CN1321153A - Telomerase inhibitors and method of their use - Google Patents

Abstract

Thiazolidinedione compounds, compositions, and methods of inhibiting telomerase activity in vitro and treatmnet of telomerase mediated conditions or diseases ex vivo and in vivo are provided. The methods, compounds and compositions of the invention may be employed alone, or in combination with other pharmacologically active agents in the treatment of conditions or diseases mediated by telomerase activity, such as in the treatment of cancer. Also disclosed are novel methods for assaying or screening for inhibitors of telomerase activity.

Description

Telomerase inhibitor and using method thereof

Invention field

The present invention relates to suppress the thiazolidone compounds of telomerase activation, the pharmaceutical composition that contains these compounds, and these compounds and pharmaceutical composition are combined in treatment by the illness of Telomerase mediation or the application of disorders such as cancers aspect separately or with the other medicines promoting agent.

Background of invention

Synthesizing of telomerase catalytic telomere.Telomere is that the characteristic series connection repeats (being TTAGGG in Mammals), and they are in the chromosomal end of most of eukaryotes.They may reach the 15-25 kilobase in people's protoblast.Along with the division of each cell, a nearly 60-100 base is lost from chromosomal end, simultaneously along with the shortening of telomere, the Zhongdao of cell critical days and programmed cell death be excited.Referring to people such as Harley, (1991) mutation research 256:271-282.Telomerase remains on the danger level length of telomere just, therefore is responsible for chromosomal stability and participates in regulation of Cell Cycle.

Telomerase is a kind of ribonucleoprotein ThermoScript II, and it contains the distinctive telomeric dna synthetic RNA template that is used for.Referring to Blackbum, 1992, biological chemistry annual review, 61:113-129.Telomerase appears in the stem cell and protoblast of normal tissue, and in the tumour more than 85% with high-content more exist (people such as Kim, 1994, science, 266:2011-2014).Thus, the medicine of target Telomerase will be separated from healthy tissues tumour and have very high selectivity.Therefore, existing people proposes to suppress the novel method of Telomerase as the treatment cancer.

Report was once arranged, by with the RNA fragment of Telomerase such as peptide nucleic acid(PNA) (people (1996) such as Norton, Nature Biotechnol, 14:615-619) and the thiophosphoric acid oligonucleotide be the activity that the antisense method of target suppresses Telomerase.Because Telomerase is a ThermoScript II, the inhibitor of use ThermoScript II such as AZT and other nucleosides all have report.By may report people such as (, (1997) Eur.J.Cancer 33:638-644) Burger also being arranged because the cis-platinum that telomere repeat sequence crosslinked causes suppresses the activity of Telomerase.

Thiazolidinedione comprises one group of antidiabetic compound that structure is close.These compounds have improved the insulin sensitivity of target tissue in the insulin resistance animal (skeletal muscle, liver, fat).Except that these influences for hyperglycemia, thiazolidinedione has also reduced in the NIDDM animal model level of fat and Regular Insulin.Recently, the patient that thiazolidinedione--troglitazone shows suffering the glucose tolerance infringement has identical beneficial effect with the patient who suffers NIDDM.The infringement of this glucose tolerance be a kind of generation before the NIDDM development metabolic disorder (people such as Nolan, (1994) N.Eng.J.Med.331,1188-1193).Although the mechanism of action of thiazolidinedione is not clear, but there is any to know, that is exactly that they can not increase insulin secretion, or the quantity or the avidity of increase insulin receptor combining site, demonstrate thiazolidinedione and enlarged back acceptor incident (Colca, J.R and Morton, D.R. (1990) new antidiabetic medicine (C.J.Bailey and the P.RFlatt edit) Smith-Gordon of insulin signaling in taking place, New York, 255-261; People such as Chang (1983) diabetes 32,839-845).

Thiazolidone is found to be effective inducement of cultivating pre-adipose cell lines (people (1988) J.Cell Physiol.134 such as Hiragun, 124-30; People such as Sparks (1991) J.Cell.Physiol.146,101-109; People such as Kleitzien (1992) Mol.Pharmacol.41,393-398).In addition, also congener of thiazolidinedione and appetite control disorderly (referring to WO94/25026A1) and the increase of bone marrow fat content.In addition, thiazolidinedione compound is proposed to be used in the treatment of psoriasis (the 5th, 824, No. 694 United States Patent (USP)s), climacteric syndrome and mesenchymal neoplasm (the 5th, 814, No. 647 United States Patent (USP)s).

We have understood for some useful compounds of realization the inventive method, and the method for making these compounds.For example, following patent disclosure some of them compounds: WO91/07107; WO92/02520; WO94/01433; WO89/08651; JP Kokai69383/92; EP0155848; EP0193256; EP0295828; And USP4,287,200; 4,340,605; 4,376,777; 4,438,141; 4,444,779; 4,461,902; 4,486,594; 4,572,912; 4,582,839; 4,687,777; 4,703,052; 4,725,610; 4,738,972; 4,775,687; 4,791,125; 4,812,570; 4,873,255; 4,897,393; 4,897,405; 4,918,091; 4,948,900; 5,002,953; 5,023,085; 5,053,420; 5,061,717; 5,120,754; 5,132,317; 5,143,928; 5,194,443; 5,223,522; 5,232,925; 5,252,735; 5,260,445; 5,814,647; 5,824,694; With 5,874,454.

Discern these compounds that suppress telomerase activations and very important benefit is arranged for the treatment of human diseases.The compound that suppresses Telomerase can be used for treating the disease of Telomerase mediation, as cancer, this is because cancer cells is expressed telomerase activation, and the normal human cell does not have telomerase activation in biological related levels (that is, keep cell fission after enough levels of telomere length).Unfortunately, only have compound seldom to be identified and to characterize, especially those have high potentiality or biological available compound active and can be oral.Therefore, still have can utilizing the needs of compound as the high potentiality of having of telomerase inhibitor or active oral property biology, and to treatment cancer and the pharmaceutical composition of other telomerase activation abnormal diseases and the needs of method.The present invention satisfies the needs of these and other.

Summary of the invention

The invention provides certain methods, compound and composition, it has the telomerase activation cell by target and for the disease that the treatment Telomerase mediates, as malignant disorders, has special and effective function.These methods of the present invention, compound and composition can be used to wide spectrum malignant cell type, and avoid present cancer therapy pattern not have specificity and very big toxic problem is arranged.

A first aspect of the present invention is following to be found: some known thiazolidinone compound and be effective for suppress telomerase activation in external, ex vivo and body at the new thiazolo alkane ketone derivatives of this announcement.Therefore, in some aspects, the invention provides by making Telomerase contact the method that compound described here suppresses Telomerase.In specific embodiment, repressed Telomerase is mammiferous Telomerase, as people's Telomerase.A related aspect of the present invention is to find that thiazolidinone compound suppresses to have the cell of telomerase activation, as the propagation of many cancer cells.Therefore, this respect of the present invention provides and suppresses to suffer from the illness of Telomerase mediation or the patient of disease, the method for preferred mammal Telomerase Activity, and it comprises acceptable salt on the thiazolidinone compound of the inhibition Telomerase of patient's drug treatment significant quantity or its pharmacology.

Another aspect of the present invention provides method, compound and the pharmaceutical composition that suppresses Telomerase, comprises making the Telomerase contact have acceptable salt on the pharmaceutical composition of following formula I or compound or its pharmacology:

Wherein X is oxygen or sulphur,

Be a singly-bound or two key; A is aryl or heteroaryl; R ₁Be hydrogen or low alkyl group; R ₂, R ₃And R ₄From following group, select independently: hydrogen, halogen, alkyl, aryl, hydroxyl, alkoxyl group, aryloxy, aralkoxy, cyano group, nitro, the alkyl urea groups, the aromatic base urea groups, the dialkyl group urea groups, the diaryl urea groups, the alkylaryl urea groups, the alkyl sulfide urea groups, the aryl thiourea base, the dialkyl thiourea base, the diaryl thioureido, the alkylaryl thioureido, amino, alkylamino, arylamino, dialkyl amido, ammonia diaryl base, aryl-alkyl amino, aminocarboxyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, dialkyl amino carbonyl, the ammonia diaryl base carbonyl, the aryl-alkyl amino carbonyl, alkane carbonyl oxygen base, virtue carbonyl oxygen base, carboxyl, alkoxy carbonyl, aryloxycarbonyl, sulfo group, the alkane sulfonamido, the aryl-sulphonamidic base, alkyl sulphonyl, aryl sulfonyl, the alkyl sulfinyl, aryl sulfinyl and heteroaryl; L is a direct key or a linking group, and it has 1-3 atom, and is independently selected from carbon, nitrogen, oxygen or sulphur in non-replacement or replacement; And n equals 1 or 2.

Method, compound and the composition that suppresses Telomerase that provide on the one hand more of the present invention comprises making the Telomerase contact have acceptable salt on the compound of formula IV or its pharmacology:

Wherein X is O or S; Be a singly-bound or two key; R ₅Be H or low alkyl group; And Ar is aryl, heteroaryl, aralkyl, heteroaralkyl, aromatic yl alkenyl, heteroaryl alkenyl, aromatic yl polysulfide yl or the heteroaryl alkynyl of replacement or non-replacement.

Another aspect of the present invention provides method, compound and the composition that suppresses Telomerase, comprises acceptable salt on the composition that makes the Telomerase contact have formula (V) or compound or its pharmacology: Wherein X is O or S; R ₆Be H or low alkyl group; W be CH=CH, S or-N=C-; R ₇Be OH, halogen, sulfydryl, nitro, cyano group, lower alkylthio, low alkyl group, lower alkoxy, lower alkanoyloxy, NR ₁₁R ₁₂(R wherein ₁₁And R ₁₂Be independently selected from following group: hydrogen, low alkyl group, low-grade alkane acidyl, aryl, heteroaryl, heteroaralkyl or R ₁₁And R ₁₂Form to replace or non-substituted heterocycle), CO ₂R ₁₃(R wherein ₁₃Be selected from following group: hydrogen, low alkyl group, aralkyl and heteroaralkyl), CONR ₁₁R ₁₂, replacement or non-substituted aryl, replacement or non-substituted heteroaryl, aryloxy, heteroaryloxy, aralkoxy, assorted aralkoxy, low-grade alkane acidyl, aroyl, low-grade alkenyl, arylthio or low-grade alkynyl; And work as W and represent S, R ₇Also can be hydrogen; L is O, S, SO, SO ₂, OCH ₂, SCH ₂, SOCH ₂, SO ₂CH ₂Or N (R ₁₀) (CH ₂) _m(R wherein ₁₀Be to replace or non-substituted aryl, heteroaryl, aralkyl or heteroaralkyl, m is 0 or 1), (CH ₂) N (R ₁₀) (CH ₂) _mOr CR ₁₃R ₁₄(R wherein ₁₃And R ₁₄Be independently selected from following group: hydrogen, hydroxyl, aryl and heteroaryl); And A ₁Be cycloalkyl with following formula (A1):

Z wherein ₁To Z ₅Independently be selected from following group: hydrogen, low alkyl group, low-grade alkenyl, lower alkanoyloxy, sulfydryl, alkylthio, NR ₁₁R ₁₂, nitro, cyano group, CO ₂R ₁₃, CONR ₁₁R ₁₂, aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, assorted aralkoxy, halogen and low-grade alkane acidyl; Its condition is when W is CH=CH, and A also can be a pyridyl.

New compound of the present invention has many valuable application as the activity inhibitor of deleterious Telomerase, for example treats cancer in Mammals such as people.Pharmaceutical composition of the present invention can be used in vivo kill cancer cell or be used to ex vivo kill cancer cell.Therefore, the invention provides people and other Mammals (as, cat that ox, horse, sheep, deer, pig and animal doctors pay close attention to and dog) in the compound and the composition of treatment cancer, and treatment cancer and other illness or disease by the Telomerase mediation.Describe I, definition in detail

Unless following other definition, the term of Shi Yonging has common received scientific meaning herein.The definition of standard chemical term can be found in book of reference, comprises Carey and Sundberg (1992) " the senior organic chemistry third edition " A and B volume, Plenum press, New York.

Term " thiazolidone " or " thiazolidinone derivatives " have following general structure as used herein: Wherein X is O or S.When X is O, derivative is a thiazolidine diketone derivative.When X is S, derivative is the thiazolidone thione derivative, also is called rhodanine (referring to following embodiment 25-28) simultaneously.

Term " alkyl " is straight, side chain or a cyclic hydrocarbon chain fragment or an atomic group as used herein, comprise 1 to about 20 carbon atoms, more preferably 1 to about 10 carbon atoms (for example, methyl, ethyl, n-propyl, sec.-propyl, cyclopropyl, normal-butyl, isobutyl-, the tertiary butyl, cyclobutyl, adamantyl, noradamantyl, or the like).The straight chain, side chain or the cyclic hydrocarbon chain that contain 8 or carbon atom still less also are called " low alkyl group " at this.Hydrocarbon chain can further comprise one or more unsaturated link(age), promptly, one or more pair or triple bond are (for example, vinyl, propargyl, allyl group, 2-butylene-1-base, 2-cyclopentenes-1-base, 1-1-base, 3-tetrahydrobenzene-1-base, or the like).Double bond containing alkyl group has for example just been mentioned also is called " alkene ".Equally, contain the triple-linked alkyl group and also be called " alkynes ".But for group of naphthene base, two keys and/or triple-linked combination do not comprise that those make cyclic hydrocarbon chain have the binding setting of aromaticity.

In addition, as used herein " alkyl " further be included in the hydrocarbon fragment or the ring in one or more carbon atoms in one or more replacements.These replacements include but not limited to: aryl; Heteroaryl; Halogen (for example forms trifluoromethyl ,-CF ₃); Nitro (NO ₂); Cyano group (CN); Hydroxyl; Alkoxyl group or aryloxy are (OR); Sulfenyl or sulfydryl, alkyl sulfenyl or arylthio are (SR); Amino, alkylamino, arylamino, dialkyl group or ammonia diaryl base, or aryl-alkyl amino (NRR '); Aminocarboxyl, alkyl amino-carbonyl, aromatic aminocarbonyl, dialkyl amino carbonyl, ammonia diaryl base carbonyl or aryl-alkyl amino carbonyl (C (O) NRR '); Carboxyl, or alkyl-or aryloxy carbonyl (C (O) OR); Carboxaldehyde radicals (carboxaldehyde), aryl carbonyl or alkyl-carbonyl (C (O) R); Imino-(iminyl), aryl imino-or alkyl imino (C (=NR) R'); Sulfo group (SO ₂OR); Alkyl sulphonyl or aryl sulfonyl (SO ₂R); Urea groups (HNC (=O) NRR '); Sulfo-urea groups (HNC (=S) NRR '); Wherein, R and R ' are hydrogen, aryl or alkyl independently.Comprise that substituent heterocyclic group (as heterocycle, heteroaryl and heteroaralkyl) is similar to above-described term and is defined.For example, term " heterocyclic oxy group " refers to-OR that wherein R is following defined heterocycle.

The moieties of " low-grade alkane acidyl ", " lower alkoxy ", " lower alkanoyloxy ", " lower alkylthio " is identical with " alkyl " defined above.

Term " methylene radical " refers to-CH ₂-.

Term " methyne " refers to that a hydrogen atom in the methylene radical is substituted by substituting group as described above.Term " methyne " can refer to that also a combined key of hydrogen atom in the methylene radical substitutes to form sp ²-hydridization carbon center (promptly＞C=O).

Term " halogen " or " halogen " refer to substituting group fluorine, bromine, chlorine and iodine.

Term " carbonyl " vial can roll into a ball-(CO)-.But the known groups that it can be had similar electronics and/or structural performance replaces, for example thiocarbonyl (C (S)-), sulfinyl (S (O)-), alkylsulfonyl (SO ₂-), phosphono (PO ₂-) and methylene radical (C (=CH ₂)-).The identical radicals of other carbonyl is known for the technician of medicine and organic chemistry filed.

Term " aryl " refers to have 20 or still less the aromatic hydrocarbon ring chain of carbon atom, for example phenyl, naphthyl, xenyl and anthryl.One or more carbon atoms of aromatic yl group also can be substituted, for example: alkyl; Aryl; Heterocycle; Formyl radical; Halogen; Nitro; Cyano group; Hydroxyl; Alkoxyl group or aryloxy; Sulphur or sulfydryl, alkyl sulfenyl or artyl sulfo; Amino, alkylamino, arylamino, dialkyl amido, ammonia diaryl base or aryl-alkyl amino; Aminocarboxyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, dialkyl amino carbonyl, ammonia diaryl base carbonyl or aryl-alkyl amino carbonyl; Carboxyl, alkoxy carbonyl or aryloxycarbonyl; Carboxaldehyde radicals, aryl carbonyl or alkyl-carbonyl; Imino-, aryl imino-or alkyl imino; Sulfo group; Alkyl sulphonyl or aryl sulfonyl; Oxyimino, aryloxy imino-or Alkoximino; Urea groups; Or thioureido.In addition, two or more alkyl of aromatic yl group or assorted alkyl substituent can combine formation fused-aryl-alkyl or aryl-assorted alkyl ring (as tetralyl).Comprise that substituent heterocyclic group (for example heterocyclic oxy group, heteroaryloxy and heteroaralkyl sulfenyl) is according to similar definition described above.

Term " aralkyl " refers to be connected to aromatic yl group on the precursor structure by an above-described alkyl group, as benzyl, α-Jia Jibianji, styroyl, or the like.Aralkyl moiety in " aralkyl alkylsulfonyl " aralkoxy is identical with above-mentioned " aralkyl " definition.

Aryl moiety in term " aroyl ", " aromatic yl alkenyl ", " aryl sulfonyl ", " artyl sulfo ", " aryloxy ", " aromatic yl alkenyl alkylsulfonyl ", " the aromatic yl polysulfide yl alkylsulfonyl " is identical with above-mentioned " aryl " definition.

Term " heterocycle " refers to group of naphthene base defined above or aromatic yl group, and wherein one or more carbon atoms are replaced by non-carbon atom, particularly nitrogen, oxygen or sulphur.Nonaromatic heterocycles also refers to " the assorted alkyl of ring ".Aromatic heterocycle also refers to " heteroaryl ".For example, such group comprises furyl, tetrahydrofuran base, pyrryl, pyrrolidyl, thienyl, tetrahydro-thienyl, oxazolyl, isoxazolyl, triazolyl, thiazolyl, isothiazolyl, pyrazolyl, pyrazolidyl, the oxadiazoles base, thiadiazolyl group, imidazolyl, imidazolinyl, pyridyl, pyridazinyl, triazinyl, piperidyl, morpholinyl, thio-morpholinyl, pyrazinyl, piperazinyl, pyrimidyl, 1, the 5-phthalazinyl, benzofuryl, benzothienyl, indyl, indolinyl, the indolizine base, indazolyl, quinolizinyl, quinolyl, isoquinolyl, the cinnolines base, the 2 base, quinazolyl, quinoxalinyl, pteridine radicals, quinuclidinyl, carbazyl, acridyl, phenazinyl, phenothiazinyl, the Phenazoxine base, purine radicals, benzimidazolyl-, benzothiazolyl, and benzoxazolyl.

The heteroaryl moieties of " heteroaralkyl ", " heterochain thiazolinyl ", " hetaryne base ", " assorted arylsulfonyl ", " heteroaralkyl alkylsulfonyl ", " heteroaralkenyl alkylsulfonyl ", " hetaryne base alkylsulfonyl ", " heteroaryloxy " and " assorted aralkoxy " is identical with above-mentioned " heteroaryl " definition.

Above-mentioned heterocyclic group can further comprise one or more substituting groups at the one or more carbon and/or the non-carbon atom place of heteroaryl, for example: alkyl; Aryl; Heterocycle; Formyl radical; Halogen; Nitro; Cyano group; Hydroxyl; Alkoxyl group or aryloxy; Sulphur or sulfydryl, alkyl sulfenyl or artyl sulfo; Amino, alkylamino, arylamino, dialkyl amido, ammonia diaryl base or aryl-alkyl amino; Aminocarboxyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, dialkyl amino carbonyl, ammonia diaryl base carbonyl or aryl-alkyl amino carbonyl; Carboxyl, alkoxy carbonyl or aryloxycarbonyl; Carboxaldehyde radicals, aryl carbonyl or alkyl-carbonyl; Imino-, aryl imino-or alkyl imino; Sulfo group; Alkyl sulphonyl or aryl sulfonyl; Oxyimino, aryloxy imino-or Alkoximino; Urea groups; Or thioureido.In addition, two or more alkyl substituents can combine formation annelated heterocycles-alkyl or heterocycle-aryl rings.Comprise that substituent heterocyclic group (for example heterocyclic oxy group, heteroaryloxy and heteroaralkyl sulfenyl) is according to similar definition described above.

Term " Heterocyclylalkyl " is meant by one or more abovementioned alkyl groups and is attached to heterocyclic group on the precursor structure, for example 2-piperidino methyl etc.Term " heteroaralkyl " refers to the heteroaryl that is connected with precursor structure by one or more abovementioned alkyl groups as used herein, as 2-thenyl etc.

Compound of the present invention can be used to suppress or reduces telomerase activation and/or have the propagation of the cell of telomerase activation.Here, the inhibition of these enzymes or cell proliferation and reduction are meant with respect to control experiment lower level activity.Enzyme and cell test compounds of no use is handled in the control experiment.In certain embodiments, this tested activity is suppressed at least or has reduced by 10%.For those skilled in the art, to be suppressed at least or to reduce by 20%, 50%, 75%, 90% or 100% be preferred to tested activity in the concrete application.II, telomerase inhibitor

As mentioned above, the immortality of cell relates to the activation of Telomerase.More particularly, telomerase activation and many tumor cell lines keep the analysis by telomerase activation of getting in touch between the not dead ability to be confirmed people such as () Kim, and these clones comprise that skin, reticular tissue, fat, mammary gland, lung, stomach, pancreas, ovary, uterine cervix, uterus, kidney, bladder, colon, prostate gland, central nervous system (CNS), retina and blood cell are.Show that data and this analysis that telomere length shortens can offer the signal (referring to WO93/23572) that normal cell duplicates aging, demonstrating the inhibition telomerase activation can be a kind of effective anti-cancer therapies." restraining effect " briefly be exactly a kind of can be in vivo or the medicament of external reduction telomerase activation, medicine or pharmaceutical chemicals.These inhibitor can be debated not at an easy rate with the standard screening method, wherein cell extract or other have the preparation of telomerase activation to contact with the potential inhibitor, measure the level of telomerase activation then under the situation that has and do not have inhibitor or inhibitor quantitative changeization.By this method, not only useful inhibitor is identified, and the preferred levels of this kind inhibitor also can still await further mensuration in vivo external determined.

At a related aspect, the invention provides a kind of method that suppresses cell proliferation or replication.In this method, during reproduction process of cell, provide of the present invention one or more can suppress the thiazolidinone compound of telomerase activation.As mentioned above, Telomerase duplicates fully for the end of linear chromosomal DNA and the terminal bases of not losing every chain 5 ' end plays a part crucial.The not dead cell and the cell of fast breeding add that at end of chromosome telomeric dna repeats with Telomerase.The restraining effect of Telomerase can cause proliferating cells can not increase telomere, and they will finally stop division.It is evident that for those of ordinary skills, the method of this inhibition ability of cell proliferation is very effective for the treatment illness relevant with the cell proliferation rate rising, for example cancer (malignant cell Telomerase Activity) and erythropoiesis (erythropoietic stem cell Telomerase Activity).

So in one aspect, the invention provides the composition and the compound that prevent or treat many types of cancer.Particularly, as at different human tumor cell lines with have in the tumour of telomerase activation shownly, compound of the present invention can provide a kind of method of general many cancers of treatment.More importantly, thiazolidinone compound of the present invention can be distinguished pernicious and normal cell to a great extent effectively, and the with medicament of having avoided simultaneously existing in the present chemotherapy is killed the many deleterious side effect of somatoblast without distinction.Representational thiazolidinone compound comprises glitazones, for example troglitazone (also being called CS-045 (Sankyo) and CI-991 (Park-Davis)), pioglitazone (also being called AD-4833 and U-72107E), rosiglitazone (also being called BRL49653), englitazone (also being called CP-68,722) and ciglitazone.

On the other hand, the invention provides the new compound that suppresses telomerase activation, about the pharmaceutical composition and the method for acceptable property salt on new compound or its pharmacology, comprise making Telomerase contact have acceptable salt on the compound of formula I or its pharmacology:

Wherein X is oxygen or sulphur,

Be a singly-bound or two key; A is aryl or heteroaryl; R ₁Be hydrogen or low alkyl group; R ₂, R ₃And R ₄From following group, select independently: hydrogen, halogen, alkyl, aryl, hydroxyl, alkoxyl group, aryloxy, aralkoxy, cyano group, nitro, the alkyl urea groups, the aromatic base urea groups, the dialkyl group urea groups, the diaryl urea groups, the alkylaryl urea groups, the alkyl sulfide urea groups, the aryl thiourea base, the dialkyl thiourea base, the diaryl thioureido, the alkylaryl thioureido, amino, alkylamino, arylamino, dialkyl amido, ammonia diaryl base, aryl-alkyl amino, aminocarboxyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, dialkyl amino carbonyl, the ammonia diaryl base carbonyl, the aryl-alkyl amino carbonyl, alkane carbonyl oxygen base, virtue carbonyl oxygen base, carboxyl, alkoxy carbonyl, aryloxycarbonyl, sulfo group, the alkane sulfonamido, the aryl-sulphonamidic base, alkyl sulphonyl, aryl sulfonyl, the alkyl sulfinyl, aryl sulfinyl and heteroaryl; L is a direct key or a linking group, and it has 1-3 atom, and is independently selected from carbon, nitrogen, oxygen or sulphur in non-replacement or replacement; And n equals 1 or 2.

In specific embodiment, new compound of the present invention has the general structure shown in the formula II: With acceptable salt on its pharmacology, wherein X is O or S, and R ₂, R ₃, R ₄, L and n as above limit.

In the compound of formula I, A can be an aryl, to form for example phenyl ring part.Perhaps, A can be a heteroaryl, as pyridine, quinoline, isoquinoline 99.9, thiophene, furans, imidazoles, benzoglyoxaline and pyrazoles etc.In the embodiment preferred, A is a phenyl, as formula II.In another embodiment preferred, when n is 1, R ₁Cannot be hydrogen.In embodiment preferred still, R ₂And R ₃In have at least one not to be hydrogen.In other particularly preferred embodiment, R ₂And R ₃In have one at least for halogen, most preferably, R ₂And R ₃All be that halogen is to form the phenyl ring part that two halogens replace.

As mentioned above, L can be a direct key, or the linking group of 1-3 atom, and wherein the atom of linking group is independently selected from carbon, nitrogen, oxygen or the sulphur in non-replacement or replacement.The useful representational linking group of The compounds of this invention for example comprises-O-,-S-,-NH-,-CH ₂-,-OCH ₂-,-OC (O)-,-CO ₂-,-NHC (O)-,-C (O) NH-,-OC (O) CH ₂-,-OC (O) NH-and-NHC (O) NH-.

Representation compound includes but not limited to: (2-(3 for 5-; the 4-dichlorophenyl) thiazolidine-2 benzylidyne); the 4-diketone; (3-(3 for 5-; the 4-dichlorophenyl) thiazolidine-2 benzylidyne); the 4-diketone; (4-(3 for 5-; the 4-dichloro-benzyloxy) thiazolidine-2 benzylidyne); the 4-diketone; (2-(3 for 5-; the 4-dichloro-benzyloxy) thiazolidine-2 benzylidyne); the 4-diketone; (4-(3 for 5-; 4-dichloro-benzoyl amino) thiazolidine-2 benzylidyne); the 4-diketone; 5-(4-(N-3; 4-dichlorophenyl urea groups) thiazolidine-2 benzylidyne); the 4-diketone; 5-(2-(N-3; 4-dichlorophenyl urea groups) thiazolidine-2 benzylidyne); the 4-diketone; 5-(2-(N-3; 4-dichlorophenyl carbamyl) thiazolidine-2 benzylidyne); the 4-diketone; 5-(3-(N-3; 4-dichlorophenyl carbamyl) thiazolidine-2 benzylidyne); the 4-diketone; 5-(4-(N-3; 4-dichlorophenyl carbamyl) thiazolidine-2 benzylidyne); the 4-diketone; 5-(4-(N-3; 4-dichlorophenyl carbamoyloxy group) thiazolidine-2 benzylidyne); the 4-diketone; (4-(3 for 5-; 4-dichlorophenoxy carbonyl) thiazolidine-2 benzylidyne); the 4-diketone; (2-(3 for 5-; 4-dichlorophenoxy carbonyl) thiazolidine-2 benzylidyne); the 4-diketone; (2-(3 for 5-; 4-dichlorophenylacetic acid base) thiazolidine-2 benzylidyne); the 4-diketone; (3-(3 for 5-; 4-dichlorophenylacetic acid base) thiazolidine-2 benzylidyne); the 4-diketone; (4-(3 for 5-; 4-dichlorophenylacetic acid base) thiazolidine-2 benzylidyne); the 4-diketone; (2-(3 for 5-; 4-dichlorobenzoic acid base) thiazolidine-2 benzylidyne); the 4-diketone; (3-(3 for 5-; 4-dichlorobenzoic acid base) thiazolidine-2 benzylidyne); the 4-diketone; (4-(3 for 5-; 4-dichlorobenzoic acid base) thiazolidine-2 benzylidyne); the 4-diketone; 5-(3; 4-two-(3; the 4-dichloro-benzyloxy) thiazolidine-2 benzylidyne); the 4-diketone; (2-(3 for 5-; the 4-dichlorophenoxy) thiazolidine-2 benzylidyne); the 4-diketone; (4-(3 for 5-; the 4-dichlorophenoxy) thiazolidine-2 benzylidyne); the 4-diketone; 5-(2; 5-two-(3; the 4-dichloro-benzyloxy) thiazolidine-2 benzylidyne); the 4-diketone; 5-(2; 4-two-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2, the 4-diketone; (2-(3 for 5-; 4-benzyl dichloride sulfenyl)-and 3H-pyrimidin-4-one-6-base methyne) rhodanine; (2-(3 for 5-; 4-benzyl dichloride sulfenyl) rhodanine pyrimidine-4-base methyne); 5-(2-(3,4-benzyl dichloride sulfenyl) pyrimidine-4-base methyne) rhodanine; 5-(3-cyano group-2-(3,4-benzyl dichloride sulfenyl) pyridine-6-base methyne) thiazolidine-2; the 4-diketone; and 5-(3-(3; the 4-dichloro-benzyloxy) thiazolidine-2 benzylidyne), the 4-diketone

In specific embodiment, new compound of the present invention has with the structure shown in the following formula III:

And acceptable salt on their pharmacology, wherein X is oxygen or sulphur, R ₁, R ₂, R ₃, R ₄As above limit with L.

In another embodiment, the invention provides the method, compound and the composition that suppress Telomerase, comprise making the Telomerase contact have acceptable salt on the compound of formula IV or its pharmacology: Wherein X is oxygen or sulphur; Be singly-bound or two key; R ₅Be hydrogen or low alkyl group; And Ar replaces or non-substituted aryl, heteroaryl, aralkyl, heteroaralkyl, aromatic yl alkenyl, heteroaryl alkenyl, aromatic yl polysulfide yl or heteroaryl alkynyl.

Formula IV compound with two keys can react by tetrahydrothiazole derivates and aromatic carbonyl and obtain.This reaction is selectively carried out in basic catalyst and solvent.The consumption of basic catalyst is usually at about 0.1 to 1 equivalent, and can be piperidines, piperidines drone acetate, diethylamine, pyridine, sodium acetate, salt of wormwood, yellow soda ash and analogue.Solvent can be an alcohols, as methyl alcohol, ethanol, propyl alcohol etc., and ethers, as ether, tetrahydrofuran (THF), dioxan etc., or hydrocarbon polymer, as benzene,toluene,xylene etc. and their mixture.Be reflected at room temperature and in about 200 ℃, carry out,, and in about 1 hour to about 50 hours, finish preferably at 50-100 ℃.In the compound of formula IV During for singly-bound, it can form by two keys of reduction above-claimed cpd.Usually, hydrogenation needs noble metal catalyst, and as palladium, platinum, rhodium etc., these are known in the field.

On the other hand, the invention provides the method, compound and the pharmaceutical composition that suppress Telomerase, comprise the compound or its acceptable salt that make the Telomerase contact have formula (V):

Wherein, X is oxygen or sulphur; R ₆Be hydrogen or low alkyl group; W be CH=CH, S or-N=C-; R ₇Be H, OH, halogen, sulfydryl, nitro, cyano group, lower alkylthio, low alkyl group, lower alkoxy, lower alkanoyloxy, NR ₁₁R ₁₂(R wherein ₁₁And R ₁₂Be independently selected from following group: hydrogen, low-grade alkane acidyl, aryl, heteroaryl, heteroaralkyl, perhaps R ₁₁And R ₁₂The heterocycle of formation replacement and non-replacement), CO ₂R ₁₃(R wherein ₁₃Be selected from following group: hydrogen, low alkyl group, aralkyl and heteroaralkyl), CONR ₁₁R ₁₂, replacement or non-substituted aryl, replacement or non-substituted heteroaryl, aryloxy, heteroaryloxy, aralkoxy, assorted aralkoxy, low-grade alkane acidyl, aroyl, low-grade alkenyl, arylthio or low-grade alkynyl; L is O, S, SO, SO ₂, OCH ₂, SCH ₂, SOCH ₂, SO ₂CH ₂Or N (R ₁₀) (CH ₂) _m(R wherein ₁₀Be to replace or non-substituted aryl, heteroaryl, aralkyl or heteroaralkyl, and m is 0 or 1), (CH ₂) N (R ₁₀) (CH ₂) _mPerhaps CR ₁₃R ₁₄(R wherein ₁₃And R ₁₄Be independently selected from following group: hydrogen, hydroxyl, aryl, heteroaryl); And A ₁For having the cyclophane alkyl of formula (A1): Wherein, Z ₁To Z ₅Be independently selected from following group: hydrogen, low alkyl group, low-grade alkenyl, lower alkanoyloxy, sulfydryl, alkylthio, NR ₁₁R ₁₂, nitro, cyano group, CO ₂R13, CONR ₁₁R ₁₂, aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, assorted aralkoxy, halogen and lower alkanoyloxy, its condition is, when W is CH=CH, A ₁Can be pyridyl.

The formula I shows to table 6 at table 1 to the example of the The compounds of this invention of V representative, but compound of the present invention is not restricted to this.

Table 1

Compound number	???X	??????R 5	???????????L	???R 2	????R 3
						????1	???O	????5-NO 2	??????????2-S	????H	????CH 3
????2	???O	????5-NH 2	??????????2-S	????H	????CH 3
						????3	???O	???5-NHCOCH 3	??????????2-S	????H	????CH 3
????4	???O	????5-NO 2	??????????2-SO	????H	????CH 3
						????5	???O	????5-NO 2	??????????2-SO 2	????H	????CH 3
????6	???O	???????H	??????????2-S	????H	????Cl
						????7	???O	???????H	??????????2-SO	????H	????Cl
????8	???O	???????H	??????????2-SO 2	????H	????Cl
						????9	???O	????3-NO 2	??????????4-S	????H	????CH 3
????10	???O	???????H	??????????2-O	????H	????H
						????11	???O	???????H	??????????3-O	????H	????H
????12	???O	???????H	??????????3-O	????H	????CH 3
						????13	???O	???????H	??????????3-O	????Cl	????Cl
????14	???O	???????H	??????????4-O	????H	????H
						????15	???O	???????H	??????????4-O	????H	????CH 3
????16	???O	????5-NO 2	??????????2-OCH 2	????H	????H
						????17	???O	????5-NO 2	??????????2-OCH 2	????Cl	????Cl
????18	???O	????5-NO 2	??????????2-OCH 2	????H	????CH 3
						????19	???O	????4-NO 2	??????????3-OCH 2	????H	????CH 3
????20	???O	????3-NO 2	??????????4-OCH 2	????H	????CH 3
						????21	???O	????2-NO 2	??????????5-OCH 2	????H	????CH 3
????46	???O	???????H	4-N-(4-bromophenyl)	????H	????Br
						????47	???O	????5-Ph	??????????2-OCH 2-	????H	????CH 3
????48	???O	5-(2-thienyl)	??????????2-OCH 2-	????H	????CH 3
						????49	???O	???????H	4-N-(4-hydroxymethyl phenyl)	????H	???CH 2OH
????50	???O	???????H	???2-NCH 2(4-bromophenyl)	????H	????H

Table 2

Compound number	??X	???R 1	???????R 6	????????L	???R 3
						????22	??O	????H	???????H	??????2-OCH 2	???CH 3
????23	??O	????H	??????5-OCH 3	??????2-OCH 2	???CH 3
						????24	??O	????H	??????5-Cl	??????2-OCH 2	???CH 3
????25	??O	????H	??????5-Br	??????2-OCH 2	???CH 3
						????26	??O	????H	???????H	??????4-NC 6H 5	????H
????27	??O	????H	???????H	??????2-	????H
						????28	??O	????H	???????H	??????3-	????H
????29	??O	????H	???????H	??????4-	????H
						????30	??O	????H	???????H	??????4-CHOH	????H
????31	??O	????H	???????H	??????4-CO	????H
						????32	??O	????H	???????H	??????4-CH 2	????H
????33	??O	????H	???????H	????4-C(OH)C 6H 5	????H
						????34	??O	????H	???????H	?????4-CHC 6H 5	????H
????35	??O	????H	???????H	????4-CH 2NC 6H 5	????H
						????36	??O	????H	???????H	??4-N(CH 2C 6H 5)CH 2	????H
????37	??S	????H	??????5-NO 2	????????2-S	???Cl
						????38	??S	????H	??????5-NO 2	????????2-S	???CH 3
????39	??O	????H	??????5-NO 2	????????2-O	???CF 3
						????40	??O	????H	??????2-Br	??????5-OCH 2	???CH 3
????41	??O	????H	??2-OCH 2(p-Tol) *	??????5-OCH 2	???CH 3
						????42	??O	???CH 3	??????5-Br	??????2-OCH 2	???CH 3

The p-Tol:4-aminomethyl phenyl

Table 3

Compound number	????????R 7	??????L	????R 3
				?????43	???????5-Br	????2-S	????Cl
?????44	??????5-C 6H 5	????2-S	????Cl
				?????45	????????H	????2-S	????Cl
?????51	???????5-Br	????2-SO	????Cl
				?????52	???????5-Br	????2-SO 2	????Cl
?????53	??????5-CO 2H	????2-S	????Cl
				?????54	??????5-CONEt 2	????2-S	????Cl
?????55	??????5-CONHPh	????2-S	????Cl
				?????56	5-CO (N methyl piperazine)	????2-S	????Cl
?????57	The 5-CO-morpholine	????2-S	????Cl
				?????58	?????5-CO 2CH 3	????2-S	????Cl

Table 4

Compound number	??????????R 7	???????????L-A
			??????59	???????????H	??????????3-OPh
??????60	???????????H	4-S-(4-chloro-phenyl-)
			??????61	4-S-(4-chloro-phenyl-)	5-S-(4-chloro-phenyl-)
??????62	???????????H	5-S-(4-chloro-phenyl-)
			??????63	??????????4-Br	5-S-(4-chloro-phenyl-)
??????64	??????????4-Br	5-SO-(4-chloro-phenyl-)
			??????65	4-CO-(4-chloro-phenyl-)	5-S-(4-chloro-phenyl-)
??????66	4-CO-(4-chloro-phenyl-)	??????5-SO 2-(4-chloro-phenyl-)

Table 5

Compound number	?????????R 6	????????????L-A
			????67	??????5-NO 2	2-S (4-chloro-phenyl-)
????68	??????5-NO 2	2-SO (4-chloro-phenyl-)
			????69	??????5-NO 2	??????2-SO 2(4-chloro-phenyl-)
????70	??????5-NO 2	2-S (3-chloro-phenyl-)
			????71	??????5-NO 2	2-S (2-chloro-phenyl-)
????72	??????5-NO 2	2-S (3, the 4-dichlorophenyl)
			????73	??????5-NO 2	2-S (4-bromophenyl)
????74	??????5-NO 2	2-S (4-p-methoxy-phenyl)
			????75	??????5-NO 2	2-S (4-ethylphenyl)
????76	??????5-NO 2	??????2-SCH 2C 6H 5
			????77	??????5-NO 2	??????2-SOCH 2C 6H 5
????78	??????5-NO 2	??????2-SO 2CH 2C 6H 5
			????79	??????5-NO 2	??????2-SCH 2-(4-chloro-phenyl-)
????80	??????3-NO 2	4-S (4-bromophenyl)
			????81	??????3-NO 2	4-S (4-chloro-phenyl-)
????82	??????3-NO 2	4-SO (4-aminomethyl phenyl)
			????83	??????3-NO 2	??????4-SO 2(4-aminomethyl phenyl)
????84	??????5-NO 2	The 2-S-cyclohexyl
			????85	??????5-NO 2	The 2-SO-cyclohexyl
????86	??????5-NO 2	??????2-SO 2-cyclohexyl
			????87	??????5-Br	2-S (4-aminomethyl phenyl)
????88	??????3-Br	4-S (4-aminomethyl phenyl)
			????89	5-(2-pyridyl)	2-S (4-aminomethyl phenyl)
????90	5-(2-furyl)	2-S (4-aminomethyl phenyl)
			????91	5-(2-furyl)	2-SO (4-aminomethyl phenyl)
????92	5-(2-thienyl)	2-S (4-aminomethyl phenyl)
			????93	5-(2-thienyl)	2-SO (4-aminomethyl phenyl)
????94	???????5-CN	2-S (4-aminomethyl phenyl)
			????95	???????3-CN	4-S (4-aminomethyl phenyl)

Table 5 (continuing)

Compound number	?????R 6	????????????????L-A
			?????96	????5-CH 2OH	2-S (4-aminomethyl phenyl)
?????97	????5-COCH 3	2-S (4-aminomethyl phenyl)
			?????98	????5-COCH 3	2-SO (4-aminomethyl phenyl)
?????99	????6-CF 3	2-S (4-aminomethyl phenyl)
			?????100	????5-CF 3	2-S (4-aminomethyl phenyl)
?????101	????4-CF 3	2-S (4-aminomethyl phenyl)
			?????102	????3-CF 3	2-S (4-aminomethyl phenyl)
?????103	????3-CF 3	2-SO (4-aminomethyl phenyl)
			?????104	????5-OCH 3	2-S (4-aminomethyl phenyl)
?????105	????4-OCH 3	2-S (4-aminomethyl phenyl)
			?????106	????5-Cl	2-S (4-aminomethyl phenyl)
?????107	????5-Cl	2-SO (4-aminomethyl phenyl)
			?????108	????4-Cl	2-S (4-aminomethyl phenyl)
?????109	????3-Cl	4-S (4-aminomethyl phenyl)
			?????110	????5-NO 2	??????????????2-OC 6H 5
?????111	????5-NO 2	2-O (4-aminomethyl phenyl)
			?????112	????5-NO 2	2-O[4-(2 ', 2 '-dimethyl-ethyl) phenyl]
?????113	????5-CF 3	2-SO (4-aminomethyl phenyl)
			?????114	????5-CN	2-SO (4-aminomethyl phenyl)
?????115	????5-NO 2	2-S[4-(trifluoromethyl) phenyl]
			?????116	????5-NO 2	2-SO (4-p-methoxy-phenyl)
?????117	????5-NO 2	2-SO (2-chloro-phenyl-)
			?????118	????5-CO 2H	2-S (4-aminomethyl phenyl)
?????119	????5-NO 2	2-S (2-pyridyl)
			?????120	????5-NO 2	2-SO (4-pyridyl)
?????121	??????H	???????????4-N(C 6H 5)CH 2C 6H 5
			?????122	????5-NO 2	2-S (2-hydroxyethyl)
?????123	????5-NO 2	2-N (propyl group) 2
			?????124	????5-NO 2	??????????????????a
?????125	????2-NO 2	??????????????????b
			?????126	????2-OCH 3	????????????????4-OH
?????127	??????H	???????????????2-OCF 3
			?????129	????5-NO 2	2-S (4-carboxyl phenyl)
?????130	????5-NO 2	??????????????????c
			?????131	????5-NO 2	??????????????????d

Table 5 (continuing)

Compound number	????????????R 6	??????????????L-A
			????132	???????????5-NO 2	2-S (4-methylthio group phenyl)
????133	???????????5-NO 2	2-SO (4-ethylphenyl)
			????134	???????????5-NO 2	2-SO (3-chloro-phenyl-)
????135	???????????5-NO 2	2-SO (3, the 4-dichlorophenyl)
			????136	???????????3-NO 2	4-S (4-bromophenyl)
????137	???????????3-OC 6H 5	4-S (4-bromophenyl)
			????138	???????????3-OCH 3	4-S (4-aminomethyl phenyl)
????139	????????5-CO 2CH 2C 6H 5	2-S (4-aminomethyl phenyl)
			????140	???????????3-CN	4-SO (4-aminomethyl phenyl)
????141	???????????3-Cl	4-SO (4-aminomethyl phenyl)
			????142	????????5-CH(OCH 3) 2	2-S (4-aminomethyl phenyl)
????143	???????????3-Br	4-SO (4-aminomethyl phenyl)
			????144	???????????5-CHO	2-S (4-aminomethyl phenyl)
????145	??????5-CH=CHCO 2C(CH 3) 3	2-S (4-aminomethyl phenyl)
			????146	????????5-CH=CHCO 2H	2-S (4-aminomethyl phenyl)
????147	???????????3-CF 3	4-S (4-aminomethyl phenyl)
			????148	???????????3-CF 3	4-SO (4-aminomethyl phenyl)
????149	????????5-CON(C 2H 5) 2	2-S (4-aminomethyl phenyl)
			????150	????????5-CON(C 2H 5) 2	2-SO (4-aminomethyl phenyl)
????151	?????????????e	2-S (4-aminomethyl phenyl)
			????152	???????????3-OCH 3	2-S (3, the 4-dichlorophenyl)
????153	???????????3-OCH 3	2-SO (3, the 4-dichlorophenyl)
			????154	???????????5-NO 2	2-S (2, the 3-dichlorophenyl)
????155	???????????5-NO 2	2-S (2 4-dichlorophenyl)
			????156	???????????5-NO 2	2-SO (2, the 3-dichlorophenyl)
????157	???????????5-NO 2	2-SO (2,4 dichloro benzene base)
			????158	???????????5-NO 2	???????2-SO 2(2, the 3-dichlorophenyl)
????159	???????????5-NO 2	2-SO2 (2,4 dichloro benzene base)
			????160	???????????5-NO 2	2-S (4-hydroxy phenyl)
????161	???????????5-NO 2	2-S (2, the 4-3,5-dimethylphenyl)
			????162	???????????5-NO 2	???????2-SO 2(3, the 4-dichlorophenyl)
????163	???????????3-NO 2	4-SO (4-chloro-phenyl-)
			????164	???????????3-NO 2	4-S (4-ethylphenyl)
????165	???????????3-NO 2	4-SO (4-ethylphenyl)

Table 5 (continuing)

Compound number	?????R 6	???????????L-A
			????166	????3-NO 2	????2-SO 2(4-ethylphenyl)
????167	????3-NO 2	4-S (3, the 4-dichlorophenyl)
			????168	????3-NO 2	4-SO (3, the 4-dichlorophenyl)
????169	????5-NO 2	2-SO (2, the 3-3,5-dimethylphenyl)
			????170	????5-NO 2	???2-SO 2(2, the 3-3,5-dimethylphenyl)
????171	????5-NO 2	????????????f

Table 6

Synthesizing of III, telomerase inhibitor

Compound of the present invention can adopt technology known in the art and material to synthesize, for example, and senior organic chemistry the 4th edition (Wiley1992); Carey and Sundberg, the senior organic chemistry third edition, A and B volume (Plenum1992); And Green and Wuts, the protecting group second edition (Wiley1991) in the organic synthesis.The initiator of The compounds of this invention can available precursor raw material prepares on standard technique and the market by using, as can be from Aldrich Chemical Co. (Milwaukee, Wis.), Sigma Chemical Co. (St.Louis, Mo.), Lancaster Synthesis (Windham, N.H.), Apin Chemicals, and Ltd. (New Brunswick, N.J.), Ryan Scientific (Columbia, S.C.), and Maybridge (Cornwall, England), Arcos (Pittsburgh, Pa.) and Trans WorldChemicals (Rockville Md.) obtains.

