8Hz, 1H), 7.91 (s, 1H), 7.74 (dd, J=8.8,1.8Hz, 1H), 7.58 (dd, J=7.8,4.6Hz, 1H) .MS (EI): value of calculation 314.0 (MH ⁺), measured value 314.2 (MH ⁺).

5-[(xenyl-4-carbonyl)-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 8.14-7.94 (m, 3H), 7.86-7.60 (m, 6H), 7.58-7.32 (m, 4H) .MS (EI): value of calculation 389.1 (MH ⁺), measured value 389.3 (MH ⁺).

5-diphenyl acetyl-amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 10.60 (s, 1H), 8.36 (s, 1H), 8.20-6.40 (m, 13H), 5.20 (s, 1H) .MS (EI): value of calculation 403.1 (MH ⁺), measured value 403.4 (MH ⁺).

5-isobutyryl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) δ 11.41 (brs, 1H), 9.98 (s, 1H), 9.27 (brs, 1H), 8.32 (d, J=1.8Hz, 1H), 8.11 (d, J=8.8Hz, 1H), 7.84 (s, 1H), 7.52 (dd, J=8.8,2.0Hz, 1H), 2.61 (?, J=6.8Hz, 1H), 1.10 (d, J=6.8Hz, 6H) .MS (EI): value of calculation 279.1 (MH ⁺), measured value 279.3 (MH ⁺).

5-[2-(4-fluoro-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 11.43 (brs, 1H), 10.34 (s, 1H), 9.28 (brs, 1H), 8.29 (d, J=2.0Hz, 1H), 7.92 (d, J=8.8Hz, 1H), 7.84 (s, 1H), 7.51 (dd, J=8.8,1.6Hz, 1H), and 7.44-7.28 (m, 2H), 7.24-7.04 (m, 2H), 3.67 (s, 2H) .MS (EI): value of calculation 345.1 (MH ⁺), measured value 345.2 (MH ⁺).

5-[2-(3-methoxyl group-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) δ 10.36 (brs, 1H), 8.24 (s, 1H), 7.86 (d, J=8.4Hz, 1H), 7.73 (s, 1H), 7.49 (d, J=9.8Hz, 1H), 7.23 (dd, J=8.1,8.1Hz, 1H), and 7.00-6.60 (m, 3H), 3.73 (s, 3H), 3.63 (s, 2H) .MS (EI): value of calculation 357.1 (MH ⁺), measured value 357.3 (MH ⁺).

5-[2-(3,4-dimethoxy-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) δ 10.27 (brs, 1H), 8.26 (s, 1H), 7.89 (d, J=8.8Hz, 1H), 7.78 (s, 1H), 7.50 (d, J=8.6Hz, 1H), 7.10-6.70 (m, 3H), 3.74 (s, 3H), 3.71 (s, 3H), 3.57 (s, 2H) .MS (EI): value of calculation 387.1 (MH ⁺), measured value 387.3 (MH ⁺).

5-[2-(2,5-dimethoxy-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) δ 10.22 (brs, 1H), 8.29 (d, J=1.6Hz, 1H), 7.90 (d, J=8.8Hz, 1H), 7.81 (s, 1H), 7.51 (dd, J=8.8,1.8Hz, 1H), 7.05-6.60 (m, 3H), 3.70 (s, 3H), 3.69 (s, 3H), 3.63 (s, 2H) .MS (EI): value of calculation 387.1 (MH ⁺), measured value 387.3 (MH ⁺).

5-(2-phenyl-butyrylamino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 10.26 (brs, 1H), 8.28 (s, 1H), 7.87 (d, J=8.8Hz, 1H), 7.77 (s, 1H), 7.60-7.10 (m, 6H), 3.58 (t, J=7.5Hz, 1H), 2.18-1.92 (m, 1H), and 1.82-1.58 (m, 1H), 0.86 (t, J=7.1Hz, 3H) .MS (EI): value of calculation 355.1 (MH ⁺), measured value 355.3 (MH ⁺).

5-[2-(4-chloro-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 361.0 (MH ⁺), measured value 361.2 (MH ⁺).

5-[2-(4-methoxyl group-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 357.1 (MH ⁺), measured value 357.2 (MH ⁺).

5-{[1-(4-chloro-phenyl)-Pentamethylene. carbonyl]-amino }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 415.1 (MH ⁺), measured value 415.2 (MH ⁺).

Sulfonamide

5-(naphthalene-2-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.Adopt and prepare 5-benzoyl-amido-benzo [b] thiophene-2-(N-hydroxyl) method that Methanamide is identical, 5-(naphthalene-2-sulfuryl amino)-benzo [b] thiophene-2-carboxylic acid ethyl ester (163.6mg, 0.40mmol) is converted into 5-(naphthalene-2-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide of light solid form. ¹H?NMR(DMSO-d ₆，200MHz)δ8.41(s，1H)，8.20-7.86(m，3H)，7.86-7.40(m，6H)，7.15(d，J＝8.4Hz，1H)。MS (EI): value of calculation 399.04 (MH ⁺), measured value 399.31 (MH ⁺).

5-(toluene-4-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆)δ10.30(br?s，1H)，9.25(br?s，1H)，7.90-7.70(m，2H)，7.68-7.50(m，3H)，7.27(d，J＝8.4Hz，2H)，7.12(dd，J＝8.4，1.6Hz，1H)，2.27(s，3H)。MS (EI): value of calculation (MH ⁺) 363.0, measured value (MH ⁺) 363.2.

5-benzenesulfonyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 7.85 (d, J=8.8Hz, 1H), 7.80-7.68 (m, 3H), 7.62-7.42 (m, 4H), 7.16 (dd, J=8.6,2.0Hz, 1H) .MS (EI): value of calculation 349.0 (MH ⁺), measured value 349.3 (MH ⁺).

5-phenyl methanesulfonamide acyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 7.95 (d, J=8.8Hz, 1H), 7.84 (s, 1H), 7.68 (s, 1H), 7.44-7.10 (m, 6H), 4.48 (s, 2H) .MS (EI): value of calculation 363.0 (MH ⁺), measured value 363.3 (MH ⁺).

5-(naphthalene-1-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 8.75 (d, J=8.4Hz, 1H), 8.30-7.94 (m, 3H), 7.88-7.38 (m, 6H), 7.08 (dd, J=8.6,2.2Hz, 1H) .MS (EI): value of calculation 399.0 (MH ⁺), measured value 399.2 (MH ⁺).

5-(xenyl-4-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 7.92-7.73 (m, 6H), 7.72-7.58 (m, 3H), 7.53-7.35 (m, 3H), 7.21 (dd, J=8.8,1.8Hz, 1H) .MS (EI): value of calculation 425.1 (MH ⁺), measured value 425.3 (MH ⁺).

Urea/carbamate

(2-hydroxyl amino formoxyl-benzo [b] thiophene-5-yl)-benzyq carbamate. ¹HNMR (DMSO-d ₆, 200MHz) δ 9.94 (s, 1H), 8.08 (s, 1H), 7.89 (d, J=8.8Hz, 1H), 7.82 (s, 1H), 7.60-7.10 (m, 6H), 5.17 (s, 2H) .MS (EI): value of calculation 343.1 (MH ⁺), measured value 343.3 (MH ⁺).

(2-hydroxyl amino formoxyl-benzo [b] thiophene-5-yl)-urethanes. ¹HNMR (DMSO-d ₆, 200MHz) δ 11.43 (brs, 1H), 9.78 (s, 1H), 9.28 (brs, 1H), 8.07 (d, J=1.8Hz, 1H), 7.88 (d, J=9.2Hz, 1H), 7.82 (s, 1H), 7.45 (dd, J=8.8,2.2Hz, 1H), 4.14 (q, J=7.0Hz, 2H), 1.25 (t, J=7.0Hz, 3H) .MS (EI): value of calculation 281.0 (MH ⁺), measured value 281.2 (MH ⁺).

5-(3-benzyl-urea groups)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 11.40 (brs, 1H), 9.25 (brs, 1H), 8.74 (s, 1H), 8.10 (s, 1H), 8.00-7.60 (m, 2H), 7.55-7.10 (m, 5H), 6.70 (brs, 1H), 4.31 (d, J=4.4Hz, 2H) .MS (EI): value of calculation 342.1 (MH ⁺), measured value 342.3 (MH ⁺).

Alkylated compound by 5-and the preparation of 6-aminobenzene bithiophene

5-dibenzyl amino-benzo [b] thiophene-2-carboxylic acid ethyl ester.5-aminobenzene bithiophene-2-Ethyl formate (74mg, 0.344mmol) is dissolved in the 1mL dry DMF, and (100 μ L, 0.84mmol) reaction is 16 hours with benzyl bromide a-bromotoluene in the presence of potassium carbonate (97mg, 0.70mmol) under 80 ℃, nitrogen atmosphere.Water and saturated sodium bicarbonate solution dilute this reactant mixture, use ethyl acetate extraction subsequently.Organic facies is through dried over sodium sulfate.Removal of solvent under reduced pressure and with crude product dried overnight under fine vacuum.Need not to be further purified and crude product can be used for next step.MS (EI): value of calculation 402 (MH ⁺), measured value 402 (MH ⁺).

5-dibenzyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.Rough ethyl ester is dissolved in the mixture of absolute methanol (1mL) and DMF (2mL).In this solution, add oxammonium hydrochloride.. (175mg, 2.52mmol), add subsequently 4.37M NaOMe solution (1mL, 4.37mmol).Under nitrogen atmosphere, this reactant was stirred 16 hours.In reactant, add entry (5mL), add 1M HCl pH is adjusted to 6.Collecting precipitation and by column chromatography (silica gel, hexane: EtOAc 80: 20-20: 80) purification, and isolate the oily product. ¹H-NMR (d ₆-DMSO): δ=11.27 (s, 1H), 9.17 (s, 1H), 7.68 (d, J=9.2Hz, 1H), 7.60 (s, 1H), 7.4-7.2 (m, 10H), 7.1-6.9 (m, 2H), 4.75 (s, 4H) .MS (EI): value of calculation 389 (MH ⁺), measured value 389 (MH ⁺).

6-dibenzyl amino-benzo [b] thiophene-2-carboxylic acid methyl ester.(29mg, 0.140mmol) is dissolved in the 1mL dry DMF with 6-aminobenzene bithiophene-2-methyl formate, and (41mg 0.30mmol) exists that (40 μ L 0.38mmol) reacted 16 hours with benzyl bromide a-bromotoluene down at potassium carbonate under 80 ℃, nitrogen atmosphere.This reactant mixture need not further separation and promptly can be used for next step.MS (EI): value of calculation 388 (MH ⁺), measured value 388 (MH ⁺).

6-dibenzyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.0.7mL 50% aqueous hydroxylamine solution is handled the DMF solution of rough methyl ester.Add some DMA (0.5mL) to prevent precipitation.At room temperature this reactant was stirred 40 hours, add azanol (0.7mL) subsequently again.Total reaction time is 5 days.Fine vacuum is removed and is desolvated, and the oily residue grinds with methanol.The insoluble product of solid collected by filtration form. ¹H-NMR (d ₆-DMSO):. δ=10.31 (s, 1H), 9.08 (s, 1H), 8.64 (s, 1H), 7.66 (s, 1H), 7.60 (d, J=8.8Hz, 1H), 7.4-7.2 (m, 10H), 6.88 (dd, J1=8.8Hz, J2=1.4Hz, 1H), 4.78 (s, 4H) .MS (EI): value of calculation 389 (MH ⁺), measured value 389 (MH ⁺).

5-(two-phenyl amino formoxyl methyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆) δ 10.74 (s, 1H), 10.34 (s, 1H), 10.21 (br s, 1H), 7.66-7.26 (m, 11H), 7.07 (t, J=6.6Hz, 2H), 6.49 (d, J=15.8Hz, 1H), 4.33 (s, 2H), 4.20 (s, 1H) .MS (EI): value of calculation (MH ⁺) 475.1, measured value (MH ⁺) 475.2.

6-(two-phenyl amino formoxyl methyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆) δ 10.88 (s, 2H), 9.10 (br s, 1H), 7.76-7.63 (m, 6H), 7.34 (t, J=7.0Hz, 4H), 7.07 (t, J=7.2Hz, 3H), 6.74 (d, J=9.08Hz, 1H), 4.44 (s, 4H) .MS (EI): value of calculation (MH ⁺) 475.1, measured value (MH ⁺) 475.2.

The preparation method of chloride substituent (chloride displacement) and the chemical compound that obtains by 6-aminobenzene bithiophene

6-(2-chloro-acetyl-amino)-benzo [b] thiophene-2-carboxylic acid methyl ester.Toward 6-amino-benzo [b] thiophene-2-carboxylic acid methyl ester (1.0g, 4.83mmol) and Na ₂CO ₃(2.05g, 19.3mmol) add in the mixture in DMF (10mL) chloracetyl chloride (460 μ L, 5.79mmoL).Stir after 18 hours, dilute this mixture, filter and concentrate with EtOAc.Residue passed through column chromatography (2: 8; EtOAc: purification hexane) obtains shallow white solid product.MS (EI): value of calculation (MH ⁺) 284.01, measured value (MH ⁺) 284.15.The impure part of also residual～50.5%.

Be used for the general experiment (by the acyl chlorides preparation) of acidylate 6-amino-benzothiophene

6-[2-(4-phenyl-Piperazine-1-yl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.In DMF (2mL) solution of 6-(2-chloro-acetyl-amino)-benzo [b] thiophene-2-carboxylic acid methyl ester (75mg, 0.26mmol), add amine (85.8mg, 0.52mmol).Reactant mixture is heated to 50 ℃.After 24 hours, in this solution, add NH ₂OH (50% aqueous solution, 1mL).Stir this solution up to the raw material total overall reaction.Except that after desolvating, add MeOH/H ₂O forms up to precipitation.Leach solid, obtain required amide. ¹H?NMR(DMSO-d ₆)δ11.32(br?s，1H)，9.97(s，1H)，9.28(br?s，1H)，8.39(s，1H)，7.85-7.72(m，2H)，7.55(d，J＝7.0Hz，1H)，7.24-7.10(m，2H)，6.94-6.84(m，2H)，6.72(t，J＝7.0Hz，1H)，3.24-3.05(m，5H)，2.70-2.58(m，4H)。MS (EI): value of calculation (MH ⁺) 411.14, measured value (MH ⁺) 411.33.

6-(2-3,4-dihydro-1H-isoquinolin-2-base-acetyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆)δ11.37(br?s，1H)，10.00(s，1H)，9.20(brs，1H)，8.41(s，1H)，7.85-7.75(m，2H)，7.56(d，J＝8.6Hz，1H)，7.15-6.99(m，4H)，3.71(s，2H)，3.35-3.15(m，2H)，2.92-2.72(m，4H)。MS (EI): value of calculation (MH ⁺) 382.1, measured value (MH ⁺) 382.3.

6-[2-(4-benzyl-piperidines-1-yl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (CDCl ₃) δ 11.32 (br s, 1H), 9.876 (s, 1H), 9.21 (br s, 1H), 8.37 (s, 1H), 7.87-7.74 (m, 2H), 7.52 (dd, 1H, J=8.2,1.8Hz), 7.30-7.05 (m, 5H), 3.07 (s, 2H), 2.88-2.74 (m, 2H), 2.54-2.44 (m, 2H), 2.14-1.94 (m, 2H), 1.60-1.20 (m, 5H) .MS (EI): value of calculation 424.1 (MH ⁺), measured value 424.4 (MH ⁺).

4-[(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-base carbamoyl)-methyl]-piperazine-1-benzyl formate. ¹H NMR (CDCl ₃) δ 11.28 (br s, 1H), 9.96 (s, 1H), 9.20 (br s, 1H), 8.37 (s, 1H), 7.87-7.72 (m, 2H), 7.52 (dd, 1H, J=8.2,1.8Hz), 7.40-7.14 (m, 5H), 5.04 (s, 2H), 3.43 (m, 4H), 3.28 (m, 4H), 3.16 (s, 2H) .MS (EI): value of calculation 469.1 (MH ⁺), measured value 469.3 (MH ⁺).

6-(2-dibenzyl amino-acetyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (CDCl ₃) δ 9.83 (s, 1H), 9.21 (br s, 1H), 8.35 (s, 1H), 7.83-7.71 (m, 2H), 7.45-7.15 (m, 11H), 3.74 (s, 4H), 3.15 (s, 2H) .MS (EI): value of calculation 446.1 (MH ⁺), measured value 446.3 (MH ⁺).

6-{2-[4-(3-methoxyl group-phenyl)-piperazine-1-yl]-acetyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (CDCl ₃) δ 11.38 (br s, 1H), 9.97 (s, 1H), 9.21 (brs, 1H), 8.39 (s, 1H), 7.87-7.75 (M, 2H), 7.56 (dd, 1H, J=8.0,1.8Hz), 7.07 (dd, 1H, J=8.0,7.9Hz), 6.49 (d, 1H, J=8.0Hz), 6.42 (s, 1H), 6.32 (d, 1H, J=8.0Hz), 3.67 (s, 3H), 3.20 (s, 2H), 3.15 (m, 4H), 2.63 (m, 4H) .MS (EI): value of calculation 441.1 (MH ⁺), measured value 441.3 (MH ⁺).

6-[2-(4-pyrimidine-2-base-piperazine-1-yl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (CDCl ₃) δ 11.38 (br s, 1H), 10.00 (s, 1H), 9.20 (br s, 1H), 8.39 (s, 1H), 8.32 (d, 2H, J=4.8Hz), and 7.85-7.75 (m, 2H), 7.56 (dd, 1H, J=8.0,1.8Hz), 6.58 (t, 1H, J=4.8Hz), 3.77 (m, 4H), 3.19 (s, 2H), 2.54 (m, 4H) .MS (EI): value of calculation 413.1 (MH ⁺), measured value 413.3 (MH ⁺).

6-{2-[4-(2-methoxyl group-phenyl)-piperazine-1-yl]-acetyl-amino }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (CDCl ₃) δ 11.38 (br s, 1H), 9.98 (s, 1H), 9.21 (brs, 1H), 8.40 (s, 1H), 7.88-7.74 (m, 2H), 7.56 (d, 1H, J=8.2Hz), and 6.94-6.79 (m, 4H), 3.73 (s, 3H), 3.19 (s, 2H), 3.00 (m, 4H), 2.65 (m, 4H) .MS (EI): value of calculation 441.1 (MH ⁺), measured value 441.2 (MH ⁺).

6-[2-(4-pyridine-2-base-piperazine-1-yl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (CDCl ₃) δ 11.39 (br s, 1H), 10.00 (s, 1H), 9.22 (br s, 1H), 8.40 (s, 1H), 8.07 (br d, 1H, J=2.0Hz), and 7.88-7.74 (m, 2H), 7.60-7.40 (m, 2H), 6.79 (d, 1H, J=8.3Hz), 6.61 (dd, 1H, J=7.0,5.2Hz), 3.53 (m, 4H), 3.20 (s, 2H), 2.59 (m, 4H) .MS (EI): value of calculation 412.1 (MH ⁺), measured value 412.3 (MH ⁺).

6-[2-(4-acetyl group-piperazine-1-yl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (CDCl ₃) δ 9.96 (s, 1H), 8.38 (s, 1H), 7.87-7.72 (m, 2H), 7.54 (d, 1H, J=8.0Hz), 3.45 (m, 4H), 3.17 (s, 2H), 2.46 (m, 4H), 1.95 (s, 3H) .MS (EI): value of calculation 377.1 (MH ⁺), measured value 377.3 (MH ⁺).

6-(2-piperidines-1-base-acetyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (CDCl ₃) δ 9.86 (s, 1H), 8.38 (s, 1H), 7.87-7.72 (m, 2H), 7.55 (d, 1H, J=8.0Hz), 3.07 (s, 2H), 2.45 (m, 4H), 1.55 (m, 4H), 1.39 (m, 2H) .MS (EI): value of calculation 334.1 (MH ⁺), measured value 334.3 (MH ⁺).

6-(2-morpholine-4-base-acetyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (CDCl ₃) δ 9.94 (s, 1H), 9.21 (br s, 1H), 8.38 (s, 1H), 7.87-7.72 (m, 2H), 7.54 (dd, 1H, J=8.0,1.8Hz), 3.61 (m, 4H), 3.13 (s, 2H), 2.48 (m, 4H) .MS (EI): value of calculation 336.1 (MH ⁺), measured value 336.2 (MH ⁺).

6-[2-(benzyl-phenethyl-amino)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (CDCl ₃) δ 11.32 (br s, 1H), 9.58 (s, 1H), 9.20 (br s, 1H), 8.18 (s, 1H), 7.83-7.71 (m, 2H), 7.45-7.05 (m, 11H), 3.78 (s, 2H), 3.15 (s, 2H), 2.85-2.60 (m, 4H) .MS (EI): value of calculation 460.1 (MH ⁺), measured value 460.3 (MH ⁺).

{ tert-butoxycarbonyl methyl-[(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-base carbamoyl)-methyl]-amino }-tert-butyl acetate. ¹H NMR (CDCl ₃) δ 10.38 (s, 1H), 9.19 (br s, 1H), 8.41 (s, 1H), 7.83-7.72 (m, 2H), 7.45 (d, 2H, J=8.0Hz), 3.49-3.45 (m, 4H), 3.15-3.11 (m, 2H), 1.38 (s, 18H) .MS (EI): value of calculation 494.1 (MH ⁺), measured value 494.3 (MH ⁺).

6-{2-[4-(2-chloro-phenyl)-piperazine-1-yl]-acetyl-amino }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (CDCl ₃) δ 11.31 (br s, 1H), 9.98 (s, 1H), 9.20 (br s, 1H), 8.40 (s, 1H), 7.88-7.76 (m, 2H), 7.56 (dd, 1H, J=8.2,1.8Hz), 7.36 (d, 1H, J=7.2Hz), 7.27 (dd, 1H, J=7.2,7.1Hz), 7.14 (d, 1H, J=7.2Hz), 7.00 (dd, 1H, J=7.2,7.1Hz), 3.22 (s, 2H), 3.02 (m, 4H), 2.69 (m, 4H) .MS (EI): value of calculation 445.1 (MH ⁺), measured value 445.2 (MH ⁺).

6-{2-[4-(3-chloro-phenyl)-piperazine-1-yl]-acetyl-amino }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (CDCl ₃) δ 9.98 (s, 1H), 9.20 (br s, 1H), 8.39 (s, 1H), and 7.88-7.76 (m, 2H), 7.56 (d, 1H, J=8.2Hz), 7.17 (dd, 1H, J=7.2,7.1Hz), 6.95-6.82 (m, 2H), 6.74 (d, 1H, J=7.2Hz) (s, 1H), 3.26 (m, 4H), 3.20 (s, 2H), 2.63 (m, 4H) .MS (EI): value of calculation 445.1 (MH ⁺), measured value 445.2 (MH ⁺).

4-[(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-base carbamoyl)-methyl]-[1,4] Diazesuberane-1-benzyl formate. ¹H NMR (CDCl ₃) δ 10.25 (br s, 1H), 9.88 (s, 1H), 8.38 (s, 1H), and 7.87-7.72 (m, 2H), 7.52 (d, 1H, J=8.0Hz), 7.32 (m, 5H), 5.04 (s, 2H), 3.55-3.33 (m, 4H), 3.29 (s, 2H), 2.76 (m, 2H), 2.69 (m, 2H), 1.77 (m, 2H) .MS (EI): value of calculation 483.1 (MH ⁺), measured value 483.3 (MH ⁺).

4-[(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-base carbamoyl)-methyl]-piperazine-1-Ethyl formate. ¹H NMR (CDCl ₃) δ 10.37 (br s, 1H), 9.94 (s, 1H), 8.37 (s, 1H), 7.87-7.72 (m, 2H), 7.54 (dd, 1H, J=8.0,1.8Hz), 4.02 (q, 2H, J=7.2Hz), 3.95 (m, 4H), 3.16 (s, 2H), 1.14 (t, 3H, J=7.2Hz) .MS (EI): value of calculation 407.1 (MH ⁺), measured value 407.3 (MH ⁺).

6-{2-[4-(4-methoxyl group-phenyl)-piperazine-1-yl]-acetyl-amino }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 441.1 (MH ⁺), measured value 441.2 (MH ⁺).

Chemical compound by the preparation of 6-carboxyl benzothiophene

Benzo [b] thiophene-2,6-dioctyl phthalate dimethyl ester.Toward 4-formoxyl-3-nitrobenzoic acid methyl ester (6.68g, 31.9mmol) and K ₂CO ₃(5.55g, 38.3mmol) slowly add in the mixture in DMF (70mL) methyl thioglycolate (2.91mL, 31.9mmol).This mixture was at room temperature stirred 1 hour, stirred 24 hours down at 50 ℃ subsequently.With the mixture impouring H that obtains ₂Also stir in the O/ ice and form up to precipitation.Leach green solid. ¹H NMR (DMSO-d ₆) δ 8.72 (s, 1H), 8.25 (s, 1H), 8.12 (d, J=8.0Hz), 7.95 (d, J=8.0Hz), 3.87 (s, 6H) .MS (EI): value of calculation (MH ⁺) 251.03, measured value (MH ⁺) 251.18.

Benzo [b] thiophene-2-carboxylic acid-6-methyl formate.Toward benzo [b] thiophene-2, add 1NNaOH (555 μ L) in THF/MeOH (2/2mL) solution of 6-dioctyl phthalate dimethyl ester (139mg, 0.56mmol).After 5 hours, use CH ₂Cl ₂Dilute this solution and with 5% citric acid acidify.The dry organic facies that merges is filtered, and concentrates, and obtains required acid, and this acid need not to be further purified and can use.MS (EI): value of calculation (MH ⁺) 237.01, measured value (MH ⁺) 237.13.

2-hydroxyl amino formoxyl-benzo [b] thiophene-6-methyl formate.Toward benzo [b] thiophene-2, add NH in DMA/MeOH (3/1mL) solution of 6-dioctyl phthalate dimethyl ester (115mg, 0.46mmol) ₂OH (50% aqueous solution, 1.5mL).Stirring gained solution shows up to the LC/MS analysis result and does not contain raw material.Except that after desolvating, add MeOH/H ₂O is up to forming precipitation.Leach solid, obtain required product. ¹H NMR (DMSO-d ₆) δ 11.57 (br s, 1H), 9.36 (br s, 1H), 8.67 (s, 1H), 8.05-7.87 (m, 3H), 3.87 (s, 3H) .MS (EI): value of calculation (MH ⁺) 252.07, measured value (MH ⁺) 252.20.

2-trityl oxygen base carbamoyl-benzo [b] thiophene-6-methyl formate.Toward benzo [b] thiophene-2-carboxylic acid-6-methyl formate (3.4g, 14.4mmol), HOBT (2.92g, 21.6mmol), the azanol of trityl as protecting group (4.76g, add in DMF 17.3mmol) (100mL) solution EDCI (4.14g, 21.6mmol).After 18 hours, remove and desolvate.Dilute residue and use H with EtOAc (200mL) ₂O (100mL) and saturated NaHCO ₃(100mL) washing.With the organic facies drying, filter, and concentrate.Form solid after adding methanol in the residue, leach light yellow solid and reuse MeOH washing, obtain the hydroxamic acid of required protection, this product need not to be further purified and can use. ¹H NMR (DMSO-d ₆) δ 11.37 (br s, 1H), 8.56 (br s, 1H), 8.01-7.85 (m, 3H), 7.79 (s, 1H), 7.45-7.18 (m, 15H), 3.85 (s, 3H) .MS (EI): value of calculation (MH ⁺) 494.1, measured value (MH ⁺), do not see parent peak.

2-trityl oxygen base carbamoyl-benzo [b] thiophene-6-formic acid.(4.12g adds 2N NaOH (16mL) in THF/MeOH 8.35mmol) (50/10mL) solution toward 2-trityl oxygen base carbamoyl-benzo [b] thiophene-6-methyl formate.1.5 after hour, add 5mL 3N NaOH again.After having spent 1 hour again, add 16mL 2N NaOH again and stir and spend the night.With EtOAc (100mL) and H ₂O (100mL) dilutes this solution, washs with EtOAc subsequently.Citric acid acidify water with 5% extracts with EtOAc subsequently.With the organic facies drying that merges, filter and concentrate, obtain required acid, this acid need not to be further purified and can use.MS (EI): value of calculation (M ^-) 478.1, measured value (M ^-) 478.6.

The general experiment of using 6-carboxyl benzothiophene to prepare amide

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-{N-[2-(1H-indole-2-yl)-ethyl] } Methanamide.

Toward 2-trityl oxygen base carbamoyl-benzo [b] thiophene-6-formic acid (130mg, 0.271mmol), HOBT (55.0g, CH 0.407mmol) ₂Cl ₂(3mL) add EDCI (78.0mg, 0.407mmol) in the solution.After 30 minutes, the solution that obtains is added to the CH of amine (56.5mg, 0.352mmol) ₂Cl ₂(1mL) in the solution.After 18 hours, add TFA/CH ₂Cl ₂(1/1; 0.5mL) solution, drip Et subsequently ₃SiH is up to color fade.Remove and desolvate.With EtOAc (2mL) and saturated NaHCO ₃(1.5mL) debris.Leach the solid that obtains and, obtain required hydroxamic acid with the EtOAc washing. ¹H NMR (CDCl ₃) δ 10.75 (br s, 1H), 8.57 (m, 1H), 8.24 (s, 1H), 7.72 (s, 2H), 7.77 (d, 1H, J=7.4Hz), 7.41 (s, 1H), 7.32-7.12 (m, 4H), 7.12-6.88 (m, 4H), 3.51 (m, 2H), 2.93 (m, 2H) .MS (EI): value of calculation 380.1 (MH ⁺), measured value 380.3 (MH ⁺).

Attention: in the preparation feedback of some amide, before removing trityl as protecting group, solid is leached.Sometimes also use MeOH to grind final hydroxamic acid.

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-(N-benzyl) Methanamide. ¹HNMR (CDCl ₃) δ 9.02 (br t, 1H, J=6.0Hz), 8.32 (s, 1H), 7.80-7.70 (m, 2H), 7.44 (m, 1H), 7.36-7.15 (m, 5H), 4.46 (d, 2H, J=6.0Hz) .MS (EI): value of calculation 327.1 (MH ⁺), measured value 327.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(pyridine-2-ylmethyl)] Methanamide. ¹HNMR (CDCl ₃) δ 9.15 (br t, 1H, J=5.2Hz), 8.52-8.40 (m, 2H), 7.80-7.80 (m, 2H), 7.78-7.64 (m, 2H), 7.36-7.18 (m, 2H), 4.55 (d, 2H, J=5.2Hz) .MS (EI): value of calculation 326..1 (MH ⁺), measured value 326.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(1-benzyl-piperidin-4-yl)] Methanamide. ¹H NMR (CDCl ₃) δ 8.42 (br s, 1H), 8.33 (d, 1H, J=8.1Hz), 7.96-7.76 (m, 3H), 7.35-7.10 (m, 5H), 3.73 (m, 1H), 3.43 (s, 2H), 2.78 (m, 2H), 1.99 (m, 2H), 1.75 (m, 2H), 1.57 (m, 2H) .MS (EI): value of calculation 410.1 (MH ⁺), measured value 410.3 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(2,2-diphenyl-ethyl)] Methanamide. ¹H NMR (CDCl ₃) δ 8.61 (m, 1H), 8.30 (s, 1H), 7.92-7.82 (m, 2H), 7.70 (d, 1H, J=8.0Hz), 7.36-7.06 (m, 10H), 4.41 (t, 1H, J=7.0Hz), 3.90 (m, 2H) .MS (EI): value of calculation 417.1 (MH ⁺), measured value 417.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[H-(1,2-diphenyl-ethyl)] Methanamide. ¹H NMR (CDCl ₃) δ 11.51 (br s, 1H), 9.28 (br s, 1H), 8.96 (d, 1H, J=8.2Hz), 8.40 (s, 1H), 7.92-7.82 (m, 2H), 7.77 (d, 1H, J=8.0Hz), 7.49-7.06 (m, 10H), 5.28 (m, 1H), 3.20-3.00 (m, 2H) .MS (EI): value of calculation 417.1 (MH ⁺), measured value 417.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-(N-benzhydryl) Methanamide. ¹HNMR (CDCl ₃) δ 11.51 (br s, 1H), 8.35 (d, 1H, J=8.2Hz), 8.59 (s, 1H), 8.02-7.85 (m, 3H), 7.49-7.06 (m, 10H), 6.40 (d, 1H, 8.2Hz) .MS (EI): value of calculation 403.1 (MH ⁺), measured value 403.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(1H-benzimidazolyl-2 radicals-ylmethyl)] Methanamide. ¹H NMR (CDCl ₃) δ 11.57 (br s, 1H), 9.54 (br t, 1H, J=4.8Hz), 8.59 (s, 1H), 8.12-7.88 (m, 3H), 7.71 (m, 2H), 7.42 (m, 2H), 4.90 (d, 2H, J=4.8Hz) .MS (EI): value of calculation 367.1 (MH ⁺), measured value 367.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(2-pyridine-2-base-ethyl)] Methanamide. ¹H NMR (CDCl ₃) δ 11.51 (br s, 1H), 8.80-8.59 (m, 2H), 8.39 (s, 1H), 8.15 (m, 1H), 7.92-7.82 (m, 2H), 7.77 (d, 1H, J=8.0Hz), 7.70-7.55 (m, 2H), 3.69 (m, 2H), 3.20-3.05 (m, 2H) .MS (EI): value of calculation 342.1 (MH ⁺), measured value 342.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(1,2,3,4-tetrahydrochysene-naphthalene-1-yl)] Methanamide. ¹H NMR (CDCl ₃) δ 11.51 (br s, 1H), 9.30 (br s, 1H), 8.84 (d, 1H, J=8.0Hz), 8.53 (s, 1H), 7.98-7.84 (m, 3H), 7.30-7.02 (m, 4H), 5.22 (m, 1H), 2.72 (m, 2H), 1.94 (m, 2H), 1.80 (m, 2H) .MS (EI): value of calculation 367.1 (MH ⁺), measured value 367.3 (MH ⁺).

6-(piperidines-1-carbonyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (CDCl ₃) δ 9.29 (br s, 1H), 8.01 (s, 1H), 7.98-7.82 (m, 2H), 7.35 (dd, 1H, J=8.0,1.2Hz), 3.69-3.12 (m, 4H), 1.52 (m, 6H) .MS (EI): value of calculation 305.1 (MH ⁺), measured value 305.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-(N-phenyl) Methanamide. ¹HNMR (CDCl ₃) δ 10.32 (br s, 1H), 8.57 (s, 1H), 8.04-7.82 (m, 3H), 7.77 (d, 2H, J=7.2Hz), 7.33 (dd, 2H, J=7.2,7.2Hz), 7.07 (t, 1H, 7.2Hz) .MS (EI): value of calculation 313.1 (MH ⁺), measured value 313.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(indane-1-yl)] Methanamide.MS (EI): value of calculation 353.1 (MH ⁺), measured value 353.2 (MH ⁺).

6-(4-phenyl-Piperazine-1-carbonyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (CDCl ₃) δ 11.48 (br s, 1H), 9.28 (br s, 1H), 8.11 (s, 1H), 8.01-7.86 (m, 2H), 7.42 (d, 1H, J=8.1Hz), 7.30-7.00 (m, 2H), 6.92 (m, 2H), 6.77 (m, 1H) .MS (EI): value of calculation 382.1 (MH ⁺), measured value 382.3 (MH ⁺).

6-[4-(4-chloro-phenyl)-piperazine-1-carbonyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 416.1 (MH ⁺), measured value 416.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(3-phenyl-propyl group)] Methanamide. ¹HNMR (CDCl ₃) δ 11.54 (br s, 1H), 9.29 (br s, 1H), 8.56 (br t, 1H, J=5.6Hz), 8.43 (s, 1H), and 7.98-7.86 (m, 2H), 7.83 (d, 1H, J=8.4Hz), 7.30-7.00 (m, 5H), 3.45-3.30 (m, 2H), 2.64-2.54 (m, 2H), 1.88-1.72 (m, 2H) .MS (EI): value of calculation 355.1 (MH ⁺), measured value 355.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-(N-phenethyl) Methanamide. ¹HNMR (CDCl ₃) δ 8.57 (br s, 1H), 8.28 (br s, 1H), 7.86-7.68 (m, 2H), 7.57 (s, 1H), 7.34-7.10 (m, 5H), 3.56-3.35 (m, 2H), 2.88-2.74 (m, 2H) .MS (EI): value of calculation 341.1 (MH ⁺), measured value 341.3 (MH ⁺).

6-(4-benzyl-piperidines-1-carbonyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (CDCl ₃) δ 11.45 (br s, 1H), 9.26 (br s, 1H), 8.01 (s, 1H), 7.98-7.82 (m, 2H), 7.68 (d, 1H, J=8.0Hz), 7.30-7.00 (m, 5H), 3.50-3.12 (m, 4H), 2.80 (m, 2H) 1.88 (m, 1H) 1.55 (m, 4H) .MS (EI): value of calculation 395.1 (MH ⁺), measured value 395.1 (MH ⁺).