The process of synthetic The compounds of this invention described here may comprise a step or multistep protection and go protection process (as the formation of acetal radical and remove).In addition, the building-up process of following discloses may comprise different methods of purification, for example column chromatography, flash chromatography, tlc (TLC), recrystallization, distillation, high pressure lipuid chromatography (HPLC) (HPLC) etc.Simultaneously, identify and the diversified technology of quantitative chemical reaction product is extensively understood at chemical field, as proton and 13C nuclear magnetic resonance ( ¹H and ¹³CNMR), infrared and ultraviolet spectrometer (IR and UV), X-ray crystallography, ultimate analysis, HPLC and mass spectrograph (MS).Protecting, going protection, purification, evaluation and quantitative methods also is well-known at chemical field.

The classes of compounds of formula I, II and III representative can be synthesized by universal process 1 and the universal process of describing in detail in following embodiment 2.The concrete grammar of synthetic above-mentioned all cpds also is provided in an embodiment.Wherein L is SO or SO ₂Formula IV compound can contain the S compound accordingly by oxidation in inert solvent and synthesize.Inert solvent can be methylene dichloride, methyl alcohol, tetrahydrofuran (THF), ether, hexane, toluene, hexanaphthene etc. and their mixture.Oxygenant can be m-chlorine peroxybenzoic acid, hydrogen peroxide etc.Temperature of reaction is at about-78 ℃ boiling point to liquid, and preferably from 0 ℃ to about 30 ℃, the reaction times was about 0.5 to 12 hour.The anti-tumor activity of telomerase inhibitor among IV, the present invention

Compound exhibits of the present invention goes out the activity that suppresses telomerase activation in the body.Compound of the present invention also can confirm with method described here in external activity.Term " exvivo " is meant and uses the cell of living to test in tissue culture just as used in this.

Be used for discerning a kind of method that the present invention suppresses the compound of telomerase activation relate to test compounds that the cell extract that makes cell, tissue or preferably contain Telomerase or other preparation know several concentration with oneself with the telomerase activation compatible buffers in contact.Measure telomerase activation level corresponding to the test compounds of each concentration, and with the IC of standard technique to compound ₅₀(reducing to its test compound concentration initial or control group level one half in the sample formulation activity) measured.Use other measure the method for inhibition concentration that the present invention suppresses the Telomerase compound with disclosed herein as basic, be conspicuous for those skilled in the art.

Measured the IC of several compounds of the present invention with aforesaid method ₅₀Value finds that they all are lower than 100 μ m.

By using compounds for treating malignant disease described here, compound of the present invention can cause the crisis of Telomerase positive cell line.Use compounds for treating Telomerase positive cell line of the present invention,, also will make the contraction in length of telomere in the processed cell as HEK-293 and HeLa cell.

Compound of the present invention will cause also that Telomerase shortens in the fission process of human tumor cell line, and described clone for example is that ovarian tumor cell is OVCAR-5 and SK-OV-3.But importantly, compare group,, find that the shortening of Telomerase length is as broad as long with contrast material such as methyl-sulphoxide (DMSO) as the BJ cell of inoblast tissue with normal people's cell.Compound of the present invention does not have significant cytotoxicity influence to normal cell when being lower than the amount of 5 μ M.

In addition, The compounds of this invention can be by comparing the activity (IC of Telomerase and other enzyme for the specificity of Telomerase ₅₀) determine that these other enzymes combine similar with the nucleic acid of Telomerase or be similar to external Telomerase correction activity.These enzymes comprise archaeal dna polymerase I, HeLa RNA polymerase II, T3RNA polysaccharase, MMLV ThermoScript II, topoisomerase I, topoisomerase II, terminal transferring enzyme and single-stranded DNA binding protein (SSB).With respect to other screened enzyme, Telomerase had low IC ₅₀The compound of value has specificity to Telomerase.

In vivo, also can measure,, mouse be used compound treatment of the present invention as the OVCAR-5 tumor cell transplantation is gone into nude mice by heteroplastic mouse model, for some time after initial dosage may increase tumor mass, will reduce in a large number but continue to handle the back tumour.On the contrary, will continue to increase with tumor mass expection in the mouse of contrast (as DMSO) processing.

By the above, those skilled in the art will recognize that the present invention also can provide selection to relate to the method for the treatment plan of administration The compounds of this invention.For this purpose, it is helpful using end limit fragment (TRF) analytical method, and wherein the DNA in the tumour cell uses the sequence-specific restriction enzyme except that telomeric sequence digested and analyzes.Behind the dna digestion, separate according to big young pathbreaker's restricted fragment by gel electrophoresis.Then, separated fragment is surveyed at the nucleic acid probe of telomeric sequence with specificity, to contain the length of the terminal fragment of telomeric dna in the working sample cell.By measuring the DNA length of telomere, can estimate the action time of telomerase inhibitor and whether also use other therapy (as operation, chemotherapy and/or radiation).In addition, in treating processes, can carry out after the cell fission telomere length and whether shorten and show the validity of treatment by being determined at.The Telomerase Depressant compositions and the method for V, treatment disease

The present invention also provides and can suppress Telomerase positive cell propagation, treatment cancer and other pharmaceutical composition by the illness that suppresses Telomerase and effectively treat effectively.These pharmaceutical compositions are included in the Telomerase of the present invention that contains the treatment effective dose in acceptable carrier on the pharmacology or the salt and suppress compound.

In one embodiment, the invention provides and suppress Telomerase, suppress the propagation of Telomerase positive cell and method, compound and the composition of treatment mammalian cancer simultaneously.Composition of the present invention is included in and contains the formula I for the treatment of significant quantity on the pharmacology in the acceptable carrier to the compound of V (or on its pharmacology acceptable salt).Compound of the present invention and composition also can be used for the treatment of the illness or the disease of other Telomerase mediation, disorder for example excess proliferative or autoimmunity, for example psoriasis, rheumatoid arthritis, need immune system disorder that immunity system suppresses, to the immune system response of Ruhus toxicifera or malicious oak etc.

In addition, telomerase inhibitor of the present invention comprises United States Patent (USP) 5,656 in conjunction with other anticancer disease medicament, and other telomerase inhibitor in 638,5,760,062,5,767,278,5,770,613 and 5,863,936 will bring benefit to treatment for cancer.The selection of these combinations depends on different factors, includes but not limited to the telomerase activation of the length of aggressiveness, the TRF of type, patient's age of disease and basic health, progression of disease, pending disease cell and the patient tolerance for medicinal composition.For example, at tumor development during to late period, proposed combination Telomerase of the present invention suppresses compound and to reducing tumour size effectively other medicaments and methods of treatment (as radiation, surgical operation, chemotherapy and/or hormonotherapy).In addition, also might with Telomerase of the present invention suppress compound make up other one or more for treatment disease side effect efficacious agents, as anodyne or stimulate the medicament (as G CFS) of patient's autoimmune response.

Wherein a kind of method is that pharmaceutical composition comprises telomerase inhibitor of the present invention and anti-angiogenic agent, as fumidil, fumidil derivative or AGM-1470.A kind of compound in back can obtain from Te Keda chemical company, and aforesaid compound is described in people such as Ingber, December 6, and 1990, " the fumidil synthetic analogues that suppresses vasculogenesis and inhibition tumor growth " is among the natural 348:555-557.Other combinations can include but not limited to make up one or more antitumor agents or additive (as folinic acid or mesna) with telomerase inhibitor of the present invention.

Be fit to include but not limited to the antitumor agent of compound combination of the present invention: alkylating agent comprises alkyl sulfonic ester such as busulphan, improsulfan and piposulfan; Aziridine is as benzodizepa, carboquone, meturedepa and urethimine; Aziridine and methylmelamine are as altretamine, triethylene melamine, triethylene phosphoramide (TEPA), triethylene thiophosphoramide and tri methylol melamine; Mustargen is as Chlorambucil, Chlornaphazine, endoxan, estramustine, ifosfamide, Nitromin hydrochloride, mustargen, melphalan, novembichine, phenesterine, prednimustine, trofosfamide and Uramustine; Nitrosourea, for example carmustine, chlorozotocin, fotemustine, lomustine, nimustine and ranomustine.Other medicament comprises Dacarbazine, Mannomustine, mitobronitol, mitolactol and pipobroman.The related agents of other classification comprises microbiotic, steroids anti-cancer drugs and metabolic antagonist.In addition, also be included as other combinations that those of ordinary skills know.

Other medicament that is suitable for making up The compounds of this invention comprises protein synthesis inhibitor, as toxalbumin, aurin tricarboxylic acid, paraxin, Colicine E3, defence line bacterium ketone, diphtheria toxin, edeine A, ipecamine, erythromycin, ethionine, fluorochemical, 5-fluorotryptophan, fusidinic acid, guanylyl Medronate, guanylyl imidodiphosphate, kantlex, kasugamycin, mocimycin and O-methylthreonine.Other protein synthesis inhibitor comprises modeccin, Xin Meisu, norvaline, U-15800, paromycin, tetracycline, ricin, xanthoglobulin, shiga toxin, showdomycin, sparsomycin, spectinomycin, Streptomycin sulphate, tsiklomitsin, Thiactin and trimethoprim.DNA synthetic inhibitor also can with the composition of compound of the present invention combination as pharmaceutical composition, it comprises alkylating agent, as dimethyl sulphide acid esters, ametycin, mustargen and sulphur mustard, MNNG and NMS; Intercalator such as acridine dye, actinomycin, Zorubicin, anthracene, benzopyrene, ethidium bromide, propidium diiodide-intertwining and other is as replacing the medicament of mycin, T-1384.DNA base analogue such as acyclovir, line purine β-1-D-Arabinoside, methotrexate, aminopterin, 2-aminopurine, the aphid rhzomorph of dwelling, the 8-azaguanine, azaserine, the 6-azauracil, 2-azido--2-deoxynucleoside, 5-bromine Deoxyribose cytidine, cytosine(Cyt) β-1-D-Arabinoside, diazonium oxygen nor-leucine, di-deoxynucleoside, 5-fluorine Deoxyribose cytidine, 5-fluorodeoxyuridine, 5 FU 5 fluorouracil, hydroxyurea and Ismipur also can be treated with compound combination of the present invention.Topoisomerase enzyme inhibitor is as tonka-bean toxin, Nalidixic Acid, Vulkamycin. PA-93 and oxolinic acid; Cell division inhibitor comprises Omaine, colchicine, vincaleucoblastine and vincristine(VCR); And rna synthesis inhibitor comprises amanitin, cordycepin (3 '-Desoxyadenosine), dichloro ribofuranosyl benzoglyoxaline, Rifampin, streptovaricin and the lydimycin of dactinomycin, α-amanitin and other mould, also can be in conjunction with compound of the present invention so that pharmaceutical composition to be provided.

In another embodiment, the present invention includes compound and composition, wherein telomerase inhibitor or in conjunction with cytotoxic agent or and covalent bonds, this cytotoxic agent has been incorporated on the target compound, as monoclonal antibody (as mouse or human monoclonal antibodies).It should be understood that a kind of combination in back can make cytotoxic agent high degree of specificity ground import in the cancer cells.Therefore, cytotoxic agent (free form promptly) will only can be present in the cell that is hit by antibody target.Certainly, telomerase inhibitor of the present invention also can be in conjunction with having the active monoclonal antibody of anticancer therapy.

Except using telomerase inhibitor of the present invention treatment Mammals is the disease of feature with the telomerase activation, and as in this announcement, it is in the agricultural plants pathogenic bacteria biology of feature that telomerase inhibitor also can be used to the telomerase activation.These biologies comprise nematode, as have the Ceanorhabditis elegans of telomerase activation through observation, also have fungi.Show according to the DNA that measures fungi Ustilago maydis that to have series connection TTAGGG multiple telomere be to keep by Telomerase, learn that fungi has telomerase activation.Simultaneously, protozoon has the TTAGGG telomere and causes people's disease.Telomerase of the present invention suppresses plant and the soil that compound can be utilized separately for the phytopathogen biological infection with telomerase activation, or is used for the medicament of controlling plant disease in conjunction with other telomerase inhibitor and/or other.Measure these phytopathogen biologies of control pharmaceutical composition and with and appropriate manufacture method for the agriculture field those of ordinary skill, be known.

Demonstrate for nematode, protozoon and mensuration with telomerase activation fungi that telomerase inhibitor provided by the present invention can be used for treating the people and the animal doctor goes up the animal of perception interest such as the nematode infections of cat and dog.The nematode infections of humans and animals are the form of hookworm and roundworm infection often, and cause the serious secondary disease of host such as meningitis, myocarditis and various nervous system disease.Therefore, these Telomerases of the present invention suppress compound to be used separately or in conjunction with other telomerase inhibitor and/or other therapeutical agent, can be used to control the infection of people and animal nematode, protozoon and fungi.

Usually, the suitable effective dose of The compounds of this invention is 0.001 to 1000 milligram of per kilogram of body weight every day, preferably in 0.001 to 100 milligram of per kilogram of body weight every day, still preferably in 0.01 to 100 milligram of per kilogram of body weight every day, more preferably in 0.1 to 10 milligram of per kilogram of body weight every day.These dosage preferably in one day reasonable time divide at interval one, two, three, four or more times take, perhaps take by continuous pump.These sub-doses can the administration of dosage unit formulation, and per unit dosage for example comprises 5 to 10,000 milligrams, preferably at 10 to 1000 milligrams activeconstituents.Preferably, dosage once a day equals TID at least, perhaps carries out with continuous pump drug delivery system.

The pharmaceutical composition that is used for these treatments can have various ways.They comprise for example solid, semisolid and liquid dosage form, as tablet, pill, powder, liquor agent or suspensoid, liposome and injectable and pourable solution.Preferred formulation depends on the expection mode of administration and treatment.As well known in the art, pharmaceutical composition also preferably includes acceptable carrier and assistant agent on the conventional pharmacology.Referring to as REMINGTON ' S PHARMACEUTICAL SCIENCES, Mack publishing company, Easton, Pa., the 17th edition (1985).Preferably by oral or parenteral route (comprising in subcutaneous, intramuscular, intravenously, the epidermis) administration.Preferred administering mode is oral.Methods of treatment of the present invention and medicament can be followed certainly or use in conjunction with other method and medicament for the treatment of specified disease or disease condition.

Although can use activeconstituents of the present invention separately, preferably use the part of a kind of therapeutical agent as formula of medicine or composition.Composition of the present invention is included in the telomerase activation of the present invention that contains at least a treatment effective dose in one or more medicines or the treatment acceptable carrier to be suppressed compound and optionally makes up other therapeutic component.The difference of preparing these compositions is for example considered to be described in people (editor) GOODMAN AND GILMAN ' S such as Gilman: therapeutic pharmacological basis, the 8th edition, Pergamon press (1990); And among above-mentioned REMINGTON ' S.At this medication is discussed, as form for oral, intravenously, intraperitoneal, intramuscular and other administration.Usually, the administration medicine method for compositions is the purpose that prevents and/or treats, and can be local, parenteral route or oral.The preferred oral administration.According to medication, pharmaceutical composition can the administration of multiple dosage unit formulation.As mentioned above, be suitable for oral dosage unit formulation and comprise powder, tablet, pill and capsule.

Can use topical compound of the present invention, its mode can be through skin with drug transport to patient's systemic circulation.Skin part comprises the anatomical area that is used for transdermal administration, as forelimb, belly, chest, back, buttocks and mastodial zone.With the topical preparation of inclusion compound or be placed on the skin for the transdermal delivery device of drug compound, thus can be to percutaneous drug delivery compound of the present invention.In arbitrary embodiment, drug administration carrier is with easy placement and to be fixed in skin comfily be foundation, carries out appearance design, moulding and size design.

Multiple transdermal delivery device can be used for compound of the present invention.For example, can use a simple adhesion sheet, it comprises support material and vinylformic acid tackiness agent.Medicine and any penetration enhancer can be formulated in the adhesion cast solution.Adhesion cast solution can cast directly on the support material or be coated in and form coating on the skin.Referring to for example the 4th, 310,509,4,560,555 and 4,542, No. 012 United States Patent (USP).

In other embodiments, compound of the present invention is transported by the fluid accumulation device that is administered systemically.These systems generally include support material, diaphragm, with acrylic tackiness agent and peeling liner.Diaphragm is fixed on the support material to form accumulating layer.Mix in the accumulating layer after medicine or compound and any carrier, promotor, stablizer, the jelling agent etc.Referring to for example the 4th, 597,961,4,485,097,4,608,249,4,505,891,3,843,480,3,948,254,3,948,262,3,053,255 and 3,993, No. 073 United States Patent (USP).

The matrix type patch that comprises supporting layer, medicine/penetration enhancer matrix, diaphragm and tackiness agent also can be used for percutaneous dosing compound of the present invention.Substrate material generally includes polyurethane foam.Medicine, any promotor, carrier, stablizer etc. mix with foam precursors.Make foam curing become sticking resilient matrix, it can be directly fixed on the support material.Referring to for example the 4th, 542,013,4,460,562,4,466,953,4,482,534 and 4,533, No. 540 United States Patent (USP)s.

Simultaneously, the present invention also comprises the preparation that local skin is used, and it contains compound of the present invention, and its concentration is mixed the acceptable topical vehicle of nontoxic pharmacology simultaneously usually 0.001 to 10%.These topical formulations can by mix according to activeconstituents of the present invention and be normally used for partially doing, the conventional medicine thinner and the carrier of liquid and emulsion prepare.Cream and emulsion can mix with liquid or oily matrix on the basis of suitable multiviscosisty and/or jelling agent.These matrix can comprise water and/or oil, as whiteruss or vegetables oil, as soya-bean oil or Viscotrol C.According to the character of matrix, the viscosifying agent that can be used comprises soft wax, aluminum stearate, cetostearyl alcohol, propylene glycol, polyoxyethylene glycol, lanolin, hydrogenated lanolin, beeswax etc.

Lotion can with the preparation of liquid or oily matrix, and also comprise following one or more usually: stablizer, emulsifying agent, dispersion agent, suspension agent, viscosifying agent, tinting material, perfume compound etc.Powder can be in conjunction with any suitable powder matrix, as talcum, lactose, starch etc.Drops can or comprise the non-aqueous matrix of one or more dispersion agents, suspension agent, solubilizing agent etc. in conjunction with aqueous matrix.The topical application of The compounds of this invention also is suitable for treating numerous disease, as skin carcinoma and dermatophytid infection (pathogenic fungus is expressed telomerase activation usually).

Also can comprise one or more sanitass or fungistat according to medicinal composition for part use of the present invention, as methyl hydroxybenzoate, nipasol, parachlorometacresol, benzalkonium chloride etc.The pharmaceutical composition of local application also can comprise other activeconstituents, as biocide, especially microbiotic, narcotic, pain killer and pruritus.

Compound of the present invention also can be transported by mucous membrane.Transmucosal delivery (being hypogloeeis, cheek and intestines) administration makes active substance effectively enter systemic circulation, has reduced the instantaneous metabolism of liver and intestines wall flora simultaneously.The formulation of mucosal (as tablet, suppository, ointment, pesseulum, diaphragm and powder) all contacts with mucous membrane and disintegration and/or dissolving rapidly usually, is absorbed rapidly by system with permission.It should be noted that this kind method even can be used for the situation that patient can not digest the oral administration composition.Telomerase inhibitor simultaneously of the present invention is carried and is enhanced, and can select to be administered to the pharmaceutical composition of mucous membrane, for example, just can use suppository to come the administration telomerase inhibitor for colorectal carcinoma.

For being administered to cheek or hypogloeeis film, use oral preparations usually, for example lozenge, tablet or capsule.The method for preparing these preparations is known in this area, and it includes but not limited to, medicament is added in the ready-formed tablet; Inert filler, tackiness agent and medicament or the material that comprises this medicament are carried out cold compaction (at United States Patent (USP) 4,806,356 in describe); And encapsulate.Another kind of oral preparations can be applied to oral mucosa with tackiness agent, and described tackiness agent for example is the derivatived cellulose hydroxy propyl cellulose, for example at United States Patent (USP) 4,940, described in 587.This cheek adhesion preparation when being used for buccal mucosa, making medicament controllably discharge into the oral cavity and passes through buccal mucosa.

Parenteral administration is a feature with the injection usually, can be subcutaneous, intramuscular or intravenous injection.Therefore, the invention provides the pharmaceutical composition of intravenously administrable, it comprises that the solution of compound of the present invention is dissolved or is suspended in the acceptable carrier.Injection can adopt conventional form, perhaps be liquor or is suspension, should be able to dissolve or be suspended in the solid form in the liquid before injection, perhaps is emulsion.The vehicle that is fit to for example is water, buffered water, salt solution, glucose, glycerine, ethanol etc.These pharmaceutical compositions adopt the conventional sterilising technology sterilization of knowing, as sterilising filtration.The solution that obtains thus can be packaged so that use or freeze-drying, freeze dried medicament mixes with aseptic solution before use.In addition, if be ready, pharmaceutical composition to be administered also can comprise a spot of non-toxic auxiliary substances, for example wetting agent or emulsifying agent, pH buffer solvent etc., for example sodium acetate, Arlacel-20, triethanolamine oleate etc.These preparations can be used for treating ovarian cancer.

The method of another kind of parenteral administration is that slowly release or sustained release system are implanted in utilization, can keep the dosage of a fixing horizontal like this.Referring to as United States Patent (USP) 3,710,795.

But the liquid medicine composition of administration can pass through technology preparations such as dissolving, dispersion, aforesaid active compound and alternative medicine assistant agent are joined in the vehicle, for example in water, salt solution, D/W, glycerine, ethanol, sweet oil and other lipophilicity solvent etc., to form solution or suspension.If desired, treat that the pharmaceutical composition of administration can comprise a spot of nontoxic auxiliary substance, as wetting agent or emulsifying agent, pH buffer solvent etc., for example sodium acetate, Arlacel-20, triethanolamine oleate etc.The concrete grammar for preparing these formulations is well known to those of ordinary skill in the art; For example, referring to above-mentioned REMINGTON ' S PHARMACEUTICALSCIENCES.These pharmaceutical compositions or the preparation for the treatment of administration comprise the active compound of the present invention for the treatment of effective dose.

For solids composition, can use conventional non-toxic solid carrier, comprise the mannitol, lactose, starch, Magnesium Stearate, sodium asccharin, talcum, Mierocrystalline cellulose, glucose, sucrose, magnesiumcarbonate of pharmaceutical grade for example etc.For oral administration, acceptable nontoxic composition can be by with any normally used vehicle on the pharmacology, as above listed carrier and 0.1-95%, preferably be about 20% activeconstituents mixing and preparing.

The composition that administration comprises The compounds of this invention can be used for prevention and or therapeutic purpose.In treatment is used, the patient that pharmaceutical composition is used for having fallen ill, as described above, consumption is the dosage that is enough to cure or alleviate to small part disease symptoms and complication thereof.The dosage that is enough to finish treatment is defined as " treatment significant quantity or dosage ".Effectively dosage depends on the severity of disease and patient's body weight and basal conditions.

Except interior therapeutic, compound of the present invention and composition can also be used for ex vivo to reach result of treatment, for example for leukemic patient.In this kind application, cell to be treated, for example blood or medullary cell are removed and are handled with the The compounds of this invention of effective dose in the patient body.These cells are retracted in the patient body after processing.Compare with other method, this process can allow cell long-time or be exposed in the therapeutical agent of high density.

In case patient's condition improved, for example the situation of cancer patient is eased, and if necessary, then gives patient's administration maintenance dose.Subsequently, owing to the effect of treatment, can reduce the dosage or the frequency of medication, or the two is reduced to the level of keeping this improvement jointly.When remission to the expection level the time, can stop the treatment.But, when patient disease's symptomatic recurrence, will treat once more.

In prevention (as chemoprophylaxis) is used, the composition that contains The compounds of this invention can be delivered medicine to a certain specified disease of easy infection or the patient of ill danger is arranged.The dosage of this medication is called as " prevention significant quantity or dosage ".In such application, concrete dosage also will depend on patient's healthy state and body weight and decide.

For the those of ordinary skill in the art who has read this specification sheets, it is evident that, the invention provides human and the valuable medicament of RNA component of telomerase.Described above only is some explanations limited and illustrative illustrative specific compound, should not be construed as limitation of the scope of the invention.Other characteristics of the present invention and advantage will obtain explanation from the following examples and claim.

Embodiment

The following examples have been carried out concrete description for the present invention is described, and provide simultaneously to suppressing telomerase activation compound identification and method for measuring, so that those of ordinary skill in the art understands and applies the invention.Embodiment should not be considered to limit in any form the present invention.

Used following universal process among the embodiment 1-24 below: universal process 1: coupling 2,4-thiazolidinedione (TZD) is an aldehyde.

With the aldehyde (1 equivalent), 2 that suitably replaces, 4-thiazolidinedione (1.5 equivalent) and send the solution of pyridine (1.5 equivalent) in EtOH to be heated to 90 ℃ of C lasting 2-16 hour.The solution of gained 1N HCl acidified aqueous solution.The solid matter of gained filters back water and/or ether washing, obtains pure products.Another kind of scheme is, the acidifying aqueous solution is with chloroform or ethyl acetate extraction, and organic phase washes with water, uses Na ₂SO ₄Drying, concentrating under reduced pressure obtains crude product, and this solid crude product is purified in suitable solvent with column chromatography or recrystallization method.

Reaction is carried out in 0.5 mmole level usually.

Embodiment 1

Preparation 5-(2-(3, the 4-dichlorophenyl) benzylidyne) thiazolidine-2, the 4-diketone

Steps A: preparation aldehyde

To 2-bromobenzaldehyde (1 equivalent) and 3, add K in the acetonitrile solution of 4-dichlorophenyl boric acid (1.2 equivalent) ₂CO ₃(1.5 equivalent) adds Pd (PPh subsequently ₃) ₄(catalyzer).Reaction is heated to 75 ℃, continues to stir 16 hours, and reactant dilutes through EtOAc afterwards, through water washing, and Na ₂SO ₄Drying, concentrating under reduced pressure, the thick aldehyde that obtains is purified with column chromatography.Step B: universal process 1

Obtain 5-(2-(3, the 4-dichlorophenyl) benzylidyne) thiazolidine-2,4-diketone after the universal process 1.

NMR(DMSO-d ₆,δ):7.70(d,1H),7.76(d,1H),7.59-7.42(m,5H),7.28(dd,1H)

MS (ESI) calculates: 349, and actual measurement: 348 (M-H) ^-

Embodiment 2

Preparation 5-(3-(3, the 4-dichlorophenyl) benzylidyne) thiazolidine-2, the 4-diketone Steps A: preparation aldehyde

Steps A by embodiment 1 prepares required aldehyde with the 3-bromobenzaldehyde.Step B: universal process 1

Obtain 5-(3-(3, the 4-dichlorophenyl) benzylidyne) thiazolidine-2,4-diketone after the universal process 1.

NMR(DMSO-d ₆,δ):7.98(s,1H),7.94(s,1H),7.84(s,1H),7.79(d,1H),

7.74-7.66(m,2H),7.63-7.53(m,2H)

MS (ESI) calculates: 349, and actual measurement: 348 (M-H) ^-

Embodiment 3

Preparation 5-(4-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2, the 4-diketone

Steps A: preparation aldehyde

In the acetonitrile solution of 4-hydroxy benzaldehyde, add K ₂CO ₃(1.5 equivalent) adds 3 subsequently, 4-dichlorobenzyl chloride (3 equivalent).The reaction mixture of gained is heated to 90 ℃, continues 2-16 hour, and filters precipitation simultaneously.Filtrate is diluted with EtOAc, washes Na with water ₂SO ₄Drying, concentrating under reduced pressure obtains crude product then.This product is by CH ₂Cl ₂Recrystallization is purified in/hexane solvent the system, to obtain pure aldehyde.Step B: universal process 1

Obtain 5-(4-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2,4-diketone after the universal process 1.

NMR(DMSO-d ₆,δ):7.69(d,2H),7.62(d,1H),7.52(d,2H),7.41(d,1H),

7.12(d,2H),5.20(s,2H)

MS (ESI) calculates: 379, and actual measurement: 378 (M-H) ^-

Embodiment 4

Preparation 5-(2-(3, the 4-dichloro-benzyloxy)-benzylidyne) thiazolidine-2, the 4-diketone

Steps A: preparation aldehyde

Process by embodiment 3 steps A prepares required aldehyde from 2-hydroxy phenyl aldehyde.Step B: universal process 1

Obtain 5-(2-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2,4-diketone after the universal process 1.

Embodiment 5

Preparation 5-(4-(3,4-dichloro-benzoyl amino)-benzylidyne) thiazolidine-2, the 4-diketone Steps A: preparation aldehyde

Add PTSA (catalyzer) in the tri-methyl ortho formate solution of 4-nitrobenzaldehyde (1 equivalent), resulting mixture heating up refluxes and continues 3-5 hour, simultaneously with the reaction mixture concentrating under reduced pressure.Resistates dissolves in ether, uses NaHCO ₃And water washing, use Na ₂SO ₄Drying, concentrating under reduced pressure is to obtain dimethylacetal.

Thick dimethylacetal is dissolved among the EtOH, adds Raney's nickel subsequently.In the time of 0 ℃, introversive this mixture dripped hydrazine hydrate (5 equivalent) to control its boiling in 15 minutes.Reactant is heated to room temperature, and restir 3 hours filters away catalyzer then.Filtrate decompression concentrates.Resistates is dissolved among the EtOAc again, washes with water, use Na ₂SO ₄Drying, concentrating under reduced pressure is to obtain thick 4-aminobenzaldehyde dimethylacetal.

At 0 ℃, to the CH of 4-aminobenzaldehyde dimethylacetal ₂Cl ₂Add TEA (2 equivalent) in the solution, add 3 afterwards, 4-dichlorobenzoyl chloride (1.5 equivalent).The mixture of gained at room temperature stirs 2-16 hour, and water and EtOAc dilution.Separate organic layer, wash with water, afterwards concentrating under reduced pressure.Resistates CHCl ₃Dissolving adds the 2N HCl aqueous solution subsequently.Stirred the mixture 1 hour, and isolated organic phase, use saturated NaHCO ₃Na is used in solution and water washing ₂SO ₄Drying, concentrating under reduced pressure is to obtain thick aldehyde.This aldehyde can obtain pure 4-(3,4-dichloro-benzoyl amino) phenyl aldehyde with column chromatography or recrystallization method from suitable solvent systems.Step B: universal process 1

Obtain 5-(2-(3, the 4-dichloro-benzyloxy)-benzylidyne) thiazolidine-2 behind the universal process 1, the 4-diketone.

NMR(DMSO-d ₆,δ):12.50(br?s,1H),10.60(s,1H),8.18(d,1H),7.90-

7.86(m,3H),7.78(d,1H),7.70(s,1H),7.56(d,1H)。

MS (ESI) calculates: 392, and actual measurement: 391 (M-H) ^-

Embodiment 6

Preparation 5-(4-(N-3,4-dichlorophenyl urea groups) benzylidyne) thiazolidine-2, the 4-diketone

Steps A: preparation aldehyde

Add PTSA (catalyzer) in the tri-methyl ortho formate solution of 4-nitrobenzaldehyde (1 equivalent), resulting mixture heating up refluxes and continues 3-5 hour, simultaneously with the reaction mixture concentrating under reduced pressure.Resistates is dissolved in the ether, uses NaHC0 ₃And water washing, use Na ₂SO ₄Drying, concentrating under reduced pressure is to obtain dimethylacetal.

Thick dimethylacetal is dissolved among the EtOH, adds Raney's nickel (catalyzer) subsequently.In the time of 0 ℃, hydrazine hydrate (5 equivalent) is added drop-wise in this mixture to control its boiling within 15 minutes.Reactant is heated to room temperature, and restir filters out catalyzer after 3 hours, filtrate decompression is concentrated.Resistates is dissolved among the EtOAc again, washes with water, use Na ₂SO ₄Drying, concentrating under reduced pressure is to obtain thick aminobenzaldehyde dimethylacetal.

In the acetonitrile solution of aminobenzaldehyde dimethylacetal (1 equivalent), add solid 3,4-dichlorophenyl isocyanate (2 equivalent).The mixture of gained stirred 6-16 hour, with the EtOAc dilution, washed with water simultaneously, used Na ₂SO ₄Drying, concentrating under reduced pressure is to obtain thick urea.With this urea at CH ₂Cl ₂Middle dissolving adds the 50%TFA aqueous solution afterwards again.The mixture that stirs gained separated organic phase in 2 hours simultaneously, used saturated NaHCO ₃Na is used in the aqueous solution and water washing ₂SO ₄Drying, concentrating under reduced pressure is to obtain crude product.Step B: universal process

Obtain 5-(4-(N-3,4-dichlorophenyl urea groups) benzylidyne) thiazolidine-2,4 diketone after the universal process 1.

NMR(DMSO-d ₆,δ):9.40(d,2H),8.58(s,1H),7.84(d,1H),7.76(d,2H),

7.54(d,2H),7.48(d,1H),7.30(dd,1H)

MS (ESI) calculates: 407, and actual measurement: 406 (M-H) ^-

Embodiment 7

Preparation 5-(2-(N-3,4-dichlorophenyl urea groups) benzylidyne) thiazolidine-2, the 4-diketone

Steps A: preparation aldehyde

Prepare required aldehyde by the process of using embodiment 6 steps A from the 2-nitrobenzaldehyde.Step B: universal process 1

Obtain 5-(2-(N-3,4-dichlorophenyl urea groups) benzylidyne) thiazolidine-2,4-diketone after the universal process 1.

NMR(DMSO-d ₆,δ):10.10(Br?s,1H),7.70(d,1H),7.62(d,1H),7.42(dd,1H),

7.26-7.22(m,2H),6.94(t,1H),6.70(d,1H),5.86(d,1H)。

Embodiment 8

Preparation 5-(2-(N-3,4-dichlorophenyl carbamyl) benzylidyne) thiazolidine-2, the 4-diketone Steps A: preparation 5-(2-carboxyl benzylidyne) thiazolidine-2,4-diketone

Method by universal process 1 prepares 5-(2-carboxyl benzylidyne) thiazolidine-2,4-diketone from the 2-carboxyl benzaldehyde.Step B: the meticulous processing of carboxylic group

With 5-(2-carboxyl benzylidyne) thiazolidine-2, the 4-diketone is at SO ₂Cl ₂Middle dissolving adds 1-2 subsequently and drips DMF.The mixture heating up of gained arrives about 80 ℃ of lasting 15-30 minutes, simultaneously concentrating under reduced pressure.Resistates dissolves in THF, and is added drop-wise to 3, in the mixing solutions of 4-dichlorphenamide bulk powder (1.5 equivalent) and TEA (2 equivalent).This mixture of restir 1-2 hour is with the solid filtering in the reaction mixture.Filtrate decompression is concentrated solid water and the ether washing that obtains, to obtain pure products.

NMR(DMSO-d ₆,δ):10.80(Br?s,1H),8.06(d,1H),7.93(s,1H),7.73-

7.54(m,6H)。

MS (ESI) calculates: 392, and actual measurement: 391 (M-H) ^-

Embodiment 9

Preparation 5-(3-(N-3,4-dichlorophenyl carbamyl) benzylidyne) thiazolidine-2, the 4-diketone

Method according to embodiment 8 prepares 5-(3-(N-3,4-dichlorophenyl carbamyl) benzylidyne) thiazolidine-2,4-diketone by the 3-carboxyl benzaldehyde in two steps.

NMR(DMSO-d ₆,δ):8.12(d,1H),8.08(s,1H),7.97(d,1H),7.82(s,1H),

7.77(d,1H),7.72-7.64(m,2H),7.60(d,2H)。

MS (ESI) calculates: 392, and actual measurement: 391 (M-H) ^-

Embodiment 10

Preparation 5-(4-(N-3,4-dichlorophenyl carbamyl) benzylidyne) thiazolidine-2, the 4-diketone

Method according to embodiment 8 prepares 5-(4-(N-3,4-dichlorophenyl carbamyl) benzylidyne) thiazolidine-2,4-diketone by the 4-carboxyl benzaldehyde.

NMR(DMSO-d ₆,δ):10-60(Br?s,1H),8.12(s,1H),8.02(d,2H),7.82(s,

1H),7.71(d,3H),7.58(d,1H)。

MS (ESI) calculates: 392, and actual measurement: 391 (M-H) ^-

Embodiment 11

Preparation 5-(4-(N-3,4-diChloroaniline methanoyl) benzylidyne) thiazolidine-2, the 4-diketone

Steps A: preparation 5-(4-hydroxyl benzylidyne) thiazolidine-2,4-diketone

Method by universal process 1 prepares 5-(4-hydroxyl benzylidyne) thiazolidine-2,4-diketone from the 4-hydroxy benzaldehyde.Step B: the meticulous processing of hydroxyl

To 5-(4-hydroxyl benzylidyne) thiazolidine-2, add K in the acetonitrile solution of 4-diketone (1 equivalent) ₂CO ₃(xs), add solid 3 subsequently, 4-dichlorophenyl isocyanate (2 equivalent).The mixture of gained stirred 6-16 hour, afterwards with solid filtering, obtained pure products after washing with water.

NMR(DMSO-d ₆,δ):12.60(Br?s,1H),10.60(br?s,1H),7.76(d,2H),7.62

(d,2H),7.56(dd,1H),7.41(dd,1H),7.37(dd,1H)。

MS (ESI) calculates: 408, and actual measurement: 407 (M-H) ^-

Embodiment 12

Preparation 5-(4-(3,4-dichlorophenoxy carbonyl) benzylidyne) thiazolidine-2, the 4-diketone

With 5-(4-carboxyl benzylidyne) thiazolidine-2,4-diketone (from embodiment 8 steps A) is at SO ₂Cl ₂Middle dissolving adds 1-2 subsequently and drips DMF.The mixture heating up of gained arrives about 80 ℃ of lasting 15-30 minutes, and with the reaction mixture concentrating under reduced pressure.Resistates dissolves in THF, and is added drop-wise to 3, in the mixing solutions of 4-chlorophenesic acid (1.5 equivalent) and TEA (2 equivalent).Stirred resulting mixture 1-2 hour, with the solid filtering in the reaction mixture.Solid water that filtrate decompression obtains after concentrating and ether washing are to obtain pure ester.Use another kind of method, at 5-(4-carboxyl benzylidyne) thiazolidine-2,4-diketone (1 equivalent) and 3, the CH of 4-chlorophenesic acid (1 equivalent) ₂Cl ₂Add DCC (1 equivalent) in the solution.Resulting reaction mixture stirs 16 hours after-filtration, the filtrate water washing, and the crude product that obtains behind the concentrating under reduced pressure is purified through recrystallization.