6-(4-benzyl-piperazine-1-carbonyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (CDCl ₃) δ 11.52 (br s, 1H), 9.30 (br s, 1H), 8.10 (s, 1H), 7.96-7.76 (m, 2H), 7.60-7.25 (m, 5H), 3.43 (s, 2H), 3.30 (m, 4H), 3.00 (m, 4H), 1.75 (m, 2H), 1.57 (m, 2H) .MS (EI): value of calculation 396.1 (MH ⁺), measured value 396.1 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(quinoline-8-yl)] Methanamide.MS (EI): value of calculation 364.1 (MH ⁺), measured value 364.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(4-phenyl-thiazol-2-yl)] Methanamide.MS (EI): value of calculation 396.1 (MH ⁺), measured value 396.2 (MH ⁺).

Chemical compound by the preparation of 6-carboxyl benzothiophene

3-formoxyl-4-nitro-essence of Niobe.(24.99g, 128.1mmol) and N, (40.0mL, solution 300mmol) is 140 ℃ of heating 22.5 hours down for the dinethylformamide dimethyl acetal with 3-methyl-4-nitro-essence of Niobe.After being cooled to room temperature, concentrated reaction mixture with residue crystallization from MeOH, obtains the purple solid.This solid is dissolved in THF (500mL) and the water (500mL), add sodium metaperiodate (62.62g, 292.8mmol), after 2 hours, add once more subsequently sodium metaperiodate (15.6g, 72.9mmol).At room temperature restir is 1 hour, makes this reactant mixture also use EtOAc (2L) washing simultaneously by diatomite filtration.Use saturated NaHCO ₃(600mL) wash filtrate, organic layer is through Na ₂SO ₄Dry.After the filtration, concentrated filtrate and with residue by silicagel pad, use CH ₂Cl ₂/ hexane (75%-100%) washing.Concentrated filtrate is also dry, obtains the 3-formoxyl-4-nitro-essence of Niobe of yellow solid form.MS (EI): value of calculation 210.0 (MH ⁺), measured value 210.2 (MH ⁺).

Benzo [b] the thiophene-2-carboxylic acid tert-butyl ester-5-methyl formate.Under 0 ℃, (7.95g, (5.80mL is 102mmol) with other DMF (100mL) 102mmol) to add acetic acid in the suspension of dry DMF (200mL) toward sodium sulfide.At 0 ℃ this mixture was stirred 30 minutes, (14.6mL 102mmol), adds other DMF (50mL) subsequently to add chloroacetic acid tert-butyl ester.The mixture that obtains was stirred 30 minutes down at 0 ℃, at room temperature stirred subsequently 30 minutes.In this mixture, add K ₂CO ₃(16.4g is 119mmol) with 3-formoxyl-4-nitro-essence of Niobe (17.68g, DMF 84.55mmol) (30mL) solution.Under 55 ℃,, be cooled in room temperature and the impouring water (1.2L) the mixture heated that obtains 22 hours.The solid that filter to form, water (300mL) washing and in MeOH recrystallization, obtain benzo [b] the thiophene-2-carboxylic acid tert-butyl ester-5-methyl formate of light solid form.MS (EI): value of calculation 237.0 (M- ^tButyl+H ⁺), measured value 237.1 (M- ^tButyl+H ⁺).

Benzo [b] thiophene-2-carboxylic acid-5-methyl formate.At room temperature with benzo [b] the thiophene-2-carboxylic acid tert-butyl ester-5-methyl formate (3.018g, 10.32mmol) and the CH of TFA (20mL) ₂Cl ₂(50mL) solution stirring is 4 days.Concentrated reaction mixture is also dry under fine vacuum, obtains benzo [b] thiophene-2-carboxylic acid-5-methyl formate of light solid form.MS (EI): value of calculation 237.0 (MH ⁺), measured value 237.1 (MH ⁺).

2-trityl oxygen base carbamoyl-benzo [b] thiophene-5-methyl formate.At room temperature with benzo [b] thiophene-2-carboxylic acid-5-methyl formate (2.592g, 10.97mmol), O-trityl-azanol (3.020g, 10.97mmol), EDC (3.150g, 16.48mmol), HOBt (1.482g, 10.97mmol) and DIEA (4.80mL, anhydrous THF (100mL) solution stirring one week 27.6mmol) also concentrates.In residue, add MeOH (10ml) and water (100ml).Water (10mL) washs the slurry that obtains, and grinds 2-trityl oxygen base carbamoyl-benzo [b] thiophene-5-methyl formate that obtains light solid form with water (90mL).MS (EI): value of calculation 243.1 (M-benzothiophene part+H ⁺), measured value 243.2 (M-benzothiophene part+H ⁺).

2-(tetrahydrochysene-pyrans-2-base oxygen base carbamoyl)-benzo [b] thiophene-5-methyl formate.At room temperature with benzo [b] thiophene-2-carboxylic acid-5-methyl formate (191.3mg, 0.81mmol), O-(tetrahydrochysene-pyrans-2-yl)-azanol (93mg, 0.79mmol), EDC (231mg, 1.20mmol), HOBt (107mg, 0.79mmol) and DIEA (0.30mL, 2.2mmol) anhydrous THF (8mL) solution stirring 3 days, concentrate subsequently.In this residue, add MeOH (1mL), water (10mL) and Et ₂O (5mL).Stir after 2 hours water (2 * 3mL) and Et ₂The solid that O (5mL) washing forms, drying obtains 2-(tetrahydrochysene-pyrans-2-base oxygen base carbamoyl)-benzo [b] thiophene-5-methyl formate of light solid form.MS (EI): value of calculation 252.0 (M-THP+H ⁺), measured value 252.1 (M-THP+H ⁺).

2-(tetrahydrochysene-pyrans-2-base oxygen base carbamoyl)-benzo [b] thiophene-5-formic acid.At room temperature THF (2mL) solution and the 1M NaOH aqueous solution (4mL) with 2-(tetrahydrochysene-pyrans-2-base oxygen base carbamoyl)-benzo [b] thiophene-5-methyl formate (131.6mg, 0.39mmol) stirred 18 hours.After removing THF, be pH ≈ 3 with aqueous phase as acidified with HOAc.Leach the solid of formation, collect and drying, obtain 2-(tetrahydrochysene-pyrans-2-base oxygen base carbamoyl)-benzo [b] thiophene-5-formic acid of white solid form. ¹H?NMR(DMSO-d ₆，200MHz)δ12.04(brs，1H)，8.54(s，1H)，8.22-8.08(m，2H)，7.97(dd，J＝8.4，1.2Hz，1H)，5.01(s，1H)，4.18-3.94(m，1H)，3.68-3.46(m，2H)，1.88-1.40(m，6H)。MS (EI): value of calculation 322.1 (MH ⁺), measured value 322.2 (MH ⁺).

2-trityl oxygen base carbamoyl-benzo [b] thiophene-5-formic acid.At room temperature (4.439g, (50mL) solution of THF 8.99mmol) and 2M NaOH aqueous solution (50mL) stirred 6 days with 2-trityl oxygen base carbamoyl-benzo [b] thiophene-5-methyl formate.After removing THF, use HOAc/H ₂O (1: 1) acidify water is to pH ≈ 4.Leach the solid of formation, collect and drying, obtain 2-trityl oxygen base carbamoyl-benzo [b] thiophene-5-formic acid of white solid form. ¹H?NMR(DMSO-d ₆，200MHz)δ11.33(brs，1H)，8.47(s，1H)，8.10-7.80(m，3H)，7.56-7.14(m，15H)。MS (EI): value of calculation 243.1 (M-benzothiophene part+H ⁺), measured value 243.1 (M-benzothiophene part+H ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(2-methoxyl group-benzyl)] Methanamide.CH toward 2-trityl oxygen base carbamoyl-benzo [b] thiophene-5-formic acid (960mg, 2.00mmol) ₂Cl ₂(15mL) add EDC (575mg, 3.00mmol) and HOBt (320mg, 2.37mmol) in the solution.At room temperature this mixture was stirred 40 minutes, be divided into 10 equal portions subsequently.Subsequently equal portions are added 2-methoxyl group-benzylamine (35 μ L, CH 0.27mmol) ₂Cl ₂(0.5mL) in the solution.After at room temperature stirring is spent the night, concentrate this reactant mixture.Be suspended in residue among the MeOH (1mL) and add entry (10mL).Filter, collect and the dry solid that forms under fine vacuum.With the solid suspension that obtains in CH ₂Cl ₂(4mL) and add TFA (0.20mL), add Et subsequently ₃SiH takes off to the greatest extent up to yellow.At room temperature this mixture was stirred 20 minutes, form solid during this period.Add CH ₂Cl ₂/ hexane (1: 1,4mL) after, leach solid, use CH ₂Cl ₂/ hexane (1: 1,4 * 1mL) washings are also dry, obtain benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(2-methoxyl group-benzyl) of light solid form] Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ8.96(t，J＝5.4Hz，1H)，8.48(s，1H)，8.11(d，J＝8.4Hz，1H)，8.06-7.84(m，2H)，7.21(d，J＝7.2Hz，2H)，7.06-6.80(m，2H)，4.48(d，J＝5.8Hz，2H)，3.83(s，3H)。MS (EI): value of calculation 357.1 (MH ⁺), measured value 357.2 (MH ⁺).

Adopt preparation benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(2-methoxyl group-benzyl)] the following chemical compound of similar approach preparation of Methanamide.

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(3-methoxyl group-benzyl)] Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ9.13(t，J＝5.8Hz，1Hz，8.45(s，1H)，8.11(d，J＝8.4Hz，1H)，8.06-7.84(m，2H)，7.24(d，J＝7.6Hz，1H)，7.00-6.70(m，3H)，4.48(d，J＝6.0Hz，2H)，3.72(s，3H)。MS (EI): value of calculation 357.1 (MH ⁺), measured value 357.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(4-methoxyl group-benzyl)] Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ9.06(t，J＝5.8Hz，1H)，8.43(s，1H)，8.09(d，J＝8.4Hz，1H)，8.04-7.84(m，2H)，7.26(d，J＝8.8Hz，2H)，6.88(d，J＝8.8Hz，2H)，4.43(d，J＝5.8Hz，2H)，3.72(s，3H)。MS (EI): value of calculation 357.1 (MH ⁺), measured value 357.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(2-chloro-benzyl)] Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ9.16(t，J＝6.0Hz，1H)，8.48(s，1H)，8.13(d，J＝8.4Hz，1H)，8.06-7.84(m，2H)，7.54-7.18(m，4H)，4.58(d，J＝5.8Hz，2H)。MS (EI): value of calculation 361.0 (MH ⁺), measured value 361.1 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(3-chloro-benzyl)] Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ9.20(t，J＝6.0Hz，1Hz，8.46(s，1H)，8.12(d，J＝8.4Hz，1H)，8.20-7.84(m，2H)，7.46-7.24(m，4H)，4.51(d，J＝5.4Hz，2H)。MS (EI): value of calculation 361.0 (MH ⁺), measured value 361.1 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(4-chloro-benzyl)] Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ9.19(t，J＝5.0Hz，1H)，8.45(s，1H)，8.11(d，J＝8.8Hz，1H)，8.04-7.84(m，2H)，7.37(s，4H)，4.49(d，J＝5.8Hz，2H)。MS (EI): value of calculation 361.0 (MH ⁺), measured value 361.1 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(5-indane-1-yl)] Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ10.24(s，1H)，8.52(s，1H)，8.15(d，J＝8.6Hz，1H)，8.10-7.90(m，2H)，7.69(s，1H)，7.50(d，J＝8.0Hz，1H)，7.18(d，J＝8.2Hz，1H)，2.98-2.70(m，3H)，2.10-1.90(m，2H)。MS (EI): value of calculation 353.1 (MH ⁺), measured value 353.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-{N-[2-(1H-indol-3-yl)-ethyl] } Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) δ 10.80 (s, 1H), 8.73 (t, J=5.2Hz, 1H), 8.40 (s, 1H), 8.10 (d, J=8.4Hz, 1H), 7.99 (s, 1H), 7.91 (dd, J=8.4,1.6Hz, 1H), 7.59 (d, J=7.4Hz, 1H), 7.33 (d, J=7.6Hz, 1H), 7.19 (d, J=2.2Hz, 1H), 7.13-6.88 (m, 2H), 3.55 (t, J=7.0Hz, part stacked (partiallyoverlap) H ₂O, 2H), 2.97 (t, J=7.6Hz, 2H).MS (EI): value of calculation 380.1 (MH ⁺), measured value 380.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(3,3-diphenyl-propyl group)] Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ8.59(t，J＝4.8Hz，1H)，8.36(s，1H)，8.08(d，J＝8.4Hz，1H)，7.98(s，1H)，7.87(dd，J＝8.4，1.4Hz，1H)，7.50-7.10(m，10H)，4.05(t，J＝7.8Hz，1H)，3.40-3.04(m，2H)，2.42-2.20(m，2H)。MS (EI): value of calculation 431.1 (MH ⁺), measured value 431.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(4-phenyl-butyl)] Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ8.57(t，J＝5.0Hz，1H)，8.38(s，1H)，8.08(d，J＝8.6Hz，1H)，7.98(s，1H)，7.88(dd，J＝8.4，1.4Hz，1H)，7.40-7.02(m，5H)，3.48-3.16(m，2H)，2.60(t，J＝6.8Hz，2H)，1.80-1.38(m，4H)。MS (EI): value of calculation 369.1 (MH ⁺), measured value 369.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-(N-phenyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ11.61(brs，1H)，11.37(brs，1H)，9.36(brs，1H)，8.53(s，1H)，8.17(d，J＝8.4Hz，1H)，8.10-7.90(m，2H)，7.79(d，J＝7.4Hz，2H)，7.36(dd，J＝7.8，7.8Hz，2H)，7.10(dd，J＝7.8，7.8Hz，1H)。MS (EI): value of calculation 313.1 (MH ⁺), measured value 313.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-(N-phenethyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ8.90(t，J＝5.2Hz，1H)，8.56(s，1H)，8.28(d，J＝8.0Hz，1H)，8.18(s，1H)，8.07(dd，J＝8.4，1.4Hz，1H)，7.60-7.20(m，5H)，3.80-3.60(m，2H)，3.05(t，J＝7.0Hz，2H)。MS (EI): value of calculation 341.1 (MH ⁺), measured value 341.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-(N-benzyl) Methanamide.At room temperature with 2-(tetrahydrochysene-pyrans-2-base oxygen base carbamoyl)-benzo [b] thiophene-5-formic acid (53mg, 0.16mmol), benzylamine (25 μ L; 0.23mmol), EDC (50mg, 0.26mmol), HOBt (25mg, 0.18mmol) and DIEA (60 μ L, THF 0.34mmol) (3mL) solution stirring 5 days.Concentrated reaction mixture is dissolved in residue MeOH (0.5mL) subsequently, adds entry.The slurry that forms handles with MeOH and water is handled once again.After the drying, the solid that obtains is dissolved in CH ₂Cl ₂(3mL) and add TFA (75 μ L) and water (30 μ L).At room temperature this mixture is stirred and spend the night, form solid during this period.After adding hexane (6mL), with solid filtering, (2 * 3mL) washings are also dry, obtain benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-(N-benzyl) Methanamide of light solid, shaped with hexane. ¹H?NMR(DMSO-d6，200MHz)δ9.16(t，J＝6.0Hz，1H)，8.46(s，1H)，8.11(d，J＝8.8Hz，1H)，8.07-7.86(m，2H)，7.50-7.10(m，5H)，4.51(d，J＝5.8Hz，2H)。MS (EI): value of calculation 327.1 (MH ⁺), measured value 327.1 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(3-phenyl-propyl group)] Methanamide.Adopt the similar approach of preparation benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-(N-benzyl) Methanamide to prepare this title compound.MS (EI): value of calculation 355.1 (MH ⁺), measured value 355.2 (MH ⁺).

Benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-(N-couple-phenyl amino formoxyl methyl) Methanamide. ¹H NMR (DMSO-d ₆) δ 11.50 (s, 1H), 10.34 (s, 1H), 10.23 (s, 1H), 9.28 (s, 1H), 8.10 (d, J=8.2Hz, 1H), 7.96 (d, J=8.8Hz, 1H), 7.64 (d, J=8.2Hz, 2H), 7.56-7.44 (m, 3H), 7.38-7.26 (m, 4H), 7.07 (t, J=7.4Hz, 2H), 4.35 (s, 2H), 4.23 (s, 2H) .MS (EI): value of calculation (MH ⁺) 503.1, measured value (MH ⁺) 503.2.

Use the chemical compound of 5-formoxyl benzothiophene preparation

5-nitro-benzo [b] thiophene-2-carboxylic acid ethyl ester.(31.01g adds K in 330mL anhydrous DMF solution 167.1mmol) toward 2-chloro-5-nitro-benzaldehyde down at 0 ℃ ₂CO ₃(27.80g, 201.1mmol), slowly drip subsequently ethyl thioglycolate (18.5mL, 168.7mmol).0 ℃ down stir 20 minutes after, allow the mixture that obtains rise to room temperature and at room temperature stir and spend the night.Subsequently with in the reactant mixture impouring 1.5L water that obtains.Leach the solid of formation and use the 600mL water washing.After the drying, obtain 5-nitro-benzo [b] thiophene-2-carboxylic acid ethyl ester of light solid form.MS (EI): value of calculation 252.0 (MH ⁺), measured value 252.1 (MH ⁺).

5-amino-benzo [b] thiophene-2-carboxylic acid ethyl ester.At room temperature, 1 atmospheric H ₂Effect down, with 5-nitro-benzo [b] thiophene-2-carboxylic acid ethyl ester (10.52g, 41.89mmol) and the suspension hydrogenation of 10%Pd/C (1.1g) in the EtOH of 450mL 4 days.Reactant mixture is filtered, subsequently filtrate is concentrated and drying, obtain 5-amino-benzo [b] thiophene-2-carboxylic acid ethyl ester of green solid form.Adopt identical method to carry out parallel reaction with 10.61g 5-nitro-benzo [b] thiophene-2-carboxylic acid ethyl ester.Total obtains 18.37g5-amino-benzo [b] thiophene-2-carboxylic acid ethyl ester.MS (EI): value of calculation 222.0 (MH ⁺), measured value 222.2 (MH ⁺).