NMR(DMSO-d ₆,δ):8.1?8(d,2H),7.80(d,2H),7.77-7.68(m,3H),7.38-

7.33(m,1H)。

MS (ESI) calculates: 393, and actual measurement: 392 (M-H) ^-

Embodiment 13

Preparation 5-(2-(3,4-dichlorophenoxy carbonyl) benzylidyne) thiazolidine-2, the 4-diketone

Method by embodiment 12 prepares 5-(2-(3,4-dichlorophenoxy carbonyl) benzylidyne) thiazolidine-2,4-diketone.

NMR(DMSO-d ₆,δ):8.28(s,1H),8.22(d,1H),7.80(t,1H),7.76(d,1H),

7.73(d,1H),7.64(d,1H),7.38(dd,1H)。

MS (ESI) calculates: 393, and actual measurement: 392 (M-H) ^-

Embodiment 14

Preparation 5-(2-(3,4-dichlorophenylacetic acid base) benzylidyne) thiazolidine-2, the 4-diketone Steps A: preparation 5-(2-hydroxyl benzylidyne) thiazolidine-2,4-diketone

Prepare 5-(2-hydroxyl benzylidyne) thiazolidine-2,4-22 ketone by universal process 1 from the 2-hydroxy benzaldehyde.Step B: the meticulous processing of oh group

With 3, the 4-fenac is at SO ₂Cl ₂Middle dissolving adds several DMF subsequently.The mixture heating up to 80 of gained ℃ lasting 15-30 minute, with the reaction mixture concentrating under reduced pressure.Resistates dissolves in THF, and (the 4-hydroxyl benzylidyne) thiazolidine-2 that slowly joins 5-, in the THF solution of 4-diketone (1.5 equivalent) and TEA (1.5 equivalent).Stirred the mixture 1-2 hour, the solid filtering in the reaction mixture is gone out.Filtrate decompression concentrates and obtains lurid solid.This solid is dissolved with EtOAc, use saturated K ₂CO ₃Solution washing.Isolate organic phase, use Na ₂SO ₄Drying, concentrating under reduced pressure is to obtain pure products.

NMR(DMSO-d ₆,δ):12.65(Br?s,1H),7.65(d,1H),7.57(d,1H),7.55(s,1H),

7.54-7.6(m,2H),7.41(d,1H),7.37(dd,1H),7.30(d,1H),4.00(s,2H)。

MS (ESI) calculates: 407, and actual measurement: 406 (M-H) ^-

Embodiment 15

Preparation 5-(3-(3,4-dichlorophenylacetic acid base) benzylidyne) thiazolidine-2, the 4-diketone

Method with embodiment 14 prepares 5-(3-(3,4-dichlorophenylacetic acid base) benzylidyne) thiazolidine-2,4-diketone by the 3-hydroxy benzaldehyde.

NMR(DMSO-d ₆,δ):12.60(Br?s,1H),7.74(s,1H),7.66(d,1H),7.59(d,1H),

7.53(t,1H),7.45(d,1H),7.38-7.33(m,2H),7.24(d,1H),4.00(s,2H)。

MS (ESI) calculates: 407, and actual measurement: 406 (M-H).

Embodiment 16

Preparation 5-(4-(3,4-dichlorophenylacetic acid base) benzylidyne) thiazolidine-2, the 4-diketone

Method with embodiment 14 prepares 5-(4-(3,4-dichlorophenylacetic acid base) benzylidyne) thiazolidine-2,4-diketone by the 4-hydroxy benzaldehyde.

NMR(DMSO-d ₆,δ):7.76(s,1H),7.66(d,1H),7.60(m,3H),7.36(dd,1H),

7.28(d,2H),4.00(s,2H)。

MS (ESI) calculates: 407, and actual measurement: 406 (M-H) ^-

Embodiment 17

Preparation 5-(2-(3,4-dichlorobenzoic acid base) benzylidyne) thiazolidine-2, the 4-diketone

Steps A: preparation 5-(2-hydroxyl benzylidyne) thiazolidine-2,4-diketone

Prepare 5-(2-hydroxyl benzylidyne) thiazolidine-2,4-diketone by universal process 1 from the 2-hydroxy benzaldehyde.Step B: the acidylate of oh group

With 3, the THF solution of 4-chloro-benzoyl chloride slowly adds 5-(hydroxyl benzylidyne) thiazolidine-2, in the THF solution of 4-diketone (1.5 equivalent) and TEA (1.5 equivalent).The mixture 1-2 that stirring obtains hour, the solid filtering in the reaction mixture is removed.Filtrate decompression concentrates and obtains lurid solid.This solid is dissolved with EtOAc, use saturated K ₂CO ₃Solution washing.Isolate organic phase, use Na ₂SO ₄Drying, concentrating under reduced pressure is to obtain pure products.

NMR(DMSO-d ₆,δ):8.30(s,1H),8.09(dd,1H),7.90(d,1H),7.68-7.62(m,

1H),7.42-7.28(m,3H),7.18(s,1H)。

MS (ESI) calculates: 393, and actual measurement: 392 (M-H) ^-

Embodiment 18

Preparation 5-(3-(3,4-dichlorobenzoic acid base) benzylidyne) thiazolidine-2, the 4-diketone

Method with embodiment 17 prepares 5-(3-(3,4-dichlorobenzoic acid base) benzylidyne) thiazolidine-2,4-diketone by the 3-hydroxy benzaldehyde.

NMR(DMSO-d ₆,δ):8.27(s,1H),8.06(d,1H),7.86(d,1H),7.52-7.38(m,

3H),7.24(s,1H),7.20(d,1H)。

MS (ESI) calculates: 393, and actual measurement: 392 (M-H) ^-

Embodiment 19

Preparation 5-(4-(3,4-dichlorobenzoic acid base) benzylidyne) thiazolidine-2, the 4-diketone

Method with embodiment 17 prepares 5-(4-(3,4-dichlorobenzoic acid base) benzylidyne) thiazolidine-2,4-diketone by the 4-hydroxy benzaldehyde.

NMR(DMSO-d ₆,δ):8.26(d,1H),8.04(dd,1H),7.85(d,1H),7.58(d,2H),

7.36(d,2H),7.39-7.34(m,3H)。

MS (ESI) calculates: 393, and actual measurement: 392 (M-H) ^-

Embodiment 20

Preparation 5-(3,4-two-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2, the 4-diketone Steps A: preparation aldehyde

(415 μ l 3mmol) join 138mg (1mmol) 3, in 4-dichloro hydroxy benzaldehyde and the mixture of 690mg salt of wormwood in DMF with 3,4 dichlorobenzyl chlorides.The mixture heating up to 70 of gained ℃ also stirs and spends the night.Reaction mixture dilutes with the water of 20ml, and mixture is filtered.It is also air-dry to collect the white precipitate that filters generation, obtains 426mg (93%) purpose product.

¹H NMR (part) (400MHz, DMSO-d ₆) δ 9.9 (s, 1H), 5.24 (s, 2H), 5.19 (s, 2H).Step B: universal process 1

NMR(400MHz,DMSO-d ₆,δ):7.68-7.66(m,H),7.65(s,1H),7.63-7.59(m,2H),7.41-7.37(m,2H),7.21-7.20(m,1H),7.18-7.15(m,2H)。

MS (ESI) calculates: 553, and actual measurement: 552 (M-H) ^-

Embodiment 21

Preparation 5-(2-(3, the 4-dichlorophenoxy) benzylidyne) thiazolidine-2, the 4-diketone

Steps A: preparation aldehyde

(248.23mg 210 μ l, 2mmol) with 3, the mixture of 4-chlorophenesic acid stirred 12 hours at 90 ℃ in the 5mL N,N-DIMETHYLACETAMIDE with salt of wormwood with the 2-fluorobenzaldehyde.Reaction mixture dilutes with the water of 20ml, and uses the 25mL ethyl acetate extraction.Organic layer is used dried over sodium sulfate afterwards with the washing of saturated sodium bicarbonate aqueous solution and saturated sodium-chloride water solution, vacuum concentration, and product is a brown oil under without situation about being further purified.Step B: universal process 1

NMR(DMSO-d ₆,δ)：7.73(s,1H),7.59(m,2H),7.46(t,1H),7.34(m,2H),

7.02(m,2H)

MS (ESI) calculates: 365, and actual measurement: 364 (M-H) ^-

Embodiment 22

Preparation 5-(4-(3, the 4-dichlorophenoxy) benzylidyne) thiazolidine-2, the 4-diketone

Use preparation 5-(2-(3, the 4-dichlorophenoxy) benzylidyne) thiazolidine-2, the method for 4-diketone (embodiment 21) preparation 5-(4-(3, the 4-dichlorophenoxy) benzylidyne) thiazolidine-2,4-diketone.

MS (ESI) calculates: 365, and actual measurement: 364 (M-H) ^-

Embodiment 23

Preparation 5-(2,5-two-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2, the 4-diketone

Use preparation 5-(3,4-two-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2, the method for 4-diketone (embodiment 20) preparation 5-(2,5-two-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2,4-diketone.

NMR(DMSO-d ₆,δ)：7.88(s,1H),7.70-7.66(m,2H),7.64-7.60(m,2H),

7.42-7.34(m,2H),7.12-7.10(m,2H),6.90(brs,1H)

MS (ESI) calculates: 553, and actual measurement: 552 (M-H) ^-

Embodiment 24

Preparation 5-(2,4-two-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2, the 4-diketone

Use preparation 5-(3,4-two-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2, the method for 4-diketone (embodiment 20) preparation 5-(2,4-two-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2,4-diketone

MS (ESI) calculates: 553, and actual measurement: 552 (M-H) ^-

In embodiment 25-28 subsequently, use following universal process 2: universal process 2: the coupling rhodanine obtains aldehyde

With the methanol solution reflux of the aldehyde (1 equivalent), rhodanine (1 equivalent) and the ethylenediamine-N,N'-diacetic acid(EDDA) (1 equivalent) that suitably replace 1-3 hour.The precipitate and separate of gained is also used methyl alcohol, water, the 10% sodium pyrosulfate aqueous solution, saturated sodium bicarbonate aqueous solution and water washing respectively, air-dry then.

Reaction is carried out in 0.1 mmole level usually.

Embodiment 25

Preparation 5-(2-(3,4-benzyl dichloride sulfenyl)-3H-pyrimidin-4-one-6-base methyne) rhodanine

Steps A: preparation aldehyde

In the DMF solution of 0.75g (3.7mmol) 6-dimethoxy-methyl-2-sulfydryl-3H-pyrimidine-4 ketone, be suspended with in the suspension of 0.66g salt of wormwood and add 0.512mL (3.7mmol) 3, the 4-dichlorobenzyl chloride.This suspension was left standstill 2 days.Mixture dilutes with the 40mL ethyl acetate and the 40mL 10% sodium pyrosulfate aqueous solution.By filtering to isolate precipitation and washing with water, obtain the pure acetal of 1.0g.

With 0.8g6-dimethoxy-methyl two 2-(3,4-benzyl dichloride the sulfenyl)-solution stirring of 3H-pyrimidine-4 ketone in 70% trifluoroacetic acid aqueous solution 12 hours.Solution neutralizes with solid sodium bicarbonate, uses ethyl acetate extraction then.Organic layer also concentrates with dried over mgso.Resistates was with 1: 1 ether: the hexane development obtains the 600g pure products.Step B: universal process 2

Obtain 5-(2-(3,4-benzyl dichloride sulfenyl)-3H-pyrimidin-4-one-6-base methyne) rhodanine behind the universal process 2.

Embodiment 26

Preparation 5-(2-(3,4-benzyl dichloride sulfenyl) pyrimidine-4-base methyne) rhodanine

Steps A: preparation aldehyde

With 1.66g (7.98mmol) 4-dimethoxy-methyl pyrimidine-2-thioketones sodium salt, 2.7g salt of wormwood and α, 3, the suspension of 4-trichlorotoluene zotrichloride stirred 2 days.In the mixture impouring water and use ethyl acetate extraction.Organic layer washs with saturated sodium-chloride water solution, uses dried over mgso, and concentrates, and obtains 1.65g sulfydryl acetal product at last.

With the described acetal of 0.8g about 5 minutes, clarify up to solution at the suspension returning of 5ml concentrated hydrochloric acid.Solution cooling back dilute with water with the saturated sodium bicarbonate aqueous solution neutralization, and is used ethyl acetate extraction.With organic layer drying (anhydrous sodium sulphate) and concentrated, obtain 100mg purpose aldehyde.Step B: universal process 2

Obtain 5-(2-(3,4-benzyl dichloride sulfenyl) pyrimidine-4-base methyne) rhodanine behind the universal process 2.

Embodiment 27

Preparation 5-(2-(3,4-benzyl dichloride sulfenyl) the basic methyne of pyrimidine-4) rhodanine

(embodiment 25,0.3mmol) and in the suspension of toluene (5ml) add 2 for rhodanine to the 5-that stirs (2-(3,4-benzyl dichloride sulfenyl) pyrimidine-4-base methyne), 6-dimethyl-1,4-dihydro-3, (109mg is 0.39mmol) with 0.3 gram activated silica gel for 5-dinicotinic acid diethyl ester.With mixture heating up to 80 ℃ and continue 20 minutes, when keeping warm, filter.Filter cake is with the ethyl acetate washing and filtrate is evaporated to dried.Resistates is dissolved in the ethyl acetate again, and extracts with the 1N aqueous hydrochloric acid.With organic layer drying (sodium sulfate) and the concentrated 11mg pure products that obtains.

Embodiment 28

Preparation 5-(3-cyano group-2-(3,4-benzyl dichloride sulfenyl) pyridine-6-base methyne) thiazolidine-2, the 4-diketone Steps A: preparation aldehyde

With 0.2g (1mmol) 3-cyano group-6-dimethoxy-methyl-pyridine-2-mercaptan, excessive salt of wormwood and α, 3, the acetonitrile suspension of 4-trichlorotoluene zotrichloride (3mmol) is heated to 75 ℃ and lasting 10 minutes.Tlc confirms that reaction finishes.With in the mixture impouring water and use ethyl acetate extraction.Organic layer drying (sodium sulfate) also concentrates, and obtains solid sulfydryl acetal and uses hexane wash.

Described acetal is dissolved in chloroform (2ml) and adds the trifluoroacetic acid aqueous solution of 2mL 50%.After 16 hours, TLC shows that reaction is near finishing.Mixture is evaporated to dry doubling and enters step B (nuclear magnetic resonance map shows that it is consistent with theoretical construct) immediately.Step B: universal process 1

Obtain 5-(3-cyano group-2-(3,4-benzyl dichloride sulfenyl) pyridine-6-base methyne) thiazolidine-2 behind the universal process 1, the 4-diketone.

NMR(DMSO-d ₆,δ):8.12(d,1H),7.68(d,1H),7.53(d,1H),7.48(d,1H),

7.38-7.34(m,1H),7.31(s,1H),4.80(s,1H)

Embodiment 29

Preparation 5-(3-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2, the 4-diketone Steps A: preparation aldehyde

In the acetonitrile solution of 3-hydroxy benzaldehyde, add salt of wormwood (1.5 equivalent), add 3 subsequently, 4-dichlorobenzyl chloride (3 equivalent).The reaction mixture that obtains is heated to 90 ℃ and lasting 2-16 hour, filters out precipitation.Filtrate is diluted with EtOAc, washes with water, obtains crude product with dried over sodium sulfate and concentrating under reduced pressure.By recrystallization from CH ₂Cl ₂Obtain pure aldehyde in the/hexane solution system.Step B: universal process 1

Obtain 5-(3-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2 behind the universal process 1, the 4-diketone.

NMR(DMSO-d ₆,δ):7.69(d,2H),7.61(d,1H),7.43-7.31(m,3H),7.12-

7.08(m,2H),6.96(d,1H),5.11(s,2H)

MS (ESI): calculate: 378.98, actual measurement: 378 (M-H) ^-

Embodiment 30

Preparation compound 1

With 2-(4-methylbenzene sulfenyl)-5-nitrobenzaldehyde (1.00g, 3.66mmol), 2, the 4-thiazolidinedione (1.72g, 14.7mmol) and piperidines (0.14mL, 1.5mmol) reflux 26 hours in ethanol (40mL).The reaction soln cool to room temperature by filtering the crystal that collecting precipitation is separated out, obtains compound 1 (577mg, 42%).

¹H?NMR(300MHz,DMSO-d ₆)δ2.38(s,3H),7.07(d,J=8.8Hz,1H),

7.37(d,J=8.1Hz,2H),7.49(d,J=7.9Hz,2H),7.89(s,1H),8.14(dd,J=8.8,

2.2Hz,1H),8.22(d,J=2.2Hz,1H),12.8(br?s,1H)

FABMS?m/z?373(M+H) ⁺C ₁₇H ₁₄N ₂O ₄S ₂=372

Embodiment 31

Preparation compound 2

(200mg 0.538mmol) is dissolved in the acetone (30mL), and (20% aqueous solution 4mL) mixes, and at room temperature stirs subsequently 30 minutes with this solution and titanous chloride with compound 1.Add saturated sodium bicarbonate aqueous solution to reaction soln, twice of ethyl acetate extraction of mixture.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates recrystallization from ethyl acetate/hexane obtains compound 2 (69mg, 38%).

¹H?NMR(300MHz,CDCl ₃)δ2.21(s,3H),5.86(br?s,2H),6.70(dd,J=8.4,

2.6Hz,1H),6.82(d,J=2.4Hz,1H),6.89(d,J=8.3Hz,2H),7.06(d,J=8.1

Hz,2H),7.33(d,J=8.4Hz,1H),8.06(s,1H),12.5(br?s,1H)

FABMS?m/z?342(M ⁺)C ₁₇H ₁₄N ₂O ₂S ₂=342

Embodiment 32

Preparation compound 3

(20mg 0.058mmol) is dissolved in the dimethyl formamide (1mL) compound 2, and (0.016mL 0.12mmol), at room temperature stirred 50 minutes subsequently to add diacetyl oxide (1mL) and triethylamine in solution.Add entry to reaction soln, the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates are purified by preparative thin layer chromatography (9/1 chloroform/methanol) and are obtained compound 3 (7.0mg, 31%).

¹H?NMR(300MHz,DMSO-d ₆)δ2.08(s,3H),2.25(s,3H),7.07(d,J=8.3

Hz,2H),7.14(d,J=8.3Hz,2H),7.45(d,J=8.6Hz,1H),7.58(dd,J=8.4,2.2

Hz,1H),8.08(s,1H),8.09(d,J=2.4Hz,1H),10.3(s,1H),12.6(br?s,1H)

FABMS?m/z?385(M+H) ⁺C ₁₉H ₁₆N ₂O ₃S ₂=384

Embodiment 33

Preparation compound 4

Ice-cooled down, (100mg 0.269mmol) is dissolved in the mixed solvent of methylene dichloride (20mL) and methyl alcohol (4mL), and (0.289mmol) mixing was at room temperature stirred 3 hours subsequently for 50% purity, 100mg with solution and m-chlorine peroxybenzoic acid with compound 1.Reaction soln mixes with 10% aqueous solution of sodium bisulfite and uses chloroform extraction.Organic layer is used anhydrous sodium sulfate drying then with saturated sodium bicarbonate aqueous solution and salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains compound 4 (86mg, 82%) with the ethyl acetate development.

¹H?NMR(300MHz,DMSO-d ₃)δ2.30(s,3H),7.32(d,J=8.1Hz,2H),

7.48(d,J=8.3Hz,2H),7.88(s,1H),8.20(d,J=2.2Hz,1H),8.32(d,J=8.6

Hz,1H),8.50(dd,J=8.6,2.2Hz,1H),12.6(br?s,1H)

FABMS?m/z?387(M-H) ^-C ₁₇H ₁₂N ₂O ₅S ₂=388

Embodiment 34

Preparation compound 5

(20mg 0.054mmol) is dissolved in the mixed solvent of methylene dichloride (5mL) and methyl alcohol (1mL) compound 1, and (50% purity, 187mg 0.540mmol) mix, and at room temperature stir subsequently 1.5 hours with solution and m-chlorine peroxybenzoic acid.Reaction soln mixes with 10% aqueous solution of sodium bisulfite and extracts four times with chloroform-methanol (9: 1).Organic layer is used anhydrous sodium sulfate drying then with saturated sodium bicarbonate aqueous solution and salt water washing.Solvent removed by evaporation at reduced pressure, resistates are purified by preparative thin layer chromatography (6: 1 chloroform/acetonitriles) and are obtained compound 5 (10mg, 46%).

¹H?NMR(300MHz,DMSO-d ₆)δ2.36(s,3H),7.43(d,J=8.3Hz,2H),

7.74(d,J=8.4Hz,2H),8.06(s,1H),8.28(br?s,1H),8.49(s,2H),12.9(br?s,

1H)

FABMS?m/z?403(M-H) ^-C ₁₇H ₁₂N ₂O ₆S ₂=404

Embodiment 35

Preparation compound 6

2-(4-chlorobenzene sulfenyl) phenyl aldehyde (249mg, 1.00mmol), 2, the 4-thiazolidinedione (176mg, 1.5mmol) and piperidines (0.10mL, 1.0mmol) reflux 3 hours in ethanol (8mL).With the reaction soln cool to room temperature, add entry and 1N HCL (1mL), use ethyl acetate extraction afterwards.Anhydrous sodium sulfate drying is used in organic layer salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains compound 6 (274mg, 70%) with the ethyl acetate development.

¹H?NMR(300MHz,DMSO-d ₆)δ7.24(d,J=8.4Hz,2H),7.42(d,J=8.6Hz,

2H),7.5-7.6(m,4H),8.03(s,1H),12.7(br?s,1H)

FABMS?m/z?348(M+H) ⁺C ₁₆H ₁₀ ³⁵ClNO ₂S ₂=347

Embodiment 36

Preparation compound 7

Under ice-cooled, (20mg 0.057mmol) is suspended in the methylene dichloride (5mL), and (50% purity, 22mg 0.063mmol) mix, and at room temperature stir subsequently 20 minutes for suspension and m-chlorine peroxybenzoic acid with compound 6.Add 10% aqueous solution of sodium bisulfite to reaction soln, mixture extracts with chloroform/methanol (9: 1).Organic layer is used anhydrous sodium sulfate drying then with sodium bicarbonate aqueous solution, water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains compound 7 (15mg, 72%) with the diisopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ7.55(d,J=9.0Hz,2H),7.59(d,J=9.0Hz,

2H),7.6-7.8(m,2H),7.9-8.0(m,2H),8.02(s,1H),12.7(br?s,1H)

FABMS?m/z?364(M+H) ⁺C ₁₆H ₁₀ ³⁵ClNO ₃S ₂=363

Embodiment 37

Preparation compound 8

Under ice-cooled, (20mg 0.057mmol) is suspended in the methylene dichloride (5mL), and (50% purity, 200mg 0.57mmol) mix, and at room temperature stir subsequently 3 hours for suspension and m-chlorine peroxybenzoic acid with compound 6.Add 10% aqueous solution of sodium bisulfite to reaction soln, mixture extracts with chloroform/methanol (9: 1).Organic layer is used anhydrous sodium sulfate drying then with saturated sodium bicarbonate aqueous solution, water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains compound 8 (16mg, 74%) with the diisopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ7.60(d,J=7.5Hz,1H),7.68(d,J=8.8Hz,

2H),7.7-7.8(m,1H),7.81(d,J=8.8Hz,2H),7.87(td,J=7.7,1.3Hz,1H),

8.11(s,1H),8.27(dd,J=7.9,1.3Hz,1H),12.8(br?s,1H)

FABMS?m/z?380(M+H) ⁺C ₁₆H ₁₀ ³⁵ClNO ₄S ₂=379

Embodiment 38

Preparation compound 9

4-(4-methylbenzene sulfenyl)-3-nitrobenzaldehyde (273mg, 1.00mmol), 2, the 4-thiazolidinedione (176mg, 1.50mmol) and piperidines (0.40mL, 0.40mmol) reflux 19 hours in ethanol (8mL).The reaction soln cool to room temperature, collection is filtered the crystal of separating out and is obtained compound 9 (175mg, 47%).

¹H?NMR(300MHz,DMSO-d ₆)δ2.41(s,3H),6.92(d,J=8.6Hz,1H),

7.40(d,J=7.9Hz,2H),7.54(d,J=8.3Hz,2H),7.72(dd,J=8.6,2.2Hz,1H),

7.73(s,1H),8.46(d,J=1.8Hz,1H),12.7(br?s,1H),

FABMS?m/z?373(M+H) ⁺C ₁₇H ₁₂N ₂O ₄S ₂=372

Embodiment 39

Preparation compound 10

2-phenoxy benzaldehyde (synthetic, 28 (1995)) (198mg, 1.00mmol), 2, the 4-thiazolidinedione (176mg, 1.50mmol) and piperidines (0.10mL, 1.0mmol) reflux 4 hours in ethanol (5mL).The reaction soln cool to room temperature adds entry and 1N HCL (1ml), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains compound 10 (199mg, 67%) with the diisopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ6.95(d,J=8.1Hz,1H),7.05(d,J=7.5

Hz,2H),7.20(t,J=7.3Hz,1H),7.32(t,J=7.7Hz,1H),7.4-7.5(m,3H),

7.58(dd,J=7.7,1.3Hz,1H),7.95(s,1H),12.6(br?s,1H)

FABMS?m/z?298(M+H) ⁺C ₁₆H ₁₁NO ₃S=297

Embodiment 40

Preparation compound 11

The 3-phenoxy benzaldehyde (0.712mL, 1.00mmol), 2, the 4-thiazolidinedione (176mg, 1.50mmol) and piperidines (0.10mL, 1.0mmol) reflux 10 hours in ethanol (5mL).The reaction soln cool to room temperature adds entry and 1N HCL (1ml), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains compound 11 (141mg, 47%) with the diisopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ7.0-7.3(m,5H),7.35(d,J=7.9Hz,1H),

7.44(dd,J=8.4,7.5Hz,2H),7.54(t,J=7.9Hz,1H),7.82(s,1H),12.6(br?s,

1H)

FABMS?m/z?298(M+H) ⁺C ₁₆H ₁₁NO ₃S=297

Embodiment 41

Preparation compound 12

3-(4-methylphenoxy) phenyl aldehyde (0.193mL, 1.00mmol), 2, the 4-thiazolidinedione (176mg, 1.50mmol) and piperidines (0.10mL, 1.0mmol) reflux 7 hours in ethanol (5mL).The reaction soln cool to room temperature adds entry and 1N HCL (1ml), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains compound 12 (98mg, 32%) from ethanol/re-crystallizing in ethyl acetate.

¹H?NMR(300MHz,DMSO-d ₆)δ2.31(s,3H),6.9-7.0(m,3H),7.12(t,

J=2.0Hz,1H),7.23(d,J=8.4Hz,2H),7.29(br?s,J=7.9Hz,1H),7.45(t,

J=7.9Hz,1H),7.49(s,1H)

FABMS?m/z?312(M+H) ⁺C ₁₇H ₁₃NO ₃S=311

Embodiment 42

Preparation compound 13

3-(3, the 4-dichlorophenoxy) phenyl aldehyde (0.198mL, 1.00mmol), 2, the 4-thiazolidinedione (176mg, 1.50mmol) and piperidines (0.10mL, 1.0mmol) reflux 7 hours in ethanol (5mL).The reaction soln cool to room temperature adds entry and 1N HCL (1ml), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains compound 13 (252mg, 69%) with the ethyl acetate development.

¹H?NMR(300MHz,DMSO-d ₆)δ7.0-7.2(m,2H),7.25(t,J=2.0Hz,1H),

7.38(d,J=7.7Hz,1H),7.38(d,J=2.8Hz,1H),7.52(t,J=8.0Hz,1H),

7.53(s,1H),7.66(d,J=8.8Hz,1H)

FABMS?m/z?366(M+H) ⁺C ₁₆H ₉ClNO ₃S=365

Embodiment 43

Preparation compound 14

The 4-phenoxy benzaldehyde (0.175mL, 1.00mmol), 2, the 4-thiazolidinedione (176mg, 1.50mmol) and piperidines (0.10mL, 1.0mmol) reflux 6 hours in ethanol (5mL).The reaction soln cool to room temperature adds entry and 1N HCL (1ml), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains compound 14 (252mg, 85%) with hexane/diisopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ7.0-7.2(m,4H),7.23(t,J=7.3Hz,1H),

7.4-7.5(m,2H),7.62(d,J=8.8Hz,2H),7.78(s,1H),12.6(br?s,1H)

FABMS?m/z?298(M+H) ⁺C ₁₆H ₁₁NO ₃S=297

Embodiment 44

Preparation compound 15

In the argon atmospher, with the 4-fluorobenzaldehyde (0.53mL, 5.0mmol) and Pyrogentisinic Acid (648mg, 6.0mmol) be dissolved in the N,N-DIMETHYLACETAMIDE (8mL), and in solution, add salt of wormwood (828mg, 6.0mmol) and cupric oxide (95mg, 0.50mmol), mixture heating up refluxed 1.5 hours.The reaction soln cool to room temperature adds entry, the mixture ethyl acetate extraction.Organic layer is used anhydrous sodium sulfate drying with 0.5N aqueous sodium hydroxide solution, water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates are purified with silica gel column chromatography (6: 1 hexane/ethyl acetate) and are obtained 4-(4-methylphenoxy) phenyl aldehyde (697mg, 66%).

¹H?NMR(300MHz,CDCl ₃)δ2.37(s,3H),6.98(d,J=8.4Hz,2H),7.03(d,

J=8.6Hz,2H),7.21(d,J=8.6Hz,2H),7.82(d,J=9.0Hz,1H),9.91(s,1H)

FABMS?m/z?213(M+H) ⁺C ₁₄H ₁₂O ₂=212

Like this 4-of Huo Deing (4-methylphenoxy) phenyl aldehyde (212mg, 1.00mmol), 2, the 4-thiazolidinedione (176mg, 1.50mmol) and piperidines (0.10mL, 1.0mmol) reflux 6 hours in ethanol (5mL).The reaction soln cool to room temperature adds entry and 1N HCL (1ml), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains compound 15 (252mg, 81%) with the diisopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ2.31(s,3H),7.01(d,J=8.4Hz,2H),

7.06(d,J=8.8Hz,2H),7.25(d,J=8.6Hz,2H),7.60(d,J=8.8Hz,2H),

7.76(s,1H),12.6(br?s,1H)

FABMS?m/z?312(M+H) ⁺C ₁₇H ₁₃NO ₃S=311

Embodiment 45

Preparation compound 16

(1) in the argon atmospher, with the 5-nitrosalicylaldehyde (334mg 2.00mmol) is dissolved in the dimethyl formamide (5mL), with solution and bromotoluene (0.238mL, 2.00mmol) and sodium hydride (88mg 2.4mmol) mixes, and 70 ℃ were stirred 13 hours.Reaction soln adds entry with ice-cooled, the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains 2-benzyloxy-5-nitrobenzaldehyde (337mg, 66%) with the diisopropyl ether development.

¹H?NMR(300MHz,CDCl ₃)δ5.33(s,2H),7.18(d,J=9.2Hz,1H),7.4-

7.5(m,5H),8.42(dd,J=9.2,2.9Hz,1H),8.73(d,J=2.9Hz,1H),10.5(s,1H)

FABMS?m/z?258(M+H) ⁺C ₁₄H ₁₁NO ₄=257

(2) the 2-benzyloxy-5-nitrobenzaldehyde that obtains like this (257mg, 1.00mmol), 2, the 4-thiazolidinedione (176mg, 1.50mmol) and piperidines (0.10mL, 1.0mmol) reflux 6 hours in ethanol (5mL).The reaction soln cool to room temperature adds entry and 1N HCL (1ml), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains compound 16 (211mg, 59%) with the diisopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ5.42(s,2H),7.3-7.6(m,6H),7.91(s,

1H),8.25(d,J=2.6Hz,1H),8.35(dd,J=9.2,2.8Hz,1H),12.7(br?s,1H)

FABMS?m/z?357(M+H) ⁺C ₁₇H ₁₂N ₂O ₅S=356

Embodiment 46

Preparation compound 17

(1) adopt the method identical with embodiment 45 (1), (334mg, 2.00mmol) with 3, (0.305mL 2.20mmol) obtains 2-(3, the 4-dichloro-benzyloxy)-5-nitro nitrobenzaldehyde (482mg, 74%) to the 4-dichlorobenzyl chloride from the 5-nitrosalicylaldehyde.

¹H?NMR(300MHz,CDCl ₃)δ5.27(s,2H),7.14(d,J=9.2Hz,1H),

7.30(dd,J=8.3,2.2Hz,1H),7.53(d,J=8.3Hz,1H),7.56(d,J=2.2Hz,1H),

8.43(dd,J=9.2,2.9Hz,1H),8.74(d,J=2.9Hz,1H),10.5(s,1H)

(2) (326mg 1.00mmol) adopts the method identical with embodiment 45 (2) to obtain compound 17 (142g, 33%) to 2-(3, the 4-the dichloro-benzyloxy)-5-nitrobenzaldehyde that obtains like this.

¹H?NMR(300MHz,DMSO-d ₆)δ5.42(s,2H),7.44(d,J=9.4Hz,1H),

7.49(dd,J=8.3,2.0Hz,1H),7.72(d,J=8.3Hz,1H),7.80(d,J=1.8Hz,1H),

7.90(s,1H),8.26(d,J=2.6Hz,1H),8.36(dd,J=9.4,2.8Hz,1H),12.8(br?s,

1H)

FABMS?m/z?425(M+H) ⁺C ₁₇H ₁₀ ³⁵Cl ₂N ₂O ₅S=424

Embodiment 47

Preparation compound 18

(1) adopt the method identical with embodiment 45 (1), (334mg, 2.00mmol) (370mg 2.00mmol) obtains 2-(4-methyl benzyloxy)-5-nitrobenzaldehyde (413mg, 76%) with 4-methyl-benzyl bromine from the 5-nitrosalicylaldehyde.

¹H?NMR(300MHz,CDCl ₃)δ2.18(s,3H),5.28(s,2H),7.18(d,J=9.4Hz,

1H),7.24(d,J=8.1Hz,2H),7.33(d,J=8.1Hz,2H),8.40(dd,J=9.2,2.9Hz,

1H),8.72(d,J=2.9Hz,1H),10.5(s,1H)

FABMS?m/z?272(M+H) ⁺C ₁₅H ₁₃NO ₄=271

(2) (271mg 1.00mmol) adopts the method identical with embodiment 45 (2) to obtain compound 18 (200mg, 54%) to 2-(4-methyl the benzyloxy)-5-nitrobenzaldehyde that obtains like this.

¹H?NMR(300MHz,DMSO-d ₆)δ2.32(s,3H),5.35(s,2H),7.24(d,J=7.9

Hz,2H),7.38(d,J=7.9Hz,2H),7.47(d,J=9.3Hz,1H),7.88(s,1H),

8.24(d,J=2.8Hz,1H),8.34(dd,J=9.2,2.8Hz,1H),12.7(br?s,1H)

FABMS?m/z?371(M+H) ⁺C ₁₈H ₁₄N ₂O ₅S=370

Embodiment 48

Preparation compound 19

(1) adopt the method identical with embodiment 45 (1), (334mg, 2.00mmol) (370mg 2.00mmol) obtains 3-(4-methyl benzyloxy)-4-nitrobenzaldehyde (315mg, 58%) with 4-methyl-benzyl bromine from 3-hydroxyl-4-nitrobenzaldehyde.

¹H?NMR(300MHz,CDCl ₃)δ2.36(s,3H),5.27(s,2H),7.20(d,J=7.9Hz,

2H),7.34(d,J=8.1Hz,2H),7.53(dd,J=8.1,1.5Hz,1H),7.64(d,J=1.5Hz,

1H),7.92(d,J=8.1Hz,1H),10.0(s,1H)

FABMS?m/z?272(M+H) ⁺C ₁₅H ₁₃NO ₄=271

(2) (271mg 1.00mmol) adopts the method processing identical with embodiment 45 (2) and obtain compound 19 (95mg, 26%) with the ethyl acetate/hexane recrystallization to 3-(4-methyl the benzyloxy)-4-nitrobenzaldehyde that obtains like this.

¹H?NMR(300MHz,DMSO-d ₆)δ2.31(s,3H),5.32(s,2H),7.22(d,J=7.9

Hz,2H),7.29(dd,J=8.4,1.5Hz,1H),7.36(d,J=8.1Hz,2H),7.64(d,J=1.7

Hz,1H),7.81(s,1H),8.02(d,J=8.4Hz,1H),12.8(br?s,1H)

FABMS?m/z?371(M+H) ⁺C ₁₈H ₁₄N ₂O ₅S=370

Embodiment 49

Preparation compound 20

(1) adopt the method identical with embodiment 45 (1), (334mg, 2.00mmol) (370mg 2.00mmol) obtains 4-(4-methyl benzyloxy)-3-nitrobenzaldehyde (365mg, 67%) with 4-methyl-benzyl bromine from 4-hydroxyl-3-nitrobenzaldehyde.

¹H?NMR(300MHz,CDCl ₃)δ2.36(s,3H),5.31(s,2H),7.21(d,J=8.1Hz,

2H),7.26(d,J=8.8Hz,1H),7.33(d,J=8.1Hz,2H),8.02(dd,J=8.6,2.0Hz,

1H),8.34(d,J=2.0Hz,1H),9.92(s,1H)

FABMS?m/z?272(M+H) ⁺C ₁₅H ₁₃NO ₄=271

(2) (271mg 1.00mmol) adopts the method processing identical with embodiment 45 (2) and obtain compound 20 (123mg, 33%) with the ethyl acetate/hexane recrystallization to 4-(4-methyl the benzyloxy)-3-nitrobenzaldehyde that obtains like this.

¹H?NMR(300MHz,DMSO-d ₆)δ2.31(s,3H),5.34(s,2H),7.22(d,J=7.9

Hz,2H),7.35(dd,J=8.1Hz,2H),7.60(d,J=9.0Hz,2H),7.81(s,1H),

7.84(dd,J=9.0,2.2Hz,1H),8.15(d,J=2.2Hz,1H),12.7(br?s,1H)

FABMS?m/z?371(M+H) ⁺C ₁₈H ₁₄N ₂O ₅S=370

Embodiment 50

Preparation compound 21

(1) adopt the method identical with embodiment 45 (1), (334mg, 2.00mmol) (370mL 2.00mmol) obtains 5-(4-methyl benzyloxy)-2-nitrobenzaldehyde (413mg, 76%) with 4-methyl-benzyl bromine from 5-hydroxyl-2-nitrobenzaldehyde.

¹H?NMR(300MHz,CDCl ₃)δ2.37(s,3H),5.16(s,2H),7.19(dd,J=9.0,2.9

Hz,1H),7.21(d,J=7.5Hz,2H),7.31(d,J=8.1Hz,2H),7.41(d,J=2.9Hz,

1H),8.15(d,J=9.2Hz,1H),10.5(s,1H)

FABMS?m/z?272(M+H) ⁺C ₁₅H ₁₃NO ₄=271

(2) 5-(4-methyl the benzyloxy)-2-nitrobenzaldehyde that obtains like this (271mg, 1.00mmol), 2, the 4-thiazolidinedione (176mg, 1.50mmol) and piperidines (0.10mL, 1.0mmol) reflux 1.5 hours in ethanol (8mL).The reaction soln cool to room temperature adds entry and 1NHCL (1mL), uses ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates is purified (19: 1 chloroform/acetonitriles) with silica gel column chromatography and preparative thin layer chromatography (10: 1 chloroform/methanol) obtains compound 21 (30mg, 8.1%).

¹H?NMR(300MHz,CDCl ₃)δ2.38(s,3H),5.16(s,2H),7.04(d,J=2.4Hz,

1H),7.09(dd,J=9.2Hz,2.6Hz,1H),7.22(d,J=7.9Hz,1H),7.30(d,J=7.8

Hz,2H),8.22(d,J=9.2Hz,1H),8.24(s,1H),9.00(br?SR1H)

FABMS?m/z?371(M+H) ⁺C ₁₈H ₁₄N ₂O ₅S=370

Embodiment 51

Preparation compound 22

In the argon atmospher, with salicylic aldehyde (0.213mL 2.00mmol) is dissolved in the dimethyl formamide (5mL), in solution, add 4-methyl-benzyl bromine (370mg, 2.00mmol) and sodium hydride (88mg, 2.4mmol), 70 ℃ of stirrings 1.5 hours.Reaction soln adds entry with ice-cooled, uses ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, to wherein adding 2, the 4-thiazolidinedione (176mg, 1.50mg), piperidines (0.10mL, 1.0mmol) and ethanol (5mL), reflux 1.5 hours.The reaction soln cool to room temperature adds entry and 1N HCL (1mL), mixture ethyl acetate extraction then.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains compound 22 (542mg, 83% obtain by two steps) with the development of hexane/diisopropyl ether.

¹H?NMR(300MHz,DMSO-d ₆)δ2.31(s,3H),5.19(s,2H),7.10(t,J=7.5

Hz,1H),7.22(d,J=7.7Hz,2H),7.24(d,J=7.5Hz,1H),7.35(d,J=8.1Hz,

2H),7.4-7.5(m,2H),8.01(s,1H),12.6(br?1H)

FABMS?m/z?326(M+H) ⁺C ₁₈H ₁₅NO ₃S=325

Embodiment 52

Preparation compound 23

In the argon atmospher, with the 5-methoxysalicyl aldehyde (0.249mL 2.00mmol) is dissolved in the dimethyl formamide (5mL), in solution, add 4-methyl-benzyl bromine (370mg, 2.00mmol) and sodium hydride (88mg, 2.4mmol), 70 ℃ of stirrings 1.5 hours.Reaction soln adds entry with ice-cooled, uses ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure adds 2, the 4-thiazolidinedione (176mg, 1.50mg), piperidines (0.10mL, 1.0mmol) and ethanol (5mL), reflux 1.5 hours.The reaction soln cool to room temperature collect to filter the crystal of separating out and obtains compound 23 (419mg, 59% obtained by two steps).

¹H?NMR(300MHz,DMSO-d ₆)δ2.31(s,3H),3.75(s,3H),5.12(s,2H),

6.90(d,J=2.9Hz,1H),7.05(dd,J=9.0,2.9Hz,1H),7.18(d,J=9.0Hz,1H),

7.20(d,J=7.7,2H),7.32(d,J=8.1Hz,2H),7.95(s,1H),12.6(br?s,1H)

FABMS?m/z?356(M+H) ⁺C ₁₉H ₁₇NO ₄S=355

Embodiment 53

Preparation compound 24

In the argon atmospher, with the 5-chloro-salicylic aldehyde (313mg 2.00mmol) is dissolved in the dimethyl formamide (5mL), in solution, add 4-methyl-benzyl bromine (370mg, 2.00mmol) and sodium hydride (88mg, 2.4mmol), 70 ℃ of stirrings 0.5 hour.Reaction soln adds entry with ice-cooled, the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure adds 2, the 4-thiazolidinedione (176mg, 1.50mg), piperidines (0.10mL, 1.0mmol) and ethanol (5mL), reflux 4 hours.The reaction soln cool to room temperature adds entry and 1N HCL (5mL), mixture ethyl acetate extraction then.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains compound 24 (428mg, 60% obtain by two steps) with the development of hexane/diisopropyl ether.