5-iodo-benzo [b] thiophene-2-carboxylic acid ethyl ester.(18.37g, 83.02mmol) (the 21mL concentrated hydrochloric acid is at 200mLH for middle adding HCl aqueous solution toward 5-amino-benzo [b] thiophene-2-carboxylic acid ethyl ester ₂Solution among the O 252mmol), is cooled to 0 ℃ with the mixture that obtains subsequently.Add NaNO ₂(6.02g is at 60mL H for solution ₂Solution among the O 87.25mmol), stirs this mixture 10 minutes under 0 ℃.(13.07g is at 60mL H slowly to add NaI solution ₂Solution among the O, 87.20mmol).Reactant mixture becomes and is difficult to stir in the process that adds NaI.Add the water that amounts to 300mL in batches.After adding, allow reactant rise to room temperature, and at room temperature stirred 2 hours.Use CH subsequently ₂Cl ₂(800mL) and water (100mL) dilute this mixture.Separate organic layer, with the saturated NaHCO of 200mL ₃The washing and through Na ₂SO ₄Dry.After the filtration, concentrated filtrate, residue filters through silicagel pad, with EtOAc/ hexane (0%-10%) washing.Subsequently filtrate is concentrated, residue is recrystallization in MeOH, obtains 5-iodo-benzo [b] the thiophene-2-carboxylic acid ethyl ester of light orange solid, shaped.MS (EI): value of calculation 332.9 (MH ⁺), measured value 333.1 (MH ⁺).

5-formoxyl-benzo [b] thiophene-2-carboxylic acid ethyl ester.((14.09g is 42.42mmol) in the solution 59.5mmol) slowly to add to 5-iodo-benzo [b] thiophene-2-carboxylic acid ethyl ester for the THF solution of 0.7M, 85mL with bromination isopropyl-magnesium solution under-40 ℃.Under-40 ℃, this mixture was stirred 2 hours, slowly add subsequently N-methyl-N-pyridine-2-base-Methanamide (7.65mL, 63.9mmol).After rising to room temperature, at room temperature restir is 2.5 hours.The HCl that slowly adds 250mL 1N in this mixture.Stir after 10 minutes, use CH ₂Cl ₂(800mL) diluted reaction mixture.Separate organic layer, with the saturated NaHCO of 200mL ₃The washing and through Na ₂SO ₄Dry.After the filtration, concentrated filtrate, residue is recrystallization in MeOH, obtains 5-formoxyl-benzo [b] thiophene-2-carboxylic acid ethyl ester of yellow solid shape. ¹H?NMR(CDCl ₃，200MHz)δ10.12(s，1H)，8.37(s，1H)，8.18(s，1H)，8.08-7.90(m，2H)，4.44(q，J＝7.2Hz，2H)，1.44(t，J＝7.4Hz，3H)。MS (EI): value of calculation 235.0 (MH ⁺), measured value 235.1 (MH ⁺).

5-[(3-methoxyl group-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.Toward 5-formoxyl-benzo [b] thiophene-2-carboxylic acid ethyl ester (85mg, 0.36mmol) and 3-methoxyl group-benzylamine (60 μ L; 0.46mmol) anhydrous dichloroethanes (5mL) solution in add sodium triacetoxy borohydride (230mg, 1.08mmol) and acetic acid (20 μ L, 0.35mmol).After reacting completely, add the saturated NaHCO of 4mL ₃Separate organic facies, use the 4mL water washing, concentrate subsequently.After the high vacuum dry, be dissolved in residue among the anhydrous MeOH (5mL) and add oxammonium hydrochloride. (95mg, 1.37mmol), add subsequently NaOMe solution (the MeOH solution of 4.37M, 0.60mL, 2.6mmol).At room temperature stir this mixture up to reacting completely.Concentrated reaction mixture also is dissolved in residue in the minimum water.With 2N HCl the solution that obtains is adjusted to pH ≈ 8.Leach the solid of formation, wash with water, collection is also passed through the rapid column chromatography purification, obtains the 5-[(3-methoxyl group-benzylamino of light yellow slurry form)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ7.94(d，J＝8.4Hz，1H)，7.88(s，1H)，7.85(s，1H)，7.44(dd，J＝8.4，1.4Hz，1H)，7.21(t，J＝7.6Hz，1H)，7.00-6.72(m，3H)，3.78(s，2H)，3.73(s，3H)，3.66(s，2H)。MS (EI): value of calculation 343.1 (MH ⁺), measured value 343.2 (MH ⁺).

Employing is similar to and prepares 5-[(3-methoxyl group-benzylamino)-methyl]-the following chemical compound of the method for benzo [b] thiophene-2-(N-hydroxyl) Methanamide preparation.

5-(benzylamino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.98-7.78(m，3H)，7.43(d，J＝8.0Hz，1H)，7.38-7.14(m，5H)，3.78(s，2H)，3.68(s，2H)。MS (EI): value of calculation 313.1 (MH ⁺), measured value 313.2 (MH ⁺).

5-phenyl amino methyl-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.93(d，J＝8.4Hz，1H)，7.83(s，2H)，7.42(d，J＝8.8Hz，1H)，7.14-6.88(m，2H)，6.70-6.40(m，3H)，6.29(t，J＝6.2Hz，1H)，4.36(d，J＝6.2Hz，2H)。MS (EI): value of calculation 299.1 (MH ⁺), measured value 299.2 (MH ⁺).

5-[(3-benzyl oxygen base-phenyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ7.94(d，J＝8.2Hz，1H)，7.84(s，2H)，7.50-7.20(m，16H)，6.91(t，J＝8.0Hz，1H)，6.40-6.10(m，4H)，4.95(s，2H)4.34(d，J＝5.8Hz，2H)。MS (EI): value of calculation 405.1 (MH ⁺), measured value 405.2 (MH ⁺).

5-[(4-methoxyl group-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.98(d，J＝8.4Hz，1H)，7.91(s，2H)，7.48(dd，J＝8.0，1.4Hz，1H)，7.31(t，J＝8.8Hz，2H)，6.90(d，J＝8.8Hz，2H)，3.91(s，2H)，3.76(s，2H)，3.73(s，3H)。MS (EI): value of calculation 343.1 (MH ⁺), measured value 343.2 (MH ⁺).

5-[(2-chloro-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.94(d，J＝8.4Hz，1H)，7.88(s，2H)，7.58(dd，J＝7.4，1.8Hz，1H)，7.51-7.20(m，4H)，3.85(s，2H)，3.77(s，2H)。MS (EI): value of calculation 347.0 (MH ⁺), measured value 347.1 (MH ⁺).

5-[(4-chloro-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.94(d，J＝8.4Hz，1H)，7.88(s，2H)，7.84(s，1H)，7.50-7.30(m，5H)，3.77(s，2H)，3.67(s，2H)。MS (EI): value of calculation 347.0 (MH ⁺), measured value 347.2 (MH ⁺).

5-[(benzhydryl-amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.93(d，J＝8.4Hz，1H)，7.87(s，1H)，7.80(s，1H)，7.50-7.12(m，11H)，4.77(s，1H)，3.71(s，2H)。MS (EI): value of calculation 389.1 (MH ⁺), measured value 389.2 (MH ⁺).

5-(phenethyl amino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.94(d，J＝8.4Hz，1H)，7.87(s，1H)，7.83(s，1H)，7.42(dd，J＝8.6，1.6Hz，1H)，7.32-7.10(m，5H)，3.88(s，2H)，2.76(s，4H)。MS (EI): value of calculation 327.1 (MH ⁺), measured value 327.2 (MH ⁺).

5-[(2,2-diphenyl-ethylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ7.90(d，J＝8.4Hz，1H)，7.84(s，1H)，7.74(s，1H)，7.40-7.10(m，11H)，4.15(t，J＝7.4Hz，1H)，3.82(s，2H)，3.11(d，J＝7.6Hz，2H)。MS (EI): value of calculation 403.1 (MH ⁺), measured value 403.3 (MH ⁺).

5-{[2-(3,4-couple-benzyl oxygen base-phenyl)-ethylamino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ7.97(d，J＝8.0Hz，1H)，7.89(s，2H)，7.52-7.22(m，12H)，7.00-6.88(m，2H)，6.70(dd，J＝8.4，2.0Hz，1H)，5.07(s，4H)，3.95(s，2H)，2.90-2.60(m，4H)。MS (EI): value of calculation 539.2 (MH ⁺), measured value 539.4 (MH ⁺).

5-[(3-phenyl-propyl group amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ8.06-7.84(m，3H)，7.51(dd，J＝8.4，1.4Hz，1H)，7.32-7.06(m，5H)，4.02(s，2H)，2.80-2.54(m，4H)，1.94-1.70(m，2H)。MS (EI): value of calculation 341.1 (MH ⁺), measured value 341.2 (MH ⁺).

5-[(3,3-diphenyl-propyl group amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ8.02-7.82(m，3H)，7.44(d，J＝8.4Hz，1H)，7.38-7.06(m，10H)，4.07(t，J＝8.0Hz，1H)，3.94(s，2H)，2.62-2.52(m，2H)，2.38-2.18(m，2H)。MS (EI): value of calculation 417.2 (MH ⁺), measured value 417.3 (MH ⁺).

5-[(4-phenyl-butyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.96(d，J＝8.6Hz，1H)，7.89(s，2H)，7.46(dd，J＝8.4，1.4Hz，1H)，7.32-7.08(m?5H)，3.90(s，2H)，2.69-2.43(m，4H)，1.68-1.40(m，4H)。MS (EI): value of calculation 355.1 (MH ⁺), measured value 355.3 (MH ⁺).

5-[(2-morpholine-4-base-ethylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ7.98(d，J＝8.4Hz，1H)，7.93(s，2H)，7.49(dd，J＝8.4，1.4Hz，1H)，3.96(s，2H)，3.55(t，J＝4.4Hz，4H)，2.72(t，J＝6.6Hz，2H)，2.46(t，J＝6.6Hz，2H)。MS (EI): value of calculation 336.1 (MH ⁺), measured value 336.3 (MH ⁺).

5-[(cyclohexyl methyl-amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.94(d，J＝8.4Hz，1H)，7.88(s，1H)，7.86(s，1H)，7.44(d，J＝8.0Hz，1H)，3.84(s，2H)，2.38(d，J＝6.6Hz，2H)，1.84-0.68(m，11H)。MS (EI): value of calculation 319.1 (MH ⁺), measured value 319.3 (MH ⁺).

5-[(2-methoxyl group-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ8.06-7.80(m，3H)，7.54-7.18(m，3H)，7.02-6.84(m，2H)，3.92(s，2H)，3.75(s，5H)。MS (EI): value of calculation 343.1 (MH ⁺), measured value 343.2 (MH ⁺).

5-[(3-chloro-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ8.00-7.78(m，3H)，7.50-7.38(m，2H)，7.36-7.20(m，3H)，3.78(s，2H)，3.69(s，2H)。MS (EI): value of calculation 347.0 (MH ⁺), measured value 347.2 (MH ⁺).

5-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ7.98(d，J＝8.4Hz，1H)，7.94-7.86(m，2H)，7.56-7.44(m，3H)，7.20-7.08(m，2H)，3.98(s，2H)，3.96(s，2H)。MS (EI): value of calculation 353.1 (MH ⁺), measured value 353.2 (MH ⁺).

5-{[(pyridine-2-ylmethyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ8.47(d，J＝3.4Hz，1H)，7.93(d，J＝8.0Hz，1H)，7.92-7.82(m，2H)，7.80-7.68(m，1H)，7.52-7.38(m，2H)，7.28-7.18(m，1H)，3.83(s，2H)，3.78(s，2H)。MS (EI): value of calculation 314.1 (MH ⁺), measured value 314.2 (MH ⁺).

5-{[2-(3,4-dimethoxy-phenyl)-ethylamino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ7.94(d，J＝8.0Hz，1H)，7.90-7.80(m，2H)，7.50-7.38(m，1H)，6.90-6.62(m，3H)，3.87(s，2H)，3.70(s，3H)，3.69(s，3H)，2.80-2.66(m，4H)。MS (EI): value of calculation 387.1 (MH ⁺), measured value 387.3 (MH ⁺).

5-{[2-(1H-indol-3-yl)-ethylamino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) δ 7.93 (d, J=8.4Hz, 1H), 7.86 (s, 2H), 7.54-7.40 (m, 2H), 7.31 (d, J=8.0Hz, 1H), 7.18-6.86 (m, 3H), 3.90 (s, 2H), 2.86 (s, 4H) .MS (EI): value of calculation 366.1 (MH ⁺), measured value 366.3 (MH ⁺).

5-[(1-benzyl-piperidin-4-yl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz, partial) δ 7.89 (d, J=8.2Hz, 1H), 7.82 (s, 2H), 7.46-7.16 (m, 6H), 3.81 (s, 2H), 2.40 (s, 2H) .MS (EI): value of calculation 396.2 (MH ⁺), measured value 396.3 (MH ⁺).

Use the chemical compound of 6-formoxyl benzothiophene preparation

Benzo [b] thiophene-2-carboxylic acid ethyl ester-6-methyl formate.With 4-formoxyl-3-nitro-essence of Niobe (15.22g, 72.78mmol), ethyl thioglycolate (8.70mL, 79.3mmol) and K ₂CO ₃(12.87g, 93.12mmol) mixture in the 140mL dry DMF is 50 ℃ of following heated overnight.After being cooled to room temperature, in the mixture of ice and water with this mixture impouring 1L, and the mixture that obtains stirred 40 minutes.Leach the solid of formation and use 70mL water washing 4 times.After the drying, obtain benzo [b] thiophene-2-carboxylic acid ethyl ester-6-methyl formate of light solid, shaped. ¹H?NMR(CDCl ₃，200MHz)δ8.56(s，1H)，8.09-7.97(m，2H)，7.88(d，J＝8.0Hz，1H)，4.40(q，J＝7.2Hz，2H)，3.95(s，3H)，1.40(t，J＝6.8Hz，3H)。MS (EI): value of calculation 265.0 (MH ⁺), measured value 265.0 (MH ⁺).

Benzo [b] thiophene-6-formic acid-2-Ethyl formate.With benzo [b] thiophene-2-carboxylic acid ethyl ester-6-methyl formate (14.90g, 56.38mmol) and LiI (37.96g, 283.6mmol) mixture in the 120mL anhydrous pyridine refluxed 3 hours.After being cooled to room temperature, with this mixture impouring with among the ice-cooled 2N HCl (800mL).Leach the solid of formation and use 100mL water washing 3 times.After the drying, in MeOH,, obtain benzo [b] thiophene-6-formic acid-2-Ethyl formate of light solid form with solid crystal. ¹H?NMR(DMSO-d ₆，200MHz)δ8.66(s，1H)，8.21(s，1H)，8.08(d，J＝8.4Hz，1H)，7.96(dd，J＝8.4，1.0Hz，1H)，4.34(q，J＝7.2Hz，2H)，1.40(t，J＝6.8Hz，3H)。MS (EI): value of calculation 251.0 (MH ⁺), measured value 251.1 (MH ⁺).

6-methylol-benzo [b] thiophene-2-carboxylic acid ethyl ester.(6.40g slowly adds BH among the anhydrous THF of 250mL 25.57mmol) toward benzo [b] thiophene-6-formic acid-2-Ethyl formate down at 0 ℃ ₃(the THF solution of 1.5M, 80.0mL, 120mmol).The mixture that obtains was stirred 30 minutes down at 0 ℃, at room temperature stir then and spend the night.After being cooled to 0 ℃, with this reactant mixture of 1N HCl (30mL) quencher.Add 120mL water and vacuum in addition and remove THF.Leach the solid of formation, with 2 * 20mL water washing.After the drying, obtain 6-methylol-benzo [b] thiophene-2-carboxylic acid ethyl ester of light solid form. ¹H?NMR(CDCl ₃，200MHz)δ8.00(s，1H)，7.88-7.76(m，2H)，7.36(d，J＝9.4Hz，1H)，4.80(s，2H)，4.38(q，J＝7.0Hz，2H)，2.00(brs，1H)，1.39(t，J＝7.0Hz，3H)。MS (EI): value of calculation 237.0 (MH ⁺), measured value 237.1 (MH ⁺).

6-formoxyl-benzo [b] thiophene-2-carboxylic acid ethyl ester.Toward 6-methylol-benzo [b] thiophene-2-carboxylic acid ethyl ester (2.651g, 110mL CH 11.22mmol) ₂Cl ₂Add MnO in the solution ₂(13.50g).Mixture was at room temperature stirred 30 minutes and filter by the Celite pad.Concentrated filtrate is also dry, obtains 6-formoxyl-benzo [b] thiophene-2-carboxylic acid ethyl ester of light solid form. ¹H?NMR(CDCl ₃，200MHz)δ10.09(s，1H)，8.34(s，1H)，8.07(s，1H)，7.97(d，J＝8.0Hz，2H)，7.88(dd，J＝8.4，1.4Hz，1H)，4.40(q，J＝7.0Hz，2H)，1.41(t，J＝7.0Hz，3H)。MS (EI): value of calculation 235.0 (MH ⁺), measured value 235.1 (MH ⁺).

2 ° of amine

Universal method:

6-(benzylamino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.Toward 6-formoxyl-benzo [b] thiophene-2-carboxylic acid ethyl ester (85mg, 0.36mmol) and benzylamine (51 μ L; 0.47mmol) anhydrous dichloroethanes (5mL) solution in add sodium triacetoxy borohydride (230mg, 1.08mmol) and acetic acid (20 μ L, 0.35mmol).After reacting completely, add the saturated NaHCO of 5mL ₃Separate organic layer, use the 5mL water washing, concentrate subsequently.After the high vacuum dry, residue is dissolved among the anhydrous MeOH (5mL), adds oxammonium hydrochloride. (95mg, 1.37mmol), add subsequently NaOMe solution (the MeOH solution of 4.37M, 0.60mL, 2.6mmol).This mixture is at room temperature stirred up to reacting completely.Concentrated reaction mixture also is dissolved in residue in the minimum water.With 2N HCl the solution that obtains is adjusted to pH ≈ 8.Filter the solid that forms, wash with water, collection is also used the rapid column chromatography purification, obtains 6-(benzylamino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide of light solid form. ¹HNMR(DMSO-d ₆，200MHz)δ7.94(d，J＝8.4Hz，1H)，7.88(s，1H)，7.85(s，1H)，7.44(dd，J＝8.4，1.4Hz，1H)，7.21(t，J＝7.6Hz，1H)，7.00-6.72(m，3H)，3.78(s，2H)，3.73(s，3H)，3.66(s，2H)。MS (EI): value of calculation 343.1 (MH ⁺), measured value 343.2 (MH ⁺). ¹H?NMR(DMSO-d ₆，200MHz)δ7.94(s，1H)，7.90-7.78(m，2H)，7.46-7.14(m，6H)，3.80(s，2H)，3.69(s，2H)。MS (EI): value of calculation 313.1 (MH ⁺), measured value 313.1 (MH ⁺).

Adopt the following chemical compound of similar approach preparation of preparation 6-(benzylamino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.

6-[(2-methoxyl group-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.95(s，1H)，7.90-7.78(m，2H)，7.46-7.30(m，2H)，7.28-7.149m，1H)，7.00-6.82(m，2H)，3.82(s，2H)，3.75(s，3H)，3.65(s，2H)。MS (EI): value of calculation 343.1 (MH ⁺), measured value 343.1 (MH ⁺).

6-[(3-methoxyl group-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.94(s，1H)，7.91-7.78(m，2H)，7.40(dd，J＝8.4，1.4Hz，1H)，7.21(t，J＝7.6Hz，1H)，6.97-6.84(m，2H)，6.82-6.72(m，1H)，3.79(s，2H)，3.73(s，3H)，3.66(s，2H)。MS (EI): value of calculation 343.1 (MH ⁺), measured value 343.1 (MH ⁺).

6-phenyl amino methyl-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ11.40(brs，1H)，9.25(brs，1H)，8.06-7.76(m，3H)，7.42(d，J＝8.4Hz，1H)，7.16-6.92(m，2H)，6.66-6.40(m，3H)，6.33(brs，1H)，4.37(d，J＝4.8Hz，2H)。MS (EI): value of calculation 299.1 (MH ⁺), measured value 299.1 (MH ⁺).

6-(phenethyl amino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.92-7.76(m，3H)，7.40-7.08(m，6H)，3.83(s，2H)，2.72(s，4H)。MS (EI): value of calculation 327.1 (MH ⁺), measured value 327.2 (MH ⁺).

6-[(3-phenyl-propyl group amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (part, DMSO-d ₆, 200MHz) δ 7.94-7.78 (m, 3H), 7.39 (d, J=8.4Hz, 1H), 7.30-7.06 (m, 5H), 3.81 (s, 2H), 2.60 (t, J=7.6Hz, 2H), 1.72 (dd, J=7.4,7.4Hz, 2H).MS (EI): value of calculation 341.1 (MH ⁺), measured value 341.1 (MH ⁺).

6-[(2-chloro-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.97(s，1H)，7.92-7.80(m，2H)，7.59(dd，J＝7.6，1.8Hz，1H)，7.48-7.18(m，4H)，3.85(s，2H)，3.76(s，2H)。MS (EI): value of calculation 347.0 (MH ⁺), measured value 347.1 (MH ⁺).

6-[(3-chloro-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.94(s，1H)，7.90-7.80(m，2H)，7.46-7.22(m，5H)，3.78(s，2H)，3.69(s，2H)。MS (EI): value of calculation 347.0 (MH ⁺), measured value 347.1 (MH ⁺).

6-[(4-chloro-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.94(s，1H)，7.90-7.80(m，2H)，7.44-7.30(m，5H)，3.78(s，2H)，3.67(s，2H)。MS (EI): value of calculation 347.0 (MH ⁺), measured value 347.1 (MH ⁺).

6-{[(benzo [1,3] dioxole-5-ylmethyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ7.93(s，1H)，7.90-7.80(m，2H)，7.40(dd，J＝8.0，1.6Hz，1H)，6.94(s，1H)，6.88-6.70(m，2H)，5.96(s，2H)，3.76(s，2H)，3.60(s，2H)。MS (EI): value of calculation 357.1 (MH ⁺), measured value 357.1 (MH ⁺).

6-(indane-1-base amino methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.98-7.76(m，3H)，7.41(d，J＝8.0，Hz，1H)，6.86(d，J＝8.2Hz，1H)，6.50-6.28(m，2H)，4.35(s，2H)，2.76-2.58(m，3H)，1.98-1.78(m，2H)。MS (EI): value of calculation 339.1 (MH ⁺), measured value 339.2 (MH ⁺).

6-[(9H-fluorenes-9-base is amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.94-7.66(m，7H)，7.44-7.26(m，5H)，4.99(s，1H)，3.41(s，2H)。MS (EI): value of calculation 387.1 (MH ⁺), measured value 387.2 (MH ⁺).

6-[(1,2-diphenyl-ethylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ7.85(s，1H)，7.76(d，J＝8.4Hz，1H)，7.63(s，1H)，7.40-7.00(m，11H)，4.08(t，J＝7.0Hz，1H)，3.82-3.42(m，3H)，2.84(d，J＝7.0Hz，2H)。MS (EI): value of calculation 403.1 (MH ⁺), measured value 403.2 (MH ⁺).

6-[(cyclohexyl methyl-amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ8.17(s，1H)，8.04-7.88(m，2H)，7.68-7.50(m，1H)，4.20(s，2H)，2.70(brs，2H)，1.88-1.46(m，6H)，1.25-0.72(m，5H)。MS (EI): value of calculation 319.1 (MH ⁺), measured value 319.2 (MH ⁺).

6-[(1,2,3,4-tetrahydrochysene-naphthalene-1-base is amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ8.00(s，1H)，7.92-7.76(m，2H)，7.48(dd，J＝8.0，1.0Hz，1H)，7.42-7.32(m，1H)，7.18-6.96(m，3H)，4.02-3.75(m，2H)，3.66(t，J＝5.2Hz，1H)，2.84-2.52(m，2H)，2.06-1.50(m，4H)。MS (EI): value of calculation 353.1 (MH ⁺), measured value 353.2 (MH ⁺).

6-{[2-(2-Methyl-1H-indole-3-yl)-ethylamino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ10.68(s，1H)，7.96-7.78(m，3H)，7.44-7.28(m，2H)，7.19(d，J＝7.0Hz，1H)，7.00-6.78(m，2H)，3.86(s，2H)，2.88-2.60(m，4H)，2.29(s，3H)。MS (EI): value of calculation 380.1 (MH ⁺), measured value 380.2 (MH ⁺).

6-{[(pyridine-2-ylmethyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ8.48(d，J＝4.0Hz，1H)，8.00-7.82(m，3H)，7.76(ddd，J＝8.2，8.2，1.8Hz，1H)，7.53-7.37(m，2H)，7.30-7.18(m，1H)，3.88(s，2H)，3.82(s，2H)。MS (EI): value of calculation 314.1 (MH ⁺), measured value 314.1 (MH ⁺).

6-[(1-benzyl-piperidin-4-yl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ7.96-7.78(m，3H)，7.40(dd，J＝8.0，1.4Hz，1H)，7.36-7.18(m，5H)，3.84(s，2H)，3.40(s，2H)，2.82-2.62(m，2H)，2.44-2.30(m，1H)，2.00-1.70(m，4H)，1.48-1.18(m，2H)。MS (EI): value of calculation 396.2 (MH ⁺), measured value 396.2 (MH ⁺).

6-[(4-methoxyl group-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ7.93(s，1H)，7.90-7.78(m，2H)，7.40(d，J＝8.0Hz，1H)，7.25(d，J＝8.6Hz，2H)，6.86(d，J＝8.8Hz，2H)，3.77(s，2H)，3.72(s，3H)，3.62(s，2H)。MS (EI): value of calculation 343.1 (MH ⁺), measured value 343.1 (MH ⁺).

6-{[2-(1H-indol-3-yl)-ethylamino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ7.94(s，1H)，7.91-7.78(m，2H)，7.52-7.36(m，2H)，7.31(d，J＝7.6Hz，1H)，7.16-6.84(m，3H)，3.92(s，2H)，2.86(s，4H)。MS (EI): value of calculation 366.1 (MH ⁺), measured value 366.1 (MH ⁺).

3 ° of amine

6-[(4-methoxyl group-benzylamino)-methyl]-benzo [b] thiophene-2-carboxylic acid ethyl ester.Toward 6-formoxyl-benzo [b] thiophene-2-carboxylic acid ethyl ester (1.05g; 4.48mmol) and 4-methoxyl group-benzylamine (0.76mL; 5.86mmol) anhydrous dichloroethanes (40mL) solution in add sodium triacetoxy borohydride (2.87g, 13.5mmol) and acetic acid (0.25mL, 4.4mmol).After reacting completely, with the CH of 60mL ₂Cl ₂With the saturated NaHCO of 40mL ₃Diluted reaction mixture.Separate organic layer, with 50mL water, the water washing of 50mL salt, with after Na ₂SO ₄Dry.After the filtration, filtrate is concentrated, residue uses the rapid column chromatography purification, obtains the 6-[(4-methoxyl group-benzylamino of white solid)-methyl]-benzo [b] thiophene-2-carboxylic acid ethyl ester.MS (EI): value of calculation 356.1 (MH ⁺), measured value 356.1 (MH ⁺).

6-{[cyclohexyl-(4-methoxyl group-benzyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.Toward 6-[(4-methoxyl group-benzylamino)-methyl]-benzo [b] thiophene-2-carboxylic acid ethyl ester (122mg, 0.34mmol) and Ketohexamethylene (46 μ L, 0.44mmol) anhydrous dichloroethanes (5mL) solution in add sodium triacetoxy borohydride (216mg, 1.02mmol) and acetic acid (20 μ L, 0.35mmol).After reacting completely, add the saturated NaHCO of 5mL ₃Separate organic layer, with 5mL water washing and concentrated.After under fine vacuum, concentrating, residue is dissolved in anhydrous MeOH (6mL), adds oxammonium hydrochloride. (90mg, 1.30mmol), add subsequently NaOMe solution (the MeOH solution of 4.37M, 0.57mL, 2.5mmol).This mixture is at room temperature stirred up to reacting completely.This reactant mixture is concentrated and residue is dissolved in minimum water.With 2N HCl this solution is adjusted to pH ≈ 8.Filter the solid that forms, wash with water, collection is also passed through the rapid column chromatography purification, obtains 6-{[cyclohexyl-(4-methoxyl group-benzyl)-amino of light brown solid form]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR(DMSO-d ₆，200MHz)δ11.35(brs，1H)，9.23(brs，1H)，7.90(s，1H)，7.87-7.74(m，2H)，7.40(d，J＝8.2Hz，1H)，7.23(d，J＝8.8Hz，2H)，6.83(d，J＝8.4Hz，2H)，3.69(s，3H)，3.67(s，2H)，3.51(s，2H)，2.46-2.24(m，1H)，1.92-0.86(m，10H)。MS (EI): value of calculation 425.2 (MH ⁺), measured value 425.1 (MH ⁺).

Adopt preparation 6-{[cyclohexyl-(4-methoxyl group-benzyl)-amino]-methyl }-the following chemical compound of similar approach preparation of benzo [b] thiophene-2-(N-hydroxyl) Methanamide.

6-{[(4-methoxyl group-benzyl)-(tetrahydrochysene-pyrans-4-yl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ11.42(brs，1H)，9.24(brs，1H)，7.92(s，1H)，7.90-7.76(m，2H)，7.40(d，J＝9.2Hz，1H)，7.24(d，J＝8.8Hz，2H)，6.84(d，J＝8.4Hz，2H)，3.74-3.64(m，5H)，3.54(s，2H)，3.94-3.78(m，2H)，3.14-3.00(m，2H)，2.80-2.54(m，1H)，1.78-1.46(m，4H)。MS (EI): value of calculation 427.2 (MH ⁺), measured value 427.1 (MH ⁺).

6-{[(2-hydroxyl-ethyl)-(4-methoxyl group-benzyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ11.43(brs，1H)，9.26(brs，1H)，7.96(s，1H)，7.90-7.78(m，2H)，7.41(d，J＝8.4Hz，1H)，7.27(d，J＝8.8Hz，2H)，6.87(d，J＝8.4Hz，2H)，4.39(t，J＝5.4Hz，1H)，3.71(s，3H)，3.67(s，2H)，3.58-3.38(m，6H)。MS (EI): value of calculation 387.1 (MH ⁺), measured value 387.1 (MH ⁺).

6-{[isopropyl-(4-methoxyl group-benzyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ7.92(s，1H)，7.88-7.76(m，2H)，7.41(dd，J＝8.4，1.6Hz，1H)，7.24(d，J＝8.8Hz，2H)，6.84(d，J＝8.8Hz，2H)，3.69(s，3H)，3.59(s，2H)，3.43(s，2H)，2.90-2.68(m，1H)，1.02(d，J＝6.6Hz，6H)。MS (EI): value of calculation 385.2 (MH ⁺), measured value 385.2 (MH ⁺).

6-{[(4-methoxyl group-benzyl)-methyl-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide. ¹H?NMR(DMSO-d ₆，200MHz)δ7.93(s，1H)，7.90-7.80(m，2H)，7.40(dd，J＝8.0，1.0Hz，1H)，7.26(d，J＝8.4Hz，2H)，6.88(d，J＝8.4Hz，2H)，3.72(s，3H)，3.57(s，2H)，3.44(s，2H)，2.05(s，3H)。MS (EI): value of calculation 357.1 (MH ⁺), measured value 357.2 (MH ⁺).

The amine of acidylate

6-(benzylamino-methyl)-benzo [b] thiophene-2-carboxylic acid ethyl ester.Adopt preparation 6-[(4-methoxyl group-benzylamino)-methyl]-similar approach of benzo [b] thiophene-2-carboxylic acid ethyl ester prepares title compound. ¹H?NMR(DMSO-d ₆，200MHz)δ8.13(s，1H)，7.98-7.86(m，2H)，7.44(dd，J＝8.0，1.0Hz，1H)，7.38-7.14(m，5H)，4.32(q，J＝7.0Hz，2H)，3.79(s，2H)，3.68(s，2H)，1.31(t，J＝6.8Hz，3H)。

6-[(acetyl group-benzyl-amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.At 0 ℃ of down past 6-(benzylamino)-methyl-benzo [b] thiophene-2-carboxylic acid ethyl ester (112mg, 0.34mmol), NMM (0.12mL, 1.09mmol) and anhydrous methylene chloride (5mL) solution of DMAP (10mg, 0.08mmol) in add acetic anhydride (48 μ L, 0.51mmol).Allow this reactant mixture rise to room temperature.After reacting completely, add the saturated NaHCO of 5mL ₃Separate organic layer, with 5mL water washing and concentrated.After the high vacuum dry, residue is dissolved in anhydrous MeOH (6mL), adds oxammonium hydrochloride. (90mg, 1.30mmol), add subsequently NaOMe solution (the MeOH solution of 4.37M, 0.57mL, 2.5mmol).This mixture is at room temperature stirred up to reacting completely.Concentrate this reactant mixture, residue is dissolved in minimum water.With 2NHCl the solution that obtains is acidified to pH ≈ 8.Leach the solid of formation, wash with water, collect and, obtain the 6-[(acetyl group-benzyl-amino of light solid form through the rapid column chromatography purification)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide (83.3mg, 69%). ¹HNMR(DMSO-d ₆，200MHz)δ11.47(brs，1H)，9.30(brs，1H)，7.98-7.74(m，3H)，7.44-7.10(m，6H)，4.65-4.40(m，4H)，2.12(s，3H)。MS (EI): value of calculation 355.1 (MH ⁺), measured value 355.2 (MH ⁺).

6-[(benzyl-mesyl-amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.Adopt preparation 6-[(acetyl group-benzyl-amino)-methyl]-similar approach of benzo [b] thiophene-2-(N-hydroxyl) Methanamide prepares title compound.When this title compound of preparation, use mesyl chloride to replace acetic anhydride. ¹H?NMR(DMSO-d ₆，200MHz)δ11.46(brs，1H)，9.29(brs，1H)，7.90-7.76(m，3H)，7.36-7.16(m，6H)，4.43(s，2H)，4.33(s，2H)，2.99(s，3H)。MS (EI): value of calculation 389.1 (M-H ^-), measured value 389.2 (M-H ^-).

Flow process 8

6-benzyl oxygen ylmethyl-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.At room temperature in 6-methylol-benzo [b] thiophene-2-carboxylic acid ethyl ester (103mg, 0.44mmol) solution, add NaH (60% dispersion liquid, 54mg, 1.35mmol).At room temperature the mixture that obtains was stirred 15 minutes, and the adding benzyl bromide a-bromotoluene (60 μ L, 0.50mmol).At room temperature restir is after 30 minutes, with this mixture impouring 1N HCl (3mL) and H ₂In the mixture of O (30mL), extract this solution with EtOAc (30mL).With 20mL salt water washing organic facies and through Na ₂SO ₄Dry.Filter the back concentrated filtrate, dry under fine vacuum, residue is dissolved among the anhydrous MeOH (7mL), add oxammonium hydrochloride. (116mg, 1.67mmol), add subsequently NaOMe solution (the MeOH solution of 4.37M, 0.74mL, 3.2mmol).At room temperature this mixture is stirred up to reacting completely.Concentrated reaction mixture is dissolved in 4mL water with residue.With 2N HCl the solution that obtains is acidified to pH ≈ 8.Leach the solid of formation, wash with water and drying, obtain 6-benzyl oxygen ylmethyl-benzo [b] thiophene-2-(N-hydroxyl) Methanamide of light orange solid form. ¹H?NMR(DMSO-d ₆，200MHz)δ7.96(s，1H)，7.92-7.81(m，2H)，7.42-7.20(m，6H)，4.64(s，2H)，4.55(s，2H)。MS (EI): value of calculation 314.1 (MH ⁺), measured value 314.1 (MH ⁺).

Contain other substituent chemical compounds

3-chloro-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.Employing is similar to the method for preparing 2-hydroxyl amino formoxyl-benzo [b] thiophene-6-methyl formate and carries out. ¹H (DMSO-d ₆) δ 11.23 (br s, 1H), 9.45 (br s, 1H), 8.15-8.02 (m, 1H), 7.90-7.80 (m, 1H), 7.63-7.50 (m, 2H) .MS (EI): value of calculation (MH ⁺) 228.03, measured value (MH ⁺) 228.17.

6-nitro-benzo [b] thiophene-2-(N-hydroxyl) Methanamide.Employing is similar to the method for preparing 2-hydroxyl amino formoxyl-benzo [b] thiophene-6-methyl formate and carries out.MS (EI): value of calculation (MH ⁺) 239.03, measured value (MH ⁺) 239.16.

The N-hydroxy-n '-(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-yl)-oxamides. ¹HNMR (DMSO-d ₆) δ 10.80 (br s, 1H), 8.47 (s, 1H), 7.90-7.70 (m, 3H), 6.37 (s, 1H) .MS (EI): value of calculation (MH ⁺) 296.1, measured value (MH ⁺) 296.2.

Thiophene

Chemical compound by the preparation of 5-phenyl thiophene

5-(4-carboxyl-phenyl)-thiophene-2-carboxylic acid ethyl ester.Under nitrogen atmosphere, 5-bromothiophene-2-Ethyl formate (318mg, 1.35mmol) and 4-carboxyl phenyl boric acid (203mg, 1.23mmol) are suspended in the 1mL water.Add tetrabutyl ammonium bromide (403mg, 1.25mmol), acid chloride (2mg, 0.009mmol) and potassium carbonate (422mg, 3.05mmol), under 70 ℃, this mixture was stirred 1 hour subsequently.By adding 1M HCl this solution is adjusted to pH 2, with the EtOAc solution extraction product of 10%MeOH.Dry organic facies is also removed and is desolvated.This solid grinds with ethyl acetate, obtains solid product. ¹H-NMR (CDCl ₃): δ=7.99 (d, J=8.6Hz, 2H), 7.88 (d, J=8.6Hz, 2H), 7.83 (d, J=4Hz, 1H), 7.49 (d, J=4Hz, 1H), 4.31 (q, J=7.4Hz, 2H), 1.31 (t, J=7.4Hz, 3H) .MS (EI): value of calculation 277 (MH ⁺), measured value 277 (MH ⁺).