¹H?NMR(300MHz,DMSO-d ₆)δ2.31(s,3H),5.19(s,2H),7.21(d,J=8.3

Hz,2H),7.27(d,J=9.0Hz,1H),7.34(d,J=8.4Hz,1H),7.36(d,J=2.9Hz,

1H),7.51(dd,J=9.0,2.8Hz,1H),7.87(s,1H),12.6(br?s,1H)

FABMS?m/z?360(M+H) ⁺C ₁₈H ₁₄ ³⁵ClNO ₃S=359

Embodiment 54

Preparation compound 25

In the argon atmospher, with the 5-bromosalicylaldehyde (1.00g 5.00mmol) is dissolved in the dimethyl formamide (10mL), in solution, add 4-methyl-benzyl bromine (925mg, 5.00mmol) and sodium hydride (220mg, 5.50mmol), 70 ℃ of stirrings 0.5 hour.Reaction soln adds entry with ice-cooled, the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure adds 2, the 4-thiazolidinedione (702mg, 6.00mmol), piperidines (0.50mL, 5.0mmol) and ethanol (40mL), reflux 4 hours.The reaction soln cool to room temperature adds entry and 1N HCL (5mL), mixture ethyl acetate extraction then.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains compound 25 (1.27mg, 63% obtained by two steps) with the development of hexane/diisopropyl ether.

¹H?NMR(300MHz,DMSO-d ₆)δ2.31(s,3H),5.19(s,3H),7.21(d,J=8.8

Hz,3H),7.34(d,J=8.0Hz,2H),7.48(d,J=2.4Hz,1H),7.62(dd,J=8.8,2.4

Hz,1H),7.86(s,J=1H),12.6(br?s,1H)

FABMS?m/z?406,404(M+H) ⁺C ₁₈H ₁₄ ⁷⁹BrNO ₃S=403

Embodiment 55

Preparation compound 26

2-diphenyl amino phenyl aldehyde (273mg, 1.00mmol), 2, the 4-thiazolidinedione (176mg, 1.50mmol) and piperidines (0.10mL, 1.0mmol) reflux 4 hours in ethanol (8mL).The reaction soln cool to room temperature adds entry and 1N HCL (2mL), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates obtains compound 26 (293mg, 79%) with the ethyl acetate development.

¹H?NMR(300MHz,DMSO-d ₆)δ6.93(d,J=7.2Hz,2H),7.1-7.2(m,6H),

7.3-7,5(m,6H),7.67(s,1H),12.6(br?s,1H)

FABMS?m/z?373(M+H) ⁺C ₂₂H ¹⁶N ₂O ₂S=372

Embodiment 56

Preparation compound 27

2-phenyl phenyl aldehyde (Tetrahedron Lett., 38 (32): 5575 (1997)) (273mg, 1.50mmol), 2, the 4-thiazolidinedione (263mg, 2.25mmol) and piperidines (0.15mL, 1.5mmol) reflux 3 hours in ethanol (8mL).The reaction soln cool to room temperature adds entry and 1N HCL (2mL), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates obtains compound 27 (344mg, 82%) with the Di Iso Propyl Ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ7.3-7.4(m,2H),7.4-7.7(m,8H),12.6(br

s,1H)

FABMS?m/z?282(M+H) ⁺C ₁₆H ₁₁BrNO ₂S=281

Embodiment 57

Preparation compound 28

3-phenyl phenyl aldehyde (Tetrahedron Lett., 38 (32): 5575 (1997)) (269mg, 1.48mmol), 2, the 4-thiazolidinedione (259mg, 2.22mmol) and piperidines (0.15mL, 1.5mmol) reflux 3 hours in ethanol (8mL).The reaction soln cool to room temperature adds entry and 1N HCL (2mL), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates obtains compound 28 (355mg, 85%) with the Di Iso Propyl Ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ7.3-7.8(m,8H),7.89(s,2H),12.6(br?s,

1H)

FABMS?m/z?282(M+H) ⁺C ₁₆H ₁₁NO ₂S=281

Embodiment 58

Preparation compound 29

4-phenyl phenyl aldehyde (182mg, 1.00mmol), 2, the 4-thiazolidinedione (176mg, 1.5mmol) and piperidines (0.10mL, 1.0mmol) reflux 3 hours in ethanol (6mL).The reaction soln cool to room temperature adds entry and 1N HCL (1mL), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates obtains compound 29 (187mg, 67%) with the diisopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ7.4-7.6(m,3H),7.70(d,J=8.4Hz,2H),

7.75(d,J=7.2Hz,2H),7.85(s,1H),7.86(d,J=8.1Hz,2H),12.6(br?s,1H)

FABMS?m/z?282(M+H) ⁺C ₁₆H ₁₁NO ₂S=281

Embodiment 59

Preparation compound 30

4-(Alpha-hydroxy benzyl) phenyl aldehyde (organic chemistry magazine, 62:4643 (1997)) (1.35g, 6.37mmol), 2, the 4-thiazolidinedione (894mg, 7.64mmol) and piperidines (0.64mL, 6.4mmol) reflux 10 hours in ethanol (6mL).The reaction soln cool to room temperature adds entry and 1N HCL (7mL), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates obtains compound 30 (1.73g, 87%) with the diisopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ5.75(d,J=2.7Hz,1H),6.03(d,J=2.7Hz,

1H),7.21(tt,J=7.2,1.5Hz,1H),7.31(t,J=7.2Hz,2H),7.38(d,J=7.3Hz,

2H),7.53(s,4H),7.75(s,1H),12.6(br?s,1H)

FABMS?m/z?312(M+H) ⁺C ₁₇H ₁₃NO ₃S=311

Embodiment 60

Preparation compound 31

(622mg 2.00mmol) is dissolved in the acetonitrile (80mL) compound 30, adds Manganse Dioxide (2.61g) and mixture heating up was refluxed 4.5 hours in this solution.The reaction soln cool to room temperature also filters solvent removed by evaporation at reduced pressure by Celite.Resistates is purified by silica gel column chromatography (9: 1 chloroform/acetonitriles), and obtains compound 31 (73mg, 12%) with the diisopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ7.58(t,J=7.5Hz,2H),7.6-7.8(m,5H),

7.86(d,J=7.9Hz,2H),7.87(s,1H),12.7(br?s,1H)

FABMS?m/z?310(M+H) ⁺C ₁₇H ₁₁NO ₃S=309

Embodiment 61

Preparation compound 32

With compound 30 (115mg 0.39mmol) is dissolved in the methylene dichloride (15mL), in solution, add trifluoroacetic acid (0.30mL, 3.9mmol) and triethyl silicane (0.81mL 5.1mmol), and refluxes mixture heating up 12 hours.Solvent removed by evaporation at reduced pressure, resistates obtains compound 32 (70mg, 61%) with the acetone/hexane recrystallization.

¹H?NMR(300MHz,DMSO-d ₆)δ4.00(s,2H),7.1-7.3(m,5H),7.39(d,

J=8.1Hz,2H),7.52(d,J=8.1Hz,2H),7.75(s,1H),12.6(br?s,1H)

FABMS?m/z?296(M+H) ⁺C ₁₇H ₁₃NO ₂S=295

Embodiment 62

Preparation compound 33

4-formyl radical trityl alcohol (organic chemistry magazine, 63:9924 (1998)) (576mg, 2.00mmol), 2, the 4-thiazolidinedione (218mg, 2.40mmol) and piperidines (0.20mL, 2.0mmol) reflux 9 hours in ethanol (15mL).The reaction soln cool to room temperature adds entry and 1N HCL (2mL), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates obtains compound 33 (684mg, 78%) with ethyl acetate/diisopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ6.61(s,1H),7.2-7.4(m,10H),7.37(d,J=8.4?Hz,2H),7.55(d,J=8.4Hz,2H),7.76(s,1H),1?2.6(br?s,1H)FABMS?m/z?388(M+H) ⁺C ₂₃H ₁₇NO ₃S=387

Embodiment 63

Preparation compound 34

With compound 33 (219mg 0.566mmol) is dissolved in the methylene dichloride (15mL), in solution, add trifluoroacetic acid (0.385mL, 0.50mmol) and triethyl silicane (0.80mL 0.50mmol), at room temperature stirred 10 minutes.Solvent removed by evaporation at reduced pressure, resistates recrystallization from hexane obtains compound 34 (198mg, 94%).

¹H?NMR(300MHz,DMSO-d ₆)δ5.70(s,1H),7.1-7.4(m,12H),7.55(d,

J=8.3Hz,2H),7.75(s,1H),12.6(br?s,1H)

FABMS?m/z?372(M+H) ⁺C ₂₃H ₁₇NO ₂S=371

Embodiment 64

Preparation compound 35

In the argon atmospher, (338mg, 2.00mmol) (500mg 2.00mmol) is dissolved in the dimethyl formamide (8mL), and under ice-cooled, (88mg 2.2mmol), at room temperature stirred 4 hours to add sodium hydride in solution with the 4-bromo benzyl bromo with pentanoic.Add entry to reaction soln, the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates are purified with silica gel column chromatography (14: 1 hexane/acetone) and are obtained N-(4-bromobenzyl) pentanoic (478mg, 71%).

¹H?NMR(300MHz,CDCl ₃)δ4.93(s,2H),6.94(tt,J=7.3,1.1Hz,2H),

7.03(dd,J=8.8,1.1Hz,4H),7.2-7.3(m,6H),7.42(d,J=8.6Hz,2H)

FABMS?m/z?339,337(M ⁺)C ₁₉H ₁₆ ⁷⁹BrN=337

In the argon atmospher, (440mg 1.30mmol) is dissolved in the tetrahydrofuran (THF) (6mL) and is cooled to-78 ℃ with resulting N-(4-bromobenzyl) pentanoic.To wherein add the 1.6M n-buli hexane solution (1.3mL, 2.0mmol), add again after 5 minutes dimethyl formamide (0.20mL, 2.6mmoL), restir 5 minutes.In reaction soln, add entry, the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer salt water washing then.Solvent removed by evaporation at reduced pressure, resistates are purified with silica gel column chromatography (9: 1 hexane/ethyl acetate) and are obtained 4-(N, N-diphenyl amino methyl) phenyl aldehyde (213mg, 57%).

¹H?NMR(300MHz,CDCl ₃)δ5.06(s,2H),6.96(t,J=7.3Hz,2H),7.03(d,

J=8.6Hz,4H),7.25(dd,J=8.6,7.3Hz,4H),7.52(d,J=8.4Hz,2H),7.83(d,

J=8.3Hz,2H),9.97(s,1H)

FABMS?m/z?287(M ⁺)C ₂₀H ₁₇NO=287

Resulting 4-(N, N-diphenyl amino methyl) phenyl aldehyde (198mg, 0.690mmol), 2, the 4-thiazolidinedione (117mg, 1.10mmol) and piperidines (0.068mL, 0.69mmol) reflux 5 hours in ethanol (6ml).The reaction soln cool to room temperature, collection is filtered the crystal of separating out and is obtained compound 35 (240mg, 90%).

¹H?NMR(300MHz,DMSO-d ₆)δ5.06(s,2H),6.92(t,J=7.2Hz,2H),

7.05(d,J=8.4Hz,4H),7.25(t,J=7.7Hz,4H),7.48(d,J=8.3Hz,2H),

7.55(d,J=8.4Hz,2H),7.75(s,1H),12.6(br?s,1H)

FABMS?m/z?386(M ⁺)C ₂₃H ₁₈N ₂O ₂S=386

Embodiment 65

Preparation compound 36

In the argon atmospher, with the 4-bromaniline (344mg 2.00mmol) is dissolved in the dimethyl formamide (5mL), ice-cooled down, in solution, add sodium hydride (200mg, 5.00mmol) and bromotoluene (0.52mL 4.4mmol), at room temperature stirred 11 hours.Add entry to reaction soln, the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates obtains 4-bromo-N with re-crystallizing in ethyl acetate, N-dibenzyl aniline (442mg, 63%).

¹H?NMR(300MHz,CDCl ₃)δ4.63(s,2H),6.59(d,J=9.0,2H),7.2-7.4(m,

12H)

FABMS?m/z?353,351(M ⁺)C ₂₀H ₁₈ ⁷⁹BrN=351

In the argon atmospher, with the 4-bromo-N of gained, (425mg 1.21mmol) is dissolved in the tetrahydrofuran (THF) (5mL) and is cooled to-78 ℃ the N-dibenzyl aniline.To wherein add the 1.6M n-buli hexane solution (1.1mL, 1.8mmol), add again after 5 minutes dimethyl formamide (0.186mL, 2.4mmoL), restir 5 minutes.In solution, add entry, the mixture ethyl acetate extraction.Organic layer washs with saturated brine, uses anhydrous sodium sulfate drying then.Solvent removed by evaporation at reduced pressure, resistates obtains 4-(dibenzyl amino) phenyl aldehyde (192mg, 53%) with silica gel column chromatography (9: 1 hexane/ethyl acetate).

¹H?NMR(300MHz,CDCl ₃)δ4.75(s,4H),6.79(t,J=9.0Hz,2H),7.2-

7.4(m,10H),7.69(d,J=9.0,2H),9.73(s,1H)

FABMS?m/z?302(M ⁺)C ₂₁H ₁₉NO=301

Resulting 4-(dibenzyl amino) phenyl aldehyde (181mg, 0.601mmol), 2, the 4-thiazolidinedione (105mg, 0.900mmol) and piperidines (0.059mL 0.60mmol) has heated in ethanol (7mL) and refluxed 5 hours.The reaction soln cool to room temperature adds entry and 1N HCL (0.6mL), then with the mixture ethyl acetate extraction.Solvent removed by evaporation at reduced pressure, resistates obtains compound 36 (207mg, 86%) with the diisopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ4.81(s,4H),6.81(d,J=8.8Hz,2H),7.2-

7.4(m,12H),7.61(s,1H),12.3(br?s,1H)

FABMS?m/z?400(M ⁺)C ₂₄H ₂₀N ₂O ₂S=400

Embodiment 66

Preparation compound 39

5-nitro-2-[(4-trifluoromethyl) phenoxy group] phenyl aldehyde (311mg, 1.00mmol), 2,4 thiazolidinediones (234mg, 2.00mmol) and piperidines (0.10mL, 1.0mmol) reflux 13 hours in ethanol (8mL).The reaction soln cool to room temperature adds entry and 1N HCL (1mL), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates is purified with silica gel column chromatography (15: 1 chloroform/acetonitriles), obtains compound 39 (146mg, 36%) with the diisopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ7.16(d,J=9.2Hz,1H),7.45(d,J=8.4Hz,

2H),7.89(d,J=8.4Hz,2H),7.93(s,1H),8.30(dd,J=9.2,2.8Hz,1H),

8.39(d,J=2.2Hz,1H),12.8(br?s,1H)

FABMS?m/z?411(M+H) ⁺C ₁₇H ₉F ₃N ₂O ₅S=410

Embodiment 67

Preparation compound 40

In the argon atmospher, (201mg 1.00mmol) is dissolved in the dimethyl formamide (3mL) with 2-bromo-5-hydroxy benzaldehyde, in this solution, add 4-methyl-benzyl bromine (185mg, 1.00mmol) and sodium hydride (48mg, 1.2mmol), subsequently 70 ℃ of stirrings 3 hours.Reaction soln adds entry with ice-cooled, the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure adds 2, and the 4-thiazolidinedione (176mg, 1.5mmo1), (0.10mL, 1.0mmol) and ethanol (6mL), reflux is 13 hours afterwards for piperidines.The reaction soln cool to room temperature adds entry and 1N HCL (5mL), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing afterwards.Solvent removed by evaporation at reduced pressure, resistates is purified with silica gel column chromatography (20: 1 chloroform/second eyeballs), obtains compound 40 (142mg, 35% obtain by two steps) with the diisopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ2.31(s,3H),5.13(s,2H),7.0-7.1(m,2H),

7.21(d,J=7.7Hz,2H),7.34(d,J=7.7Hz,1H),

7.69(d,J=8.6Hz,1H),7.79(s,1H),12.7(br?s,1H)

FABMS?m/z?406,404(M ⁺)C ₁₈H ₁₄ ⁷⁹BrNO ₃S=403

Embodiment 68

Preparation compound 41

In the argon atmospher, with 2,5-Dihydroxy benzaldehyde (138mg, 1.00mmol) be dissolved in the dimethyl formamide (35mL), in this solution, add 4-methyl-benzyl bromine (370mg, 2.00mmol) and sodium hydride (88mg, 2.2mmol), stirred 2 hours at 70 ℃ subsequently.Reaction soln adds entry with ice-cooled, the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure adds 2, and the 4-thiazolidinedione (176mg, 1.5mmol), (0.10mL, 1.0mmol) and ethanol (8mL), reflux is 2 hours afterwards for piperidines.The reaction soln cool to room temperature adds entry and 1N HCL (5mL), the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing afterwards.Solvent removed by evaporation at reduced pressure, resistates be with the development of hexane/diisopropyl ether, obtains compound 41 (340mg, 76% obtain by two steps).

¹H?NMR(300MHz,DMSO-d ₆)δ2.30(s,6H),5.05(s,2H),5.11(s,2H),6.93(br?s,1H),7.1-7.2(m,2H),7.20(d,J=7.7Hz,4H),7.32(d,J=7.9Hz,4H),7.93(s,1H),12.6Hz,1H)FABMS?m/z?446(M+H) ⁺C ₂₆H ₂₃NO ₄S=445

Embodiment 69

Preparation compound 42

In the argon atmospher, 5 '-bromo-2 '-(215mg 1.00mmol) is dissolved in the dimethyl formamide (5mL) hydroxy acetophenone, in solution, add 4-methyl-benzyl bromine (185mg, 1.00mmol) and salt of wormwood (152mg, 1.1mmol), subsequently 70 ℃ of stirrings 5 hours.Reaction soln adds entry with ice-cooled, the mixture ethyl acetate extraction.Organic layer is used anhydrous sodium sulfate drying then with 0.1N aqueous sodium hydroxide solution, water and salt water washing.Solvent removed by evaporation at reduced pressure adds 2, the 4-thiazolidinedione (176mg, 1.5mmol) and sodium acetate (123mg, 1.0mmol), subsequently 190 ℃ of stirrings 3-5 hour.The reaction soln cool to room temperature adds entry and 1N HCL (1mL), uses ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and saturated brine washing.Solvent removed by evaporation at reduced pressure, resistates are purified with silica gel column chromatography (30: 1 chloroform/second eyeballs) and are obtained compound 42 (102mg, 24% obtain by two steps).

¹H?NMR(300MHz,DMSO-d ₆)δ2.35(s,3H),2.61(s,3H),6.88(d,J=9.0

Hz,1H),7.1-7.3(m,5H),7.41(dd,J=8.8,2.6Hz,1H),8.14(br?s,1H)

FABMS?m/z?419,418(M+H) ⁺C ₁₉H ₁₆ ⁷⁹BrNO ₃S=417

Embodiment 70

Preparation compound 43

5-bromo-2-(4-chlorobenzene sulfenyl) thiophene-3-carboxyl aldehyde (167mg, 0.500mmol), 2, the 4-thiazolidinedione (88mg, 0.75mmol) and piperidines (0.049mL is 0.5mmol) ethanol (5mL) reflux 6 hours.The reaction soln cool to room temperature adds entry and 1N HCL (0.5mL), the mixture chloroform extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing.Solvent removed by evaporation at reduced pressure, resistates grinds with diisopropyl ether/ethyl acetate, obtains compound 43 (138mg, 64%).

¹H?NMR(300MHz,DMSO-d ₆)δ7.32(d,J=8.6Hz,2H),7.47(d,J=8.6Hz,

2H),7.82(s,1H),7.98(s,1H),12.7(br?s,1H)

FABMS?m/z?43?3,431(M ⁺)C ₁₄H ₇ ⁷⁹Br ³⁵ClNO ₂S ₃=431

Embodiment 71

Preparation compound 44

In the argon atmospher, (22mg 0.051mmol) is dissolved in the glycol dimethyl ether (2mL) with compound 43, in this solution, add tetrakis triphenylphosphine palladium (6mg, 10mol%), aqueous sodium carbonate (0.5M, 0.6mL) and phenyl-boron dihydroxide (31mg, 0.25mmol), reflux 12 hours.The reaction soln cool to room temperature adds entry, the mixture ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer salt water washing then.Solvent removed by evaporation at reduced pressure, resistates are purified with preparation of lamina chromatogram (10: 1 chloroform/acetone) and are obtained compound 44 (8.3mg, 38%).

¹H?NMR(300MHz,DMSO-d ₆)δ7.17(d,J=8.4Hz,2H),7.2-7.5(m,8H),

7.91(s,1H),8.16(br?s,1H)

FABMS?m/z?429(M ⁺)C ₂₀H ₁₂ ³⁵ClNO ₂S ₃=429

Embodiment 72

Preparation compound 45

In the argon atmospher, (32mg 0.075mmol) is dissolved in tetrahydrofuran (THF) (5mL) and be cooled to-78 ℃ with compound 43.(the 1.6mol/L hexane solution 0.3mL), stirred 15 minutes to add n-Butyl Lithium.Reaction soln mixes with water and uses ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer salt water washing then.Solvent removed by evaporation at reduced pressure, resistates are purified with preparation of lamina chromatogram (10: 1 chloroform/acetone) and are obtained compound 45 (3.8mg, 14%).

¹H?NMR(300MHz,DMSO-d ₆)δ7.24(d,J=4.2Hz,1H),7.27(d,J=9.0Hz,

2H),7.30(d,J=3.9Hz,1H),7.31(d,J=9.2Hz,2H),7.91(s,1H),8.42(br?s,

1H)

FABMS?m/z?353(M ⁺)C ₁₄H ₈ ³⁵ClNO ₂S ₃=353

Embodiment 73

Preparation compound 46

In the argon atmospher, (964mg 2.00mmol) is dissolved in the tetrahydrofuran (THF) (10mL), and is cooled to-78 ℃ with three (4-bromophenyl) amine.(2.4mmol), (0.19mL 2.4mmol), stirred 10 minutes to drip dimethyl formamide under-60 ℃ or lower temperature for 1.6mol/L hexane solution, 1.5mL to add n-Butyl Lithium.Add entry to reaction soln, and use the ethyl acetate extraction product.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, (eluting solvent: hexane/ethyl acetate=8/1) purification obtains 4-(two (4-bromophenyl) amino) phenyl aldehyde (377mg, 44%) to resistates with silica gel column chromatography.

¹H?NMR(300MHz,CDCl ₃)δ(ppm)7.02(d,J=8.8Hz,4H),7.04(d,J=8.6

Hz,2H),7.45(d,J=8.8Hz,4H),7.71(d,J=8.8Hz,2H),9.84(s,1H)

FABMS?m/z?433,431,429(M ⁺)C ₁₉H ₁₃ ⁷⁹BR ₂NO=429

With 4-(two (4-bromophenyl) amino) phenyl aldehyde (356mg, 0.826mmol), 2, the 4-thiazolidinedione (145mg, 1.24mmol) and piperidines (0.083mL, 0.83mmol) reflux 4 hours in ethanol (8mL).Reaction soln is cooled to room temperature, sneaks into water and 1N HCL (1mL), uses chloroform extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, (eluting solvent: chloroform/acetonitrile=15/1) purification obtains compound 46 (388mg, 89%) with the hexane development to resistates with silica gel column chromatography.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.03(d,J=8.8Hz,2H),7.06(d,

J=8.8Hz,4H),7.51(d,J=8.8Hz,2H),7.54(d,J=8.8Hz,4H),7.70(s,1H),

12.5(br?s,1H)

FABMS?m/z?532,530,528(M ⁺)C ₂₂H ₁₄ ⁷⁹BR ₂N ₂O ₂S=528

Embodiment 74

Preparation compound 47

In the argon atmospher, with compound 25 (40mg, 0.10mmol) be dissolved in 1, in the 2-glycol dimethyl ether (4mL), to wherein adding phenyl-boron dihydroxide (24mg, 0.20mmol), 2mol/L aqueous sodium carbonate (0.15mL), water (0.5mL) and tetrakis triphenylphosphine palladium (6mg, 5mol%), product reflux 8 hours.Reaction soln is cooled to room temperature, sneaks into water and 1N HCL (1mL), use ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates (launches solvent: chloroform/acetonitrile=12/1) purify, obtain compound 47 (27mg, 67%) with the isopropyl ether development with the preparation of lamina chromatogram.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)2.32(s,3H),5.25?2H),7.23(d,

J=8.1Hz,2H),7.3-7.4(m,4H),7.49(t,J=7.6Hz,2H),7.63(d,J=8.6Hz,

2H),7.64(d,J=1.7Hz,1H),7.76(dd,J=8.6,2.2Hz,1H),8.03(s,1H),

12.6(br?s,1H)

FABMS?m/z?401(M ⁺)C ₂₄H ₁₉NO ₃S=401

Embodiment 75

Preparation compound 48

(26mg 0.20mmol) replaces phenyl-boron dihydroxide, and the same procedure of employing and embodiment 74 is from compound 25 (40mg, 0.10mmol) preparation compound 48 (7.5mg, 18%) with 2-thienyl boric acid.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)2.32(s,3H),5.23(s,2H),7.14(dd,

J=5.0,3.7Hz,1H),7.22(d,J=7.9Hz,2H),7.30(d,J=8.8Hz,1H),7.36(d,

J=8.1Hz,2H),7.44(d,J=3.5Hz,1H),7.53(d,J=4.8Hz,1H),7.62(d,

J=2.0Hz,1H),7.75(dd,J=8.8,2.0Hz,1H),7.98(s,1H),12.6(br?s,1H)

FABMS?m/z?407(M ⁺)C ₂₂H ₁₇NO ₃S ₂=407

Embodiment 76

Preparation compound 49

In the argon atmospher, (7.23g 15.0mmol) is dissolved in the tetrahydrofuran (THF) (100mL) and is cooled to-78 ℃ with three (4-bromophenyl) amine.(54mmol), (4.6mL 60mmol), stirred 10 minutes to drip dimethyl formamide under-60 ℃ or lower temperature for 1.6mol/L hexane solution, 34mL to add n-Butyl Lithium.Add entry to reaction soln, the product ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, and the resistates silica gel column chromatography (eluting solvent: hexane/ethyl acetate=4/1, use chloroform/acetonitrile=30/1 subsequently) purifying obtains three (4-formyl radical phenyl) amine (2.97g, 60%).

¹H?NMR(300MHz,CDCl ₃)δ(ppm)7.25(d,J=8.8Hz,6H),7.85(d,J=8.8

Hz,6H),9.95(s,3H)

FABMS?m/z?330(M+H) ⁺C ₂₁H ₁₅NO ₃=329

(165mg 0.502mmol) is dissolved in methyl alcohol (8mL) and the chloroform (5mL) with three (4-formyl radical phenyl) amine.Under ice-cooled, (9.5mg 0.25mmol), at room temperature stirred 15 minutes to add sodium borohydride in solution.Add entry to reaction soln, the product chloroform extraction.Anhydrous sodium sulfate drying is used in organic layer salt water washing then.Solvent removed by evaporation at reduced pressure, (eluting solvent: chloroform/acetonitrile=20/1-10/1) purification obtains 4-((two (4-methylol) phenyl) amino) phenyl aldehyde (107mg, 64%) to resistates with silica gel column chromatography.

¹H?NMR(300MHz,CDCl ₃)δ(ppm)2.46(br?s,2H),4.66(s,4H),6.99(d,

J=8.8Hz,2H),7.13(d,J=8.4Hz,4H),7.32(d,J=8.4Hz,4H),7.64(d,

J=8.8Hz,2H),9.75(s,1H)

FABMS?m/z?333(M ⁺)C ₂₁H ₁₉NO ₃=333

With 4-((two (4-methylol) phenyl) amino) phenyl aldehyde (100mg, 0.300mmol), 2, the 4-thiazolidinedione (53mg, 0.45mmol) and piperidines (0.030mL, 0.30mmol) reflux 3 hours in ethanol (5mL).Reaction soln is cooled to room temperature, sneaks into water and 1NHCL (1mL), the product chloroform extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure obtains compound 49 (113mg, 87%) with the hexane development.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)4.48(d,J=4.4Hz,4H),5.16(br?t,

J=5.1Hz,2H),6.89(d,J=8.8Hz,2H),7.09(d,J=8.3Hz,4H),7.32(d,

J=8.5Hz,4H),7.44(d,J=9.0Hz,2H),7.66(s,1H),12.4(br?s,1H)

FABMS?m/z?432(M ⁺)C ₂₄H ₂₀N ₂O ₄S=432

Embodiment 77

Preparation compound 50

In the argon atmospher, (169mg 0.500mmol) is dissolved in the dimethyl formamide (1.5mL) N-(4-bromobenzyl) diphenylamine that embodiment 64 is obtained, and (0.116mL, 1.25mmol), 100 ℃ were stirred 30 minutes to add phosphoryl chloride.Reaction soln is cooled to room temperature and is poured in the saturated aqueous sodium acetate solution, and use ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer salt water washing then.Solvent removed by evaporation at reduced pressure, (eluting solvent: hexane/ethyl acetate=4/1) purification obtains 4-(N-(4-bromobenzyl)-N-phenyl amino) phenyl aldehyde (159g, 87%) to resistates with silica gel column chromatography.

¹H?NMR(300MHz,CDCl ₃)δ(ppm)4.98(s,2H),6.78(d,J=8.8Hz,2H),

7.18(d,J=8.3Hz,2H),7.26(m,1H),7.27(d,J=8.4Hz,2H),7.42(m,2H),

7.45(d,J=8.4Hz,2H),7.65(d,J=8.8Hz,2H),9.75(s,1H)

FABMS?m/z?368,366(M+H) ⁺C ₂₀H ₁₆ ⁷⁹BrNO=365

With 4-(N-(4-bromobenzyl)-N-phenyl amino) phenyl aldehyde (153g, 0.418mmol), 2, the 4-thiazolidinedione (73mg, 0.63mmol) and piperidines (0.042mL, 0.42mmol) reflux 3 hours in ethanol (5mL).Reaction soln is cooled to room temperature, mixes entry and 1N HCL (1mL), uses ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure obtains compound 50 (150mg, 87%) with hexane/isopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)5.06(s,2H),6.88(d,J=8.8Hz,

2H),7.21(t,J=7.3Hz,1H),7.27(d,J=8.3Hz,2H),7.32(d,J=7.5Hz,2H),

7.40(d,J=8.8Hz,2H),7.42(t,J=7.3Hz,2H),7.51(d,J=8.3Hz,2H),

7.64(s,1H),12.4(br?s,1H)

FABMS?m/z?466,464(M ⁺)C ₂₃H ₁₇ ⁷⁹BrN ₂O ₂S=464

Embodiment 78

Preparation compound 51

Under ice-cooled, (50mg 0.12mmol) is dissolved in the mixed solvent of methylene dichloride (8mL) and methyl alcohol (2mL) with compound 43.(50% purity, 65mg 0.19mmol), at room temperature stirred 18 hours to add m-chlorine peroxybenzoic acid.In solution, add 5% aqueous solution of sodium bisulfite, product chloroform extraction.Organic layer is used anhydrous sodium sulfate drying then with sodium bicarbonate aqueous solution and salt water washing.Solvent removed by evaporation at reduced pressure obtains compound 51 (30mg, 56%) with the methyl alcohol development.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.73(d,J=8.4Hz,2H),7.75(s,

1H),7.84(d,J=8.6Hz,2H),7.98(s,1H),12.8(br?s,1H)

FABMS?m/z?450,448(M-H) ^-C ₁₄H ₇ ⁷⁹Br ³⁵Cl ₁NO ₃S ₃=449

Embodiment 79

Preparation compound 52

Under ice-cooled, (50mg 0.12mmol) is dissolved in the mixed solvent of methylene dichloride (8mL) and methyl alcohol (2mL) with compound 43.(50% purity, 398mg 1.2mmol), at room temperature stirred 17 hours to add m-chlorine peroxybenzoic acid.In solution, add 5% aqueous solution of sodium bisulfite, product chloroform extraction.Organic layer is used anhydrous sodium sulfate drying then with aqueous sodium carbonate and salt water washing.Solvent removed by evaporation at reduced pressure obtains compound 52 (23mg, 41%) with the methyl alcohol development.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.71(d,J=8.6Hz,2H),7.78(s,

1H),8.00(s,1H),8.05(d,J=8.6Hz,2H),12.9(br?s,1H)

FABMS?m/z?466,464(M-H) ^-C ₁₄H ₇ ⁷⁹Br ³⁵ClNO ₄S ₃=465

Embodiment 80

Preparation compound 53

With available 5-bromo-2-(4-chloro-phenyl-sulfenyl) thiophene-3-formaldehyde (1.00g, 2.99mmol) (MAYBRIDGE, catalog number (Cat.No.): KM05476) be dissolved in the methyl alcohol (75mL) on the market.(52mg, 0.30mol), mixture heating up refluxed 1.5 hours to add the p-toluenesulphonic acids.Solvent removed by evaporation at reduced pressure to cumulative volume is about 30mL.Add entry and saturated sodium bicarbonate aqueous solution, the product ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure obtains 5-bromo-2-(4-chlorobenzene sulfenyl)-3-(dimethoxy-methyl) thiophene (1.12g, 100%).

¹H?NMR(300MHz,CDCl ₃)δ(ppm)3.36(s,6H),5.55(s,1H),7.07(s,

1H),7.15(d,J=8.6Hz,2H),7.24(d,J=8.8Hz,2H)

FABMS?m/z?380,378(M ⁺)C ₁₃H ₁₂ ⁷⁹Br ³⁵ClO ₂S ₂=378

In the argon atmospher, (1.04g 2.75mmol) is dissolved in the tetrahydrofuran (THF) (15mL), and mixed solution is cooled to-78 ℃ with 5-bromo-2-(4-chlorobenzene sulfenyl)-3-(dimethoxy-methyl) thiophene.(1.6mol/L hexane solution, 2.5mL 4.1mmol), stirred 5 minutes to add n-Butyl Lithium.Add dry ice (about 1g), stirred then 10 minutes.Adding entry and 1mol/L aqueous sodium hydroxide solution to reaction soln, to make its pH value be 10, and mixture washs with ether.Add 1mol/L hydrochloric acid to aqueous phase layer, making its pH value is 3, and uses the ethyl acetate extraction aqueous phase layer.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure.Resistates is dissolved in the tetrahydrofuran (THF) (10mL).Add 1mol/L hydrochloric acid (2mL), at room temperature stirred 2 hours.Add entry to reaction soln, the product ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates with isopropyl ether develop 2-(4-chloro-phenyl-sulfenyl)-3-formyl radical-5-thiophene carboxylic acid (439mg, 54%).

¹H?NMR(300MHz,CDCl ₃)δ(ppm)7.50(d,J=8.6Hz,2H),7.62(d,

J=8.6Hz,2H),8.06(s,1H),9.68(s,1H)

FABMS?m/z?299(M+H) ⁺C ₁₂H ₇ ³⁵ClO ₃S ₂=298

With 2-(4-chloro-phenyl-sulfenyl)-3-formyl radical-5-thiophene carboxylic acid (400mg, 1.34mmol), 2, the 4-thiazolidinedione (188mg, 1.01mmol) and piperidines (0.133mL, 1.34mmol) reflux 3.5 hours in ethanol (12mL).Reaction mixture is cooled to room temperature, adds 1mol/LHCL (1.5mL), and collection is filtered the crystal of separating out and obtained compound 53 (411mg, 77%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.66(d,J=8.4Hz,2H),7.77(d,

J=8.4Hz,2H),7.83(s,1H),7.90(s,1H),12.6(br?s,1H),13.4(br?s,1H),

FABMS?m/z?396(M-H) ^-C ₁₅H ₈ ³⁵ClNO ₄S ₃=397

Embodiment 81

Preparation compound 54

With compound 53 (80mg, 0.20mmol) be dissolved in the dimethyl formamide (3mL), add 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (77mg, 0.40mmol) and diethylamide (0.041mL, 0.40mmol), at room temperature stirred 3 hours.Add entry to reaction soln, the product ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates are purified with preparation of lamina chromatogram (9: 1 chloroform/methanol) and are obtained compound 54 (22mg, 24%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)1.06(br?s,6H),3.13(br?s,2H),

3.41(br?s,2H),7.41(d,J=8.6Hz,2H),7.47(d,J=8.6Hz,2H),7.69(s,1H),

8.00(s,1H),12.7(br?s,1H)

FABMS?m/z?451(M-H) ^-C ₁₉H ₁₇ ³⁵ClN ₂O ₃S ₃=452

Embodiment 82

Preparation compound 55

(0.037mL 0.40mmol) replaces diethylamide, adopts the method identical with embodiment 81 to obtain compound 55 (37mg, 39%) with aniline.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.13(t,J=7.3Hz,1H),7.37(t,

J=7.7Hz,2H),7.60(d,J=8.4Hz,2H),7.68(d,J=8.6Hz,2H),7.71(d,

J=7.7Hz,2H),7.84(s,1H),8.04(s,1H),10.3(s,1H),12.6(br?s,1H)

FABMS?m/z?471(M-H) ^-C ₂₁H ₁₃ClN ₂O ₃S ₃=472

Embodiment 83

Preparation compound 56

(0.044mL 0.40mmol) replaces diethylamine, adopts the method identical with embodiment 81 to obtain compound 56 (11mg, 12%) with the 1-methylpiperazine.Compound 56 obtains with the form of hydrochloride.

¹H NMR (300MHz, DMSO-d ₆, hydrochloride) δ (ppm) 2.80 (s, 3H), 3.25 (m,

8H),7.46(d,J=8.8Hz,2H),7.49(d,J=8.8Hz,2H),7.69(s,1H),7.98(s,1H)

FABMS?m/z?478(M-H) ^-C ₂₀H ₁₈ClN ₃O ₃S ₃=479

Embodiment 84

Preparation compound 57

(0.035mL 0.40mmol) replaces diethylamine, adopts the method identical with embodiment 81 to obtain compound 57 (22mg, 24%) with morpholine.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)3.32(m,4H),3.55(m,4H),

7.43(d,J=8.6Hz,2H),7.47(d,J=8.6Hz,2H),7.69(s,1H),7.98(s,1H),

12.7(br?s,1H)

FABMS?m/z?465(M-H) ^-C ₁₉H ₁₅ClN ₂O ₄S ₃=466

Embodiment 85

Preparation compound 58

(36mg 0.090mmol) is dissolved in methylene dichloride (2mL) and the tetrahydrofuran (THF) (2mL) with compound 53.(0.032mL 0.36mmol), refluxes mixture heating up 2 hours to add thionyl chloride in solution.Reaction soln is with ice-cooled.(0.038mL 0.27mmol), stirred 10 minutes to add methyl alcohol (1mL) and triethylamine.Add entry to reaction soln, the product ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates is purified with preparation of lamina chromatogram (9: 1 chloroform/methanol), obtains compound 58 (22mg, 24%) with the isopropyl ether development.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)3.85(s,3H),7.67(d,J=8.6Hz,

2H),7.77(d,J=8.4Hz,2H),7.88(s,1H),7.92(s,1H)12.6(br?s,1H)

FABMS?m/z?410(M-H) ^-C ₁₆H ₁₀ ³⁵ClNO ₄S ₃=411

Embodiment 86

Preparation compound 59

Adopt the method identical with embodiment 70, by available 3-phenoxy group thiophene-2-formaldehyde (204mg on the market, 1.00mmol) (MAYBRIDGE, catalog number (Cat.No.): KM05428), 2,4-thiazolidinedione (176mg, 1.5mmol) and piperidines (0.099mL 1.0mmol) obtains compound 59 (260mg, 86%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)6.93(d,J=5.5Hz,1H),7.02(dd,J=8.6,1.1Hz,2H),7.15(t,J=7.5Hz,1H),7.39(dd,J=8.6,7.5Hz,2H)7.61(s,1H),7.91(d,J=5.5Hz,1H)

FABMS?m/z?302(M-H) ^-C ₁₄H ₉NO ₃S ₂=303

Embodiment 87

Preparation compound 60

(2.00g 10.5mmol) is dissolved in the methyl alcohol (80mL) with 4-bromothiophene-2-formaldehyde.(181mg 1.05mmol), stirred 3 hours to add the p-toluenesulphonic acids.Solvent removed by evaporation at reduced pressure is about 20mL until cumulative volume.Add sodium bicarbonate aqueous solution, the product extracted with diethyl ether.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure obtains 4-bromo-2-dimethoxy-methyl thiophene (2.36mg, 100%).

¹H?NMR(300MHz,CDCl ₃)δ(ppm)3.36(s,6H),5.58(s,1H),7.00(t,

J=1.0Hz,1H),7.20(d,J=1.3Hz,1H)

In the argon atmospher, (236mg 1.00mmol) is dissolved in the tetrahydrofuran (THF) (4mL) and is cooled to-78 ℃ with 4-bromo-2-dimethoxy-methyl thiophene.Add n-Butyl Lithium (the 1.6mol/L hexane solution, 0.81mL, 1.3mmol) and 4,4 '-tetrahydrofuran solution (1.5mL) of DCBP base disulfide, stirred 15 minutes.Add entry to reaction soln, and use the extracted with diethyl ether product.Organic layer water and salt water washing are used anhydrous sodium sulfate drying, solvent removed by evaporation at reduced pressure then.Resistates is dissolved in tetrahydrofuran (THF) (6mL) and the 1mol/L hydrochloric acid, at room temperature stirs 1 hour.Add sodium bicarbonate aqueous solution, product ethyl acetate extraction to reaction soln.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates is purified by preparation of lamina chromatogram (9: 1 hexane/ethyl acetate) and is obtained 4-(4-chloro-phenyl-sulfenyl) thiophene-2-formaldehyde (71mg, 28%), 2,3-two (4-chloro-phenyl-sulfenyl) thiophene-5-formaldehyde (29mg, 7.4%) and 5-(4-chloro-phenyl-sulfenyl) thiophene-2-formaldehyde (53mg, 21%).

4-(4-chloro-phenyl-sulfenyl) thiophene-2-formaldehyde:

¹H?NMR(300MHz,CDCl ₃)δ(ppm)7.21(d,J=8.8Hz,2H),7.28(d,J=9.0

Hz,2H),7.65(d,J=1.5Hz,1H),7.69(d,J=1.4Hz,1H),9.87(d,J=1.3Hz,

1H)

FABMS?m/z?254(M ⁺)C ₁₁H ₇ ³⁵ClOS ₂=254

2,3-two (4-chloro-phenyl-sulfenyl) thiophene-5-formaldehyde:

¹H?NMR(300MHz,CDCl ₃)δ(ppm)7.19(d,J=8.4Hz,2H),7.29(d,J=8.4

Hz,2H),7.37(d,J=8.6Hz,2H),7.43(d,J=8.6Hz,2H),7.53(s,1H)9.67(s,

1H)

FABMS?m/z?397(M+H) ⁺C ₁₇H ₁₀ ³⁵Cl ₂OS ₃=396

5-(4-chloro-phenyl-sulfenyl) thiophene-2-formaldehyde:

¹H?NMR(300MHz,CDCl ₃)δ(ppm)7.13(d,J=3.9Hz,1H),7.33(d,J=8.8

Hz,2H),7.37(d,J=9.0Hz,2H),7.63(d,J=3.9Hz,1H),9.78(s,1H)

FABMS?m/z?255(M+H) ⁺C ₁₁H ₇ ³⁵ClOS ₂=254

With 4-(4-chloro-phenyl-sulfenyl) thiophene-2-formaldehyde (70mg, 0.28mmol), 2, the 4-thiazolidinedione (39mg, 0.33mmol) and piperidines (0.028mL, 0.28mmol) reflux 4 hours in ethanol (4mL).Reaction soln is cooled to room temperature, sneaks into water and 1N HCL (1mL), the product ethyl acetate extraction.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates obtains compound 60 (57mg, 58%) with re-crystallizing in ethyl acetate.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.25(d,J=8.6Hz,2H),7.41(d,

J=8.6Hz,2H),7.65(m,1H),8.02(s,1H),8.12(m,1H),12.6(br?s,1H)

FABMS?m/z?352(M-H) ^-C ₁₃H ₈ ³⁵Cl ₂NO ₂S ₂=353

Embodiment 88

Preparation compound 61

Adopt the method identical with embodiment 87, with embodiment 87 prepare 2,3-two (4-chloro-phenyl-sulfenyl) thiophene-5-formaldehyde (28mg, 0.071mmol), 2, the 4-thiazolidinedione (10mg, 0.085mmol) and piperidines (0.007mL, 0.07mmol) preparation compound 61 (19mg, 54%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.30(d,J=8.6Hz,2H),7.35(d,

J=8.6Hz,2H),7.42(d,J=8.6Hz,2H),7.46(d,J=8.6Hz,2H),7.56(s,1H),

7.96(s,1H),12.7(br?s,1H)

FABMS?m/z?494(M-H) ^-C ₁₉H ₁₁ ³⁵Cl ₂NO ₂S ₄=495

Embodiment 89

Preparation compound 62

Adopt the method identical with embodiment 87, and 5-(the 4-chloro-phenyl-sulfenyl) thiophene-2-formaldehyde for preparing with embodiment 87 (132mg, 0.520mmol), 2,4-thiazolidinedione (73mg, 0.62mmol) and piperidines (0.052mL, 0.52mmol) preparation compound 62 (113mg, 62%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.33(d,J=8.6Hz,2H),7.44(d,

J=8.6Hz,2H),7.68(d,J=3.9Hz,1H),8.01(s,1H),12.6(br?s,1H)

FABMS?m/z?352(M-H) ^-C ₁₃H ₈ ³⁵ClNO ₂S ₂=353

Embodiment 90

Preparation compound 63

In the argon atmospher, (0.21mL, tetrahydrofuran (THF) 1.5mol) (3mL) solution are with ice-cooled, and (1.6mol/L hexane solution, 0.81mL 1.3mmol), are cooled to mixture-78 ℃ to add n-Butyl Lithium with Diisopropylamine.(236mg, tetrahydrofuran (THF) 1.00mmol) (1mL) solution stirred 30 minutes the 4-bromo-2-dimethoxy-methyl thiophene of adding embodiment 87 preparations.Adding 4,4 '-(287mg 1.0mmol), stirred 10 minutes DCBP base disulfide then.Add entry to reaction soln, and extract with ether.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure obtains 3-bromo-2-(4-chloro-phenyl-sulfenyl)-5-dimethoxy-methyl thiophene (355mg, 94%).

¹H?NMR(300MHz,CDCl ₃)δ(ppm)3.36(s,6H),5.55(d,J=0.7Hz,1H),

7.07(d,J=0.9Hz,1H),7.16(d,J=8.4Hz,2H),7.24(d,J=8.6Hz,2H)

FABMS?m/z?380,378(M ⁺)C ₁₃H ₁₂ ⁷⁹Br ³⁵ClO ₂S ₂=378

3-bromo-2-(4-chloro-phenyl-sulfenyl)-5-dimethoxy-methyl thiophene (170mg, 0.449) is dissolved in the tetrahydrofuran (THF) (4mL), adds 1mol/L hydrochloric acid (0.5mL), at room temperature stirred 4.5 hours.Add sodium bicarbonate aqueous solution, product ethyl acetate extraction to reaction soln.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates are purified with silica gel column chromatography (9: 1 hexane/ethyl acetate) and are obtained 3-bromo-2-(4-chlorobenzene sulfenyl) tetramethylene sulfide-5-formaldehyde (126mg, 85%).

¹H?NMR(300MHz,CDCl ₃)δ(ppm)7.38(d,J=8.4Hz,2H),7.43(d,J=8.6

Hz,2H),7.63(s,1H),9.71(s,1H)

FABMS?m/z?335,333(M+H) ⁺C ₁₁H ₆ ⁷⁹Br ³⁵ClOS ₂=332

Adopt the method identical with embodiment 87, and usefulness 3-bromo-2-(4-chloro-phenyl-sulfenyl) thiophene-5-formaldehyde (114mg, 0.342mmol), 2,4-thiazolidinedione (48mg, 0.41mmol) and piperidines (0.034mL, 0.34mmol) preparation compound 63 (73mg, 49%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.31(d,J=8.8Hz,2H),7.47(d,

J=8.6Hz,2H),7.81(s,1H),7.96(s,1H),12.7(br?s,1H)

FABMS?m/z?432,430(M-H) ^-C ₁₄H ₇ ⁷⁹Br ³⁵ClNO ₂S ₃=431

Embodiment 91

Preparation compound 64

Adopt the method identical with embodiment 78, with compound 63 (19mg, 0.044mmol) and m-chlorine peroxybenzoic acid (50% purity, 23mg 0.066mmol) prepare compound 64 (14mg, 49%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.73(d,J=9.0Hz,2H),7.75(s,

1H),7.84(d,J=8.6Hz,1H),7.98(s,1H),12.8(br?s,1H)

FABMS?m/z?448,446(M-H) ^-C ₁₄H ₇ ⁷⁹Br ³⁵ClNO ₃S ₃=447

Embodiment 92

Preparation compound 65

In the argon atmospher, (500mg 1.32mmol) is dissolved in the tetrahydrofuran (THF) (6mL) 3-bromo-2-(4-chloro-phenyl-sulfenyl)-5-dimethoxy-methyl thiophene that embodiment 90 is prepared, and is cooled to-78 ℃.(1.3mmol) (528mg, tetrahydrofuran (THF) 2.64mmol) (1mL) solution stirred 10 minutes with 4-chloro-N-methoxyl group-N-methyl-benzamide for 1.6mol/L hexane solution, 0.81mL to add n-Butyl Lithium.Add entry to reaction soln, and use the ether extraction product.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates obtains 3-(4-chlorobenzene formacyl)-2-(4-chloro-phenyl-sulfenyl)-5-dimethoxy-methyl thiophene (345mg, 60%) by silica gel column chromatography (15: 1 hexane/ethyl acetate)

¹H?NMR(300MHz,CDCl ₃)δ(ppm)3.31(s,6H),5.45?1H),7.15(d,J=1.1

Hz,114),7.39(d,J=8.8Hz,2H),7.46(d,J=8.6Hz,2H),7.53(d,J=8.8Hz,

2H),7.73(d,J=8.6Hz,2H),

FABMS?m/z?439(M+H) ⁺C ₂₀H ₁₆ ³⁵Cl ₂O ₃S ₂=438

(335mg 0.736mmol) is dissolved in the tetrahydrofuran (THF) (6mL) with 3-(4-chlorobenzene formacyl)-2-(4-chloro-phenyl-sulfenyl)-5-dimethoxy-methyl thiophene.Add 1mol/L hydrochloric acid (1mL), at room temperature stirred 1.5 hours.Add sodium bicarbonate aqueous solution, product ethyl acetate extraction to reaction soln.Anhydrous sodium sulfate drying is used in organic layer water and salt water washing then.Solvent removed by evaporation at reduced pressure, resistates is purified with silica gel column chromatography (5: 1 hexane/ethyl acetate), obtains 3-(4-chlorobenzene formacyl)-2-(4-chloro-phenyl-sulfenyl) thiophene-5-formaldehyde (203mg, 68%) with the ethyl acetate/hexane recrystallization.

¹H?NMR(300MHz,CDCl ₃)δ(ppm)7.50(d,J=8.4Hz,2H),7.52(d,

J=8.4Hz,2H),7.62(d,J=8.8Hz,2H),7.74(d,J=8.8Hz,2H),7.83(s,1H),

9.65(s,1H)

FABMS?m/z?393(M+H) ⁺C ₁₆H ₁₀ ⁷⁹Cl ₂O ₂S ₂=392

Adopt the method identical with embodiment 70, and usefulness 3-(4-chlorobenzene formacyl)-2-(4-chloro-phenyl-sulfenyl) thiophene-5-formaldehyde (193mg, 0.490mmol), 2; 4-thiazolidinedione (69mg; 0.59mmol) and piperidines (0.049mL, 0.49mmol) preparation compound 65 (211mg, 88%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.64(d,J=8.6Hz,2H),7.65(d,

J=8.6Hz,2H),7.73(d,J=8.4Hz,2H),7.81(d,J=8.4Hz,2H),7.87(s,

1H),7.94(s,1H),12.6(br?s,1H)

FABMS?m/z?490(M-H) ^-C ₂₁H ₁₁ ³⁵Cl ₂NO ₃S ₃=491

Embodiment 93

Preparation compound 66

Adopt the method identical with embodiment 78, (50mg, 0.10mmol) (50% purity, 53mg 0.15mol) obtain compound 66 (14mg, 28%) to usefulness compound 65 with m-chlorine peroxybenzoic acid.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.60(d,J=8.4Hz,2H),7.71(d,

J=8.4Hz,2H),7.72(d,J=8.8Hz,2H),7.82(s,1H),7.89(d,J=8.8Hz,2H),

8.04(s,1H),12.8(br?s,1H)

FABMS?m/z?506(M-H) ^-C ₂₁H ₁₁ ³⁵Cl ₂NO ₄S ₃=507

Embodiment 94

Preparation compound 67

With available 2-on the market ((4-chloro-phenyl-) sulfenyl)-5-nitrobenzaldehyde (0.3g, 1.0mmol) (MAYBRIDGE, catalog number (Cat.No.): XAX00154) be dissolved in the ethanol (8mL).Add thiazolidinedione (0.36mg, 3.0mmol) and piperidines (0.1mol, 1.0mmol), mixture is being equipped with reflux exchanger and drying tube (CaCl ₂) flask in reflux 5.5 hours.Temperature is reduced to room temperature, adds 1M HCL solution.After conventional processing, (chloroform-chloroform: pure system methyl alcohol=99: 1) obtains compound 67 (0.109mg, 27.9%) by the purification of recrystallization from ethyl acetate and hexane to resistates then by silica gel column chromatography.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.24(d,J=8.8Hz,1H),

7.59(s,4H),7.88(s,1H),8.17(dd,J=2.6,8.8Hz,1H),8.24(d,J=2.6Hz,

1H),12.84(br?s,1H)

FABMS?m/z?393(M+H) ⁺C ₁₆H ₉ ³⁵ClN ₂O ₄S ₂=392

Embodiment 95

Preparation compound 68

The method of employing and embodiment 78 is by compound 67 (0.02g, 0.051mmol) preparation compound 68 (0.0137g, 65.7%).

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)7.61(d,J=2.6Hz,4H),

7.67(s,1H),8.25(d,J=8.8Hz,1H),8.35(d,J=2.3Hz,1H),8.40(dd,J=2.3,

8.8Hz 1H), NH does not find.

FABMS?m/z?409(M+H) ⁺C ₁₆H ₉ ³⁵ClN ₂O ₅S ₂=408

Embodiment 96

Preparation compound 69

(0.03g 0.077mmol) is dissolved in methylene dichloride (5mL) and the methyl alcohol (1mL), and (0.03g 0.0092mmol), at room temperature stirred 1 hour to add m-chlorine peroxybenzoic acid with compound 67.Add 10% aqueous solution of sodium bisulfite, after routine was handled, (chloroform: methyl alcohol=12: 1) purify, (chloroform: acetonitrile=6: 1) purification obtained compound 69 (0.041g, 15,9%) to resistates by thin-layer chromatography again by thin-layer chromatography.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.71(dt,J=2.0,8.8Hz,2H),

7.87(dt,J=2.0,8.8Hz,1H),7.98(s,1H),8.31(s,1H),8.49(d,J=2.0Hz,

2H), NH does not find.

FABMS?m/z?423(M-H) ^-C ₁₆H ₉ ³⁵ClN ₂O ₆S ₂=424

Embodiment 97

Preparation compound 70

With the 2.5mol/L aqueous sodium hydroxide solution (1.2mL, 3.1mmol) and Tetrabutyl amonium bromide (0.012g, 0.031mmol) join 3-chlorobenzene mercaptan (0.11g, 0.73mmol) in, 25 ℃ were stirred 10 minutes.With 2-fluoro-5-nitrobenzaldehyde (0.12g, toluene 0.73mmol) (1.2mL) solution joins in the reaction soln, 110 ℃ were stirred 1.5 hours.After conventional aftertreatment, resistates is purified by silica gel column chromatography (through the chloroform wash-out) and is obtained the 2-[(3-chloro-phenyl-) sulfenyl]-5-nitrobenzaldehyde (72mg, 34%).

¹H?NMR(300MHz,CDCl ₃)δ(ppm)7.01(d,J=8.8Hz,1H),7.44-7.54(m,

3H),7.58(br?s,1H),8.17(dd,J=2.4,8.8Hz,1H),8.69(d,J=2.6Hz,1H),

10.29(s,1H)

FABMS?m/z?294(M+H) ⁺C ₁₃H ₈ ³⁵ClNO ₃S=293

With the 2-[(3-chloro-phenyl-) sulfenyl]-5-nitrobenzaldehyde (70mg, 0.24mmol) be dissolved in the toluene (3.5mL), add 2,4-thiazolidinedione (0.11mg, 0.95mmol), piperidines (0.0094mL, 0.095mmol), (0.0054mL, 0.095mmol) and molecular sieve 4A (0.35g), 110 ℃ were stirred 3 hours acetate.After conventional aftertreatment, resistates is purified by thin-layer chromatography (launching with chloroform/acetonitrile=10/1) and is obtained compound 70 (41mg, 440).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.34(d,J=8.8Hz,1H),7.60-7.47

(m,3H),7.63(br?s,1H),7.88(s,1H),8.20(dd,J=8.8,2.6Hz,1H),8.26(d,

J=2.6Hz,1H),12.83(m,1H)

FABMS?m/z?391(M-H) ^-C ₁₆H ₉ ³⁵ClN ₂O ₄S ₂=392

Embodiment 98

Preparation compound 71

With the 2.5mol/L aqueous sodium hydroxide solution (1.7mL, 4.4mmol) and Tetrabutyl amonium bromide (0.017g, 0.051mmol) join 2-chlorobenzene mercaptan (0.17g, 1.0mmol) in, 25 ℃ were stirred 10 minutes.(110 ℃ were stirred 2 hours for 0.18g, toluene 1.0mmol) (1.7mL) solution to add 2-fluoro-5-nitrobenzaldehyde to reaction soln.After conventional aftertreatment, resistates is purified by silica gel chromatography (through the chloroform wash-out) and is obtained the 2-[(2-chloro-phenyl-) sulfenyl]-5-nitrobenzaldehyde (0.25g, 83%).

¹H?NMR(300MHz,CDCl ₃)δ(ppm)6.88(d,J=8.8Hz,1H),7.42(ddd,

J=7.5,7.5,1.4Hz,1H),7.51(ddd,J=7.3,7.3,1.6Hz,1H),7.62(dd,J=8.1,

1.5Hz,1H),7.69(dd,J=7.5,1.7Hz,1H),8.16(dd,J=8.8,2.6Hz,1H),

8.70(d,J=2.5Hz,1H),10.32(s,1H)

FABMS?m/z?293(M ⁺)C ₁₃H ₈ ³⁵ClNO ₃S=293

With the 2-[(2-chloro-phenyl-) sulfenyl]-the 5-nitrobenzaldehyde (0.14g 0.49mmol) is dissolved in the ethanol (5.8mL), adds 2, the 4-thiazolidinedione (0.23mg, 2.0mmol) and piperidines (0.039mL, 0.39mmol), 80 ℃ of stirrings 3 hours.After conventional aftertreatment, resistates is purified by thin-layer chromatography (launching with chloroform/7 nitriles=10/1) and is obtained compound 71 (24mg, 13%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.20(d,J=8.8Hz,1H),7.43-

7.62(m,3H),7.71(m,1H),7.89(s,1H),8.20(dd,J=8.8,2.6Hz,1H),

8.28(m,1H),12.82(m,1H)

FABMS?m/z?391(M-H) ^-C ₁₆H ₉ ³⁵ClN ₂O ₄S ₂=392

Embodiment 99

Preparation compound 72

Adopt the method identical with embodiment 97, by 3,4-dichlorobenzene mercaptan (0.12g, 0.68mmol), 2.5mol/L aqueous sodium hydroxide solution (1.2mL, 2.9mmol), Tetrabutyl amonium bromide (0.011 g, 0.034mmol) and 2-fluoro-5-nitrobenzaldehyde (0.12g, toluene 0.68mmol) (1.2mL) formulations prepared from solutions 2-[(3, the 4-dichlorophenyl) sulfenyl]-5-nitrobenzaldehyde (0.16g, 79%).

¹H?NMR(300MHz,CDCl ₃)δ(ppm)7.02(d,J=8.8Hz,1H),7.41(dd,

J=8.2,2.0Hz,1H),7.60(d,J=8.2Hz,1H),7.69(d,J=2.0Hz,1H),

8.18(dd,J=8.8,2.5Hz,1H),8.69(d,J=2.6Hz,1H),10.28(s,1H)

FABMS?m/z?328(M+H) ⁺C ₁₃H ₇ ³⁵Cl ₂NO ₃S=327

Adopt the method identical with embodiment 97, by 2-[(3, the 4-dichlorophenyl) sulfenyl]-5-nitrobenzaldehyde (0.12g, 0.35mmol), toluene (5.8mL), 2, the 4-thiazolidinedione (0.16g, 1.4mmol), piperidines (0.014g, 0.14mmol), acetate (0.0080mL, 0.14mmol) and molecular sieve 4A (0.58g) preparation compound 72 (74mg, 49%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.39(d,J=8.8Hz,1H),7.50(dd,

J=8.4,1.8Hz,1H),7.75(d,J=8.5Hz,1H),7.88-7.83(m,2H),8.18(d,

J=8.6,2.2Hz,1H),8.25(m,1H),12.82(m,1H)

FABMS?m/z?425(M-H) ^-C ₁₆H ₈ ³⁵Cl ₂N ₂O ₄S ₂=426

Embodiment 100

Preparation compound 73

Adopt the method identical with embodiment 97, by 4-bromobenzene mercaptan (0.19g, 1.0mmol), 2.5mol/L aqueous sodium hydroxide solution (1.7mL, 4.3mmol), Tetrabutyl amonium bromide (0.016g, 0.051mmol) and 2-fluoro-5-nitrobenzaldehyde (0.17g, 1.0mmol) toluene (1.7mL) formulations prepared from solutions 2-[(4-bromophenyl) sulfenyl]-5-nitrobenzaldehyde (0.28g, 82%).

¹H?NMR(300MHz,CDCl ₃)δ(ppm)6.98(d,J=8.9Hz,1H),7.41-7.46(m,

2H),7.63-7.69(m,2H),8.13(dd,J=8.8,2.4Hz,1?H),8.68(d,J=2.6Hz,

1H),10.29(s,1H)

FABMS?m/z?338(M+H) ⁺C ₁₃H ₈ ⁷⁹BrNO ₃S=337

Adopt the method identical with embodiment 97, by the 2-[(4-bromophenyl) sulfenyl]-5-nitrobenzaldehyde (0.031g, 0.091mmol), toluene (1.5mL), 2,4-thiazolidinedione (0.043g, 0.36mmol), piperidines (0.0036g, 0.036mmol), acetate (0.0025mL, 0.036mmol) and molecular sieve 4A (0-092g) preparation compound 73 (26mg, 66%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.25(d,J=8.8Hz,1H),7.48-

7.52(m,2H),7.20-7.25(m,2H),7.88(s,1H),8.18(dd,J=8.8,2.6Hz,1H),

8.25(d,J=2.4Hz,1H),12.85(br?s,1H)

FABMS?m/z?435(M-H) ^-C ₁₆H ₉ ⁷⁹BrN ₂O ₄S ₂=436

Embodiment 101

Preparation compound 74

Adopt the method identical with embodiment 98, by 4-anisole mercaptan (0.14g, 0.99mmol), 2.5mol/L aqueous sodium hydroxide solution (1.8mL, 4.4mmol), Tetrabutyl amonium bromide (0.016g, 0.050mmol) and 2-fluoro-5-nitrobenzaldehyde (0.17g, 0.99mmol) toluene (1.8mL) formulations prepared from solutions 2-[(4-p-methoxy-phenyl) sulfenyl]-5-nitrobenzaldehyde (0.22g, 76%).

¹H?NMR(300MHz,CDCl ₃)δ(ppm)3.89(s,3H),6.92(d,J=8.9Hz,

1H),7.03(d,J=8.6Hz,2H),7.49(d,J=8.6Hz,2H),8.08(dd,J=9.0,

2.4Hz,1H),8.63(d,J=2.2Hz,1H),10.29(s,1H)

FABMS?m/z?289(M ⁺)C ₁₄H ₁₁N ₂O ₄=289

Adopt the method identical, by the 2-[(4-p-methoxy-phenyl with embodiment 98) sulfenyl]-the 5-nitrobenzaldehyde (0.11g, 0.39mmol), ethanol (1.5mL), 2,4-thiazolidinedione (0.18g, 1.5mmol) and piperidines (0.015g, 0.15mmol) preparation compound 74 (26mg, 18%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)3.34(s,3H),6.98(d,J=8.8Hz,

1H),7.13(d,J=9.0Hz,2H),7.57(d,J=8.6Hz,2H),7.89(s,1H),

8.14(dd,J=8.6,2.4Hz,1H),8.21(d,J=2.4Hz,1H)

FABMS?m/z?387(M-H) ^-C ₁₇H ₁₂N ₂O ₅S ₂=388

Embodiment 102

Preparation compound 75

Adopt the method identical by 4-ethyl phenyl mercaptan (0.13g with embodiment 97,0.95mmol), 2.5mol/L aqueous sodium hydroxide solution (1.6mL, 4.0mmol), Tetrabutyl amonium bromide (0.015g, 0.047mmol) and 2-fluoro-5-nitrobenzaldehyde (0.16g, 0.95mmol) toluene (1.6mL) formulations prepared from solutions 2-[(4-ethylphenyl) sulfenyl]-5-nitrobenzaldehyde (0.22g, 82%).

¹H?NMR(300MHz,CDCl ₃)δ(ppm)1.30(t,J=7.6Hz,3H),2.74(q,J=7.5

Hz,2H),6.96(d,J=9.0Hz,1H),7.36(d,J=7.5Hz,2H),7.48(d,J=8.1Hz,

2H),8.10(dd,J=9.0,2.2Hz,1H),8.66(d,J=2.6Hz,1H),10.31(s,1H)

FABMS?m/z?288(M+H) ⁺C ₁₅H ₁₃NO ₃S=287

Adopt the method identical with embodiment 97, by the 2-[(4-ethylphenyl) sulfenyl]-5-nitrobenzaldehyde (0.20g, 0.69mmol), toluene (9.9mL), 2,4-thiazolidinedione (0.32g, 2.7mmol) and piperidines (0.027g, 0.27mmol), acetate (0.016mL, 0.27mmol) and molecular sieve 4A (0.99g) preparation compound 75 (0.14g, 51%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)1.21(t,J=7.7Hz,3H),2.68(q,

J=7.7Hz,2H),7.09(d,J=8.8Hz,1H),7.39(d,J=8.1Hz,2H),7.51(d,

J=8.1Hz,2H),7.39(s,1H),8.16(dd,J=8.6,2.3Hz,1H),8.22(d,J=2.0

Hz,1H),12.82(m,1H)

FABMS?m/z?385(M-H) ^-C ₁₈H ₁₄N ₂O ₄S ₂=386

Embodiment 103

Preparation compound 76

Adopt the method identical with embodiment 94, (MAYBRIDGE, catalog number (Cat.No.): XAX00131) (0.27g 1.0mmol) makes compound 76 (0.134g, 35.9%) to 2-benzylthio--5-nitrobenzaldehyde by available on the market.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm).51(s,2H),7.31(m,3H)7.46(dt,

J=1.7,6.6Hz,2H),7.78(s,1H),7.81(d,J=8.9Hz,1H),8.17(d,J=2.6

Hz,1H),8.22(dd,J=2.6,8.9Hz,1H),12.82(br?s,1H)

EIMS?m/z?371(M-H) ^-C ₁₇H ₁₂N ₂O ₄S ₂=372

Embodiment 104

Preparation compound 77

Adopt the method identical with embodiment 96, (0.03g 0.081mmol) prepares compound 77 (0.0055g, 17.6%) by compound 76.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)4.24(d,J=6.8Hz,2H),6.94(dd,

J=2.2,5.0Hz,2H),7.20(dd,J=2.2,5.0Hz,3H),7.4(s,1H),7.89(d,

J=8.7Hz,1H),8.21(d,J=2.2Hz,1H),8.38(dd,J=2.2,8.7Hz,1H),

NH does not find

EIMS?m/z?369(M+H) ⁺C ₁₇H ₁₂N ₂O ₅S ₂=388

Embodiment 105

Preparation compound 78

Adopt the method identical with embodiment 96, (0.03g 0.081mmol) prepares compound 78 (0.0192g, 59.0%) by compound 76.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)4.78(s,2H),7.10(dd,J=1.8,4.5

Hz,3H),7.27(dd,J=1.8,4.5Hz,3H),8.06(d,J=8.8Hz,1H),8.08(s,1H),

8.36 (dd, J=2.5,8.8Hz, 1H), 8.39 (1H), NH does not find for d, J=2.5Hz

EIMS?m/z?403(M-H) ^-C ₁₇H ₁₂N ₂O ₆S ₂=404

Embodiment 106

Preparation compound 79

Adopt the method identical with embodiment 97, by 4-chloro benzyl sulfur alcohol (0.11g, 0.83mmol), 2.5mol/L aqueous sodium hydroxide solution (1.4mL, 3.5mmol), Tetrabutyl amonium bromide (0.013g, 0.041mmol) and 2-fluoro-5-nitrobenzaldehyde (0.14g, 0.83mmol) toluene (1.4mL) formulations prepared from solutions 2-[(4-benzyl chloride base) sulfenyl]-5-nitrobenzaldehyde (0.17g, 67%).Adopt the method identical with embodiment 97, by the 2-[(4-chloro-phenyl-) sulfenyl]-5-nitrobenzaldehyde (0.12g, 0.39mmol), toluene (6.1mL), 2,4-thiazolidinedione (0.18g, 1.6mmol), piperidines (0.016mL, 0.16mmol), acetate (0.0090mL, 0.16mmol) and molecular sieve 4A (0.61g) preparation compound 79 (0.11g, 70%).

2-[(4-benzyl chloride base) sulfenyl]-the 5-nitrobenzaldehyde:

¹H?NMR(300MHz,CDCl ₃)δ(ppm)4.26(s,2H),7.34(s,4H),7.49(d,

J=8.8Hz,1H),8.29(dd,J=8.8,2.6Hz,1H),8.65(d,J=2.5Hz,1H),

10.23(s,1H)

FABMS?m/z?307(M ⁺)C ₁₄H ₁₀ ³⁵ClNO ₃S=307

Compound 79:

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)4.50(s,2H),7.39(d,J=8.5Hz,

2H),7.46(d,J=8.4Hz,2H),7.77(s,1H),7.80(d,J=8.8Hz,1H),8.17(d,

J=2.4Hz,1H),8.21(dd,J=9.0,2.6Hz,1H),12.81(m,1H)

FABMS?m/z?405(M-H) ^-C ₁₇H ₁₁ ³⁵ClN ₂O ₄S ₂=406

Embodiment 107

Preparation compound 80

With available on the market (MAYBRIDGE, catalog number (Cat.No.): sulfenyl XAX00146) 4[(4-bromophenyl)]-(0.12g 0.35mmol) is dissolved in the toluene (5.9mL) the 3-nitrobenzaldehyde.Add 2, the 4-thiazolidinedione (0.16mg, 1.04mmol), piperidines (0.014mL, 0.14mmol), (0.0080mL, 0.14mmol) and molecular sieve 4A (0.59g), 110 ℃ were stirred 3 hours acetate.After conventional aftertreatment, resistates obtains compound 80 (21mg, 14%) by the ethanol development.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.01(d,J=8.6Hz,1H),7.58-

7.62(m,2H),7.73-7.82(m,4H),8.50(d,J=2.0Hz,1H),12.71(m,1H)

FABMS?m/z?435(M-H) ^-C ₁₆H ₉ ⁷⁹BrN ₂O ₄S ₂=436

Embodiment 108

Preparation compound 81

With available on the market (MAYBRIDGE, catalog number (Cat.No.): sulfenyl NRBOO117) 4[(4-chloro-phenyl-)]-(0.31g 1.0mmol) is dissolved in the ethanol (12mL) the 3-nitrobenzaldehyde.Add 2, and the 4-thiazolidinedione (0.16mg, 1.4mmol), (0.014mL, 0.14mmol), 80 ℃ were stirred 3 hours piperidines.Reaction solution is cooled to 25 ℃, and filtration is collected the crystal of separating out and obtained compound 81 (O.15g, 36%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)6.98(d,J=8.5Hz,1H),7.08br?s,

1H),7.70-7.59(m,5H),7.73(dd,J=8.6,2.0Hz,1H),8.45(d,J=2.0Hz,

1H)

FABMS?m/z?391(M-H) ^-C ₁₆H ₉ ³⁵ClN ₂O ₄S ₂=392

Embodiment 109

Preparation compound 82

Adopt the method identical with embodiment 96, (0.03g 0.081mmol) prepares compound 82 (0.0195g, 62.0%) by compound 9.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.49(s,3H),7.31(d,J=8.2Hz,

2H),7.56(d,J=8.2Hz,2H),7.84(s,1H),8.28(dd,J=1.8,8.4Hz,1H),

8.46 (s, 1H), 8.49 (1H), NH does not find for t, J=1.8Hz

EIMS?m/z?389(M+H) ⁺C ₁₇H ₁₂N ₂O ₅S ₂=388

Embodiment 110

Preparation compound 83

(0.07g 0.19mmol) is dissolved in the methylene dichloride (12mL), and (0.13g 0.38mmol), stirred 1 hour under the room temperature to add methyl alcohol (2.3mL) and m-chlorine peroxybenzoic acid with compound 9.Add 10% aqueous solution of sodium bisulfite.Through after the conventional processing, (chloroform: purification methyl alcohol=12: 1) obtains compound 83 (0.019g, 25.4%) with the chloroform development to resistates with thin-layer chromatography.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.41(s,3H),7.50(d,J=8.3Hz,

2H),7.84(s,1H),7.86(d,J=8.1Hz,2H),8.03(d,J=8.3Hz,1H),8.23(d,

J=1.7Hz, 1H), 8.44 (1H), NH does not find for d, J=8.3Hz

EIMS?m/z?405(M+H) ⁺C ₁₇H ₁₂N ₂O ₆S ₂=404

Embodiment 111

Preparation compound 84

Adopt the method identical with embodiment 94, (MAYBRIDGE, catalog number (Cat.No.): XAX00135) (0.26g 1.0mmol) prepares compound 84 (0.152g, 41.8%) to 2-(cyclohexyl sulfenyl)-5-nitrobenzaldehyde by available on the market.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)1.30(m,1H),1.46(m,4H),

1.61(m,1H),1.73(m,2H),2.00(m,2H),3.67(m,1H),7.79(d,J=8.5Hz,

1H),7.83(s,1H),8.19(d,J=2.4Hz,1H),8.22(dd,J=2.4,8.5Hz,1H),

12.82(br?s,1H)

FABMS?m/z?363(M-H) ^-C ₁₆H ₁₆N ₂O ₄S ₂=364

Embodiment 112

Preparation compound 85

Adopt the method identical with embodiment 96, (0.02g 0.055mmol) prepares compound 85 (0.0149g, 71.3%) by compound 84.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)1.30(m,8H),1.77(m,2H),

2.73(m,2H),7.60(s,1H),8.24(s,1H),8.05(d,J=8.6Hz,1H),8.36(d,

J=2.2Hz, 1H), 8.43 (dd, J=2.2,8.6Hz, 1H), NH does not find.

FABMS?m/z?381(M+H) ^-C ₁₆H ₁₆N ₂O ₅S ₂=380

Embodiment 113

Preparation compound 86

Adopt the method identical with embodiment 96, (0.03g 0.082mmol) prepares compound 86 (0.0034g, 10.9%) by compound 84.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)1.27(m,6H),1.59(m,1H),

1.69(m,4H),8.23(d,J=8.4Hz,1H),8.24(s,1H),8.44(s,1H),8.46(d,

J=8.4Hz, 1H), NH does not find.

FABMS?m/z?395(M-H) ^-C ₁₆H ₁₆N ₂O ₆S ₂=396

Embodiment 114

Preparation compound 87

(0.12g 1.0mmol) is dissolved in 10% aqueous sodium hydroxide solution (1.7mL), and (0.016g 0.05mmol), at room temperature stirred 5 minutes to add Tetrabutyl amonium bromide with the p-toluenethiol.To toluene (1.7mL) solution of Dropwise 5-bromo-2-fluorobenzaldehyde (0.2gm1.0mmol) wherein, at room temperature stirred 4 hours.After conventional processing,, obtain 5-bromo-2-[(4-aminomethyl phenyl with ethanol and hexane recrystallization and purification) sulfenyl] phenyl aldehyde (0.23g, 74.1%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.39(s,3H),6.90(d,J=8.4Hz,1H),

7.22(d,J=7.9Hz,2H),7.35(dd,J=1.7,8.1Hz,2H),7.46(dd,J=2.4,8.4

Hz,1H),7.96(d,J=2.2Hz,1H),10.32(s,1H)

FABMS?m/z?308(M+H) ⁺C ₁₄H ₁₁ ⁷⁹BrOS=307

Adopt the method identical, by 5-bromo-2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl] (0.03g 0.1mmol) prepares compound 87 (0.021g, 52%) to phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.31(m,3H),7.14(d,J=8.8Hz,

1H),8.23(d,J=8.3Hz,2H),8.28(d,J=8.3Hz,2H),7.60(s,1H),7.62(dd,

J=2.2,8.8Hz,1H),7.90(s,1H),12.82(br?s,1H)

EIMS?m/z?407(M+H) ⁺C ₁₇H ₁₂ ⁷⁹BrNO ₂S ₂=406

Embodiment 115

Preparation compound 88

Adopt sulfenyl with embodiment 114 (synthetic 5-bromo-2-[(4-aminomethyl phenyl)] phenyl aldehyde) identical method, by 3-bromo-4-fluorobenzaldehyde (0.2g, 0.99mmol) preparation 3-bromo-4-[(4-aminomethyl phenyl) sulfenyl] phenyl aldehyde (0.19g, 63.6%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.44(s,3H),6.73(d,J=8.3Hz,1H),

7.30(d,J=8.4Hz,2H),7.47(d,J=8.1Hz,2H),7.54(dd,J=1.7,8.4Hz,

1H),8.00(d,J=1.7Hz,1H),9.84(s,1H)

FABMS?m/z?307(M ⁺)C ₁₄H ₁₁BrOS=307

Adopt the method identical, by 3-bromo-4-[(4-aminomethyl phenyl with embodiment 94) sulfenyl] (0.15g 0.49mmol) prepares compound 88 (0.087g, 43.9%) to phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.49(s,3H),6.74(d,J=8.3Hz,

1H),7.37(d,J=8.1Hz,2H),7.44(dd,J=2.0,8.5Hz,1H),7.48(d,J=8.1

Hz,2H),7.70(s,1H),7.89(d,J=2.0,Hz,1H),12.64(br?s,1H)

EIMS?m/z?407(M+H) ⁺C ₁₇H ₁₂ ⁷⁹BrNO ₂S ₂=406

Embodiment 116

Preparation compound 89

Reaction is according to document (Tetrahedron Lett.Vol.36, No.50,9085-9088 page or leaf, 1995) method of Miao Shuing is carried out, product 5-bromo-2-[(4-aminomethyl phenyl) sulfenyl] (0.06g, 0.2mmol) (0.03g 0.2mmol) handles phenyl aldehyde with 2-pyridine trifluoro-methanyl sulfonate.Resistates is by thin-layer chromatography (hexane: ethyl acetate=8: 1) pure system obtains the 2-[(4-aminomethyl phenyl) sulfenyl]-5-(2-pyridyl) phenyl aldehyde (0.024g, 38.5%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.41(s,3H),7.09(d,J=8.4Hz,1H),

7.24(m,3H),7.42(d,J=8.4Hz,2H),7.76(dd,J=1.7,6.6Hz,2H),

8.01(dd,J=2.2,8.5Hz,1H),8.50(d,J=2.2Hz,1H),8.69(d,J=4.6Hz,

1H),10.43(s,1H)

FABMS?m/z?306(M ⁺)C ₁₉H ₁₅NOS=305

Adopt the method identical, by the 2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl]-(0.024g 0.08mmol) prepares compound 89 (0.026g, 84.4%) to 5-(2-pyridyl) phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.32(s,3H),7.26(d,J=8.4Hz,

2H),7.30(d,J=8.4Hz,2H),7.33(dd,J=8.3,2H),7.41(m,1H),7.92(m,

1H),7.97(d,J=7.7Hz,1H),8.08(s,1H),8.07(dd,J=2.0,7.7Hz,1H),

8.32(d,J=1.7Hz,1H),8.71(d,J=4.8Hz,1H),12.70(br?s,1H)

EIMS?m/z?405(M-H) ^-C ₂₂H ₁₆N ₂O ₂S ₂=406

Embodiment 117

Preparation compound 90

With three (dibenzenyl acetone)-two palladiums (0.18g, 0.2mmol) and triphenylphosphine (0.21g 0.8mmol) is dissolved in the tetrahydrofuran (THF) (60mL), at room temperature stirs 30 minutes.Afterwards, add 5-bromo-2-fluorobenzaldehyde (0.4g, 2.0mmol) and 2-(tributyl stannyl)-furans (1.25mL, 4.0mmol), and reflux 10 hours.The mixture cool to room temperature, after conventional processing, (hexane: ethyl acetate=8: 1) purification obtains 2-fluoro-5-(2-furyl) phenyl aldehyde (0.38g, 100%) to resistates by silica gel column chromatography.

¹H-NMR(300MHz,CDCl ₃)δ(ppm)6.49(dd,J=1.8,3.5Hz,1H),6.69(d,

J=3.3Hz,1H),7.21(t,J=9.9Hz,1H),6.49(d,J=1.8Hz,1H),7.90(m,

1H),8.14(dd,J=2.4,6.6Hz,1H),10.39(s,1H)

FABMS?m/z?190(M ⁺)C ₁₁H ₇ ¹⁹FO ₂=190

Adopt sulfenyl with embodiment 114 (synthetic 5-bromo-2-[(4-aminomethyl phenyl)] phenyl aldehyde) identical method, by 2-fluoro-5-(2-furyl) phenyl aldehyde (0.1g, 0.53mmol) preparation 2-[(4-aminomethyl phenyl) sulfenyl]-5-(2-furyl) phenyl aldehyde (0.14g, 87.8%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.39(s,3H),6.59(d,J=1.8Hz,

1H),6.69(d,J=3.3Hz,1H),7.07(d,J=8.4Hz,1H),7.21(d,J=8.3Hz,

2H),7.36(d,J=8.1Hz,2H),7.48(s,1H),7.66(dd,J=2.0,8.3Hz,1H),

8.14(d,J=2.0Hz,1H),10.41(s,1H)

FABMS?m/z?294(M ⁺)C ₁₈H ₁₄O ₂S=294

Adopt the method identical, by the 2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl]-(0.14g 0.47mmol) prepares compound 90 (0.17g, 92.8%) to 5-(2-furyl) phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.50(s,3H),6.65(m,1H),7.04(d,

J=3.5Hz,1H),7.22(d,J=8.4Hz,2H),7.26(d,J=8.4Hz,2H),7.32(d,

J=8.4Hz,1H),7.74(d,J=8.2Hz,1H),7.81(d,J=7.7Hz,1H),8.03(s,1H),

12.71(br?s,1H)

EIMS?m/z?392(M-H) ^-C ₂₁H ₁₅NO ₃S ₂=393

Embodiment 118

Preparation compound 91

Adopt the method identical with embodiment 96, (0.1g 0.25mmol) prepares compound 91 (0.069g, 66.5%) by compound 74.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.30(s,3H),6.67(dd,J=1.8,3.5

Hz,1H),7.17(d,J=8.6Hz,1H),7.31(d,J=8.6Hz,2H),7.45(d,J=8.3Hz,

2H),7.76(s,1H),7.87(d,J=1.8Hz,1H),8.01(d,J=5.9Hz,2H),8.02(s,

1H),12.77(br?s,1H)

EIMS?m/z?410(M+H) ⁺C ₂₁H ₁₅NO ₄S ₂=409

Embodiment 119

Preparation compound 92

Adopt and the identical method of embodiment 117 (Synthetic 2-fluoro-5-(2-furyl) phenyl aldehyde), by 2-(tributyl stannyl)-thiophene (0.63mL, 2.0mmol) preparation 2-fluoro-5-(2-thienyl) phenyl aldehyde (0.2g, 100%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)7.10(t,J=4.4Hz,1H),7.21(dd,

J=8.8,9.9Hz,1H),7.33(d,J=4.4Hz,2H),7.83(m,1H),8.08(dd,

J=2.6,6.5Hz,1H),10.40(s,1H)

FABMS?m/z?206(M ⁺)C ₁₁H ₇ ¹⁹FOS=206

Adopt sulfenyl with embodiment 114 (synthetic 5-bromo-2-[(4-aminomethyl phenyl)] phenyl aldehyde) identical method, by 2-fluoro-5-(2-thienyl) phenyl aldehyde (0.1g, 0.49mmol) preparation 2-[(4-aminomethyl phenyl) sulfenyl]-5-(2-thienyl) phenyl aldehyde (0.12g, 77.4%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.39(s,3H),7.06(t,J=3.8Hz,1H),

7.10(m,1H),7.24(d,J=8.3Hz,2H),7.33(m,4H),7.37(d,J=8.1Hz,

2H),7.60(dd,J=2.4,8.3Hz,1H),8.03(d,J=2.4Hz,1H),10.42(s,1H)

FABMS?m/z?310(M ⁺)C ₁₈H ₁₄OS ₂=310

Adopt the method identical, by the 2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl]-(0.12g 0.38mmol) prepares compound 92 (0.14g, 91.3%) to 5-(2-thienyl) phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.30(s,3H),7.18(d,J=3.8Hz,

1H),7.24(d,J=4.8Hz,4H),7.56(d,J=7.7Hz,1H),7.63(d,J=5.1Hz,

1H),7.72(s,1H),7.73(d,J=7.5Hz,1H),8.03(s,1H),12.71(br?s,1H)

EIMS?m/z?408(M-H) ^-C ₂₁H ₁₅NO ₂S ₃=409

Embodiment 120

Preparation compound 93

Adopt the method identical with embodiment 96, (0.1g 0.24mmol) prepares compound 93 (0.051g, 49.4%) by compound 92.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.30(s,3H),7.20(dd,J=3.7,5.0

Hz,1H),7.32(d,J=8.1Hz,1H),7.46(d,J=8.3Hz,2H),7.66(d,J=3.7Hz,

2H),7.69(d,J=3.7Hz,2H),8.01(m,3H),12.78(br?s,1H)

EIMS?m/z?426(M+H) ⁺C ₂₁H ₁₅NO ₃S ₃=425

Embodiment 121

Preparation compound 94

(0.35mL 2.5mmol) is dissolved in the tetrahydrofuran (THF) (3.5mL), and with temperature regulation to 0 ℃ with diisopropylamine.(1.24mL 2.0mmol), stirred 10 minutes to drip n-Butyl Lithium (hexane solution).Temperature of reaction is reduced to-78 ℃.(0.2g 1.65mmol), stirred 1 hour to add 4-fluorine benzonitrile.(0.19mL 2.5mmol), stirred 20 minutes, carried out conventional processing then to drip dimethyl formamide.(hexane: ethyl acetate=8: 1) pure system obtains 2-fluoro-5-cyanobenzaldehyde (0.11g, 43.4%) to resistates by thin-layer chromatography.