5-(4-formoxyl-phenyl)-thiophene-2-carboxylic acid ethyl ester.Adopt the similar approach of preparation 5-(4-carboxyl-phenyl)-thiophene-2-carboxylic acid ethyl ester to prepare title compound.Product is with EtOAc: hexane is that 2: 1 mixture grinds, and separates and obtain solid. ¹NMR (CDCl ₃): δ=10.03 (s, 1H), 7.99 (m, 4H), 7.85 (d, J=4Hz, 1H), 7.80 (d, J=4Hz, 1H), 4.31 (q, J=7.4Hz, 2H), 1.31 (t, J=7.4Hz, 3H) .MS (EI): value of calculation 261 (MH ⁺), measured value 261 (MH ⁺).

5-(3-formoxyl-phenyl)-thiophene-2-carboxylic acid ethyl ester.Adopt the similar approach of preparation 5-(4-carboxyl-phenyl)-thiophene-2-carboxylic acid ethyl ester to prepare title compound.(silica gel, hexane: EtOAc 100: 0-100: 12) purification obtains white solid to crude product through chromatography. ¹NMR (CDCl ₃): δ=10.07 (s, 1H), 8.14 (m, 1H), 7.92-7.80 (m, 2H), 7.79 (d, J=4Hz, 1H), 7.60 (t, J=7.8Hz, 1H), 7.39 (d, 4H, 1H), 4.31 (q, J=7.4Hz, 2H), 1.31 (t, J=7.4Hz, 3H) .MS (EI): value of calculation 261 (MH ⁺), measured value 261 (MH ⁺).

The general experiment for preparing amine with (formoxyl-phenyl)-thiophene

N-alkyl-5-(3-amino methyl-phenyl)-thiophene-2-carboxylic acid ethyl ester.5-(3-formoxyl-phenyl)-thiophene-2-carboxylic acid ethyl ester (0.6mmo1) and primary amine (1.1 equivalent) were refluxed 4 hours in methanol.Add sodium triacetoxy borohydride (1.5 equivalent), under nitrogen atmosphere, solution at room temperature stirred and spend the night.Removal of solvent under reduced pressure is dissolved in residue in the dichloromethane, washs with saturated sodium bicarbonate solution.Dry organic facies is removed and is desolvated, and obtains the oily product equally, and this product need not further separation and promptly can be used for next step.

N, N-dialkyl group-5-(3-amino methyl-phenyl)-thiophene-2-carboxylic acid ethyl ester.To be dissolved in dichloroethanes by the secondary amine of the rapid preparation of previous step.In this solution, add acetaldehyde (1.5 equivalent) and sodium triacetoxy borohydride (2.5 equivalent).Under nitrogen atmosphere, the suspension that obtains at room temperature stirred and spend the night.Removal of solvent under reduced pressure is through this product of column chromatography purification (silica gel, hexane: EtOAc100: 0-70: 30).

N, N-dialkyl group-5-(3-amino methyl-phenyl)-thiophene-2-(N-hydroxyl) Methanamide.To be dissolved in the absolute methanol by the tertiary amine ethyl ester that previous step obtains suddenly.The absolute methanol solution that adds oxammonium hydrochloride. (5-10 equivalent) adds the methanol solution (1.8 equivalents are with respect to oxammonium hydrochloride .) of Feldalat NM subsequently.Form precipitation (NaCl) at once.At room temperature this reactant is stirred and spend the night.Removal of solvent under reduced pressure also is dissolved in the water residue once more.Add 1M HCl this solution that neutralizes.This crude product of isolated by filtration, or extract with EtOAc.Again through column chromatography or preparation thin layer chromatography (silica gel, the purification of hexane-EtOAc).

The 5-{3-[(dibenzyl amino)-methyl]-phenyl }-thiophene-2-(N-hydroxyl) Methanamide. ¹H-NMR (CD ₃OD): δ=7.70 (s, 1H), 7.56 (m, 1H), 7.45-7.20 (m, 13H), 3.56 (s, 2H), 3.55 (s, 4H) .MS (EI): value of calculation 429 (MH ⁺), measured value 429 (MH ⁺).

5-{3-[(benzyl-quinoline-3-ylmethyl-amino)-methyl]-phenyl }-thiophene-2-(N-hydroxyl) Methanamide. ¹H-NMR (d ₆-DMSO): δ=11.28 (s, 1H), 9.18 (m, 1H), 8.90 (d, J=1.8Hz, 1H), 8.29 (d, J=1.8Hz, 1H), 8.01-7.96 (m, 2H), 7.77-7.20 (m, 13H), 3.75 (s, 2H), 3.63 (s, 2H), 3.61 (s, 2H) .MS (EI): value of calculation 480 (MH ⁺), measured value 480 (MH ⁺).

5-[3-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-phenyl]-thiophene-2-(N-hydroxyl) Methanamide. ¹H-NMR (CD ₃OD, 200MHz): δ=7.75 (brs, 1H), 7.64-7.50 (m, 2H), 7.43-7.39 (m, 3H), 7.12-7.06 (m, 3H), 7.04-6.96 (m, 1H), 3.76 (s, 2H), 3.67 (s, 2H), 2.96-2.86 (m, 2H), 2.86-2.76 (m, 2H) .MS (ED: value of calculation 365 (MH ⁺), measured value 365 (MH ⁺).

5-[3-(4-phenyl-Piperazine-1-ylmethyl)-phenyl]-thiophene-2-(N-hydroxyl) Methanamide. ¹H-NMR (CD ₃OD, 200MHz): δ=8.64 (d, J=4.4Hz, 1H), 8.11 (d, J=8.8Hz, 1H), 7.95 (d, J=7.0Hz, 1H), 7.74-7.64 (m, 1H), 7.58-7.40 (m, 5H), 7.28-7.10 (m, 6H), 7.10-7.03 (m, 2H), 4.12 (s, 2H), 3.76 (s, 2H), 2.88 (br s, 4H) .MS (EI): value of calculation 394 (MH ⁺), measured value 394 (MH ⁺).

5-{3-[(benzyl-quinolyl-4 methyl-amino)-methyl]-phenyl }-thiophene-2-(N-hydroxyl) Methanamide. ¹H-NMR (CD ₃OD, 200MHz): δ=8.73 (d, J=4.8Hz, 1H), 8.16 (dd, J1=8.4Hz, J2=0.8Hz, 1H), 7.96 (d, J=9.2Hz, 1H), 7.78-7.62 (m, 3H), and 7.60-7.46 (m, 3H), 7.42-7.18 (m, 8H), 4.05 (s, 2H), 3.64 (s, 2H), 3.62 (s, 2H) .MS (EI): value of calculation 480 (MH ⁺), measured value 480 (MH ⁺).

5-{3-[(benzyl-phenethyl-amino)-methyl]-phenyl }-thiophene-2-(N-hydroxyl) Methanamide. ¹H-NMR (CD ₃OD, 200MHz): δ=7.60-7.45 (m, 3H), 7.31-7.00 (m, 13H), 3.62 (s, 2H), 3.61 (s, 2H), 2.80-2.72 (m, 2H), 2.72-2.60 (m, 2H) .MS (EI): value of calculation 443 (MH ⁺), measured value 443 (MH ⁺).

5-{3-[(pair-phenyl amino formoxyl methyl-amino)-methyl]-phenyl }-thiophene-2-(N-hydroxyl) Methanamide. ¹H-NMR (DMSO-d ₆, 200MHz): δ=11.25 (br s, 1H), 10.68 (s, 1H), 10.26 (s, 2H), 9.92 (s, 1H), 7.77 (br s, 1H), 7.61 (d, J=8.0Hz, 4H), 7.62-7.59 (m, 1H), 7.46-7.39 (m, 3H), 7.32 (t, J=8.0Hz, 1H), 7.34-7.30 (m, 1H), 7.05 (t, J=7.0Hz, 2H), 3.34 (s, 2H), 2.93 (s, 2H), 2.77 (s, 2H) .MS (EI): value of calculation 515 (MH ⁺), measured value 515 (MH ⁺).

5-{3-[(phenethyl-quinoline-3-ylmethyl-amino)-methyl]-phenyl }-thiophene-2-(N-hydroxyl) Methanamide. ¹H-NMR (DMSO-d ₆, 200MHz): δ=11.23 (brs, 1H), 9.18 (br s, 1H), 8.79 (d, J=1.8Hz, 1H), 8.13 (br s, 1H), 7.97 (d, J=8.0Hz, 1H), 7.87 (d, J=7.6Hz, 1H), 7.76-7.50 (m, 5H), 7.44 (d, J=3.6Hz, 1H), 7.42-6.98 (m, 7H), 3.83 (s, 2H), 3.75 (s, 2H), and 2.92-2.80 (m, 2H), 2.76-2.64 (m, 2H) .MS (EI): value of calculation 494 (MH ⁺), measured value 494 (MH ⁺).

5-{3-[(phenethyl-quinolyl-4 methyl-amino)-methyl]-phenyl }-thiophene-2-(N-hydroxyl) Methanamide. ¹H-NMR (CD ₃OD, 200MHz): δ=8.64 (d, J=4.4Hz, 1H), 8.11 (d, J=8.8Hz, 1H), 7.95 (d, J=7.0Hz, 1H), 7.69 (t, J=7.0Hz, 1H), and 7.59-7.42 (m, 5H), 7.29-7.02 (m, 8H), 4.11 (s, 2H), 3.76 (s, 2H), 2.87 (br s, 4H) .MS (EI): value of calculation 494 (MH ⁺), measured value 494 (MH ⁺).

5-(3-{[(3-phenyl-propyl group)-quinolyl-4 methyl-amino]-methyl }-phenyl)-thiophene-2-(N-hydroxyl) Methanamide. ¹H-NMR (DMSO-d ₆, 200MHz): δ=11.22 (br s, 1H), 9.18 (br s, 1H), 8.80 (d, J=4.4Hz, 1H), 8.25 (d, J=7.4Hz, 1H), 8.01 (d, J=7.4Hz, 1H), 7.78-7.54 (m, 5H), and 7.43-7.26 (m, 4H), 7.20-6.94 (m, 5H), 4.05 (s, 2H), 3.69 (s, 2H), 3.38-3.28 (m, 4H), 1.88-1.72 (m, 2H) .MS (EI): value of calculation 508 (MH ⁺), measured value 508 (MH ⁺).

5-(3-{[(3-phenyl-propyl group)-quinoline-3-ylmethyl-amino]-methyl }-phenyl)-thiophene-2-(N-hydroxyl) Methanamide. ¹H-NMR (DMSO-d ₆, 200MHz): δ=11.22 (br s, 1H), 9.18 (br s, 1H), 8.88 (d, J=2.2Hz, 1H), 8.22 (br s, 1H), 7.97 (t, J=8.8Hz, 2H), 7.76-7.30 (m, 8H), 7.16-6.98 (m, 5H), 3.78 (s, 2H), 3.67 (s, 2H), 2.60-2.40 (m, 4H), 1.90-1.74 (m, 2H) .MS (EI): value of calculation 508 (MH ⁺), measured value 508 (MH ⁺).

5-(3-{[benzyl-(3-phenyl-propyl group)-amino]-methyl }-phenyl)-thiophene-2-(N-hydroxyl) Methanamide. ¹H-NMR (DMSO-d ₆, 200MHz): δ=11.23 (br s, 1H), 9.17 (br s, 1H), and 7.68-7.56 (m, 3H), 7.48 (d, J=4.0Hz, 1H), 7.40-7.02 (m, 13H), 3.57 (s, 2H), 3.56 (s, 2H), 2.56-2.37 (m, 4H), 1.86-1.68 (m, 2H) .MS (EI): value of calculation 457 (MH ⁺), measured value 457 (MH ⁺).

The general experiment of using (carboxyl-phenyl)-thiophene to prepare amide

5-(4-alkyl-carbamoyl-phenyl)-thiophene-2-carboxylic acid ethyl ester.1: 1 anhydrous acetonitrile toward 5-(4-carboxyl-phenyl)-thiophene-2-carboxylic acid ethyl ester (0.26mmol): add aryl-or alkyl-amine (1.6 equivalent) in the DMF solution, add EDC (2 equivalent) subsequently.At room temperature, stirred 3 hours down at 40 ℃ subsequently this solution stirring 6 hours.Removal of solvent under reduced pressure is dissolved in residue EtOAc (20mL) and uses 1M HCl, saturated sodium bicarbonate and water washing.Organic facies is removed and is desolvated through dried over sodium sulfate, obtains the product of white solid form.

5-(4-alkyl-carbamoyl-phenyl)-thiophene-2-(N-hydroxyl) Methanamide.To be dissolved in by the carboxylic acid amide esters (amide ester) of above-mentioned prepared in reaction and also at room temperature use oxammonium hydrochloride. (7 equivalent) and NaOMe (1.8 equivalents are with respect to oxammonium hydrochloride .) processing to spend the night in the absolute methanol.Removal of solvent under reduced pressure is dissolved in the water residue.Add 1M HCl this solution that neutralizes, filter and collect product.Under the situation of needs, this product ground with dichloromethane be further purified this product.

5-(4-phenyl amino formoxyl-phenyl)-thiophene-2-(N-hydroxyl) Methanamide. ¹H-NMR (d ₆-DMSO): δ=10.15 (s, 1H), 8.05-7.60 (m, 8H), 7.36 (t, J=8.4Hz, 2H), 7.10 (t, J=7.2Hz, 1H), 3.56 (s, 2H), 3.55 (s, 4H) .MS (EI): value of calculation 339 (MH ⁺), measured value 339 (MH ⁺).

5-(4-benzylamino formoxyl-phenyl)-thiophene-2-(N-hydroxyl) Methanamide. ¹H-NMR (d ₆-DMSO)): δ=9.11 (m, 1H), 8.62 (s, 1H), 7.96 (d, J=8.4Hz, 2H), 7.80 (d, J=8.4Hz, 2H), 7.63 (s, 2H), 7.33-7.2 (m, 4H), 4.48 (d, J=6.2Hz, 2H) .MS (EI): value of calculation 353 (MH ⁺), measured value 353 (MH ⁺).

Chemical compound by the preparation of 5-alkylthrophene

5-(2-phenyl amino formoxyl-vinyl)-thiophene-2-(N-hydroxyl) Methanamide.Add in THF (5mL) solution of 5-(2-carboxyl-vinyl)-thiophene-2-carboxylic acid ethyl ester (80mg, 0.35mmol), HOBt (50mg, 0.37mmol) and EDC (105mg, 0.55mmol) aniline (40 μ L, 0.44mmol).At room temperature the mixture that obtains was stirred 2 days.After concentrating, in residue, add 1mL MeOH, add about 10mL water subsequently.After at room temperature stirring 2 hours, filter the solid that forms, collect and drying, and be directly used in next reaction.

In the solution of the solid that obtains by said method in the anhydrous MeOH of 5mL, add NH ₂OHHCl (73mg, 1.05mmol), add subsequently NaOMe solution (the MeOH solution of 4.37M, 0.44mL, 1.92mmol).After at room temperature stirring 20.5 hours, concentrate this reactant mixture.Subsequently residue is dissolved in and also uses 2N HCl acidified aqueous solution in the minimum water to pH ≈ 8.Filter the solid that forms,, collect and high vacuum dry, obtain 5-(2-phenyl amino formoxyl-vinyl)-thiophene-2-(N-hydroxyl) Methanamide of light brown solid form with 2mL water washing 2 times.MS (EI): value of calculation 289.06 (MH ⁺), measured value 289.18 (MH ⁺).

5-(2-phenyl amino formoxyl-ethyl)-thiophene-2-(N-hydroxyl) Methanamide.Use is similar to the two-step method of preparation 5-(2-phenyl amino formoxyl-vinyl)-thiophene-2-(N-hydroxyl) Methanamide; with 5-(2-carboxyl-ethyl)-thiophene-2-carboxylic acid ethyl ester (THF solution of 0.50M; 0.70mL, 0.35mmol) change into 5-(2-phenyl amino formoxyl-ethyl)-thiophene-2-(N-hydroxyl) Methanamide of light solid form.MS (EI): value of calculation 291.07 (MH ⁺), measured value 291.20 (MH ⁺).

Use is similar to the two-step method of preparation 5-(2-phenyl amino formoxyl-vinyl)-thiophene-2-(N-hydroxyl) Methanamide, following various thiophene-2-(N-hydroxyl) Methanamide of preparation.

5-(2-benzylamino formoxyl-vinyl)-thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 11.31 (brs, 1H), 9.23 (brs, 1H), 8.68 (t, J=5.7Hz, 1H), 7.72-7.08 (m, 8H), 6.52 (d, J=15.4Hz, 1H), 4.38 (d, J=5.6Hz, 2H) .MS (EI): value of calculation 303.1 (MH ⁺), measured value 303.2 (MH ⁺).

5-(2-phenethyl carbamoyl-vinyl)-thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 11.32 (brs, 1H), 9.21 (brs, 1H), 8.26 (t, J=5.5Hz, 1H), 7.62-7.44 (m, 2H), 7.40-7.08 (m, 6H), 6.44 (d, J=15.4Hz, 1H), 3.41 (t, J=7.3Hz, 2H) 2.75 (t, J=7.3Hz, 2H) .MS (EI): value of calculation 317.1 (MH ⁺), measured value 317.2 (MH ⁺).

5-[2-(3-phenyl-propyl group carbamoyl)-vinyl]-thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) δ 11.29 (brs, 1H), 9.22 (brs, 1H), 8.22 (t, J=5.2Hz, 1H), 7.64-7.44 (m, 2H), and 7.40-7.06 (m, 6H), 6.46 (d, J=15.4Hz, 1H), 3.16 (td, J=6.6,5.8Hz, 2H) 2.60 (t, J=7.7Hz, 2H), 1.73 (tt, J=7.3,7.3Hz, 2H) .MS (EI): value of calculation 331.1 (MH ⁺), measured value 331.3 (MH ⁺).

5-[2-(cyclohexyl methyl-carbamoyl)-vinyl]-thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) δ 11.26 (brs, 1H), 9.20 (brs, 1H), 8.13 (t, J=5.5Hz, 1H), 7.64-7.40 (m, 2H), 7.33 (d, J=4.0,1H), 6.48 (d, J=15.8Hz, 1H), 3.00 (dd, J=6.3,6.3Hz, 2H), 1.94-0.68 (m, 11H) .MS (EI): value of calculation 309.1 (MH ⁺), measured value 309.3 (MH ⁺).