¹H-NMR(300MHz,CDCL ₃)δ(ppm)7.46(t,J=8.8Hz,1H),7.90(m,

1H),7.71(dd,J=2.2,6.2Hz,1H),10.36(s,1H)

EIMS?m/z?148(M-H)C ₈H ₄ ¹⁹FNO=149

Adopt sulfenyl with embodiment 114 (synthetic 5-bromo-2-[(4-aminomethyl phenyl)] phenyl aldehyde) identical method, by 2-fluoro-5-cyanobenzaldehyde (0.1g, 0.67mmol) preparation 5-cyano group-2-[(4-aminomethyl phenyl) sulfenyl] phenyl aldehyde (0.15g, 86.9%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.44(s,3H),6.92(d,J=8.6Hz,1H),

7.31(d,J=7.9Hz,2H),7.44(d,J=8.3Hz,2H),7.49(dd,J=1.8,8.4Hz,

1H),8.07(d,J=2.0Hz,1H),10.27(s,1H)

FABMS?m/z?253(M ⁺)C ₁₅H ₁₁NOS=253

Adopt the method identical, by 5-cyano group-2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl]-(0.1g 0.4mmol) prepares compound 94 (0.09g, 64.5%) to phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.37(s,3H),7.00(d,J=8.3Hz,

1H),7.34(d,J=8.3Hz,2H),7.46(d,J=8.3Hz,2H),7.76(dd,J=1.7,8.4

Hz,1H),7.80(s,1H),7.84(s,1H),12.01(br?s,1H)

EIMS?m/z?353(M+H) ⁺C ₁₈H ₁₂N ₂O ₂S ₂=352

Embodiment 122

Preparation compound 95

Adopt sulfenyl with embodiment 114 (synthetic 5-bromo-2-[(4-aminomethyl phenyl)] phenyl aldehyde) identical method, by 2-fluoro-5-formyl radical benzonitrile (0.2g, 1.34mmol) preparation 3-cyano group-4-[(4-aminomethyl phenyl) sulfenyl] phenyl aldehyde (0.3g, 89.9%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.44(s,3H),6.94(d,J=8.4Hz,1H),

7.31(d,J=7.9Hz,2H),7.47(dd,J=1.8,8.1Hz,2H),7.78(dd,J=1.8,8.4

Hz,1H),8.07(d,J=5Hz,1H),9.90(s,1H)

FABMS?m/z?254(M+H) ⁺C ₁₅H ₁₁NOS=253

Adopt the method identical, by 3-cyano group-4-[(4-aminomethyl phenyl with embodiment 94) sulfenyl]-(0.2g 0.79mmol) prepares compound 95 (0.126g, 45.3%) to phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.50(s,3H),7.06(d,J=8.6Hz,

1H),7.36(d,J=8.4Hz,2H),7.49(d,J=8.3Hz,2H),7.66(s,1H),7.71(dd,

J=2.0,8.5Hz, 1H), 8.08 (1H), NH does not find for d, J=2.0Hz

EIMS?m/z?352(M ⁺)C ₁₈H ₁₂N ₂O ₂S ₂=352

Embodiment 123

Preparation compound 96

Adopt method (the synthesize 5-bromo-2-[(4-aminomethyl phenyl) sulfenyl identical with embodiment 114] phenyl aldehyde), prepare 3-bromo-4-[(4-aminomethyl phenyl by 3-bromo-4-fluorobenzaldehyde) and sulfenyl] phenyl aldehyde (0.18g, 59.0%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.44(s,3H),6.73(d,J=8.3Hz,1H),

7.30(d,J=7.9Hz,2H),7.47(d,J=8.1Hz,2H),7.54(dd,J=1.7,8.3Hz,

1H),7.99(d,J=1.7Hz,1H),9.84(s,1H)

EIMS?m/z?307(M ⁺)C ₁₄H1179BrOS=307

With 3-bromo-4-[(4-aminomethyl phenyl) sulfenyl] (0.2g 0.65mmol) is dissolved in methyl alcohol (6.0mL) and the methylene dichloride (6.0mL) phenyl aldehyde.(0.025g 0.65mmol), stirred 15 minutes and carries out conventional processing to add sodium borohydride.Solvent is removed with vacuum drier.Resistates is dissolved in the methylene dichloride (7.0mL).Add tert-butyldimethylsilyl chloride (0.12g, 0.78mmol) and imidazoles (0.053g 0.65mmol), stirred 2 hours and carries out conventional processing.Product is by silica gel look general (hexane: ethyl acetate=16: 1) pure system obtains 3-bromo-4-[(4-aminomethyl phenyl) sulfenyl] benzyl (t-butyldimethylsilyl) ether (0.27g, 96.4%).

¹H-NMR(300MHz,CDCl ₃)(0.62(s,6H),0.84(s,9H),2.29(s,3H),4.56(s,

2H),6.76(d,J=8.3Hz,1H),7.00(dd,J=1.8,8.3Hz,1H),7.11(d,J=8.4

Hz,2H),7.26(d,J=1.8Hz,2H),7.43(d,J=1.7Hz,1H),

EIMS?m/z?424(M+H) ⁺C20H2779BrOSSi=423

In the argon atmospher, hexane (1.4mL) and ether (10.4mL) are cooled to-78 ℃.Add n-Butyl Lithium (hexane solution) (2.17mL, 3.47mmol) and Tetramethyl Ethylene Diamine (0.52mL 3.47mmol), stirred 15 minutes.Add 3-bromo-4-[(4-aminomethyl phenyl) sulfenyl] (0.37ml 0.87mmol), stirred 30 minutes benzyl t-butyldimethylsilyl ether then.(0.3ml, the 3.47mmol) solution in ether (4.3mL) stirred 45 minutes to drip dimethyl formamide.Heated mixt carries out conventional processing to room temperature.Product is by thin-layer chromatography (hexane: ethyl acetate=16: 1) purification obtains 5-methylol-2-[(4-aminomethyl phenyl) sulfenyl] phenyl aldehyde (0.58g, 66.7%)

¹H-NMR(300MHz,CDCl ₃)((ppm)0.62(s,6H),0.84(s,9H),2.28(s,3H),

4.64(s,2H),6.95(d,J=8.1Hz,1H),7.09(d,J=7.9,2H),7.23(d,J=8.3Hz,

2H),7.28(dd,J=2.2,8.2Hz,1H),7.70(d,J=1.8Hz,1H),10.29(9,1H)

EIMS?m/z?373(M+H) ⁺C ₂₁H ₂₈O ₂SSi=372

Adopt the method identical, by 5-methylol-2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl] (0.1g 0.27mmol) prepares compound 96 (0.067g, 70.4%) to phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.27(s,3H),4.53(d,J=5.5Hz,

2H),5.37(t,J=5.5Hz,1H),7.16(d,J=3.5,4H),7.31(s,1H),7.58(s,1H),

7.98(s,1H),12.00(br?s,1H)

EIMS?m/z?356(M-H) ^-C ₁₈H ₁₅O ₃S ₂=357

Embodiment 124

Preparation compound 97

In the argon atmospher, (0.2g 1.0mmol) is dissolved in the toluene (2mL) with 5-bromo-2-fluorobenzaldehyde.Add tributyl (1-vinyl ethyl ether base tin) (0.37mL, 1.1mmol) and two (triphenylphosphine) Palladous chloride (0.007g, 0.01mmol), postheating to 100 ℃ continues 10 hours.When reducing to room temperature, the temperature of resistates carries out conventional processing.Product is by thin-layer chromatography (hexane: ethyl acetate=8: 1) purify, obtain 5-ethanoyl-2-fluorobenzaldehyde (0.19g, 58.3%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.65(s,3H),7.31(d,J=9.3Hz,1H),

8.27(m,1H),8.45(dd,J=2.4,6.6Hz,1H),10.40(s,1H)

EIMS?m/z?167(M+H) ⁺C ₉H ₇ ¹⁹FO ₂=166

Adopt method (the synthetic 5-bromo-2-[(4-aminomethyl phenyl) sulfenyl identical with embodiment 114] phenyl aldehyde), by 5-ethanoyl-2-fluorobenzaldehyde (0.1g 0.6mmol) prepares 5-ethanoyl-2-[(4-aminomethyl phenyl) sulfenyl] and phenyl aldehyde (0.043g, 26.5%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.43(s,3H),2.60(s,3H),6.93(d,

J=8.6Hz,1H),7.29(d,J=7.9,2H),7.44(d,J=8.3,2H),7.86(dd,J=8.5,2.0

Hz,1H),8.38(d,J=2.0Hz,1H),10.34(s,1H)

FABMS?m/z?271(M+H) ⁺C ₁₆H ₁₄O ₂S ₂=270

Adopt the method identical, by 5-ethanoyl-2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl] (0.043g 0.16mmol) prepares compound 97 (0.059g, 99.8%) to phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.49(s,3H),2.51(s,3H),

7.09(d,J=8.3Hz,1H),7.31(d,J=8.3Hz,2H),7.41(d,J=6.8Hz,2H),

7.89(d,J=8.6Hz,1H),7.95(s,1H),8.01(s,1H),12.00(br?s,1H)

EIMS?m/z?370(M+H) ⁺C ₁₉H ₁₅NO ₃S ₂=369

Embodiment 125

Preparation compound 98

Adopt the method identical with embodiment 96, (0.083g 0.21mmol) prepares compound 98 (0.040g, 49.8%) by compound 97.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.29(s,3H),2.50(s,3H),

7.30(d,J=8.3Hz,2H),7.47(d,J=7.9Hz,2H),7.78(s,1H),7.88(s,

1H), 8.04 (s, 1H), 8.16 (s, 1H), 8.17 (1H), NH does not find for d, J=3.3Hz

EIMS?m/z?386(M+H) ⁺C ₁₉H ₁₅NO ₄S ₂=385

Embodiment 126

Preparation compound 99

Adopt method (the synthesize 5-bromo-2-[(4-aminomethyl phenyl) sulfenyl identical with embodiment 114] phenyl aldehyde), by 2-fluoro-6-(trifluoromethyl) phenyl aldehyde (0.19g, 1.5mmol) preparation 2-[(4-aminomethyl phenyl) sulfenyl]-6-(trifluoromethyl) phenyl aldehyde (0.44g, 100%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.42(s,3H),7.08(d,J=8.3,1H),

7.27(d,J=7.3Hz,2H),7.33(t,J=7.7Hz,1H),7.43(d,J=8.1Hz,2H),

7.50(d,J=7.7Hz,1H),10.53(q,J=2.2Hz,1H)

EIMS?m/z?296(M ⁺)C ₁₅H ₁₁ ¹⁹F ₃OS=296

Adopt the method (synthetic compound 67) identical, by the 2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl]-(0.1g 0.3mmol) prepares compound 99 (0.11g, 81.2%) to 6-(trifluoromethyl) phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.34(s,3H),7.23(d,J=7.7Hz,

1H),7.29(d,J=7.9Hz,2H),7.37(d,J=8.3Hz,2H),7.51(t,J=7.7Hz,1H),

7.66(d,J=7.7Hz,1H),7.70(s,1H),12.00(br?s,1H)

EIMS?m/z?394(M-H) ^-C ₁₈H ₁₂ ¹⁹FNO ₂S ₂=395

Embodiment 127

Preparation compound 100

Adopt method (the synthesize 5-bromo-2-[(4-aminomethyl phenyl) sulfenyl identical with embodiment 114] phenyl aldehyde), by 2-fluoro-5 (trifluoromethyl) phenyl aldehyde (0.1g, 0.5mmol) preparation 2-[(4-aminomethyl phenyl) sulfenyl]-5-(trifluoromethyl) phenyl aldehyde (0.45g, 86.4%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.43(s,3H),6.99(d,J=8.6Hz,1H),

7.28(d,J=11.0,2H),7.43(d,J=8.1,2H),7.52(d,J=8.4Hz,1H),8.07(s,

1H),10.34(s,1H)

FABMS?m/z?296(M ⁺)C ₁₅H ₁₁ ¹⁹F ₃OS=296

Adopt the method identical, by the 2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl]-(0.1g 0.34mmol) prepares compound 100 (0.068g, 50.9%) to 5-(trifluoromethyl) phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.35(s,3H),7.15(d,J=8.8Hz,

1H),7.32(d,J=7.7Hz,2H),7.43(d,J=7.7Hz,2H),7.70(s,1H),

7.71(d,J=7.0Hz,1H),7.92(s,1H),12.8(br?s,1H)

EIMS?m/z?394(M-H) ^-C ₁₈H ₁₂ ¹⁹F ₃NO ₂S ₂=395

Embodiment 128

Preparation compound 101

Adopt method (the synthesize 5-bromo-2-[(4-aminomethyl phenyl) sulfenyl identical with embodiment 114] phenyl aldehyde), by 2-fluoro-4 (trifluoromethyl) phenyl aldehyde (0.1g, 0.5mmol) preparation 2-[(4-aminomethyl phenyl) sulfenyl]-4-(trifluoromethyl) phenyl aldehyde (0.47g, 89.5%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.41(s,3H),7.23(d,J=4.6Hz,2H),

7.24(m,1H),7.38(d,J=8.1,2H),7.50(d,J=8.1Hz,1H),7.95(d,J=7.9,

1H),10.41(s,1H)

EIMS?m/z?296(M ⁺)C ₁₅H ₁₁ ¹⁹F ₃OS=296

Adopt the method identical, by the 2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl]-(0.1g 0.34mmol) prepares compound 101 (0.082g, 60.9%) to 4-(trifluoromethyl) phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.33(s,3H),7.28(d,J=8.1Hz,

2H),7.35(d,J=8.3Hz,2H),7.38(s,1H),7.71(d,J=8.1Hz,1H),

7.77(d,J=8.8Hz,1H),7.96(s,1H),12.78(br?s,1H)

EIMS?m/z?394(M-H) ^-C ₁₆H ₁₂ ¹⁹F ₃NO ₂S ₂=395

Embodiment 129

Preparation compound 102

Adopt method (the synthesize 5-bromo-2-[(4-aminomethyl phenyl) sulfenyl identical with embodiment 114] phenyl aldehyde), by 2-fluoro-3-(trifluoromethyl) phenyl aldehyde (0.19g, 1.5mmol) preparation 2-[(4-aminomethyl phenyl) sulfenyl]-3-(trifluoromethyl) phenyl aldehyde (0.44g, 100%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.26(s,3H),6.97(d,J=2.2Hz,2H),

7.03(d,J=8.1,2H),7.64(t,J=7.9Hz,1H),8.02(d,J=7.9,1H),8.09(d,

J=7.7Hz,1H),10.60(d,J=0.7Hz,1H)

EIMS?m/z?296(M ⁺)C ₁₅H ₁₁ ¹⁹F ₃OS=296

Adopt the method identical, by the 2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl]-(0.1g 0.3mmol) prepares compound 102 (0.13g, 97.5%) to 3-(trifluoromethyl) phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.19(s,3H),6.89(d,J=8.3Hz,

2H),7.05(d,J=7.9Hz,2H),7.80(s,1H),7.81(d,J=4.0Hz,1H),7.87(s,

1H),8.00(dd,J=2.8,6.6Hz,1H),12.01(br?s,1H)

EIMS?m/z?394(M-H) ^-C ₁₈H ₁₂19F ₃NO ₂S ₂=395

Embodiment 130

Preparation compound 103

Adopt the method identical with embodiment 96, (0.1g 0.25mmol) prepares compound 103 (0.043g, 41.7%) by compound 102.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.27(s,3H),7.23(d,J=8.3Hz,

2H),7.27(d,J=8.8Hz,2H),7.79(d,J=7.7Hz,1H),7.93(t,J=7.7Hz,

1H),8.07(d,J=7.7Hz,1H),8.18(s,1H),12.62(br?s,1H)

EIMS?m/z?412(M+H) ⁺C ₁₈H ₁₂ ¹⁹F ₃NO ₃S ₂=411

Embodiment 131

Preparation compound 104

Adopt as embodiment 114 described reactions (synthetic 5-bromo-2-[(4-aminomethyl phenyl) sulfenyl] phenyl aldehyde), and by thin-layer chromatography (hexane: ethyl acetate=8: 1) purify, again by another thin-layer chromatography (hexane: ethyl acetate=24: 1) purify, by 2-fluoro-5-methoxybenzaldehyde (0.25g, 2.0mmol) acquisition 2-[(4-aminomethyl phenyl) sulfenyl]-5-methoxybenzaldehyde (0.05g, 10.1%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.32(s,3H),3.86(s,3H),7.07(dd,

J=3.1,8.6Hz,2H),7.13(m,4H),7.32(d,J=8.6Hz,1H),7.44(d,J=3.1

Hz,1H),10.51(s,1H)

EIMS?m/z?258(M ⁺)C ₁₅H ₁₄O ₂S=258

Adopt the method identical, by the 2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl]-(0.05g 0.2mmol) prepares compound 104 (0.07g, 97.1%) to the 5-methoxybenzaldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.24(s,3H),3.84(s,3H),

7.02(d,J=8.3Hz,2H),7.09(m,2H),7.12(d,J=8.1Hz,2H),7.52(d,

J=8.6Hz,1H),8.04(s,1H),12.01(br?s,1H)

EIMS?m/z?356(M-H) ^-C ₁₈H ₁₅NO ₃S ₂=357

Embodiment 132

Preparation compound 105

Adopt method (the synthesize 5-bromo-2-[(4-aminomethyl phenyl) sulfenyl identical with embodiment 114] phenyl aldehyde), by 2-fluoro-4-methoxybenzaldehyde (0.1g, 0.65mmol) preparation 2-[(4-aminomethyl phenyl) sulfenyl]-4-methoxybenzaldehyde (0.078g, 46.2%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.39(s,3H),3.70(s,3H),6.45(d,

J=2.4Hz,1H),6.76(dd,J=2.4,8.6Hz,1H),7.22(d,J=7.7Hz,2H),7.39(d,

J=8.1,2H),7.80(d,J=8.6Hz,1H),10.20(s,1H)

EIMS?m/z?259(M+H) ⁺C ₁₅H ₁₄O ₂S=258

Adopt the method (synthetic compound 67) identical, by the 2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl]-(0.078g 0.3mmol) prepares compound 105 (0.091g, 85.2%) to the 4-methoxybenzaldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.49(s,3H),3.74(s,3H),

6.75(d,J=2.7Hz,2H),7.07(dd,J=2.7,8.6Hz,1H),7.23(d,J=8.3Hz,

2H),7.49(d,J=8.8Hz,1H),8.04(s,1H),12.59(br?s,1H)

EIMS?m/z?358(M+H) ⁺C ₁₆H ₁₅NO ₃S ₂=357

Embodiment 133

Preparation compound 106

Adopt the method (Synthetic 2-fluoro-5-cyanobenzaldehyde) identical with embodiment 121, (0.48mL 4.5mmol) prepares 5-chloro-fluorobenzaldehyde (0.55g, 77.6%) by the 4-chlorofluorobenzene.

¹H-NMR(300MHz,CDCl ₃)δ(ppm)7.16(t,J=9.4Hz,1H),7.56(m,

1H),7.84(dd,J=2.8,5.9Hz,1H),10.32(s,1H)

EIMS?m/z?157(M-H)C ₇H ₄ ³⁵Cl ¹⁹FNO=158

Adopt method (the synthetic 5-bromo-2-[(4-aminomethyl phenyl) sulfenyl identical with embodiment 114] phenyl aldehyde), by 5-chloro-2-fluorobenzaldehyde (0.15g 0.95mmol) prepares 5-chloro-2-[(4-aminomethyl phenyl) sulfenyl] and phenyl aldehyde (0.21g, 85.1%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.38(s,3H),6.99(d,J=8.6Hz,1H),

7.21(d,J=7.9Hz,2H),7.33(m,1H),7.35(d,J=8.3Hz,2H),7.82(d,

J=2.4Hz,1H),10.34(s,1H),

FABMS?m/z?262(M ⁺)C ₁₄H ₁₁ ³⁵ClOS=262

Adopt the method identical, by 5-chloro-2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl] (0.1g 0.38mmol) prepares compound 106 (0.096g, 70.1%) to phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.30(s,3H),7.23(d,J=8.6Hz,

2H),7.25(m,1H),7.27(d,J=8.4Hz,2H),7.48(s,1H),7.49(d,J=7.0Hz,

1H),7.91(s,1H),12.01(br?s,1H)

EIMS?m/z?362(M+H) ⁺C ₁₇H ₁₂ ³⁵ClNO ₂S ₂=361

Embodiment 134

Preparation compound 107

Adopt the method identical with embodiment 96, (0.1g 0.28mmol) prepares compound 107 (0.094g, 90.0%) by compound 106.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.30(s,3K),7.31(d,J=8.4Hz,

2H),7.43(d,J=8.1Hz,2H),7.49(d,J=2.0Hz,1H),7.79(dd,J=2.0,

8.5Hz 1H), 7.88 (s, 1H), 8.02 (1H), NH does not find for d, J=8.4Hz

EIMS?m/z?378(M+H) ⁺C ₁₇H ₁₂ ³⁵ClNO ₃S ₂=377

Embodiment 135

Preparation compound 108

Adopt method (the synthetic 5-bromo-2-[(4-aminomethyl phenyl) sulfenyl identical with embodiment 114] phenyl aldehyde), by 4-chloro-2-fluorobenzaldehyde (0.32g 2.0mmol) prepares 4-chloro-2-[(4-aminomethyl phenyl) sulfenyl] and phenyl aldehyde (0.32g, 60.4%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.41(s,3H),6.90(d,J=1.8Hz,1H),

7.24(m,3H),7.40(d,J=8.1Hz,2H),7.76(d,J=8.3Hz,1H),10.29(s,1H),

EIMS?m/z?262(M ⁺)C ₁₄H ₁₁ ³⁵ClO=262

Adopt the method identical, by 4-chloro-2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl] (0.05g 0.2mmol) prepares compound 108 (0.052g, 75.1%) to phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.33(s,3H),7.11(d,J=1.5Hz,

1H),7.28(d,J=8.3Hz,2H),7.35(d,J=8.3Hz,2H),7.508(d,J=2.2Hz,

2H),7.51(s,1H),7.95(s,1H),12.72(br?s,1H)

EIMS?m/z?326(M ⁺)C ₁₇H ₁₂NO ₂S ₂=326

Embodiment 136

Preparation compound 109

Adopt method (the synthetic 5-bromo-2-[(4-aminomethyl phenyl) sulfenyl identical with embodiment 114] phenyl aldehyde), by 3-chloro-4-fluorobenzaldehyde (0.2g 1.26mmol) prepares 3-chloro-4-[(4-aminomethyl phenyl) sulfenyl] and phenyl aldehyde (0.29g, 87.9%).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.44(s,3H),6.77(d,J=8.3Hz,1H),

7.30(d,J=8.4Hz,2H),7.46(d,J=8.1Hz,2H),7.50(dd,J=1.8,8.4Hz,

1H),7.82(d,J=1.7Hz,1H),9.85(s,1H),

FABMS?m/z?262(M ⁺)C ₁₄H ₁₁ ³⁵ClOS=262

Adopt the method identical, by 3-chloro-4-[(4-aminomethyl phenyl with embodiment 94) sulfenyl] (0.15g 0.57mmol) prepares compound 109 (0.13g, 65.1%) to phenyl aldehyde.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.38(s,3H),6.79(d,J=8.4Hz,

1H),7.37(d,J=7.9Hz,2H),7.41(dd,J=2.2,8.7Hz,1H),7.48(d,J=8.1

Hz, 2H), 7.71 (s, 1H), 7.75 (1H), NH does not find for d, J=1.8Hz

EIMS?m/z?361(M ⁺)C ₁₇H ₁₂ ³⁵ClNO ₂S ₂=361

Embodiment 137

Preparation compound 110

With 2-fluoro-5-nitrobenzaldehyde (0.055g 0.33mmol) is dissolved in N, in the dinethylformamide (2.8mL), add phenol (0.077g, 0.82mmol) and salt of wormwood (0.11g, 0.82mmol), 25 ℃ of stirrings 1 hour.After conventional processing, resistates obtains 5-nitro-2-phenoxy benzaldehyde (77mg, 98%) by the pure system of silica gel chromatography (using the chloroform wash-out).

¹H-NMR(300MHz,CDCl ₃)δ(ppm)6.91(d,J=9.4Hz,1H),7.20-

7.14(m,2H),7.35(dd,J=7.2Hz,7.2Hz,1H),7.47-7.55(m,2H),

8.31(dd,J=9.2,2.8Hz,1H),8.79(d,J=3.0Hz,1H),10.60(s,1H),

FABMS?m/z?244(M+H) ⁺C ₁₃H ₉NO ₄=243

With 5-nitro-2-phenoxy benzaldehyde (77mg, 0.32mmol) be dissolved in the toluene (3.9mL), add 2,4-thiazolidinedione (0.15g, 1.3mmol), piperidines (0.013mL, 0.13mmol), (0.0073mL, 0.13mmol) and molecular sieve 4A (0.39g), 110 ℃ were stirred 3 hours acetate.After conventional processing, resistates obtains compound 110 (67mg, 61%) by tlc (launching with chloroform/acetonitrile=10/1).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)6.94(d,J=9.2Hz,1H),7.27(d,

J=7.7Hz,2H),7.36(d,J=7.1,7.1Hz,1H),7.50-7.58(m,2H),7.99(s,

1H),8.28(dd,J=2.7,9.2Hz,1H),8.38(d,J=2.8Hz,1H),12.81(m,1H)

FABMS?m/z?341(M-H) ^-C ₁₆H ₁₀N ₂O ₅=342

Embodiment 138

Preparation compound 111

With 2-fluoro-5-nitrobenzaldehyde (0.13g 0.79mmol) is dissolved in N, in the dinethylformamide (6.7mL), add p-cresol (0.22g, 2.0mmol) and salt of wormwood (0.27g, 2.0mmol), 25 ℃ of stirrings 1.5 hours.After conventional processing, resistates obtains 5-nitro-2-(4-methylphenoxy) phenyl aldehyde (0.20g, 98%) by the pure system of silica gel chromatography (using the chloroform wash-out).

¹H?NMR(300MHz,CDCl ₃)δ(ppm)2.41(s,2H),6.89(d,J=9.4Hz,1H),

7.04(d,J=8.5Hz,2H),7.25-7.32(m,2H),8.39(dd,J=9.2,3.0Hz,1H),

8.79(d,J=2.9Hz,1H),10.60(s,1H),

FABMS?m/z?257(M ⁺)C ₁₄H ₁₁NO ₄S=257

With 5-nitro-2-(4-methylphenoxy) phenyl aldehyde (0.11g, 0.41mmol) be dissolved in the toluene (5.3mL), add 2,4-thiazolidinedione (0.19g, 1.6mmol), piperidines (0.016mL, 0.16mmol), (0.0094mL, 0.16mmol) and molecular sieve 4A (0.53g), 110 ℃ were stirred 2 hours acetate.After conventional processing, resistates is developed with ethanol, obtains compound 111 (60mg, 41%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)2.36(s,3H),6.90(d,J=9.2Hz,

1H),7.15(d,J=8.2Hz,2H),7.33(d,J=8.6Hz,2H),7.99(s,1H),

8.25(dd,J=9.2,1.8Hz,1H),8.36(d,J=2.6Hz,1H),12.80(m,1H)

FABMS?m/z?355(M-H) ^-C ₁₇H ₁₂N ₂O ₅S=356

Embodiment 139

Preparation compound 112

With available 2-[4-on the market (2, the 2-dimethyl ethyl) phenoxy group]-5-nitrobenzaldehyde (0.12g, 0.41mmol) (MAYBRIDGE, catalog number (Cat.No.): XAX00137) be dissolved in the ethanol (4.9mL).Add thiazolidinedione (0.19g, 1.6mmol) and piperidines (0.016mL, 0.16mmol), 80 ℃ of stirrings 2 hours.After conventional processing, resistates obtains compound 112 (49mg, 30%) by the pure system of thin-layer chromatography (chloroform/acetonitrile=10/1).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)1.31(s,9H),6.92(d,J=9.2Hz,

1H),7.18(d,J=8.6Hz,2H),7.53(d,J=8.6Hz,2H),7.98(s,1H),8.27(dd,

J=9.2,2.4Hz,1H),8.35(d,J=2.2Hz,1H),12.78(br?s,1H)

FABMS?m/z?397(M-H) ^-C ₂₀H ₁₈N ₂O ₅S=398

Embodiment 140

Preparation compound 113

Adopt the method identical with embodiment 96, (0.11g 0.27mmol) prepares compound 113 (0.079g, 71.1%) by compound 100.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)2.29(s,3H),7.31(d,J=8.3Hz,

2H),7.47(d,J=8.1Hz,2H),7.74(s,1H),7.77(s,1H),8.03(d,J=7.9Hz,

1H), 8.24 (1H), NH does not find for d, J=7.9Hz

EIMS?m/z?412(M+H) ⁺C ₁₈H ₁₂ ¹⁹F ₃NO ₃S ₂=411

Embodiment 141

Preparation compound 113

Adopt the method identical with embodiment 96, (0.1g 0.28mmol) prepares compound 114 (0.046g, 43.5%) by compound 94.

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.29(s,3H),7.29(d,J=8.1Hz,

2H),7.47(d,J=8.3Hz,2H),7.83(s,1H),7.86(d,J=7.9Hz,1H),8.01(d,

J=8.1Hz, 1H), 8.15 (1H), NH does not find for d, J=8.3Hz

EIMS?m/z?369(M+H) ⁺C ₁₆H ₁₂N ₂O ₃S ₂=368

Embodiment 142

Preparation compound 115

Adopt the method identical with embodiment 97, by 4-trifluoromethyl benzenethiol (74mg, 0.42mmol), 2.5mol/L aqueous sodium hydroxide solution (0.71mL, 1.8mmol), Tetrabutyl amonium bromide (6.7mg, 0.021mmol) and toluene (0.71mL) the formulations prepared from solutions 2-[(4-trifluoromethyl of 2-fluoro-5-nitrobenzaldehyde) sulfenyl]-5-nitrobenzaldehyde (0.13g, 93%).

¹H?NMR(300MHz,CDCl ₃)δ(ppm)7.04(d,J=8.8Hz,1H),7.70(d,

J=8.1Hz,2H),7.77(d,J=8.6Hz,2H),8.18(dd,J=8.8,2.5Hz,1H),8.71(d,

J=2.5Hz,1H),10.31(s,1H)

FABMS?m/z?327(M ^-)C ₁₄H ₈ ¹⁹NO ₃S=327

Adopt the method identical with embodiment 97, by the 2-[(4-trifluoromethyl) sulfenyl]-5-nitrobenzaldehyde (0.12g, 0.35mmol), toluene (5.8mL), 2,4-thiazolidinedione (0.17g, 1.4mmo1), piperidines (0.014mL, 0.14mmol), acetate (0.0080mL, 0.14mmol) and molecular sieve 4A (0.58g) preparation compound 115 (44mg, 51%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.52(d,J=8.7Hz,1H),7.65(d,

J=8.3Hz,2H),7.81(d,J=8.2Hz,2H),7.88(s,1H),8.24(dd,J=8.6,2.5Hz,

1H),8.29(d,J=2.4Hz,1H),12.82(m,1H)

FABMS?m/z?425(M-H) ^-C ₁₇H ₉ ¹⁹N ₂O ₄S ₂=426

Embodiment 143

Preparation compound 116

(57mg 0.15mmol) is dissolved in methylene dichloride (11mL) and the methyl alcohol (2.3ml) compound 74 that embodiment 101 is prepared.(55mg 0.16mmol), stirred 1.5 hours down at 25 ℃ to add m-chlorine peroxybenzoic acid.After conventional aftertreatment, resistates is purified by thin-layer chromatography (chloroform/methanol=15/1) and is obtained compound 116 (34mg, 57%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)3.76(s,3H),7.02-7.08(m,2H),

7.49-7.55(m,2H),7.81(s,1H),8.19(d,J=2.0Hz,1H),8.33(d,J=8.6Hz,

1H),8.52(dd,J=8.6,2.2Hz,1H),12.86(m,1H)

FABMS?m/z?403(M-H) ^-C ₁₇H ₁₂N ₂O ₆S ₂=404

Embodiment 144

Preparation compound 117

Adopt the method identical with embodiment 143, by the compound 71 of embodiment 98 preparations (52mg, 0.13mmol), (50mg 0.15mmol) prepares compound 117 (37mg, 68%) for methylene dichloride (10mL), methane (2.1mL) and m-chlorine peroxybenzoic acid.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.55-7.66(m,3H),7.80-7.85(m,

1H),8.08(s,1H),8.15(d,J=8.6Hz,1H),8.27(m,1H),8.45(dd,J=8.6,2.2

Hz,1H),12.88(m,1H)

FABMS?m/z?407(M-H) ^-C ₁₆H ₉ ³⁵ClN ₂O ₅S ₂=408

Embodiment 145

The preparation compound 118

With 3-bromo-4-[(4-aminomethyl phenyl) sulfenyl] (0.2g 0.65mmol) is dissolved in the acetone (3mL) phenyl aldehyde, is cooled to 0 ℃, adds Jones reagent (0.082mL), stirs 3.5 hours.Then, add Virahol (0.1mL).After conventional processing, resistates obtains 3-bromo-4-[(4-aminomethyl phenyl with hexane and re-crystallizing in ethyl acetate and purification) sulfenyl] phenylformic acid (0.18g, 84.7%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)2.39(s,3H),6.70(d,J=8.4Hz,

1H),7.37(d,J=8.3Hz,2H),7.49(d,J=7.9Hz,2H)7.76(dd,J=1.1,8.7

Hz, 1H), 8.07 (d, J=1.1Hz, 1H), CO ₂H does not find

FABMS?m/z?322(M-H) ^-C ₁₄H ₁₁ ⁷⁹BrOS=323

Adopt method (the synthesize 3-bromo-4-[(4-aminomethyl phenyl) sulfenyl identical with embodiment 115] phenyl aldehyde), by 3-bromo-4-[(4-aminomethyl phenyl) sulfenyl] phenylformic acid (0.1g, 0.31mmol) preparation 5-carboxyl-2-[(4-aminomethyl phenyl) sulfenyl] phenyl aldehyde (0.031g, 36.7%).

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)2.50(s,3H),6.84(d,J=8.4Hz,

1H),7.36(d,J=8.1Hz,2H),7.46(d,J=8.1Hz,2H)7.93(dd,J=2.0,8.4

Hz, 1H), 8.46 (d, J=2.0Hz, 1H), 10.22 (s, 1H), CO ₂H does not find

FABMS?m/z?271(M-H) ^-C ₁₅H ₁₂O ₃S=272

Adopt the method identical, by 5-carboxyl-2-[(4-aminomethyl phenyl with embodiment 94) sulfenyl] (0.094g 0.34mmol) prepares compound 18 (0.032g, 25.3%) to phenyl aldehyde.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)2.34(s,3H),6.96(d,J=8.6Hz,

1H),7.29(d,J=8.1Hz,2H),7.33(s,1H),7.37(d,J=7.2Hz,2H),7.64(s,

1H), 7.69 (1H), 8.20 (s, 1H), NH does not find for d, J=8.4Hz

FABMS?m/z?370(M-H) ^-C ₁₈H ₁₃NO ₄S ₂=371

Embodiment 146

Preparation compound 119

Adopt the method identical, by obtainable 5-nitro-2-on the market (pyridine-2-base sulfenyl) phenyl aldehyde (0.26g, 1.0mmol) (MAYBRIDGE, catalog number (Cat.No.): XAX00153) prepare compound 119 (0.120g, 33.5%) with embodiment 94.

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.28(dd,J=4.8,7.7Hz,1H),

7.40(dd,J=0.9,7.7Hz,1H),7.78(dd,J=1.3,7.7Hz,1H),7.86(s,1H),

7.87(d,J=8.4Hz,1H),8.28(dd,J=2.4,8.4Hz,1H),8.32(d,J=2.4Hz,1H),

8.42(dd,J=0.9,4.8Hz,1H),12.78(br?s,1H)

EIMS?m/z=360(M+H) ⁺C ₁₅H ₉N ₃O ₄S ₂=359

Embodiment 147

Preparation compound 120

Adopt the method identical with embodiment 96, (0.02g 0.056mmol) prepares compound 120 (0.0044g, 21.2%) by compound 119.

¹H NMR (300MHz, DMSO-d ₆) δ (ppm) 7.49 (m, 1H), 7.87 (s, 1H), 7.98 (d, J=7.9Hz, 1H), 8.07 (m, 1H), 8.08 (d, J=8.5Hz, 1H), 8.26 (dd, J=2.2,8.5Hz, 1H), 8.43 (1H), 8.54 (1H), NH does not find for d, J=4.8Hz for d, J=2.2Hz

EIMS?m/z=360(M+H) ⁺C ₁₅H ₉N ₃O ₅S ₂=359

Embodiment 148

Preparation compound 121

With N, (935mg 3.60mmol) is suspended in the acetate (20mL) N-phenylbenzene benzylamine, and (1.12g, 7.96mmol), 90 ℃ were stirred 12 hours to add the hexa-methylene triamine.The reaction solution cool to room temperature adds 6mol/L aqueous sodium hydroxide solution and water, the product chloroform extraction.Anhydrous sodium sulfate drying is used in organic layer salt water washing.Solvent removed by evaporation at reduced pressure, (elutriant: hexane/ethyl acetate=20/1 → 10/1) pure system obtains 4-(N-phenylbenzyl amino) phenyl aldehyde (742mg, 72%) to resistates by silica gel column chromatography.

¹H?NMR(270MHz,CDCl ₃)δ(ppm)5.04(s,2H),6.80(d,J=8.6Hz,2H),

7.2-7.45(m,10H),7.63(d,J=8.6Hz,2H),9.73(s,1H)

With 4-(N-phenylbenzyl amino) phenyl aldehyde (109mg, 0.378mmol), 2, the 4-thiazolidinedione (59.9mg, 0.511mmol) and piperidines (0.045mL, 0.46mmol) reflux 6 hours in ethanol (5mL).The reaction solution cool to room temperature adds 1mol/L HCL, the product chloroform extraction.Anhydrous sodium sulfate drying is used in organic layer salt water washing.Solvent removed by evaporation at reduced pressure, resistates obtains compound 121 (123mg, 84%) by preparation of lamina chromatogram (chloroform/methanol=20/1).

¹H?NMR(270MHz,CDCl ₃)δ(ppm)5.08(s,2H),6.88(d,J=8.6Hz,2H),

7.15-7.45(m,12H),7.61(s,2H),12.38(br?s,1H)

Embodiment 149

Preparation compound 129

With 2-fluoro-5-nitrobenzaldehyde (31mg 0.18mmol) is dissolved in N, in the dinethylformamide (3.1mL), add the 4-Thiosalicylic acid (85mg, 0.55mmol) and triethylamine (0.13mL.0.92mmol), 25 ℃ of stirrings 20 minutes.After conventional aftertreatment, product is purified (launching with chloroform/methanol=10/1) with thin-layer chromatography, obtains 5-nitro-2-[(4-carboxyl phenyl) sulfenyl] phenyl aldehyde (60mg, 100%).

With 5-nitro-2-[(4-carboxyl phenyl) sulfenyl] phenyl aldehyde (60mg, 0.20mmol) be dissolved in the ethanol (2.4mL), add 2,4-thiazolidinedione (92mg, 0.79mmol), piperidines (0.027mL, 0.28mmol), (0.0045mL, 0.079mmol) and molecular sieve 4A (0.30g), 80 ℃ were stirred 2.5 hours acetate.After conventional aftertreatment, resistates is purified by thin-layer chromatography (launching with chloroform/methanol=5/1) and is obtained compound 129 (12mg, 15%).

5-nitro-2-[(4-carboxyl phenyl) sulfenyl] phenyl aldehyde:

¹H?NMR(300MHz,CDCl ₃)δ(ppm)7.04(d,J=8.8Hz,1H),7.74(d,

J=8.0Hz,2H),8.09(d,J=8.2Hz,2H),8.28(dd,J=8.8,2.5Hz,1H),

8.87(d,J=2.5Hz,1H),10.28(s,1H),13.10(m,1H)

Compound 129:

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.46(d,J=8.8Hz,1H),7.55(d,

J=8.3Hz,2H),7.87(s,1H),7.98(d,J=8.7Hz,2H),8.21(dd,J=8.7,2.4

Hz,1H),8.30(d,J=2.4Hz,1H),12.57-13.31(m,2H)

FABMS?m/z?401(M-H) ^-C ₁₇H ₁₀N ₂O ₆S ₂=402

Embodiment 150

Preparation compound 130

5-nitro-2[(2-carboxyl phenyl with embodiment 149 acquisitions) sulfenyl] phenyl aldehyde (71mg, 0.23mmol) be dissolved in N, in the dinethylformamide (7.1mL), add 2.0mol/L dimethylamine methanol solution (0.23mL, 0.47mmol), 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (90mg, 0.47mmol) and the I-hydroxybenzotriazole hydrate (0.11g, 0.94mmol), 25 ℃ were stirred 30 minutes.After conventional aftertreatment, product is purified (using the chloroform wash-out) with silica gel chromatography, obtains N, N-dimethyl-4-[(2-formyl radical-4-oil of mirbane) sulfenyl] benzamide (59mg, 75%).

With N; N-dimethyl-4-[(2-formyl radical-4-oil of mirbane) sulfenyl] benzamide (0.12g; 0.36mmol) be dissolved in the toluene (6.0mL); add 2; the 4-thiazolidinedione (0.17g, 1.5mmol), piperidines (0.014mL, 0.15mmol), acetate (0.0083mL; 0.15mmol) and molecular sieve 4A (0.60g), 110 ℃ were stirred 4.5 hours.After conventional aftertreatment, resistates is purified by thin-layer chromatography (launching with chloroform/acetonitrile=3/1), obtains compound 130 (48mg, 31%).

N, N-dimethyl-4-[(2-formyl radical-4-oil of mirbane) sulfenyl] benzamide:

¹H?NMR(300MHz,CDCl ₃)δ(ppm)3.02(br?s,3H),3.16(br?s,3H),7.02(d,J=9.0Hz,1H),7.53-7.64(m,4H),8.13(dd,J=8.8,2.6Hz,1H),8.69(d,J=2.6Hz,1H),10.31(s,1H),

FABMS?m/z?331(M+H) ⁺C ₁₆H ₁₄N ₃O ₄S=330

Compound 130:

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)2.92(br?s,3H),2.99(br?s,3H),7.36(d,J=8.8Hz,1H),7.50(d,J=8.2Hz,2H),7.57(d,J=8.0Hz,2H),7.89(s,1H),8.21(dd,J=8.8,2.2Hz,1H),5.27(d,J=2.2Hz,1H),12.83(m,1H),

FABMS?m/z?428(M-H) ^-C ₁₉H ₁₅N ₃O ₅S ₂=429

Embodiment 151

Preparation compound 131

Adopt the method identical with embodiment 150; 5-nitro-2[(4-carboxyl phenyl by embodiment 149 acquisitions) sulfenyl] phenyl aldehyde (0.13g; 0.42mmol), N; dinethylformamide (7.1mL), morpholine (0.073mL; 0.83mmol); 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (0.16g 0.83mmol) prepares 4-{4-[(2-formyl radical-4-nitrophenyl with the I-hydroxybenzotriazole monohydrate) sulfenyl] benzoyl } morpholine (0.13g, 78%).

By 4-{4-[(2-formyl radical-4-nitrophenyl) sulfenyl] benzoyl } morpholine (0.13g; 0.34mmol), toluene (6.3mL), 2; 4-thiazolidinedione (0.16g; 1.3mmol), piperidines (0.013mL; 0.13mmol), acetate (0.0077mL; 0.13mmol) and molecular sieve 4A (0.63g) preparation compound 131 (48mg, 31%).

4-{4-[(2-formyl radical-4-nitrophenyl) sulfenyl] benzoyl } morpholine:

¹H?NMR(300MHz,CDCl ₃)δ(ppm)3.39-3.93(m,8H),7.04(d,J=9.0Hz,1H),7.56(d,J=8.2Hz,2H),7.62(d,J=8.3Hz,2H),8.13(dd,J=8.8,2.5Hz,1H),8.69(d,J=2.6Hz,1H),10.31(s,1H),

FABMS?m/z?373(M+H) ⁺C ₁₈H ₁₆N ₂O ₅S=372

Compound 131:

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)3.27-3.45(m,4H),3.61(br?s,4H),7.39(d,J=8.9Hz,1H),7.51(d,J=8.4Hz,2H),7.57(d,J=8.4Hz,2H),7.89(s,1H),8.21(dd,J=8.8,2.6Hz,1H),8.27(d,J=2.2Hz,1H),12.83(m,1H),

FABMS?m/z?470(M-H) ^-C ₂₁H ₁₇N ₃O ₆S ₃=471

Embodiment 152

Preparation compound 132

To 4-(methylthio group) benzenethiol (0.15mL, add in 0.93mmol) the 2.5mol/L sodium hydroxide solution (1.6mL, 4.0mmol) and Tetrabutyl amonium bromide (0.15mL, 0.047mmol), 25 ℃ of stirrings 10 minutes.With 2-fluoro-5-nitrobenzaldehyde (0.16g, toluene solution 0.93mmol) (1.6mL) joins in the reaction soln, 110 ℃ were stirred 1.5 hours.After conventional aftertreatment, product obtains 5-nitro-2-[(first sulphur by the pure system of silica gel chromatography (using the chloroform wash-out)) phenyl] thio phenyl formaldehyde (0.25g, 89%).

With 5-nitro-2-[(methylthio group) phenyl] thio phenyl formaldehyde (0.23g, 0.76mmol) be dissolved in the methyl alcohol (12mL), add 2,4-thiazolidinedione (0.35g, 3.0mmol), piperidines (0.030mL, 0.30mmol), (0.017mL, 0.30mmol) and molecular sieve 4A (1.2g), 110 ℃ were stirred 4 hours acetate.After conventional aftertreatment, product obtains compound 132 (12mg, 15%) by the ethanol development.

5-nitro-2-[(methylthio group) phenyl] thio phenyl formaldehyde:

¹H?NMR(300MHz,CDCl ₃)δ(ppm)2.55(s,3H),6.98(d,J=9.0Hz,1H),7.32-7.38(m,2H),7.44-7.50(m,2H),8.11(dd,J=9.0,2.5Hz,1H),8.66(d,J=2.4Hz,1H),10.30(s,1H),

FABMS?m/z?306(M+H) ⁺C ₁₄H ₁₁NO ₃S ₂=305

Compound 132:

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)2.52(s,3H),7.09(d,J=9.2Hz,1H),7.41(d,J=8.6Hz,2H),7.52(d,J=8.3Hz,2H),7.38(s,1H),8.16(dd,J=8.8,2.6Hz,1H),8.23(d,J=2.4Hz,1H),12.83(m,1H),

FABMS?m/z?403(M-H) ^-C ₁₇H ₁₂N ₂O ₄S ₃=464

Embodiment 153

Preparation compound 133

Adopt the method identical with embodiment 134, by the compound 75 of embodiment 102 preparations (0.11g, 0.27mmol), (0.10g 0.30mmol) prepares compound 133 (0.12g, 100%) for methylene dichloride (21mL), methyl alcohol (4.2mL) and m-chlorine peroxybenzoic acid.

Compound 133:

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)2.46-2.55(m,3H),3.93-4.04(m,2H),8.73(br?d,J=7.7Hz,2H),8.88(br?d,J=7.5Hz,2H),9.27(s,1H),9.58(s,1H),9.72(d,J=8.6Hz,1H),9.91(br?d,J=8.3Hz,1H),14.21(m,1H),

FABMS?m/z?401(M-H) ^-C ₁₈H ₁₄N ₂O ₅S ₂=402

Embodiment 154

Preparation compound 134

Adopt the method identical with embodiment 134, by the compound 70 of embodiment 97 preparations (0.11g, 0.29mmol), (0.11g 0.32mmol) prepares compound 134 (90mg, 76%) for methylene dichloride (23mL), methyl alcohol (4.5mL) and m-chlorine peroxybenzoic acid.

Compound 134:

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.49-7.62(m,3H),7.66(s,1H),7.99(s,1H),8.21(d,J=1.7Hz,2H),8.30(d,J=8.9Hz,1H),8.49(dd,J=8.4,2.0Hz,1H),12.89(m,1H),

FABMS?m/z?407(M-H) ^-C ₁₆H ₉ ³⁵ClN ₂O ₅S ₂=408

Embodiment 155

Preparation compound 135

Adopt the method identical with embodiment 134, by the compound 72 of embodiment 99 preparations (83mg, 0.19mmol), (74mg 0.21mmol) prepares compound 135 (32mg, 37%) for methylene dichloride (17mL), methyl alcohol (3.3mL) and m-chlorine peroxybenzoic acid.

Compound 135:

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.52(dd,J=8.4,1.8Hz,1H),7.79(d,J=8.4Hz,2H),7.86(d,J=2.1Hz,1H),7.99(s,1H),8.22(d,J=2.0Hz,1H),8.30(d,J=8.6Hz,1H),8.48(dd,J=8.6,2.0Hz,1H),12.88(m,1H),

FABMS?m/z?441(M-H) ^-C ₁₆H ₈ ³⁵Cl ₂N ₂O ₅S ₂=442

Embodiment 156

Preparation compound 136

(60mg 0.14mmol) is dissolved in N to the compound 80 that embodiment 107 is prepared, and in the dinethylformamide (3.0mL), (0.11g, 0.33mmol), 25 ℃ were stirred 1 hour to add m-chlorine peroxybenzoic acid.After conventional aftertreatment,, obtain compound 136 (20mg, 33%) with the pure system of thin-layer chromatography (launching) with chloroform/methanol=20/1.

Compound 136:

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)7.66(d,J=8.6Hz,2H),7.73(d,J=8.4Hz,2H),7.99(s,1H),8.27-8.32(m,1H),8.48(d,J=8.2Hz,1H),8.54(d,J=1.8Hz,1H),12.83(m,1H),

FABMS?m/z?451(M-H) ^-C ₁₆H ₉ ⁷⁹BrN ₂O ₅S ₂=452

Embodiment 157

Preparation compound 137

Using 4-fluoro-3-phenoxy benzaldehyde (0.20g 0.93mmol), carries out the 114 synthetic 5-bromo-2-[(4-aminomethyl phenyls with embodiment) sulfenyl] phenyl aldehyde similarly reacts, and carries out conventional processing subsequently.

Solvent is removed from reactant and mixture of products by vacuum drier, and the method that application class is similar to synthetic compound 67 obtains compound 137 (0.11g, 45%).

Compound 137:

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.50(s,3H),6.90(d,J=8.3Hz,1H),7.06(d,J=9.0Hz,2H),7.07(m,1H),7.21(t,J=7.3Hz,1H),7.30(m,1H),7.32(d,J=8.1Hz,2H),7.43(d,J=8.1Hz,4H),7.63(s,1H),12.55(br?s,1H),

EI-MS?m/z?419(M ⁺)C ₂₃H ₁₇NO ₃S ₂=419

Embodiment 158

Preparation compound 138

Using 4-fluoro-3-methoxybenzaldehyde (0.20g 1.3mmol), carries out the 114 synthetic 5-bromo-2-[(4-aminomethyl phenyls with embodiment) sulfenyl] phenyl aldehyde similarly reacts, and carries out conventional processing subsequently.

Solvent is removed from reactant and mixture of products by vacuum drier, and the method that application class is similar to synthetic compound 67 obtains compound 138 (0.11g, 45%).

Compound 138:

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.36(s,3H),3.90(s,3H),6.71(d,J=8.1Hz,1H),7.06(d,J=8.1Hz,1H),7.24(t,J=1.3Hz,1H),7.31(d,J=8.3Hz,2H),7.39(d,J=8.1Hz,2H),7.74(s,1H),12.57(br?s,1H),

EI-MS?m/z?357(M ^-)C ₁₈H ₁₅NO ₃S ₂=357

Embodiment 159

Preparation compound 139

With the compound 118 of embodiment 145 preparation (0.33g 0.89mmol) is dissolved in the dimethyl formamide (15mL), add salt of wormwood (0.12g, 0.89mmol) and bromotoluene (0.13mL 1.1mmol), at room temperature stirred 10 hours.Carry out conventional processing then, product is purified by thin-layer chromatography (hexane/ethyl acetate=8/1) and is obtained compound 139 (0.077g, 50%).

Compound 139:

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.33(s,3H),5.37(s,2H),7.11(d,J=8.4Hz,1H),7.31(d,J=8.3Hz,2H),7.38(d,J=8.3Hz,2H),7.39(m,1H),7.41(d,J=8.3Hz,2H),7.46(d,J=7.3Hz,2H),7.91(d,J=1.8,8.4Hz,1H),7.96(s,1H),8.08(d,J=1.5Hz,1H),12.76(br?s,1H),

EI-MS?m/z?461(M ^-)C ₂₅H ₁₉NO ₄S ₂=461

Embodiment 160

Preparation compound 140

Adopt the method (synthetic compound 69) identical with embodiment 96, (0.1g 0.28mmol) prepares compound 140 (0.067g, 64.0%) by compound 95.

Compound 140:

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.34(s,3H),7.40(d,J=8.4Hz,2H),7.63(d,J=8.1Hz,2H),7.80(s,1H),8.09(dd,J=1.7,8.4Hz,1H),8.19(d,J=1.5Hz,1H),8.22(d,J=8.3Hz,1H),12.80(br?s,1H),

FABMS?m/z?369(M+H) ⁺C ₁₈H ₁₂N ₂O ₃S ₂=368

Embodiment 161

Preparation compound 141

Adopt the method (synthetic compound 69) identical with embodiment 96, (0.1g 0.28mmol) prepares compound 141 (0.094g, 89.9%) by compound 109.

Compound 141:

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.49(s,3H),7.36(d,J=8.4Hz,2H),7.62(d,J=8.1Hz,2H),7.76(s,1H),7.79(s,1H)7.82(d,J=8.3Hz,1H),8.10(d,J=8.3Hz,1H),12.77(br?s,1H),

FABMS?m/z?377(M-H) ^-C ₁₇H ₁₂ ³⁵ClNO ₃S ₂=378

Embodiment 162

Preparation compound 142

3-bromo-4-[(4-aminomethyl phenyl with embodiment 123 preparations) sulfenyl] phenyl aldehyde (0.1g, 0.33mmol) be dissolved in the methyl alcohol (5mL), (0.0006g is 0.003mmol) with methyl orthoformic acid (0.035mL to add tosic acid-hydrate, 0.33mmol), product reflux 3 hours.After conventional processing, solvent is removed by vacuum drier, obtains 3-bromo-4-[(4-aminomethyl phenyl) sulfenyl] phenyl aldehyde dimethylacetal crude product.

Utilize all 3-bromo-4-[(4-aminomethyl phenyls) sulfenyl] phenyl aldehyde dimethylacetal crude product; employing is similar among the embodiment 123 synthetic 5-[methylol-2-[(4-aminomethyl phenyl) sulfenyl] method of benzaldehyde obtains compound 3-formyl radical-4-[(4-aminomethyl phenyl) sulfenyl] phenyl aldehyde dimethylacetal (0.09g, yield is 90.3%).

Adopt and the identical method of embodiment 94 (synthetic compound 67), by 3-formyl radical-4-[(4-aminomethyl phenyl) sulfenyl] phenyl aldehyde dimethylacetal (0.2g, 0.67mmol) preparation compound 142 (0.21g, 76.3%).

3-formyl radical-4-[(4-aminomethyl phenyl) sulfenyl] the phenyl aldehyde dimethylacetal:

¹H-NMR(300MHz,CDCl ₃)δ(ppm)2.39(s,3H),3.32(s,6H),5.39(s,1H),6.99(d,J=8.3Hz,1H),7.22(d,J=7.9Hz,2H),7.38(d,J=8.3Hz,2H),7.43(dd,J=2.0,8.3Hz,1H),7.94(d,J=2.0Hz,1H),10.35(s,1H),

FAB-MS?m/z?302(M ^-)C ₁₇H ₁₈O ₃S=302

Compound 142:

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.49(s,3H),3.27(s,6H),5.44(s,1H),7.26(d,J=2.6Hz,4H),7.40(d,J=8.4Hz,1H),7.54(s,1H),8.04(s,1H),12.68(br?s,1H),

FABMS?m/z?401(M-H) ^-C ₂₀H ₁₉NO ₄S ₂=402

Embodiment 163

Preparation compound 143

Adopt the method (synthetic compound 69) identical with embodiment 96, (0.07g 0.17mmol) prepares compound 143 (0.049g, 69.4%) by compound 88.

Compound 143:

¹H-NMR(300MHz,DMSO-d ₆)δ(ppm)2.33(s,3H),7.35(d,J=8.1Hz,2H),7.63(d,J=8.3Hz,2H),7.79(s,1H),7.86(d,J=8.4Hz,1H),7.91(s,1H),8.08(d,J=8.3Hz,1H),12.76(br?s,1H),

FABMS?m/z?422(M ⁺)C ₁₇H ₁₂ ⁷⁹BrNO ₃S ₂=422

Embodiment 164

Preparation compound 144

(0.17g 0.43mmol) is dissolved in methylene dichloride (14mL) and the methyl alcohol (2.6mL), adds 1mol/L hydrochloric acid soln (0.5mL) with compound 142.Reflux 2 hours, the product cool to room temperature is used ethyl acetate extraction.Solvent removed by evaporation at reduced pressure, resistates recrystallization from ethyl acetate and hexane obtains compound 144 (0.15g, 98.2%).

Compound 144:

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)2.49(s,3H),7.12(d,J=8.4Hz,1H),7.34(d,J=8.3Hz,2H),7.45(d,J=8.1Hz,2H),7.83(d,J=8.3Hz,1H),7.95(s,1H),7.97(s,1H),9.97(s,1H),12.78(br?s,1H),

FABMS?m/z?356(M+H) ⁺C ₁₈H ₁₃NO ₃S ₂=355

Embodiment 165

Preparation compound 145

With compound 144 (0.05g 0.14mmol) is dissolved in the chloroform (4mL), add [(tert-butoxycarbonyl) methylene radical] triphenylphosphine (0.13g, 0.35mmol).After 2 hours, the product cool to room temperature is used ethyl acetate extraction in reflux.Solvent removed by evaporation at reduced pressure, resistates preparation of lamina chromatogram (developping solution: chloroform/acetonitrile=18/1) purify.Product recrystallization from ethyl acetate and hexane obtains compound 145 (0.038g, 59.8%).

Compound 145:

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)1.48(s,9H),2.33(s,3H),6.49(d,J=16.1Hz,1H),7.08(d,J=8.3Hz,1H),7.27(d,J=8.6Hz,2H),7.35(d,J=8.3Hz,2H),7.56(d,J=16.1Hz,1H),7.69(s,1H),7.72(d,J=8.3Hz,1H),7.95(s,1H),12.70(br?s,1H),

FABMS?m/z?435(M-H) ^-C ₂₄H ₂₃NO ₄S ₂=454

Embodiment 166

Preparation compound 146

(0.02g 0.04mmol) is dissolved in the methylene dichloride (4mL), adds trifluoroacetic acid (1mL), at room temperature stirs 1 hour with compound 145.Carry out conventional processing, solvent removed by evaporation at reduced pressure, resistates obtains compound 146 (0.015g, 87.5%) with the ethyl acetate development.

Compound 146:

¹H?NMR(300MHz,DMSO-d ₆)δ(ppm)2.50(s,3H),6.51(d,J=16.0Hz,1H),7.11(d,J=8.1Hz,1H),7.27(d,J=8.4Hz,2H),7.34(d,J=8.1Hz,2H),7.60(d,J=16.0Hz,1H),7.70(s,1H),7.72(d,J=8.4Hz,1H),7.96(s,1H),12.50(br?s,1H),12.71(br?s,1H),

FABMS?m/z?396(M-H) ^-C ₂₀H ₁₅NO ₄S ₂=397

Embodiment 167

Preparation compound 147

Adopt and synthetic 5-bromo-2[(4-aminomethyl phenyl) sulfenyl] the similar method of phenyl aldehyde, by 4-fluoro-5-(trifluoromethyl) phenyl aldehyde (0.20g, 1.0mmol) preparation 4-[(4-aminomethyl phenyl) sulfenyl]-3-(trifluoromethyl) phenyl aldehyde (0.30g, 100%).

Adopt the method (synthetic compound 67) identical, by the 4-[(4-aminomethyl phenyl with embodiment 94) sulfenyl]-(0.2g 0.7mmol) prepares compound 147 (0.13g, 50.2%) to 3-(trifluoromethyl) phenyl aldehyde.

The 4-[(4-aminomethyl phenyl) sulfenyl]-3-(trifluoromethyl) phenyl aldehyde:

¹HNMR(300MHz,CDCl ₃)δ(ppm)2.43(s,3H),7.01(d,J=8.3Hz,1H),7.29(d,J=7.9Hz,2H),7.46(d,J=8.1Hz,2H),7.73(d,J=8.4Hz,1H),8.11(s,1H),9.93(s,1H)

FABMS?m/z?296(M ⁺)C ₁₅H ₁₁F ₃OS=296

Compound 147:

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)2.49(s,3H),7.08(d,J=8.3Hz,1H),7.35(d,J=8.1Hz,2H),7.46(d,J=8.1Hz,2H),7.67(d,J=8.4Hz,1H),7.82(s,1H),8.02(s,1H),12.68(br?s,1H),

FABMS?m/z?395(M ⁺)C ₁₈H ₁₂ ¹⁹F ₃NO ₂S ₂=395

Embodiment 168

Preparation compound 148

Adopt the method (synthetic compound 69) identical with embodiment 96, (0.07g 0.18mmol) prepares compound 148 (0.047g, 64.3%) by compound 147.

Compound 148:

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)2.49(s,3H),7.37(d,J=8.4Hz,2H),7.53(d,J=8.3Hz,2H),7.93(s,1H),8.10(d,J=7.7Hz,1H),8.11(s,1H),8.35(d,J=8.3Hz,1H),12.80(br?s,1H),

FABMS?m/z?412(M+H) ⁺C ₁₈H ₁₂ ¹⁹F ₃NO ₃S ₂=411

Embodiment 169

Preparation compound 149

Adopt 5-carboxyl-2-[(4-aminomethyl phenyl) sulfenyl] phenyl aldehyde (0.10g 0.37mmol), carries out the reaction similar with embodiment 81, obtains 5-(N, N-diethylamino carbonyl)-2-[(4-aminomethyl phenyl) sulfenyl] phenyl aldehyde (0.046g, 36.7%).

Adopt identical method, by 5-(N, N-diethylamino carbonyl)-2-[(4-aminomethyl phenyl with embodiment 94 (synthesizing of compound 67)) sulfenyl] phenyl aldehyde (0.046g, 0.13mmol) preparation compound 149 (0.043g, 76.1%).

5-(N, N-diethylamino carbonyl)-2-[(4-aminomethyl phenyl) sulfenyl] phenyl aldehyde:

¹HNMR(300MHz,CDCl ₃)δ(ppm)1.19(m,3H),1.53(m,4H)2.41(s,3H),6.98(d,J=8.3Hz,1H),7.23(d,J=8.4Hz,2H),7.36(dd,J=2.0,8.3Hz,1H),7.40(d,J=8.3Hz,2H),7.86(d,J=2.0,8.3Hz,1H),10.35(s,1H),

FABMS?m/z?328(M+H) ⁺C ₁₉H ₂₁NO ₂S=327

Compound 149:

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)1.1(m,6H),2.50(s,3H)3.38(m,4H),7.16(d,J=8.3Hz,1H),7.27(d,J=8.3Hz,2H),7.34(d,J=8.4Hz,2H),7.37(d,J=8.1Hz,1H),7.39(s,1H),7.97(s,1H),12.03(br?s,1H),

FABMS?m/z?427(M) ⁺C ₂₂H ₂₂N ₂O ₃S ₂=427

Embodiment 170

Preparation compound 150

Adopt the method (synthetic compound 69) identical with embodiment 96, (0.09g 0.21mmol) prepares compound 150 (0.024g, 26.2%) by compound 149.

Compound 150:

¹HNMR (300MHz, DMSO-d ₆) (m, 6H), 2.29 (s, 3H) 2.49 (m, 4H), 7.31 (2H), 7.40 (s, 1H), 7.46 (2H), 7.63 (1H), 7.84 (s, 1H), 8.05 (1H), NH does not find δ (ppm) 1.1 for d, J=8.1Hz for d, J=7.9Hz for d, J=8.1Hz for d, J=8.4Hz

FABMS?m/z?443(M) ⁺C ₂₂H ₂₂N ₂O ₄S ₂=443

Embodiment 171

Preparation compound 151

Adopt the method identical with embodiment 81; use 5-carboxyl-2-[(4-aminomethyl phenyl) sulfenyl] phenyl aldehyde (0.3g; 1.1mmol) and use morpholine (0.19ml; 2.2mmol) replace diethylamine to prepare 4{3-formyl radical-4-[(4-aminomethyl phenyl) sulfenyl] benzoyl-morpholine (0.092g, 24.4%).

Adopt the method (synthetic compound 67) identical, by 4-{3-formyl radical-4-[(4-aminomethyl phenyl with embodiment 94) sulfenyl] benzoyl }-(0.092g 0.27mmol) prepares compound 151 (0.066g, 55.8%) to morpholine.

4-{3-formyl radical-4-[(4-aminomethyl phenyl) sulfenyl] benzoyl }-morpholine:

¹HNMR(300MHz,CDCl ₃)δ(ppm)2.41(s,3H),2.89(s,4H)2.97(s,4H),6.97(d,J=8.3Hz,1H),7.22(m,1H),7.26(d,J=7.9Hz,2H),7.41(d,J=8.1Hz,2H),7.89(d,J=1.8Hz,1H),10.34(s,1H)

FABMS?m/z?342(M+H) ⁺C ₁₉H ₁₉NO ₃S=341

Compound 151:

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)2.30(s,3H),3.40(s,4H)3.60(s,4H),7.13(d,J=8.3Hz,1H),7.27(d,J=8.4Hz,2H),7.35(d,J=7.7Hz,2H),7.39(d,J=8.3Hz,1H),7.92(s,1H),8.29(d,J=3.9Hz,1H),12.02(br?s,1H)

FABMS?m/z?441(M) ⁺C ₂₂H ₂₀N ₂O ₄S ₂=441

Embodiment 172

Preparation compound 152

Adopt the similar method of method of synthesizing 5-ethanoyl-2-fluorobenzaldehydes, by 5-bromo-4-fluorobenzaldehyde (1.0g, 4.9mmol) preparation 3-ethanoyl-4-fluorobenzaldehyde (0.38g, 47.0%) with embodiment 124.

Adopt 114 synthetic 5-bromo-2-[(4-aminomethyl phenyls with embodiment) sulfenyl] the similar method of method of benzaldehyde; by 3-ethanoyl-4-fluorobenzaldehyde (0.38g; 2.3mmo1) and with 3; the 4-thiophenol dichlorobenzene replaces 4-methylbenzene thiophenol to prepare 3-ethanoyl-4-[(3; the 4-dichlorophenyl) sulfenyl] phenyl aldehyde (0.l0g, 13.7%).

Adopt the method (synthetic compound 67) identical with embodiment 94, by 3-ethanoyl-4-[(3, the 4-dichlorophenyl) sulfenyl] (0.1g 0.32mmol) prepares compound 152 (0.044g, 32.5%) to phenyl aldehyde.

3-ethanoyl-4-fluorobenzaldehyde:

¹HNMR(300MHz,CDCl ₃)δ(ppm)2.64(s,3H),7.25(dd,J=8.4,10.4Hz,1H),8.01(m,1H),8.35(dd,J=2.4,7.1Hz,1H),9.95(s,1H)

CIMS?m/z?167(M+H) ⁺C ₉H ₇FO ₂=166

3-ethanoyl-4-[(3, the 4-dichlorophenyl) sulfenyl] phenyl aldehyde:

¹HNMR(300MHz,CDCl ₃)δ(ppm)2.72(s,3H),6.95(d,J=2.0Hz,1H)7.37(dd,J=2.0,8.1Hz,1H),7.53(d,J=2.0Hz,1H),7.62(d,J=2.0Hz,1H),7.72(dd,J=1.8,8.3Hz,1H),8.35(d,J=1.8Hz,1H),9.95(s,1H)

FABMS?m/z?325(M ⁺)C ₁₅H ₁₀Cl ₂O ₂S=325

Compound 152:

¹HNMR (300MHz, DMSO-d ₆) δ (ppm) 2.69 (s, 3H), 6.96 (d, J=8.4Hz, 1H) 7.53 (dd, J=2.0,8.3Hz, 1H), 7.66 (dd, J=1.8,8.5Hz, 1H), 7.74 (s, 1H), 7.78 (d, J=8.3Hz, 1H), 7.86 (1H), 8.32 (1H), NH does not find for d, J=1.8Hz for d, J=2.0Hz

FABMS?m/z?424(M ⁺)C ₁₈H ₁₁Cl ₂NO ₃S ₂=424

Embodiment 173

Preparation compound 153

Adopt the method (synthetic compound 69) identical with embodiment 96, (0.03g 0.071mmol) prepares compound 153 (0.094g, 89.9%) by compound 152.

Compound 153:

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)2.50(s,3H),7.65(dd,J=2.0,8.3Hz,1H)7.74(dd,J=8.6Hz,1H),7.93(d,J=1.7Hz,1H),7.96(s,1H),8.11(dd,J=1.8,8.3Hz,1H),8.34(s,1H),8.46(d,J=8.8Hz,1H),12.77(br?s,1H)

FABMS?m/z?440(M ⁺)C ₁₈H ₁₁Cl ₂NO ₄S ₂=440

Embodiment 174

Preparation compound 154

Adopt synthetic 5-bromo-2-[(4-aminomethyl phenyl with embodiment 114) sulfenyl] the similar method of method of benzaldehyde, by 5-nitro-2-fluorobenzaldehyde (0.30g, 1.77mmol) and with 2, the 3-thiophenol dichlorobenzene replaces the p-toluenethiol to prepare 2-[(2, the 3-dichlorophenyl) sulfenyl]-5-nitrobenzaldehyde (0.57g, 97.9%).

Adopt the method (synthetic compound 69) identical with embodiment 96, by 2-[(2, the 3-dichlorophenyl) sulfenyl]-(0.3g 0.91mmol) prepares compound 154 (0.088g, 22.5%) to the 5-nitrobenzaldehyde.

2-[(2, the 3-dichlorophenyl) sulfenyl]-the 5-nitrobenzaldehyde:

¹HNMR(300MHz,CDCl ₃)δ(ppm)6.91(d,J=8.8Hz,1H),7.34(d,J=8.1Hz,1H),7.58(dd,J=1.5,7.7Hz,1H),7.66(dd,J=1.7,8.1Hz,1H),8.19(dd,J=2.6,8.9Hz,1H),8.72(d,J=2.6Hz,1H),10.31(s,1H)

FABMS?m/z?328(M ⁺)C ₁₃H ₇Cl ₂NO ₃S=328

Compound 153:

¹HNMR (300MHz, DMSO-d ₆) δ (ppm) 7.25 (d, J=8.6Hz, 1H), 7.55 (d, J=2.0Hz, 1H), 7.57 (s, 1H), 7.81 (s, 1H), 7.92 (d, J=2.0Hz, 1H), 8.16 (dd, J=2.4,8.7Hz, 1H), 8.30 (1H), NH does not find for d, J=2.4Hz

FABMS?m/z?425(M-H) ^-C ₁₆H ₈ ³⁵Cl ₂N ₂O ₄S ₂=426

Embodiment 175

Preparation compound 155

Adopt synthetic 5-bromo-2-[(4-aminomethyl phenyl with embodiment 114) sulfenyl] the similar method of method of benzaldehyde, by 5-nitro-2-fluorobenzaldehyde (0.30g, 1.77mmol) and with 2, the 4-thiophenol dichlorobenzene replaces the p-toluenethiol to prepare 2-[(2, the 4-dichlorophenyl) sulfenyl]-5-nitrobenzaldehyde (0.53g, 91.7%).

Adopt the method (synthetic compound 69) identical with embodiment 96, by 2-[(2, the 4-dichlorophenyl) sulfenyl]-(0.3g 0.91mmol) prepares compound 155 (0.13g, 32.4%) to the 5-nitrobenzaldehyde.

2-[(2, the 4-dichlorophenyl) sulfenyl]-the 5-nitrobenzaldehyde:

¹HNMR(300MHz,CDCl ₃)δ(ppm)6.86(d,J=8.8Hz,1H),7.40(dd,J=2.2,8.3Hz,1H),7.61(s,1H),7.64(t,J=2.6Hz,1H),8.17(dd,J=2.6,8.8Hz,1H),8.71(d,J=2.6Hz,1H),10.30(s,1H)

FABMS?m/z?328(M ⁺)C ₁₃H ₇ ³⁵Cl ₂NO ₃S=327

Compound 155:

¹HNMR (300MHz, DMSO-d ₆) δ (ppm) 7.38 (d, J=8.8Hz, 1H), 7.41 (s, 1H), 7.43 (d, J=1.3Hz, 1H), 7.75 (dd, J=3.9,5.7Hz, 1H), 7.80 (s, 1H), 8.20 (dd, J=2.4,8.8Hz, 1H), 8.32 (1H), NH does not find for d, J=2.4Hz

FABMS?m/z?425(M-H) ^-C ₁₆H ₈ ³⁵Cl ₂N ₂O ₄S ₂=426

Embodiment 176

Preparation compound 156

Adopt the method (synthetic compound 69) identical with embodiment 96, (0.037g 0.085mmol) prepares compound 156 (0.016g, 43.1%) by compound 154.

Compound 156:

¹HNMR (300MHz, DMSO-d ₆) δ (ppm) 7.74 (dd, J=2.0,8.4Hz, 1H), 7.77 (s, 1H), 7.79 (s, 1H), 7.82 (t, J=2.2Hz, 1H), 8.00 (d, J=8.6Hz, 1H), 8.30 (dd, J=2.2,8.7Hz, 1H), 8.42 (1H), NH does not find for d, J=2.2Hz

FABMS?m/z?441(M-H) ^-C ₁₆H ₈ ³⁵Cl ₂N ₂O ₅S ₂=442

Embodiment 177

Preparation compound 157

Adopt the method (synthetic compound 69) identical with embodiment 96, (0.066g 0.15mmol) prepares compound 157 (0.030g, 44.1%) by compound 155.

Compound 157:

¹HNMR (300MHz, DMSO-d ₆) (1H), 7.85 (1H), 7.88 (s, 1H), 8.10 (1H), 8.14 (s, 1H), 8.28 (1H), 8.42 (1H), NH does not find δ (ppm) 7.67 for d, J=2.4Hz for d, J=2.2Hz for d, J=8.8Hz for d, J=0.9Hz for t, J=7.7Hz

FABMS?m/z?441(M-H) ^-C ₁₆H ₈ ³⁵Cl ₂N ₂O ₅S ₂=442

Embodiment 178

Preparation compound 158

Adopt the method (synthetic compound 69) identical with embodiment 96, (0.03g 0.070mmol) prepares compound 158 (0.0085g, 26.4%) by compound 154.

Compound 157:

¹HNMR (300MHz, DMSO-d ₆) δ (ppm) 7.19 (d, J=8.8Hz, 1H), 7.55 (d, J=1.7Hz, 1H), 7.55 (s, 1H), 7.70 (s, 1H), 7.92 (s, 1H), 8.11 (dd, J=2.6,8.8Hz, 1H), 8.36 (1H), NH does not find for d, J=2.4Hz

Embodiment 179

Preparation compound 159

Adopt the method (synthetic compound 69) identical with embodiment 96, (0.03g 0.070mmol) prepares compound 159 (0.13g, 38.9%) by compound 155.

Compound 159:

¹HNMR (300MHz, DMSO-d ₆) δ (ppm) 7.35 (d, J=8.8Hz, 1H), 7.40 (s, 1H), 7.42 (d, J=4.4Hz, 1H), 7.75 (dd, J=2.4,6.7Hz, 1H), 7.76 (s, 1H), 8.18 (dd, J=2.6,8.8Hz, 1H), 8.35 (1H), NH does not find for d, J=2.6Hz

Embodiment 180

Preparation compound 160

With 2-fluoro-nitrobenzaldehyde (0.16mL 0.95mmol) is dissolved in N, in the dinethylformamide (8.1mL), in solution, add 4-sulfydryl phenol (0.11mg, 0.86mmol) and triethylamine (0.27mL, 1.9mmol), 25 ℃ of stirrings 1 hour.After conventional processing, product is with silica gel column chromatography (purify obtain 5-nitro-2-[(4-hydroxy phenyl with n-hexane/acetone=4/1-1/1)) sulfenyl] phenyl aldehyde (0.18g, 70%).

With 5-nitro-2-[(4-hydroxy phenyl) sulfenyl] phenyl aldehyde (0.17g, 0.61mmol) be dissolved in the toluene (8.4mL), add 2,4-thiazolidinedione (0.29mg, 2.4mmol), piperidines (0.024mL, 0.24mmol), (0.014mL, 0.24mmol) and molecular sieve 4A (0.84g), 110 ℃ were stirred 2 hours acetate.After conventional aftertreatment,, obtain compound 160 (34mg, 15%) through the pure system of thin-layer chromatography (with chloroform/methanol=10/1).

5-nitro-2-[(4-hydroxy phenyl) sulfenyl] phenyl aldehyde:

¹H?NMR(300MHz,CDCl ₃)δ(ppm)6.97(d,J=9.0Hz,1H),7.03(d,J=8.6Hz,2H),7.40(d,J=8.8Hz,2H),8.06(m,1H),8.61(br?s,1H),8.63(d,J=2.3Hz,1H),12.29(s,1H)

Compound 160:

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)6.94(d,J=8.8Hz,3H),7.45(d,J=8.6Hz,2H),7.87(s,1H),8.13(dd,J=2.4,8.8Hz,1H),8.20(d,J=2.2Hz,1H),10.20(s,1H),12.86(br?s,1H)

FABMS?m/z?373(M-H) ^-C ₁₆H ₁₀N ₂O ₅S ₂=374

Embodiment 181

Preparation compound 161

Adopt the method identical with embodiment 97, by 3,4-dimethyl benzene mercaptan (0.16mL, 1.2mmol), 2.5mol/L aqueous sodium hydroxide solution (2.1mL, 5.2mmol), Tetrabutyl amonium bromide (0.020mg, 0.61mmol) and 2-fluoro-5-nitrobenzaldehyde (0.21mg, toluene solution 1.2mmol) (2.1mL) preparation 2-[(3, the 4-3,5-dimethylphenyl) sulfenyl]-5-nitrobenzaldehyde (0.16g, 45%).

Compound 161 (0.13g, 64%) by 2-[(3, the 4-3,5-dimethylphenyl) sulfenyl]-5-nitrobenzaldehyde (0.16g, 0.54mmol), toluene (7.8mL), 2,4-thiazolidinedione (0.26mg, 2.2mmol), piperidines (0.022mL, 0.22mmol), acetate (0.0l2mL, 0.22mmol) and molecular sieve 4A (0.78g) preparation.

2-[(3, the 4-3,5-dimethylphenyl) sulfenyl]-the 5-nitrobenzaldehyde:

¹HNMR(300MHz,CDCl ₃)δ(ppm)2.31(s,3H),2.36(s,3H),6.97(d,J=9.0Hz,1H),7.24-7.36(m,3H),8.09(dd,J=9.0,2.5Hz,1H),8.67(d,J=2.6Hz,1H),10.31(s,1H)

FABMS?m/z?287(M) ₊C ₁₅H ₁₃NO ₃S=287

Compound 169:

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)2.25(s,3H),2.28(s,3H),7.06(d,J=9.0Hz,1H),7.33(s,2H),7.40(s,1H),7.88(s,1H),8.15(m,1H),8.21(m,1H),12.86(br?s,1H)

FABMS?m/z?385(M-H) ^-C ₁₈H ₁₄N ₂O ₄S ₂=386

Embodiment 182

Preparation compound 162

Adopt the method identical with embodiment 134, compound 72 (0.061g by embodiment 56 preparations, 0.14mmol), methylene dichloride (6.1mL), methyl alcohol (1.2mL) and m-chlorine peroxybenzoic acid (0.75g, 2.1mmol) preparation compound 162 (0.60mg, 0.9%).

Compound 162:

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)7.96(d,J=8.4Hz,1H),8.02(dd,J=8.7,2.2Hz,1H),8.17(s,1H),8.28(s,1H),8.32(d,J=2.2Hz,1H),8.44(d,J=1.3Hz,2H),

Compound 183

Preparation compound 163

Adopt the method identical with embodiment 156, (0.10g, 0.26mmol), N, (0.14g 0.82mmol) prepares compound 163 (0.0034g, 32%) for dinethylformamide (5.1mL) and m-chlorine peroxybenzoic acid by the compound 81 of embodiment 108 preparations.

Compound 163:

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)7.58(d,J=8.4Hz,2H),7.74(d,J=8.4Hz,2H),8.00(s,1H),8.30(dd,J=8.2Hz,1H),8.48(d,J=8.2Hz,1H),8.53(d,J=1.4Hz,1H),12.83(br?s,1H)

FABMS?m/z?407(M-H) ^-C ₁₆H ₉ ³⁵ClN ₂O ₅S ₂=408

Embodiment 184

Preparation compound 164

To the 4-ethyl phenyl mercaptan (0.20g, add in 1.2mmol) the 2.5mol/L aqueous sodium hydroxide solution (2.0mL, 4.9mmol) and Tetrabutyl amonium bromide (0.019g, 0.58mmol), 25 ℃ of stirrings 5 minutes.(25 ℃ were stirred 12 hours for 0.20g, toluene solution 1.2mmol) (2.0ml) to add 4-fluoro-3-nitrobenzaldehyde again.After conventional processing, product is purified with silica gel column chromatography (using the chloroform wash-out) and is obtained the 4-[(4-ethylphenyl) sulfenyl]-3-nitrobenzaldehyde (0.25g, 75%).

With the 4-[(4-ethylphenyl) sulfenyl]-the 3-nitrobenzaldehyde (0.25g 0.86mmol) is dissolved in the ethanol (9.9mL), adds 2, the 4-thiazolidinedione (0.40mg, 3.4mmol) and piperidines (0.034mL, 0.34mmol), 80 ℃ of stirrings 7 hours.Filtration is collected the crystal of separating out and is obtained compound 164 (0.061g, 19%).

The 4-[(4-ethylphenyl) sulfenyl]-the 3-nitrobenzaldehyde:

¹H?NMR(300MHz,CDCl ₃)δ(ppm)1.31(t,J=7.7Hz,3H),2.76(q,J=7.5Hz,2H),7.01(d,J=8.4Hz,1H),7.37(d,J=8.2Hz,2H),7.50(d,J=8.2Hz,2H),7.81(dd,J=8.4Hz,1.8Hz,1H),8.69(d,J=1.6Hz,1H),9.97(s,1H)

FABMS?m/z?287(M) ⁺C ₁₅H ₁₃NO ₃S=287

Compound 164:

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)1.24(t,J=7.5Hz,3H),2.70(q,J=7.3Hz,2H),6.92(d,J=8.6Hz,1H),7.08(br?s,1H),7.43(d,J=8.1Hz,2H),7.56(d,J=8.0Hz,2H),7.58(s,1H),7.72(dd,J=8.6,2.0Hz,1H),8.44(d,J=1.8Hz,1H)

FABMS?m/z?385(M-H) ^-C ₁₈H ₁₄N ₂O ₄S ₂=386

Compound 185

Preparation compound 165 and 166

Adopt the method identical with embodiment 156, compound 164 (0.052g by embodiment 184 preparations, 0.14mmol), N, dinethylformamide (2.6mL) and m-chlorine peroxybenzoic acid (0.44g, 1.3mmol) preparation compound 165 (0.014g, 26%) and compound 166 (0.016g, 26%).

Compound 165:

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)1.13(t,J=7.7Hz,3H),2.61(q,J=7.5Hz,2H),7.34(d,J=8.3Hz,2H),7.51-7.56(m,2H),7.95(2,1H),8.30(dd,J=8.4,1.6Hz,1H),8.48-8.52(m,2H),12.87(m,1H)

FABMS?m/z?401(M-H) ^-C ₁₈H ₁₄N ₂O ₅S ₂=402

Compound 166:

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)1.19(t,J=7.7Hz,3H),2.71(q,J=8.4Hz,2H),7.51-7.60(m,2H),7.80(s,1H),7.86-7.95(m,2H),8.03(dd,J=8.8,1.5Hz,1H),8.21(d,J=1.1Hz,1H),8.45(d,J=8.2Hz,1H),12.90(m,1H)

FABMS?m/z?417(M-H) ^-C ₁₈H ₁₄N ₂O ₆S ₂=418

Embodiment 186

Preparation compound 167

Adopt the method identical with embodiment 184, by 3,4-dichlorobenzene mercaptan (0.13g, 1.0mmol), 2.5mol/L aqueous sodium hydroxide solution (1.8mL, 4.4mmol), Tetrabutyl amonium bromide (0.017g, 0.52mmol) and 4-fluoro-3-nitrobenzaldehyde (0.18g, toluene 1.0mmol) (1.8mL) formulations prepared from solutions 4-[(3, the 4-dichlorophenyl) sulfenyl]-3-nitrobenzaldehyde (0.29g, 84%).

Compound 167 (0.077g, 15%) is by 4-[(3, the 4-dichlorophenyl) sulfenyl]-the 3-nitrobenzaldehyde (0.40g, 1.2mmol), ethanol (16mL), 2, the 4-thiazolidinedione (0.57mg, 4.9mmol) and piperidines (0.048mL, 0.49mmol) preparation.