5-(2-cyclohexyl carboxyamide base-vinyl)-thiophene-2-(N-hydroxyl) Methanamide. ¹HNMR (DMSO-d ₆, 200MHz) δ 8.05 (d, J=7.6Hz, 1H), 7.64-7.40 (m, 2H), 7.33 (d, J=4.2,1H), 6.45 (d, J=15.8Hz, 1H), 3.60 (brs, 1H), 2.05-0.90 (m, 10H) .MS (EI): value of calculation 295.1 (MH ⁺), measured value 295.2 (MH ⁺).

5-[2-(2,2-diphenyl-ethylamino formoxyl)-vinyl]-thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 393.1 (MH ⁺), measured value 393.3 (MH ⁺).

5-[2-(3-benzyl oxygen base-phenyl amino formoxyl)-vinyl]-thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 395.1 (MH ⁺), measured value 395.3 (MH ⁺).

5-(2-benzylamino formoxyl-ethyl)-thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 305.1 (MH ⁺), measured value 305.2 (MH ⁺).

5-(2-phenethyl carbamoyl-ethyl)-thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 319.1 (MH ⁺), measured value 319.3 (MH ⁺).

5-[2-(3-phenyl-propyl group carbamoyl)-ethyl]-thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 333.1 (MH ⁺), measured value 333.3 (MH ⁺).

5-[2-(2,2-diphenyl-ethylamino formoxyl)-ethyl]-thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) δ 7.97 (t, J=4.9Hz, 1H), 7.50-6.94 (m, 11H), 6.71 (d, J=3.6Hz, 1H), 4.14 (t, J=7.7Hz, 1H), 3.68 (dd, J=7.1,5.7Hz, 2H), 2.92 (t, J=7.2Hz, 2H), 2.32 (t, J=7.1Hz, 2H) .MS (EI): value of calculation 395.1 (mH ⁺), measured value 395.3 (MH ⁺).

5-(2-cyclohexyl carboxyamide base-ethyl)-thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 297.1 (MH ⁺), measured value 297.3 (MH ⁺).

Chemical compound by the preparation of 5-aminothiophene

5-phenyl acetyl amino-thiophene-2-(N-hydroxyl) Methanamide.In 5-phenyl acetyl amino-thiophene-2-carboxylic acid methyl ester (92.7mg, 0.34mmol), add NH ₂OHHCl (110.0mg, 1.58mmol) and the anhydrous MeOH of 5mL.Adding NaOMe solution (the MeOH solution of 4.37M, 0.75mL, 3.28mmol).The mixture that obtains was stirred 6 hours down at 50 ℃, at room temperature stirred 14 hours, stirred 3 days down at 50 ℃ once more, subsequently restir 2 days at room temperature.Add 5mL water, this mixture was at room temperature stirred 3 days.Add subsequently NaOMe solution (the MeOH solution of 4.37M, 0.75mL, 3.28mmol), at room temperature with the mixture restir that obtains 3 days.After reacting completely, remove MeOH, water layer is acidified to pH ≈ 2 with the 2N aqueous hydrochloric acid solution.After 15mL EtOAc extracting twice, concentrate the organic layer that merges, dry under fine vacuum.Subsequently residue is dissolved in the 6mL dry DMF, this mixture is cooled to 0 ℃.Add diisopropylethylamine (0.20mL, 1.15mmol) and HBTU (210.7mg, 0.56mmol).Stirring is after 1 hour down at 0 ℃, and at room temperature restir is 1 hour, adds 1.3mL 50%NH ₂The OH aqueous solution at room temperature stirs this mixture and to spend the night.After concentrating under fine vacuum, the residue that obtains obtains 5-phenyl acetyl amino-thiophene-2-(N-hydroxyl) Methanamide of light solid form through rapid column chromatography (the 70%EtOAc/ hexane is used EtOAc subsequently, uses 10%MeOH/EtOAc subsequently) purification. ¹HNMR(DMSO-d ₆，200MHz)δ7.55-7.15(m，6H)，6.64(d，J＝4.0Hz，1H)，3.68(s，2H)。MS (EI): value of calculation 277.31 (MH ⁺), measured value 277.25 (MH ⁺).

5-benzenesulfonyl amino-thiophene-2-(N-hydroxyl) Methanamide.Adopt the same procedure of preparation 5-phenyl acetyl amino-thiophene-2-(N-hydroxyl) Methanamide, 5-benzenesulfonyl amino-thiophene-2-carboxylic acid methyl ester (110.0mg, 0.37mmol) is converted into 5-benzenesulfonyl amino-thiophene-2-(N-hydroxyl) Methanamide of light green color solid form.MS (EI): value of calculation 299.01 (MH ⁺), measured value 299.13 (MH ⁺).

Adopt the similar approach of preparation 5-phenyl acetyl amino-thiophene-2-(N-hydroxyl) Methanamide, following various thiophene-2-(N-hydroxyl) Methanamide of preparation.

5-benzoyl-amido-thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) δ 8.10-7.84 (m, 2H), 7.74-7.26 (m, 4H), 6.90 (d, J=4.0Hz, 1H) .MS (EI): value of calculation 263.0 (MH ⁺), measured value 263.2 (MH ⁺).

5-[(naphthalene-1-carbonyl)-amino]-thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) δ 8.54-8.14 (m, 3H), 8.10-7.54 (m, 5H), 7.00 (d, J=4.4Hz, 1H) .MS (EI): value of calculation 313.1 (MH ⁺), measured value 313.3 (MH ⁺).

5-[(naphthalene-2-carbonyl)-amino]-thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) δ 8.64 (s, 1H), 8.24-7.90 (m, 4H), 7.74-7.40 (m, 3H), 6.93 (d, J=4.0Hz, 1H) .MS (EI): value of calculation 313.1 (MH ⁺), measured value 313.3 (MH ⁺).

5-phenyl methanesulfonamide acyl amino-thiophene-2-(N-hydroxyl) Methanamide.MS (EI): value of calculation 313.0 (MH ⁺), measured value 313.2 (MH ⁺).

5-(naphthalene-2-sulfuryl amino)-thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) δ 8.41 (s, 1H), 8.22-7.92 (m, 3H), 7.84-7.52 (m, 3H), 7.25 (d, J=3.8Hz, 1H), 6.47 (d, J=3.6Hz, 1H) .MS (EI): value of calculation 349.0 (MH ⁺), measured value 349.2 (MH ⁺).

5-(naphthalene-1-sulfuryl amino)-thiophene-2-(N-hydroxyl) Methanamide. ¹H NMR (DMSO-d ₆, 200MHz) δ 8.65 (d, J=8.4Hz, 1H),, 1H), 8.32-8.02 (m, 3H), 7.84-7.52 (m, 4H), 6.41 (d, J=4.0Hz, 1H) .MS (EI): value of calculation 349.0 (MH ⁺), measured value 349.2 (MH ⁺).

Embodiment 2-new compound is to the inhibitory action of HDAC

HDAC1-flag form (Flag) test:

Adopt external deacetylated measurements determination new compound inhibition of histone deacetylase, the ability of hypotype 1 (HDAC1).The enzyme source that is used for this test is to derive from the epitope tagged people HDAC1 that immune purification of stable is expressed mammalian cell.Substrate by the commodity that comprise acetylizad lysine side-chain form (BIOMOL Research Laboratories, Inc., PlymouthMeeting, PA).Thereby by with the HDAC1 complex incubation of purification with substrate deacetylated after, produce the fluorogen that matches with deacetylated level.The concentration of substrate that uses in the enzyme preparation is Km, and the concentration that increases new compound is carried out deacetylated test, determines to suppress 50% the needed compound concentration of deacetylated reaction (IC50) with sxemiquantitative ground.

The result:

Measured the IC of each chemical compound of the present invention according to the method described above ₅₀Value.All chemical compounds all can suppress 50% deacetylated reaction being lower than under the concentration of about 5000nm.Several compounds can be in the deacetylated reaction that is lower than inhibition 50% under the concentration of about 1000nm.Several compounds can be in the deacetylated reaction that is lower than inhibition 50% under the concentration of about 500nm.Several compounds can be in the deacetylated reaction that is lower than inhibition 50% under the concentration of about 100nm.Several compounds can be in the deacetylated reaction that is lower than inhibition 50% under the concentration of about 20nm.Several compounds can suppress 50% deacetylated reaction under the concentration of about 15-20nm.Several compounds can suppress 50% deacetylated reaction under the concentration of about 10-15nm.Several compounds can suppress 50% deacetylated reaction under the concentration of about 5-10nm.Several compounds can be in the deacetylated reaction that is lower than inhibition 50% under the concentration of about 5nm.

Following table 1 expression is selected to comprise the specified benzothiophene skeleton of the present invention and according to the chemical constitution and the HDAC enzyme test result of the synthetic new compound of method of the present invention.

Table 1

Following table 2 expression is selected to comprise the specified thiophene skeleton of the present invention and according to the chemical constitution and the HDAC enzyme test result of the synthetic new compound of method of the present invention.

Table 2

HDAC inhibitory action in the embodiment 3-cell line

The MTS test

Test new compound of the present invention and suppress the ability that the murine erythroleukemia cell is a SC9 propagation.

The MTS test, be called Cell Titer 96Aqueous One Solution CellProliferation Assay (96 porocyte titer plate list aqueous solution cell proliferating determining method) again, the colorimetric method of analyzing for the viable count that is used for measuring propagation, cytotoxicity or chemosensitivity.MTS reagent contains novel tetrazolium  chemical compound [3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxyl methoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium , inner salt] and electronic coupling reagent (azophenlyene ethyl-sulfate; PES).With murine erythroleukemia cell (SC-9) and carrier or increase the chemical compound incubation 48 hours of concentration.Come quantitative cell proliferation by the following method: in culture hole, directly add a small amount of MTS reagent, incubation 1-4 hour, subsequently with 96 orifice plate readers record 490nM place trap.The first  product amount of measuring by 490nM place trap directly and the living cells number in the culture medium proportional.

The result

The MTS test result based on the SC9-cell of selected one group of new compound is shown that described chemical compound can suppress cell proliferation being lower than under the concentration of 1000nm.Several compounds can suppress cell proliferation under the concentration of about 500-1000nm.Several other chemical compounds can suppress cell proliferation under the concentration of about 100-500nm.Several other chemical compounds can suppress cell proliferation being lower than under the concentration of 100nm.Several other chemical compounds can suppress cell proliferation under the concentration of about 50-100nm.Several other chemical compounds can suppress cell proliferation being lower than under the concentration of 50nm.Several other chemical compounds can suppress cell proliferation under the concentration of about 50-100nm.Several other chemical compounds can suppress cell proliferation being lower than under the concentration of 10nm.Several other chemical compounds can suppress cell proliferation under the concentration of about 1-10nm.

The MTS test based on the SC9-cell to selected one group of new compound is summarized in following table 3.

Table 3

Although the present invention represents specifically with embodiment preferred and describes that those skilled in the art should be understood that in the variation that can carry out under the situation that does not depart from implication of the present invention on various forms and the details.And scope of the present invention is by following claim regulation.

Claims

1. the chemical compound that structural formula is represented below a kind or its stereoisomer, enantiomer, racemic modification, pharmaceutically acceptable salt, solvate, hydrate or polymorphic,

Wherein A is alkyl, aryl or the group that is selected from following formula:

R wherein ₁-R ₁₇Separate separately is hydrogen or alkyl, thiazolinyl, aryl, assorted alkyl, cycloalkyl, heterocyclic radical, alkylaryl, cycloalkyl aryl, alkyl-cycloalkyl, acyl group, sulfonyl or alkyl heterocyclic for not replacing or replacing; Or one or more R ₁And R ₂, R ₆And R ₇And R ₁₁And R ₁₂Connected nitrogen-atoms forms nitrogenous heterocycle together;

M, p and q are separate separately to be 0,1 or 2.

2. the chemical compound of claim 1, described chemical compound is chemical compound or its stereoisomer, enantiomer, racemic modification, pharmaceutically acceptable salt, solvate, hydrate or the polymorphic of formula I,

Wherein A is alkyl, aryl or the group that is selected from following formula:

M, p and q are separate separately to be 0,1 or 2.

3. the chemical compound of claim 1, wherein A is selected from:

4. the chemical compound of claim 1, wherein A is

Wherein m is 0 or 1.

5. the chemical compound of claim 4, wherein R ₁And R ₂In at least one be phenyl, naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH ₂CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.

6. the chemical compound of claim 1, wherein A is

7. the chemical compound of claim 6, wherein R ₅For phenyl, naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.

8. the chemical compound of claim 1, wherein A is

9. the chemical compound of claim 8, wherein R ₆And R ₇In at least one be phenyl, naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.

10. the chemical compound of claim 1, wherein A is

11. the chemical compound of claim 10, wherein R ₈For phenyl, naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.

12. the chemical compound of claim 1, wherein A is

13. the chemical compound of claim 13, wherein R ₉For phenyl, 1-naphthyl, 2-naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl, thienyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.

14. the chemical compound of claim 1, wherein A is

15. the chemical compound of claim 14, wherein R ₁₁And R ₁₂In at least one be phenyl, naphthyl, xenyl, benzyl ,-CH ₂CH ₂Ph ,-CH=CHPh, cyclohexyl, quinolyl, isoquinolyl ,-CH ₂-cyclohexyl ,-CH ₂-quinolyl ,-CH ₂-isoquinolyl, pyridine radicals ,-CH (Ph) ₂, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group, sec-butyl or the tert-butyl group.

16. the chemical compound that following structural formula is represented or its stereoisomer, enantiomer, racemic modification, pharmaceutically acceptable salt, solvate, hydrate or polymorphic,

Wherein

A is alkyl, aryl or the group that is selected from following formula:

B is

Or

N is 0 or 1:

M and p are separate separately to be 0,1 or 2.

17. the chemical compound of claim 16, described chemical compound are chemical compound or its stereoisomer, enantiomer, racemic modification, pharmaceutically acceptable salt, solvate, hydrate or the polymorphic of formula II,

Wherein

A is alkyl, aryl or the group that is selected from following formula:

B is

Or

N is 0 or 1;

M, p and q are separate separately to be 0,1 or 2.

18. the chemical compound of claim 16, wherein n is 0.

19. the chemical compound of claim 16, wherein n is 1.

20. the chemical compound of claim 16, wherein A is

21. the chemical compound of claim 16, wherein A is

22. the chemical compound of claim 16, wherein A is

23. the chemical compound of claim 16, wherein A is

24. a chemical compound, described chemical compound is selected from:

1) 6-phenyl acetyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

2) 6-benzoyl-amido-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

3) 6-[(xenyl-4-carbonyl)-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

4) 6-(3-phenyl-propiono amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

5) 6-[(naphthalene-2-carbonyl)-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

6) 6-isobutyryl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

7) quinoline-2-[N-(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-yl)] Methanamide

8) N-(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-yl)-nicotiamide

9) 6-diphenyl acetyl-amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

10) 6-[(naphthalene-1-carbonyl)-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

11) 6-(3,4-dimethoxy-benzoyl-amido)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

12) 6-[2-(3,4-dimethoxy-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

13) 6-[2-(4-fluoro-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

14) 6-[2-(2,5-dimethoxy-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

15) 6-[2-(3-methoxyl group-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

16) 6-[2-(4-chloro-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

17) 6-[2-(4-methoxyl group-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

18) 6-(2-phenyl-butyrylamino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

19) 6-(methyl-phenyl acetyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

20) 6-(2-pyridine-2-base-acetyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

21) 6-(2-pyridin-3-yl-acetyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

22) 6-(2-phenyl-propiono amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

23) 6-{[1-(4-chloro-phenyl)-cyclopropane carbonyl]-amino }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

24) 6-[(1-phenyl-cyclopropane carbonyl)-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

25) 6-{[1-(4-chloro-phenyl)-Tetramethylene. carbonyl]-amino }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

26) 6-[2-(4-chloro-phenyl)-2-methyl-propiono amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

27) 6-(2S-phenyl-butyrylamino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

28) 6-(2R-phenyl-butyrylamino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

29) 6-(benzoyl-amido-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

30) 6-(phenyl acetyl amino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

31) 6-{[(naphthalene-1-carbonyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

32) 6-[(2-methyl-benzoyl-amido)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

33) 6-[(4-methyl-benzoyl-amido)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

34) 6-[(3-methoxyl group-benzoyl-amido)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

35) 6-[(4-methoxyl group-benzoyl-amido)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

36) 6-[(3,4-dimethoxy-benzoyl-amido)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

37) N-(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-ylmethyl)-nicotiamide

38) 6-(isobutyryl amino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

39) 6-[(2-methoxyl group-benzoyl-amido)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

40) 6-[(4-chloro-benzoyl-amido)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

41) 6-phenyl methanesulfonamide acyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

42) 6-benzenesulfonyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

43) 6-(xenyl-4-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

44) 6-(naphthalene-1-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

45) 6-(naphthalene-2-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

46) 6-(toluene-4-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

47) 6-(benzenesulfonyl amino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

48) 6-(phenyl methanesulfonamide acyl amino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

49) 6-[(naphthalene-1-sulfuryl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

50) 6-[(naphthalene-2-sulfuryl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

51) 6-[(toluene-4-sulfuryl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

52) 6-[(2,4,6-trimethyl-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

53) the 6-[(4-tert-butyl group-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

54) 6-[(4-fluoro-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

55) 6-[(4-chloro-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

56) 6-[(3-chloro-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

57) 6-[(4-bromo-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

58) 6-[(3-bromo-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

59) 6-[(3-methoxyl group-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

60) 6-[(4-nitro-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

61) 6-[(4-methoxyl group-benzenesulfonyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

62) 6-[(thiophene-2-sulfuryl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

63) 6-{[3-(4-methoxyl group-phenoxy group)-propane-1-sulfuryl amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

64) 6-(3-benzyl-urea groups)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

65) (2-hydroxyl amino formoxyl-benzo [b] thiophene-6-yl)-urethanes

66) (2-hydroxyl amino formoxyl-benzo [b] thiophene-6-yl)-benzyq carbamate

67) 6-(3-phenethyl-urea groups)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

68) 6-(3-benzyl-urea groups methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

69) (2-hydroxyl amino formoxyl-benzo [b] thiophene-6-ylmethyl)-benzyq carbamate

70) 6-[3-(4-isopropyl-phenyl)-urea groups methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

71) 6-[3-(the 4-tert-butyl group-phenyl)-urea groups methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

72) 6-[3-(3,5-couple-trifluoromethyl-phenyl)-urea groups methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

73) 6-[3-(3-phenoxy group-phenyl)-urea groups methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

74) 5-benzoyl-amido-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

75) 5-phenyl acetyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

76) 5-(3-phenyl-propiono amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

77) 5-(3-phenyl-acryloyl group amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

78) 5-[(naphthalene-1-carbonyl)-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

79) 5-[(naphthalene-2-carbonyl)-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

80) quinoline-2-[N-(2-hydroxyl amino formoxyl-benzo [b] thiophene-5-yl)] Methanamide

81) N-(2-hydroxyl amino formoxyl-benzo [b] thiophene-5-yl)-nicotiamide

82) 5-[(xenyl-4-carbonyl)-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

83) 5-diphenyl acetyl-amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

84) 5-isobutyryl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

85) 5-[2-(4-fluoro-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

86) 5-[2-(3-methoxyl group-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

87) 5-[2-(3,4-dimethoxy-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

88) 5-[2-(2,5-dimethoxy-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

89) 5-(2-phenyl-butyrylamino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

90) 5-[2-(4-chloro-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

91) 5-[2-(4-methoxyl group-phenyl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

92) 5-{[1-(4-chloro-phenyl)-Pentamethylene. carbonyl]-amino }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

93) 5-(naphthalene-2-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

94) 5-(toluene-4-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

95) 5-benzenesulfonyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

96) 5-phenyl methanesulfonamide acyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

97) 5-(naphthalene-1-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

98) 5-(xenyl-4-sulfuryl amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

99) (2-hydroxyl amino formoxyl-benzo [b] thiophene-5-yl)-benzyq carbamate

100) (2-hydroxyl amino formoxyl-benzo [b] thiophene-5-yl)-urethanes

101) 5-(3-benzyl-urea groups)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

102) 5-dibenzyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

103) 6-dibenzyl amino-benzo [b] thiophene-2-carboxylic acid methyl ester

104) 6-dibenzyl amino-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

105) 5-(two-phenyl amino formoxyl methyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

106) 6-(two-phenyl amino formoxyl methyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

107) 6-[2-(4-phenyl-Piperazine-1-yl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

108) 6-(2-3,4-dihydro-1H-isoquinolin-2-base-acetyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

109) 6-[2-(4-benzyl-piperidines-1-yl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

110) 4-[(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-base carbamoyl)-methyl]-piperazine-1-benzyl formate

111) 6-(2-dibenzyl amino-acetyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

112) 6-{2-[4-(3-methoxyl group-phenyl)-piperazine-1-yl]-acetyl-amino }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

113) 6-[2-(4-pyrimidine-2-base-piperazine-1-yl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

114) 6-{2-[4-(2-methoxyl group-phenyl)-piperazine-1-yl]-acetyl-amino }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

115) 6-[2-(4-pyridine-2-base-piperazine-1-yl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

116) 6-[2-(4-acetyl group-piperazine-1-yl)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

117) 6-(2-piperidines-1-base-acetyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

118) 6-(2-morpholine-4-base-acetyl-amino)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

119) 6-[2-(benzyl-phenethyl-amino)-acetyl-amino]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

120) { tert-butoxycarbonyl methyl-[(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-base carbamoyl)-methyl]-amino }-tert-butyl acetate

121) 6-{2-[4-(2-chloro-phenyl)-piperazine-1-yl]-acetyl-amino }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

122) 6-{2-[4-(3-chloro-phenyl)-piperazine-1-yl]-acetyl-amino }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

123) 4-[(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-base carbamoyl)-methyl]-[1,4] Diazesuberane-1-benzyl formate

124) 4-[(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-base carbamoyl)-methyl]-piperazine-1-Ethyl formate

125) 6-{2-[4-(4-methoxyl group-phenyl)-piperazine-1-yl]-acetyl-amino }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

126) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-{N-[2-(1H-indole-2-yl)-ethyl] } Methanamide

127) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-(N-benzyl) Methanamide

128) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(pyridine-2-ylmethyl)] Methanamide

129) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(1-benzyl-piperidin-4-yl)] Methanamide

130) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(2,2-diphenyl-ethyl)] Methanamide

131) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(1,2-diphenyl-ethyl)] Methanamide

132) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-(N-benzhydryl) Methanamide

133) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(1H-benzimidazolyl-2 radicals-ylmethyl)] Methanamide

134) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(2-pyridine-2-base-ethyl)] Methanamide

135) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(1,2,3,4-tetrahydrochysene-naphthalene-1-yl)] Methanamide

136) 6-(piperidines-1-carbonyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

137) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-(N-phenyl) Methanamide

138) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(indane-1-yl)] Methanamide

139) 6-(4-phenyl-Piperazine-1-carbonyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

140) 6-[4-(4-chloro-phenyl)-piperazine-1-carbonyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

141) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(3-phenyl-propyl group)] Methanamide

142) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-(N-phenethyl) Methanamide

143) 6-(4-benzyl-piperidines-1-carbonyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

144) 6-(4-benzyl-piperazine-1-carbonyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

145) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(quinoline-8-yl)] Methanamide

146) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-6-[N-(4-phenyl-thiazol-2-yl)] Methanamide

147) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(2-methoxyl group-benzyl)] Methanamide

148) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(3-methoxyl group-benzyl)] Methanamide

149) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(4-methoxyl group-benzyl)] Methanamide

150) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(2-chloro-benzyl)] Methanamide

151) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(3-chloro-benzyl)] Methanamide

152) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(4-chloro-benzyl)] Methanamide

153) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(5-indane-1-yl)] Methanamide

154) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-{N-[2-(1H-indol-3-yl)-ethyl] } Methanamide

155) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(3,3-diphenyl-propyl group)] Methanamide

156) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(4-phenyl-butyl)] Methanamide

157) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-(N-phenyl) Methanamide

158) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-(N-phenethyl) Methanamide

159) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-(N-benzyl) Methanamide

160) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-[N-(3-phenyl-propyl group)] Methanamide

161) benzo [b] thiophene-2-(N-hydroxyl) Methanamide-5-(N-couple-phenyl amino formoxyl methyl) Methanamide

162) 5-[(3-methoxyl group-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

163) 5-(benzylamino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

164) 5-phenyl amino methyl-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

165) 5-[(3-benzyl oxygen base-phenyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

166) 5-[(4-methoxyl group-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

167) 5-[(2-chloro-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

168) 5-[(4-chloro-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

169) 5-[(benzhydryl-amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

170) 5-(phenethyl amino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

171) 5-[(2,2-diphenyl-ethylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

172) 5-{[2-(3,4-couple-benzyl oxygen base-phenyl)-ethylamino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

173) 5-[(3-phenyl-propyl group amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

174) 5-[(3,3-diphenyl-propyl group amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

175) 5-[(4-phenyl-butyl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

176) 5-[(2-morpholine-4-base-ethylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

177) 5-[(cyclohexyl methyl-amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

178) 5-[(2-methoxyl group-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

179) 5-[(3-chloro-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

180) 5-{[(1H-benzimidazolyl-2 radicals-ylmethyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

181) 5-{[(pyridine-2-ylmethyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

182) 5-{[2-(3,4-dimethoxy-phenyl)-ethylamino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

183) 5-{[2-(1H-indol-3-yl)-ethylamino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

184) 5-[(1-benzyl-piperidin-4-yl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

185) 6-(benzylamino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

186) 6-[(2-methoxyl group-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

187) 6-[(3-methoxyl group-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

188) 6-phenyl amino methyl-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

189) 6-(phenethyl amino-methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

190) 6-[(3-phenyl-propyl group amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

191) 6-[(2-chloro-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

192) 6-[(3-chloro-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

193) 6-[(4-chloro-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

194) 6-{[(benzo [1,3] dioxole-5-ylmethyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

195) 6-(indane-1-base amino methyl)-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

196) 6-[(9H-fluorenes-9-base is amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

197) 6-[(1,2-diphenyl-ethylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

198) 6-[(cyclohexyl methyl-amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

199) 6-[(1,2,3,4-tetrahydrochysene-naphthalene-1-base is amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

200) 6-{[2-(2-Methyl-1H-indole-3-yl)-ethylamino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

201) 6-{[(pyridine-2-ylmethyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

202) 6-[(1-benzyl-piperidin-4-yl amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

203) 6-[(4-methoxyl group-benzylamino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

204) 6-{[2-(1H-indol-3-yl)-ethylamino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

205) 6-[(4-methoxyl group-benzylamino)-methyl]-benzo [b] thiophene-2-carboxylic acid ethyl ester

206) 6-{[cyclohexyl-(4-methoxyl group-benzyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

207) 6-{[(4-methoxyl group-benzyl)-(tetrahydrochysene-pyrans-4-yl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

208) 6-{[(2-hydroxyl-ethyl)-(4-methoxyl group-benzyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

209) 6-{[isopropyl-(4-methoxyl group-benzyl)-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

210) 6-{[(4-methoxyl group-benzyl)-methyl-amino]-methyl }-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

211) 6-[(acetyl group-benzyl-amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

212) 6-[(benzyl-mesyl-amino)-methyl]-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

213) 6-benzyl oxygen ylmethyl-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

214) 3-chloro-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

215) 6-nitro-benzo [b] thiophene-2-(N-hydroxyl) Methanamide

216) the N-hydroxy-n '-(2-hydroxyl amino formoxyl-benzo [b] thiophene-6-yl)-oxamides

217) 5-{3-[(dibenzyl amino)-methyl]-phenyl }-thiophene-2-(N-hydroxyl) Methanamide

218) 5-{3-[(benzyl-quinoline-3-ylmethyl-amino)-methyl]-phenyl }-thiophene-2-(N-hydroxyl) Methanamide

219) 5-[3-(3,4-dihydro-1H-isoquinolin-2-ylmethyl)-phenyl]-thiophene-2-(N-hydroxyl) Methanamide

220) 5-[3-(4-phenyl-Piperazine-1-ylmethyl)-phenyl]-thiophene-2-(N-hydroxyl) Methanamide

221) 5-{3-[(benzyl-quinolyl-4 methyl-amino)-methyl]-phenyl }-thiophene-2-(N-hydroxyl) Methanamide

222) 5-{3-[(benzyl-phenethyl-amino)-methyl]-phenyl }-thiophene-2-(N-hydroxyl) Methanamide

223) 5-{3-[(pair-phenyl amino formoxyl methyl-amino)-methyl]-phenyl }-thiophene-2-(N-hydroxyl) Methanamide

224) 5-{3-[(phenethyl-quinoline-3-ylmethyl-amino)-methyl]-phenyl }-thiophene-2-(N-hydroxyl) Methanamide

225) 5-{3-[(phenethyl-quinolyl-4 methyl-amino)-methyl]-phenyl }-thiophene-2-(N-hydroxyl) Methanamide

226) 5-(3-{[(3-phenyl-propyl group)-quinolyl-4 methyl-amino]-methyl }-phenyl)-thiophene-2-(N-hydroxyl) Methanamide

227) 5-(3-{[(3-phenyl-propyl group)-quinoline-3-ylmethyl-amino]-methyl }-phenyl)-thiophene-2-(N-hydroxyl) Methanamide

228) 5-(3-{[benzyl-(3-phenyl-propyl group)-amino Bu Jiaji }-phenyl)-thiophene-2-(N-hydroxyl) Methanamide

229) 5-(4-phenyl amino formoxyl-phenyl)-thiophene-2-(N-hydroxyl) Methanamide

230) 5-(4-benzylamino formoxyl-phenyl)-thiophene-2-(N-hydroxyl) Methanamide

231) 5-(2-phenyl amino formoxyl-vinyl)-thiophene-2-(N-hydroxyl) Methanamide

232) 5-(2-phenyl amino formoxyl-ethyl)-thiophene-2-(N-hydroxyl) Methanamide

233) 5-(2-benzylamino formoxyl-vinyl)-thiophene-2-(N-hydroxyl) Methanamide

234) 5-(2-phenethyl carbamoyl-vinyl)-thiophene-2-(N-hydroxyl) Methanamide

235) 5-[2-(3-phenyl-propyl group carbamoyl)-vinyl]-thiophene-2-(N-hydroxyl) Methanamide

236) 5-[2-(cyclohexyl methyl-carbamoyl)-vinyl]-thiophene-2-(N-hydroxyl) Methanamide

237) 5-(2-cyclohexyl carboxyamide base-vinyl)-thiophene-2-(N-hydroxyl) Methanamide

238) 5-[2-(2,2-diphenyl-ethylamino formoxyl)-vinyl]-thiophene-2-(N-hydroxyl) Methanamide

239) 5-[2-(3-benzyl oxygen base-phenyl amino formoxyl)-vinyl]-thiophene-2-(N-hydroxyl) Methanamide

240) 5-(2-benzylamino formoxyl-ethyl)-thiophene-2-(N-hydroxyl) Methanamide

241) 5-(2-phenethyl carbamoyl-ethyl)-thiophene-2-(N-hydroxyl) Methanamide

242) 5-[2-(3-phenyl-propyl group carbamoyl)-ethyl]-thiophene-2-(N-hydroxyl) Methanamide

243) 5-[2-(2,2-diphenyl-ethylamino formoxyl)-ethyl]-thiophene-2-(N-hydroxyl) Methanamide

244) 5-(2-cyclohexyl carboxyamide base-ethyl)-thiophene-2-(N-hydroxyl) Methanamide

245) 5-phenyl acetyl amino-thiophene-2-(N-hydroxyl) Methanamide

246) 5-benzenesulfonyl amino-thiophene-2-(N-hydroxyl) Methanamide

247) 5-benzoyl-amido-thiophene-2-(N-hydroxyl) Methanamide

248) 5-[(naphthalene-1-carbonyl)-amino]-thiophene-2-(N-hydroxyl) Methanamide

249) 5-[(naphthalene-2-carbonyl)-amino]-thiophene-2-(N-hydroxyl) Methanamide

250) 5-phenyl methanesulfonamide acyl amino-thiophene-2-(N-hydroxyl) Methanamide

251) 5-(naphthalene-2-sulfuryl amino)-thiophene-2-(N-hydroxyl) Methanamide and

252) 5-(naphthalene-1-sulfuryl amino)-thiophene-2-(N-hydroxyl) Methanamide

25. each chemical compound among the claim 1-23, wherein said chemical compound are first kind histone deacetylase (Class I HDAC) inhibitor.

26. the chemical compound of claim 24, wherein said first kind histone deacetylase are histone deacetylase 1 (HDAC-1), histone deacetylase 2 (HDAC-2), histone deacetylase 3 (HDAC-3) or histone deacetylase 8 (HDAC-8).

27. the chemical compound of claim 24, wherein said first kind histone deacetylase are histone deacetylase 1 (HDAC-1).

28. each chemical compound among the claim 1-23, wherein said chemical compound are the second class histone deacetylase (Class II HDAC) inhibitor.

29. the chemical compound of claim 27, the wherein said second class histone deacetylase are histone deacetylase 4 (HDAC-4), histone deacetylase 5 (HDAC-8), histone deacetylase 6 (HDAC-6), histone deacetylase 7 (HDAC-7) or histone deacetylase 9 (HDAC-9).

30. a pharmaceutical composition, described pharmaceutical composition comprise among the claim 1-23 of medicine effective quantity each chemical compound and pharmaceutically acceptable carrier.

31. the active method of an inhibition of histone deacetylase 1 (HDAC-1), described method comprise each chemical compound among the claim 1-23 of HDAC-1 and effective dose is contacted to suppress the activity of HDAC-1.

32. a method for cancer for the treatment of the curee who needs treatment, described method comprise the chemical compound that gives among the claim 1-23 that described curee treats effective dose each.

33. the method for claim 31, wherein said cancer are selected from acute leukemia for example acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML); Chronic leukemia is chronic lymphocytic leukemia (CLL) and chronic lymphocytic leukemia (CML), hairy cell leukemia, skin T-cell lymphoma (CTCL), non-skin Peripheral T-cell lymphoma, the lymphoma relevant with human T lymphotrophic virus (HTLV) such as Adult T-cell leukemia/lymphoma (ATLL), Hodgkin, non-Hodgkin lymphoma, large celllymphoma, the big B-cell lymphoma of dispersivity (DLBCL) for example; Burkitt lymphoma; Constitutional central nervous system (CNS) lymphoma; Multiple myeloma; Child's solid tumor is cerebroma, neuroblastoma, retinoblastoma, wilms' tumor, osteoma and soft tissue sarcoma, head and neck cancer (for example mouth, larynx and the esophageal carcinoma), urogenital cancer (for example prostate, bladder, kidney, uterus, ovary, testis, rectum and colon cancer), pulmonary carcinoma, breast carcinoma, cancer of pancreas, melanoma and other skin carcinomas, gastric cancer, cerebroma, hepatocarcinoma and thyroid carcinoma for example.

34. the method for the disease of sulfur oxygen cyclase protein (TRX)-mediation for the treatment of the curee who needs treatment, described method comprises the step that gives each chemical compound among the claim 1-75 that described curee treats effective dose, and the amount of wherein said chemical compound can effectively be treated the disease of described curee's TRX-mediation.

35. the method for claim 33, the disease of wherein said TRX-mediation be inflammatory diseases, allergic disease, autoimmune disease, with the oxidative stress diseases associated or be characterized as the disease of cell hyperproliferation.

36. a method for the treatment of the curee's who needs treatment central nervous system disease, described method comprise the chemical compound that gives among the claim 1-23 that described curee treats effective dose each.

37. the method for claim 35, wherein said disease is polyglutamyl amine expansion disease.

38. thereby the interior tumor sexual cell of selective induction curee body breaks up the method that suppresses described cell proliferation in described curee's body in the end eventually, described method comprises the step that gives each chemical compound among described curee's claim 1-23, and its amount can effectively be induced tumor sexual cell end differentiation eventually in described curee's body.

39. thereby the growth retardation of tumor sexual cell suppresses the method for described cell proliferation in described curee's body in the selective induction curee body, described method comprises the step that gives each chemical compound among described curee's claim 1-23, and its amount can effectively be induced tumor sexual cell growth retardation in described curee's body.

40. thereby tumor sexual cell apoptosis suppresses the method for described cell proliferation in described curee's body in the selective induction curee body, described method comprises the step that gives each chemical compound among described curee's claim 1-23, and its amount can effectively be induced tumor sexual cell apoptosis in described curee's body.

41. one kind treat suffer from the method that tumor is characterised in that the curee of tumor sexual cell propagation, described method comprises the step that gives each chemical compound among curee's claim 1-23, thereby its amount can effective selectivity be induced the end differentiation eventually of these tumor sexual cells, inducing cell growth retardation and/or apoptosis-induced its propagation that suppresses.

42. each method among the claim 30-40, wherein said administration comprises the pharmaceutical composition that comprises described chemical compound and pharmaceutically acceptable carrier.

43. the method for claim 41, wherein said pharmaceutical composition per os gives.