4-[(3, the 4-dichlorophenyl) sulfenyl]-the 3-nitrobenzaldehyde:

¹H?NMR(300MHz,CDCl ₃)δ(ppm)7.03(d,J=8.4Hz,1H),7.44(dd,J=8.3,2.0Hz,1H),7.63(d,J=8.3Hz,1H),7.72(d,J=2.0Hz,1H),7.88(dd,J=8.4,1.8Hz,1H),8.73(d,J=1.8Hz,1H),10.00(s,1H)

FABMS?m/z?328(M+H) ⁺C ₁₃H ₇ ³⁵Cl ₂NO ₃S=327

Compound 167:

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)7.11(d,J=8.6Hz,1H),7.65(dd,J=8.3,2.2Hz,2H),7.77(dd,J=2.0,8.6Hz,1H),7.85(d,J=8.2Hz,1H),7.87(s,1H),8.02(d,J=2.0Hz,1H),8.52(d,J=2.0Hz,1H),12.74(br?s,1H)

FABMS?m/z?425(M-H) ^-C ₁₆H ₈ ³⁵Cl ₂N ₂O ₄S ₂=426

Compound 187

Preparation compound 168

Adopt the method identical with embodiment 156, (0.031g, 0.073mmol), N, (0.035g 0.10mmoL) prepares compound 168 (0.017g, 54%) for dinethylformamide (1.6mL) and m-chlorine peroxybenzoic acid by the compound 167 of embodiment 186 preparations.

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)7.69(m,1H),7.78(d,J=8.5Hz,1H),8.00(s,2H),8.28(d,J=8.1Hz,1H),8.48(d,J=8.9Hz,1H),8.53(s,1H),12.84(br?s,1H)

FABMS?m/z?441(M-H) ^-C ₁₆H ₈ ³⁵Cl ₂N ₂O ₅S ₂=442

Embodiment 188

Preparation compound 169 and compound 170

Adopt the method identical with embodiment 156, and the compound 161 for preparing by embodiment 181 (0.10g, 0.27mmol), N, dinethylformamide (5.2mL) and m-chlorine peroxybenzoic acid (0.46g, 4.0mmoL) preparation compound 169 (0.080g, 75%) and compound 170 (2.5mg, 2.3%).

Compound 169:FABMS m/z 401 (M-H) ^-C ₁₈H ₁₄N ₂O ₅S ₂=402

Compound 170:FABMS m/z 417 (M-H) ^-C ₁₈H ₁₄N ₂O ₆S ₂=418

Embodiment 189

Preparation N-(4-chloro-phenyl-)-4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-benzsulfamide

Steps A: universal process 1

Universal process 1 back obtains 5-benzylidyne-thiazolidine-2 with phenyl aldehyde, the 4-diketone.

NMR(DMSO-d ₆):7.75(s,1H),7.6-7.4(m,5H)

MS (ESI) 205, actual measurement 204 (M-H) step B: preparation 4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-benzene sulfonyl chloride

In the flask that chlorsulfonic acid (10 equivalent) is housed with the ice bath refrigerative, add 5-benzylidyne-thiazolidine-2,4-diketone.Solution stirred 1 hour down at 0 ℃, was warming to room temperature and stirred and spend the night.Afterwards, reaction solution is poured on ice carefully, sedimentation and filtration and the dry air that obtains obtained pure products.

NMR(DMSO-d ₆):7.72(s,1H),7.66(d,2H),7.51(d,2H)

MS (ESI) 303, actual measurement 302 (M-H) step C: sulfonylation

SULPHURYL CHLORIDE and 4-chloro-aniline are stirred in pyridine together, be heated to 60 ℃ and continue 12 hours.Solution dilutes with EtOAC, uses 10%NaHSO then successively ₄With the NaCl solution washing.Separate organic layer, use Na ₂SO ₄Drying, concentrating under reduced pressure obtains pure compound.

MS (ESI) 394, actual measurement 393 (M-H)

Embodiment 190

Preparation 4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-N-p-tolyl-benzsulfamide

Adopt the method for embodiment 189, prepare 4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-N-p-tolyl-benzsulfamide by the p-Tolylamine

MS (ESI) 374, actual measurement 373 (M-H)

Embodiment 191

Preparation 4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-N-(4-methoxyl group-phenyl)-benzsulfamide

Adopt the method for embodiment 189, prepare 4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-N-(4-methoxyl group-phenyl)-benzsulfamide by the p-methyl oxyaniline

MS (ESI) 390, actual measurement 389 (M-H)

Embodiment 192

Preparation 4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-N-(4-trifluoromethyl-phenyl)-benzsulfamide

Adopt the method for embodiment 189, prepare 4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-N-(4-trifluoromethyl-phenyl)-benzsulfamide by 4-(trifluoromethyl) aniline.

MS (ESI) 428, actual measurement 427 (M-H)

Embodiment 193

Preparation 4,5-two chloro-N-[3-(2,4-dioxy-thiazolidine-5-subunit-methyl)-phenyl]-adjacent carbamyl phenylformic acid

Steps A: coupling 2 under sour environment, and 4-thiazolidinedione (TZD) is an aldehyde

3-nitrobenzaldehyde, TZD (1.25 equivalent), NaOAc (2 equivalent) and diacetyl oxide (1 equivalent) are dissolved in the acetate reflux 12 hours.The cooling reactant is also collected the precipitation of separating out, and washing and dry air obtain pure products.Filtrate is poured in the water, filters the precipitation that obtains and obtain extra product.

MS (ESI) 250, actual measurement 249 (M-H) step B: the reduction of nitro

With 5-(3-nitro-benzylidyne) thiazolidine-2, the 4-diketone is dissolved in the excessive acetic acid.Add small amount of methanol so that reactant fully dissolves.Solution is slowly heated, add iron powder (5 equivalent).After 4 hours, filtering mixt is to remove iron powder, and water gagings such as usefulness dilute, and extract with EtOAc.With the organic layer vacuum concentration, obtain brown solid.Resistates is dissolved in the methyl alcohol, by removing by filter impurity.Concentrated filtrate, the gained resistates is developed with hexane, collects after filtration and obtains product.

MS (ESI) 220, actual measurement 219 (M-H) step C: with the diacetyl oxide condensation

With 5-(3-amino-benzylidyne)-thiazolidine-2, the 4-diketone is dissolved among the THF, and with 4, the DMAP of 5-two chloro-phthalic anhydrides and catalytic amount handles.With solution stirring 8 hours, filter and vacuum concentration.Be dissolved in resistates among the EtOAc and wash with water.Organic layer is concentrated to oily, develops resulting solid product, filter collection and obtain product, be solid with hexane.

MS (ESI) 436, actual measurement 435 (M-H)

Embodiment 194

Preparation 3,6-two chloro-N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl]-phthalamic acid

The method of Application Example 193, by 3,6-two chloro-phthalic anhydrides preparation 3,6-two chloro-N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl]-phthalamic acid.

MS (ESI) 436, actual measurement 435 (M-H)

The embodiment 1954-tertiary butyl-N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl]-phthalamic acid

The method of Application Example 193 prepares the 4-tertiary butyl-N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl by the 4-tertiary butyl-Tetra hydro Phthalic anhydride]-phthalamic acid, its form of mixtures with 64: 36 regional isomers is separated.

MS (ESI) 425, actual measurement 423 (M-2H)

Embodiment 196

Preparation N-[3-(2,4-dioxy-thiazolidine-5 ylidenylmethyl)-phenyl]-3-hydroxyl-phthalamic acid

The method of Application Example 193 prepares N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl by the 3-hydroxyl phthalic anhydride]-3-hydroxyl-phthalamic acid, what obtain is the mixture of 80: 20 regional isomer.

MS (ESI) 384, actual measurement 383 (M-H)

Embodiment 197

Preparation 3-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenylamino formyl radical]-pyrazine-2-carboxylic acid

The method of Application Example 193, by 2,3-pyrazine dicarboxylic acid anhydride prepares 3-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenylamino formyl radical]-pyrazine-2-carboxylic acid.

MS (ESI) 370, actual measurement 369 (M-H)

Embodiment 198

Preparation 3-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenylamino formyl radical]-Yi Yansuan

The method of Application Example 193, by pyridine-3, the 4-dicarboxylic acid anhydride obtains 3-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenylamino formyl radical]-Yi Yansuan, it exists with 70: 30 mixture of isomers forms.

MS (ESI) 369, actual measurement 368 (M-H)

Embodiment 199

Preparation 3-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenylamino formyl radical]-pyridine-2-carboxylic acids

The method of Application Example 193, by 2,3-dinicotinic acid acid anhydride prepares 3-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenylamino formyl radical]-than pyridine-2-carboxylic acid, and separation obtains its mixture of isomers.

MS (ESI) 369, actual measurement 368 (M-H)

Embodiment 200

Preparation 4-(4-chloro-benzenesulfonyl amino)-N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl]-benzamide

Steps A: with the acyl chlorides condensation

With 5-(3-amino-benzylidyne)-thiazolidine-2 that makes, the 4-diketone is dissolved in the pyridine, and handles with the DMAP of 4-nitrobenzoyl chloride and catalytic amount.Reaction soln stirred 20 minutes, then by filtering collecting precipitation.Solid is water, saturated NaHCO repeatedly ₃The aqueous solution and the washing of 10% aqueous hydrochloric acid.With the solid air drying that obtains.

MS (ESI) 369, actual measurement 368 (M-H) step B: the reduction of nitro

With 4-nitro-N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl]-benzamide is suspended in the Virahol.A small amount of ammonium chloride is dissolved in the water, and joins in the above-mentioned solution.With mixture heating up to 70 ℃ lasting a few hours.Add iron powder, continue to stir 4 hours.By solids removed by filtration, the filtrate vacuum concentration.Resistates is dissolved among the EtOAc, and washes with water.Organic layer is concentrated to oily, makes the product precipitation by adding hexane.

MS (ESI) 339, actual measurement 338 (M-H) step C: with the SULPHURYL CHLORIDE condensation

With 4-amino-N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl]-benzamide is dissolved in the pyridine, and under 60 ℃, in pyridine, handled 12 hours with 4-chloro-benzene sulfonyl chloride.Cooling solution is with the EtOAc dilution, then with the 10% sodium pyrosulfate aqueous solution and saturated sodium-chloride water solution washing.Separate organic phase, use dried over sodium sulfate, concentrating under reduced pressure becomes oily matter then.Grind with hexane, obtain pure products.

MS (ESI) 513, actual measurement 512 (M-H)

Embodiment 201

Preparation N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl]-4-(toluene-4-sulfonamido)-benzamide

The method of Application Example 200 prepares N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl by the p-toluene sulfonyl chloride]-4-(toluene-4-sulfonamido)-benzamide.

MS (ESI) 493, actual measurement 492 (M-H)

Embodiment 202 preparation N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl]-4-(4-methoxyl group-phenylsulfonamido)-benzamide

The method of Application Example 200 prepares N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl by 4-anisole SULPHURYL CHLORIDE]-4-(4-methoxyl group-phenylsulfonamido)-benzamide.

MS (ESI) 509, actual measurement 508 (M-H)

Embodiment 203

Preparation N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl]-4-(4-trifluoromethoxy-phenylsulfonamido)-benzamide

The method of Application Example 200 prepares N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl by 4-(trifluoromethoxy) benzene sulfonyl chloride]-4-(4-trifluoromethoxy-phenylsulfonamido)-benzamide.

MS (ESI) 563, actual measurement 562 (M-H)

Embodiment 204

Preparation 4-phenylsulfonamido-N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl]-benzamide

The method of Application Example 200 prepares 4-phenylsulfonamido-N-[3-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenyl by benzene sulfonyl chloride]-benzamide.

MS (ESI) 479, actual measurement 478 (M-H).

Embodiment 205

Preparation N-(4-chloro-phenyl)-4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-benzsulfamide Steps A: preparation 4-phenoxy group-phenyl aldehyde

The suspension of salt of wormwood (1 equivalent), 4-fluorobenzaldehyde and phenol (1.2 equivalent) is heated to 150 ℃ and stirred 2 days.The reaction solution cool to room temperature and be poured into saturated sodium bicarbonate solution and ice in.The solution extracted with diethyl ether.The organic layer that merges washes with water, uses Na ₂SO ₄Dry.Vacuum concentration obtains orange buttery pure products.Step B: obtain 5-(4-phenoxy group-benzylidyne)-thiazolidine-2,4-diketone with the TZD condensation

The ethanolic soln of 4-phenoxy group-phenyl aldehyde, TDZ (1.5 equivalent) and piperidines (2 equivalent) is heated to 70 ℃, and stirring is spent the night.With the reaction solution cool to room temperature, be poured in 10% hydrochloric acid soln.With the sedimentation and filtration that obtains, wash with water and dry air.

MS (ESI) 297, actual measurement 296 (M-H).Step C: chlorosulfonylation obtains 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-benzene sulfonyl chloride

With 5-(4-phenoxy group-benzylidyne)-thiazolidine-2, the 4-diketone is dissolved in the chlorsulfonic acid, stirs 30 minutes down at 0 ℃.Then solution is poured in the ice, filters collecting precipitation, dry air obtains pure products.

MS (ESI) 395, actual measurement 394 (M-H).Step D: obtain sulphonamide with the condensation of 4-chloroaniline

With 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-pyridine solution of benzene sulfonyl chloride and 4-chloroaniline (1.1 equivalent) stirs down warm.Vacuum is removed pyridine then, and resistates is dissolved among the EtOAc.Organic layer washs with 10% aqueous hydrochloric acid, sodium bicarbonate aqueous solution and sodium chloride aqueous solution, then vacuum concentration.The reaction residue that obtains obtains pure products with the hexane development.

MS (ESI) 486, actual measurement 485 (M-H).

Embodiment 206

Preparation 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-N-p-tolyl-benzsulfamide

The method of Application Example 205 prepares 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group by the p-Tolylamine]-N-p-tolyl-benzsulfamide.

MS (ESI) 466, actual measurement 465 (M-H).

Embodiment 207

Preparation 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-N-(4-trifluoromethoxy-phenyl)-benzsulfamide

The method of Application Example 205 prepares 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group by 4-(trifluoromethoxy) aniline]-N-(4-trifluoromethoxy-phenyl)-benzsulfamide.

MS (ESI) 536, actual measurement 535 (M-H).

Embodiment 208

Preparation 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-N-(4-methoxyl group-phenyl)-benzsulfamide

The method of Application Example 205 prepares 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group by the p-methyl oxyaniline]-N-(4-methoxyl group-phenyl)-benzsulfamide.

MS (ESI) 482, actual measurement 481 (M-H).

Embodiment 209

Preparation 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-N-phenyl-benzsulfamide

The method of Application Example 205 prepares 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group by aniline]-N-phenyl-benzsulfamide.

MS (ESI) 452, actual measurement 451 (M-H).

Embodiment 210

Preparation 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-N-(3,4,5-trimethoxy-phenyl)-benzsulfamide

The method of Application Example 205, by 3,4, the 5-trimethoxy-aniline prepares 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-N-(3,4,5-trimethoxy-phenyl)-benzsulfamide.

MS (ESI) 542, actual measurement 541 (M-H).

Embodiment 211 preparation 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy groups]-N-(4-morpholine-4-base phenyl)-benzsulfamide

The method of Application Example 205 prepares 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group by 4-morpholino aniline]-N-(4-morpholine-4-base phenyl)-benzsulfamide.

MS (ESI) 537, actual measurement 536 (M-H).

Embodiment 212

Preparation 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-N-(4-sec.-propyl-phenyl)-benzsulfamide

The method of Application Example 205 prepares 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group by the 4-isopropyl aniline]-N-(4-sec.-propyl-phenyl)-benzsulfamide.

MS (ESI) 494, actual measurement 493 (M-H).

Embodiment 213

Preparation N-(2-chloro-phenyl)-4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-benzsulfamide

The method of Application Example 205 prepares N-(2-chloro-phenyl)-4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group by the 2-chloroaniline]-benzsulfamide.

MS (ESI) 486, actual measurement 485 (M-H).

Embodiment 214

Preparation N-(3-chloro-phenyl)-4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-benzsulfamide

The method of Application Example 205 prepares N-(3-chloro-phenyl)-4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group by the 3-chloroaniline]-benzsulfamide.

MS (ESI) 486, actual measurement 485 (M-H).

Embodiment 215

Preparation 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-N-(4-hydroxyl-phenyl)-benzsulfamide

The method of Application Example 205 prepares 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group by the 4-amino-phenol]-N-(4-hydroxyl-phenyl)-benzsulfamide.

MS (ESI) 486, actual measurement 467 (M-H).

Embodiment 216

Preparation 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-N-(2-hydroxyl-phenyl)-benzsulfamide

The method of Application Example 205 prepares 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group by the 2-amino-phenol]-N-(2-hydroxyl-phenyl)-benzsulfamide.

MS (ESI) 468, actual measurement 467 (M-H).

Embodiment 217

Preparation N-(the 2-tertiary butyl-phenyl)-4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group] benzsulfamide

The method of Application Example 205 prepares N-(the 2-tertiary butyl-phenyl)-4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group by 2-tertiary butyl aniline] benzsulfamide.

MS (ESI) 508, actual measurement 507 (M-H).

Embodiment 218

Preparation 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-N-sec.-propyl-N-phenyl-benzsulfamide

The method of Application Example 205 prepares 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group by the N-isopropyl aniline]-N-sec.-propyl-N-phenyl-benzsulfamide.

MS (ESI) 494, actual measurement 493 (M-H).

Embodiment 219

Preparation 4-[4-(2,4-dioxy-thiazolidine-5-ylidenylmethyl)-phenoxy group]-N-(3-hydroxyl-phenyl)-benzsulfamide

The method of Application Example 205 prepares 4-[4-(2,4-dioxy-thiazolidine-5 ylidenylmethyl)-phenoxy group by the 3-amino-phenol]-N-(3-hydroxyl-phenyl)-benzsulfamide.

MS (ESI) 468, actual measurement 467 (M-H).

Embodiment 220

Preparation 5-[2-(3,4-two chloro-benzyl sulfo groups)-pyrimidine-4-ylidenylmethyl]-2-sulfo--thiazolidin-4-one

Steps A: pyrimidine mercaptan is carried out alkylation with benzyl halide

In the suspension of sodium salt in DMF and salt of wormwood (2 equivalent) of 4-dimethoxy-methyl-pyrimidine-2-mercaptan, add α, 3,4-trichlorotoluene zotrichloride (1 equivalent) stirs suspension two days.The reaction mixture dilute with water extracts with EtOAc.Organic layer water, sodium chloride aqueous solution washing are used dried over mgso, vacuum concentration.Step mule B: acetal go protection

With the concentrated hydrochloric acid suspension returning of 2-(3,4-two chloro-benzyl sulfo groups)-4-dimethoxy-methyl-pyrimidine 5 minutes.With reaction solution cooling and be poured in the water.Add saturated sodium bicarbonate aqueous solution, the solution after the neutralization is extracted with EtOAc.Organic layer Na ₂SO ₄Drying, vacuum concentration obtains product.Step C: with the rhodanine condensation

With rhodanine (1 equivalent), ethylenediamine-N,N'-diacetic acid(EDDA) (1 equivalent) and 2-(3,4-two chloro-benzyl sulfo groups)-pyrimidine-4-formaldehyde stirring and refluxing 1 hour in methyl alcohol.The gained precipitation is collected by filtering, with methyl alcohol, water, the sodium pyrosulfate aqueous solution and sodium bicarbonate aqueous solution washing.The solid matter dry air.Step D: two key reduction

2,6-dimethyl-1,4-dihydro-3 is under the existence of 5-pyridine carboxylic acid salt (1.1 equivalent) and activated silica gel, with 5-[2-(3,4-two chloro-benzyl sulfo groups)-Mi pyridine-4-ylmethyl]-suspension of 2-sulfo--thiazolidin-4-one in toluene is heated to 80 ℃.Wash with suspension filtered and with EtOAc.Filtrate vacuum-evaporation, gained resistates are dissolved among the EtOAc again, with 1N HCL solution washing.Organic layer Na ₂SO ₄Drying, vacuum concentration obtains crude product.Obtain pure products by flash chromatography.

MS (ESI) 415, actual measurement 414 (M-H).

Embodiment 221

Preparation 5-[3-amino-2-(2,4-two chloro-benzoyls)-thieno-[2,3-b] pyridine-6-methylene]-thiazolidine-2, the 4-diketone

Steps A: the alkylation and the cyclisation of 6-dimethoxy-methyl-2-sulfydryl-nicotinoyl nitrile

With 2,4-two bromoacetyl benzenes (3.1 equivalent) are handled with the mixture of 6-dimethoxy methyl-2-sulfydryl-nicotinoyl nitrile and salt of wormwood (1.52 equivalent), and stirring is spent the night.The product of alkylation and cyclisation is separated as solid matter.Step B: acetal go the protection

(3-amino-6-dimethoxy-methyl-thieno-[2,3-b] pyridine-2-yl)-(2,4-two chloro-the phenyl)-solution of ketone solution in the mixture of TFA and water at room temperature stirs, and shows that up to TLC reaction finishes.Reaction solution is with cold NaHCO ₃The aqueous solution neutralizes, and extracts with EtOAc.Organic layer washs with sodium chloride aqueous solution, and the vacuum lower section concentrates, and 0 ℃ of preservation is spent the night.The precipitation that collection is separated out obtains product, is pure yellow powder.Step C: with the TZD condensation

Aldehyde and TZD and piperidines are heated to 90 ℃ in ethanol, continue 3 days.With the reaction solution cooling, be poured into then in the 10%HCL aqueous solution.Obtain pure products by filtering separation, be yellow solid.MS (ESI) 449, actual measurement 448 (M-H).

Embodiment 222

Preparation 2-chloro-3-(2,4-dioxy thiazolidine-5-subunit-methyl) quinoline Steps A: with 2,4-thiazolidinedione (TZD) coupling is an aldehyde under alkaline condition

2-chloro-3-quinoline aldehyde, TZD (1.5 equivalent) and piperidines (1.5) are dissolved in the ethanol, and reflux 5 hours.The reaction mixture cool to room temperature is poured in the ethanol, adds 1N HCL, collects yellow mercury oxide, and with the ether washing for several times, dry air obtained pure products (yield is 45%) in 24 hours under the room temperature.

¹HNMR(DMSO-d ₆)δ:12.8(br?s,1H,NH),8.5(s,1H),8.2(d,1H),8.0-

7.8(m,3H),7.7(t,1H)

MS (ESI) 290, actual measurement 289 (M-H).HPLC:92% purity

Embodiment 223

Preparation 2-thiophenyl-3-(2,4-dioxy thiazolidine-5-subunit-methyl) quinoline

Steps A: 2-chloro-3-(2,4-dioxy thiazolidine-5-subunit-methyl) quinoline and thiophenol (1.2 equivalent) are mixed with ethoxy ethanol, and reflux is 2 hours under nitrogen protection.With the reaction mixture cool to room temperature, add ether, remove by filter light-yellow precipitate, to clean for several times with ether, dry air obtained pure products (yield is 36%) in 24 hours under the room temperature.

¹HNMR(DMSO-d ₆)δ(br?s,1H,NH),8.3(s,1H),8.1(d,1H),7.7(t,1H),

7.6-7.5(m,4H),7.5-7.4(m,3H)

MS (ESI) 364, actual measurement 363 (M-H).HPLC:88% purity

Embodiment 224

Preparation 2-(4-chlorobenzene sulfenyl)-3-(2,4-dioxy thiazolidine-5-subunit-methyl) quinoline Title compound is by the method preparation of embodiment 223.Yield is 69%.

¹HNMR(DMSO-d ₆)δ12.8(br?s,1H,NH),8.3(s,1H),8.00(d,2H),7.9(s,1H),7.7(t,1H),7.6-7.4(m,6H)

MS (ESI) 398, actual measurement 397 (M-H); 399 (M+H).HPLC:92% purity

Embodiment 225

Preparation 2-(3,4-dichlorobenzene sulfenyl)-3-(2,4-dioxy thiazolidine-5-subunit-methyl) quinoline

It is the solvent preparation with ethanol also that title compound adopts the method for embodiment 223.Yield is 72%.

¹HNMR(DMSO-d ₆)δ12.8(br?s,1H,NH),8.34(s,1H),8.05(d,1H,J=8),

7.87(d,1H,J=1.6),7.83(s,1H),7.71-7.53(m,6H)

MS (ESI) 433, actual measurement 431; 432; 433 (M-H) 433; 435; 436 (M+H), HPLC: pure

Degree is 96%

Embodiment 226

Preparation 2-(4-fluorobenzene sulfenyl)-3-(2,4-dioxy thiazolidine-5-subunit-methyl) quinoline

Above-claimed cpd is by the method preparation of embodiment 223, and yield is 23%.

¹HNMR (DMSO-d ₆) δ 12.6 (br s 1H, NH), 8.3 (s, 1H), 8.00 (d, 1H), 7.9 (s, 1H), 7.7-7.4 (m, 5H), 7.3 (t, 2H) MS (ESI) 382, actual measurement 381 (M-H) HPLC:100% purity

Embodiment 227

Preparation 2-(4-methylbenzene sulfenyl)-3-(2,4-dioxy thiazolidine-5-subunit-methyl) quinoline title compound adopts the method preparation of embodiment 223.Yield is 24%. ¹HNMR (DMSO-d ₆) δ 12.8 (br s, 1H, NH), 8.3 (s, 1H), 8.00 (d, 1H), 7.9 (s, 1H), 7.7 (t, 1H), 7.6-7.5 (m, 2H), 7.4 (d, 2H), 7.3 (d, 2H), 2.1 (s, 3H) MS (ESI) 378, actual measurement 377 (M-H) HPLC:86% purity

Embodiment 228

Preparation 2-(4-anisole sulfenyl)-3-(2,4-dioxy thiazolidine-5-subunit-methyl) quinoline Title compound adopts the method preparation of embodiment 223.Yield is 35%.

¹HNMR (DMSO-d ₆) δ 12.8 (br s, 1H, NH), 8.2 (s, 1H), 8.0 (d, 1H), 7.9 (s, 1H), 7.8-7.4 (m, 5H), 7.0 (d, 2H), 3.8 (s, 3H) MS (ESI) 394, actual measurement 393 (M-H) HPLC:98% purity

Embodiment 229

Preparation 2-[4-(trifluoromethyl) thiophenyl]-3-(2,4-dioxy thiazolidine-5-subunit-methyl) quinoline

Title compound adopts the method preparation of embodiment 223.Yield is 55%.

¹HNMR (DMSO-d ₆) δ 12.8 (br s, 1H, NH), 8.3 (s, 1H), 8.1 (d, 1H), 7.9 (s, 1H), 7.8-7.6 (m, 5H), 7.5 (t, 2H) MS (ESI) 432, actual measurement 431 (M-H) .HPLC:100% purity

Embodiment 230

Preparation 2-(4-chloro-phenyl-sulfinyl)-3-(2,4-dioxy thiazolidine-5-subunit-methyl) quinoline

Steps A: with the compound dissolution of embodiment 224 preparation at CH ₂Cl ₂/ CH ₃Among the OH (5: 1), in this solution, add 3-chloroperoxybenzoic acid (2 normal 77% highest purity material).Before TLC analyzes the disappearance of demonstration initial reactant, at room temperature stirred the mixture 4 hours.Reaction mixture additionally stirred 2 hours again.When reaction finished, the white crystals product was separated out.Filter and collect product, with the ether washing for several times, dry air obtained final product in 48 hours, and yield is 30%.

¹HNMR(DMSO-d ₆)δ12.8(br?s,1H,NH),8.5(s,1H),8.4(s,1H),8.2(d,

1H),8.1(d,1H),7.9(t,1H),7.7(t,1H),7.6-7.4(m.4H)

MS (ESI) 414, actual measurement 413 (M-H); 415 (M+H) .HPLC:100% purity

Reference example 1

Preparation compound 122

With the compound 5 of embodiment 5 preparation (23mg, 0.056mmol) be dissolved in dimethyl sulfoxide (DMSO) (2.0mL) and 0.04mol/L buffered soln (pH7.2) (4.1mL) in, add 2 mercapto ethanol (0.012mL, 0.17mmo1), 25 ℃ of stirrings 40 minutes.After conventional aftertreatment, resistates obtains the product of preliminary purification by the pure system of thin-layer chromatography purification (launching with chloroform/methanol=10/1).Product is further with preparation HPLC[ODS post; With acetonitrile/Sodium phosphate dibasic-potassium dihydrogen phosphate buffer solution wash-out (0.04mol/L; PH7.2)=30/70], obtain compound 122 (5.7mg, 31%).

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)3.26-3.39(m,2H),3.65-3.73(m,

2H),5.12(m,1H),7.73(d,J=8.6Hz,1H),7.82(s,1H),8.16-8.24(m,2H),

12.80(m,1H)

FABMS?m/z?325(M-H) ^-C ₁₂H ₁₀N ₂O ₅S ₂=326

Reference example 2

Preparation compound 123

With 2-fluoro-5-nitrobenzaldehyde (48mg 0.28mmol) is dissolved in N, in the dinethylformamide (2.4mL), add di-n-propyl amine (0.15mL, 1.1mmol) and salt of wormwood (0.16g, 1.1mmol), 25 ℃ of stirrings 1 hour.After conventional aftertreatment, resistates is purified (using the chloroform wash-out) with silica gel chromatography, obtains 2-(N, N-two-n-propyl amino)-5-nitrobenzaldehyde (49mg, 69%).

¹HNMR(300MHz,CDCl ₃)δ(ppm)0.89(t,J=7.6Hz,6H),1.66(tq,J=7.6,

7.6Hz,4H),3.38(m,4H),7.03(d,J=9.1Hz,1H),8.21(dd,J=9.1,2.7Hz,

1H),8.60(d,J=3.0Hz,1H),10.01(s,1H)

FABMS?m/z?251(M+H) ⁺C ₁₃H ₁₈O ₃N ₂=250

With 2-(N, N-two-n-propyl amino)-5-nitrobenzaldehyde (46mg 0.18mmol) is dissolved in the ethanol (1.8mL), adds 2, the 4-thiazolidinedione (86mg, 0.74mmol) and piperidines (0.0073mL, 0.073mmol), 80 ℃ of stirrings 6.5 hours.After conventional aftertreatment, resistates is purified by thin layer column chromatography (launching with chloroform/acetonitrile=10/1), obtains compound 123 (53mg, 82%).

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)0.81(t,J=7.3Hz,6H),1.48-

1.61(m,4H),3.21(t,J=7.2Hz,4H),7.24(d,J=9.4Hz,1H),7.62(s,1H),

8.13(m,1H),8.20(m,1H),12,63(br?s,1H)

FABMS?m/z?348(M-H) ^-C ₁₆H ₁₉O ₄N ₃S=349

Reference example 3

Preparation compound 124

With 2-fluoro-5-nitrobenzaldehyde (0.11g 0.63mmol) is dissolved in the ethanol (4.2mL), adds 2, the 4-thiazolidinedione (0.29mg, 2.5mmol) and piperidines (0.025mL, 0.25mmol), 80 ℃ of stirrings 6.5 hours.After conventional aftertreatment, resistates is purified by thin layer column chromatography (launching with chloroform/7 nitriles=10/1), obtains compound 124 (24mg, 12%).

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)1.57-1.72(m,6H),3.08-3.14(m,

4H),7.26(d,J=8.6Hz,1H),7.56(s,1H),8.20(m,1H),8.21(s,1H),

12.66(m,1H)

FABMS?m/z?332(M-H) ^-C ₁₅H ₁₅N ₃O ₄S=333

Reference example 4

Preparation compound 125

With obtainable 2-morpholino-5-nitrobenzaldehyde on the market (0.11g, 0.44mmol) (MAYBRIDGE, catalog number (Cat.No.): RHO1290) be dissolved in the ethanol (4.2mL), add 2, and the 4-thiazolidinedione (0.21mg, 1.8mmol) and piperidines (0.018mL, 0.18mmol), 80 ℃ were stirred 6 hours.Reaction soln is cooled to 25 ℃, filters and collect the crystal of separating out, obtain compound 125 (0.12g, 82%).

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)3.10-3.16(m,4H),3.73-3.80(m,

4H),7.30(m,1H),7.67(br?s,1H),8.221-8.28(m,2H),12.65(m,1H)

FABMS?m/z?334(M-H) ^-C ₁₄H ₁₃N ₃O ₅S=335

Reference example 5

Preparation compound 126

Adopt the method identical with reference example 4, by 4-hydroxyl-2-methoxybenzaldehyde (71mg, 0.47mmol), ethanol (2.8mL), 2,4-thiazolidinedione (0.22mg, 1.9mmol) and piperidines (0.019mL, 0.19mmol) preparation compound 126 (85mg, 73%).

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)3.82(s,3H),6.51(s,1H),6.53(dd,

J=11.7,2.2Hz,1H),7.25(d,J=8.5Hz,1H),7.93(s,1H),10.39(s,1H),

12.38(br?s,1H)

FABMS?m/z?250(M-H) ^-C ₁₁H ₉NO ₄S=251

Reference example 6

Preparation compound 127

Adopt the method identical with reference example 3, by the 2-trifluoro-methoxybenzaldehyde (73mg, 0.38mmol), ethanol (2.9mL), 2,4-thiazolidinedione (0.18g, 1.5mmol) and piperidines (0.015mL, 0.15mmol) preparation compound 127 (53mg, 47%).

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)7.53-7.68(m,4H),7.80(s,1H)

FABMS?m/z?288(M-H) ^-C ₁₁H ₆ ¹⁹NO ₃S=289

Reference example 7

Preparation compound 128

Adopt the method identical, by the 10-[(4-chloro-phenyl-with reference example 4) sulfenyl] anthracene-9-formaldehyde (0.13mg, 0.38mmol), ethanol (5.4mL), 2,4-thiazolidinedione (0.18g, 1.5mmol) and piperidines (0.015mL, 0.15mmol) preparation compound 128 (34mg, 20%).

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)6.92(d,J=8.6Hz,2H),7.25(d,

J=8.4Hz,2H),7.64-7.77(m,4H),8.18(d,J=7.9Hz,2H),8.65(2,1H),

8.78(d,J=8.1Hz,2H),12.68(m,1H)

FABMS?m/z?446(M-H) ^-C ₂₄H ₁₄ ³⁵ClNO ₂S ₂=447

Reference example 8

Preparation compound 171

In the 2-naphthyl mercaptan, add the 2.5mol/L aqueous sodium hydroxide solution (2.1mL, 5.2mmol) and Tetrabutyl amonium bromide (0.020g, 0.0061mmol), subsequently 25 ℃ of stirrings 15 minutes.(0.21g, toluene 1.2mmol) (2.1mL) solution stirred 3.5 hours at 110 ℃ subsequently to add 2-fluoro-5-nitrobenzaldehyde in reaction soln.After conventional aftertreatment, obtain 2-[(2-formyl radical-4-nitrophenyl) sulfenyl] naphthalene.With 2-[(2-formyl radical-4-nitrophenyl) sulfenyl] naphthalene (0.3g; 0.98mmol) be dissolved in the toluene (15mL); add 2; 4-thiazolidinedione (0.46g; 3.9mmol), piperidines (0.039mL; 0.39mmol), (0.022mL, 0.039mmol) and molecular sieve 4A (1.5g), 110 ℃ were stirred 2.5 hours acetate.After conventional aftertreatment, product obtains compound 171 (0.13g, yield is 33%) with the ethanol development.

2-[(2-formyl radical-4-nitrophenyl) sulfenyl] naphthalene:

¹HNMR(300MHz,CDCl ₃)δ(ppm)6.99(d,J=8.8Hz,1H),7.52(dd,J=8.4,1.7Hz,1H),7.56-7.68(m,2H),7.85-7.98(m,3H),8.05(dd,J=2.4,8.8Hz,1H),8.15(s,1H),8.68(d,J=2.4Hz,1H),10.33(s,1H)

FABMS?m/z?310(M+H) ⁺C ₁₇H ₁₁NO ₃S=309

Compound 171:

¹HNMR(300MHz,DMSO-d ₆)δ(ppm)7.19(d,J=8.8Hz,1H),7.57(br?d,J=8.5Hz,1H),7.59-7.68(m,2H),7.95(s,1H),7.97-8.04(m,2H),8.08(d,J=8.8Hz,1H),8.13(dd,J=8.4,1.8Hz,1H),8.28(br?s,2H),12.82(m,1H)

FABMS?m/z?407(M-H) ⁺C ₂₀H ₁₂N ₂O ₄S ₂=464

Embodiment 231

The pure extracting solution that preparation has avidity

The extracting solution that is used to screen telomerase inhibitor prepares from 293 cells of the albumen catalytic subunit (hTERT) of overexpression Telomerase usually.These cell telomerase activations than 293 big 2-5 of cell telomerase activation of parent doubly.200ml piles up cell (obtaining) resuspending in isopyknic isotonic buffer solution (10mM Hepes pH7.9,1mM MgCl from about 100 liters of cultures ₂, lmM DTT, 20mM KCL, 1mM PMSF) in, with the dissolving of dounce homogenizer.Glycerol concentration adjustment to 10% slowly adds NaCl solution, makes ultimate density become 0.3M.The dissolved cell stirred 30 minutes, under 100000xg centrifugal 1 hour.In the S100 supernatant liquor, add solid ammonium sulfate and reach 42% saturation concentration.Material is carried out centrifugal treating, and the throw out resuspending is in 1/5 capacity of original solution, with respect to dialysis in the buffered soln that contains 50mM NaCl " A ".After the dialysis, extracting solution under 25000xg centrifugal 30 minutes.Before affinity chromatography, add trotyl X-100 (0.5%), KCL (0.3M) and tRNA (50 μ g/ml).In extracting solution, add few affinant (affinity oligo) (5 ' vitamin H TEG-vitamin H TEG-vitamin H TEG-GTAGAC CTG TTA CCA guu agg guu ag3 '; Represent 2 ' O-methyl ribonucleotides under the situation of rudimentary affinant, represent deoxyribonucleotide under the situation of senior affinant) (the per 10 milliliters of extracting solutions of 1nmol).After cultivating 10 minutes under 30 ℃, add Nneutravidin globule (Pierce; 50% suspension of 250 μ l), mixture spends the night 4 ℃ of stirrings.Bead precipitation is with damping fluid " B " washing that contains 0.3M KCL three times, with damping fluid " B " washed twice that contains 0.6M KCL, with the damping fluid " B " that contains 0.3M KCL washed twice again.Telomerase the alternative few affinant that contains 0.3M KCl, 0.15% trotyl X-100 and 2.5 molar excess (5 '-CTAACC CTA ACT GGT AAC AGG TCT AC-3 ', be the Neutravidin globule that the per 125 μ l of 0.5ml pile up) damping fluid " B " under room temperature wash-out 30 minutes.Carry out wash-out and elutriant and elutriant for the first time the merged second time.The every μ l of the common tool per minute of the extracting solution extracting solution of purifying has the 10fmol specific activity of bonded Nucleotide, or every milligram of total protein of per minute 200 Nucleotide.

Damping fluid " A "	Damping fluid " B "
		????20mM?Hepes?pH7.9	????20mM?Hepes?pH7.9
??????1mM?MgCl 2	????????1mM?EDTA
		???????1mM?DTT	????????1mM?DTT
???????1mM?EGTA	10% glycerine
		10% glycerine	???????0.5?Triton

Embodiment 232

The mensuration of Telomerase specific activity

Set up 3 independently 100 μ l Telomerase analyses with following buffered soln: 50mM Tris-acetate, pH8.2,1mM DTT, 1mM EGTA, 1mM MgCl ₂, 100mM potassium acetate, 500 μ M dATP, 500 μ M TTP, 10 μ M ³²P-dGTP (25Ci/mmol) and a00 nMd (TTAGGG) ₃Add the Telomerase (referring to embodiment 231) of the affine purification of 2.5,5 or 10 μ l respectively to each reaction solution, reactant is 37 ℃ of cultivations.At 45 and 90 minutes, remove 40 μ l five equilibriums from each reaction, add 160 μ l and stop buffered soln (100mM NaCl, 10mM trisodium phosphate, 0.2%SDS, 2mM EDTA, 100 μ g/ml tRNA).Add 10 μ l trichoroacetic acid(TCA)s (TCA) (100%), sample was cultivated on ice 30 minutes.Sample descended centrifugal 15 minutes in little centrifugal (12000xg power).Precipitation 1ml95% washing with alcohol was descended centrifugal 5 minutes in little centrifugal (12000xg power) again.Be deposited in 50 μ l dH ₂Resuspending among the O is transferred in 12 * 75 glass test tubees of the ice-cold solution that contains 2.5ml5%TCA and 10mM trisodium phosphate.Sample was cultivated on ice 30 minutes.Sample is in the vacuum filtration pipe, by the wet (dH of 2.5cm ₂O) GFC film (S﹠amp; S) filter.Filtrate with the ice-cold 1%TCA washing of 5ml 3 times, is used 5ml95% washing with alcohol 1 time under vacuum.Filtrate is dried, and uses scintillating liquid and counts at scintillometer.The fmol of bonded Nucleotide is by the concrete determination of activity of radiotracer.The activity of extracting solution is a basic calculation with bonded dNTP, represents with fmol dNTP/min/ μ l extracting solution.

Embodiment 233

Telomerase activation test b io-Tel flicker is coated with layer analysis

Join biotinylation Telomerase substrate primer--the reaction of telomerase catalytic by measuring TTAGGG Telomerase repeated fragment, a kind of detection and/or the active method of measuring junction granzyme are provided.Biotinylated product obtains in the microtiter plate of streptavidin bag quilt.As described below, few riboprobe supply and be marked with [ ³³P] 3.5 Telomerases repeat to be used to detecting end granzyme product.Unconjugated probe is removed by washing, and the quantity that is used for the probe of thermal treatment Telomerase product is measured by the flicker numeration.Method:

1. compound stores to concentrate stock liquid, and is dissolved in 100% dimethyl sulfoxide (DMSO) (DMSO).

2. in order to test, compound dilutes in 50%DMSO for 15X work stock liquid, and 2 μ l are assigned in two 96-hole droplet price fixings (double analysis).

3. to be diluted to specific activity be the unconjugated dNTP/ per minute of 0.04-0.09fmol/every μ l Telomerase damping fluid to the Telomerase extracting solution, and the diluent of 18 these extracting solutions of μ l is added in each sample well, at room temperature cultivated 30 minutes with compound is pre-.

4. the Telomerase reaction causes by add 10 μ lMaster Mix in the hole of containing Telomerase extract and compound.These dishes are sealed, cultivate 90 minutes at 37 ℃.

5. reaction stops by adding 10 μ l HCS.

6.25 μ l reaction mixture moves into the scintillating disc (NEN) of the mould avidin bag of 96-pore chain quilt, cultivates 2 hours under the room temperature gentle agitation.

7. each hole does not have the 2X SSC that cultivates to wash 3 times with 180 μ l.

8. the quantity that is used for the probe of the biotinylated Telomerase product of thermal treatment is measured by the flicker numeration.Damping fluid: Telomerase dilution buffer liquid

50mM Tris-acetate, pH8.2

1mM?DTT

1mM?EGTA

1mM?MgCl ₂

830nM?BSAMaster?Mix(MM)

50mM Tris-acetate, pH8.2

1mM?DTT

1mM?EGTA

1mM?MgCl ₂

The 150mM potassium acetate

10μM?dATP

20μM?dGTP

120μM?dTTP

100nM biotinylation primer (5 '-vitamin H-AATCCGTCGAGCAGAGTT-3 ')

5.4nM the probe of mark [5 '-CCCTAACCCTAACCCTAACCC-( ³³P) A _1-50-3 ']; Specific activity is about 10 ⁹Cpm/ μ g or higher hydridization are captured solution (HCS)

12X SSC (1X=150mM NaCl/30mM trisodium citrate)

40mM?EDTA

40mM?Tris-HCl,pH7.0

Use above-mentioned detection method, detected result shows the Telomerase IC of the compound of embodiment 1-29 ₅₀Be lower than 100 μ M.

Embodiment 234

Anti-tumor activity Exvivo research

A. telomere length shortens in the tumour cell

The method of application standard and material are organized (as normal people BJ cell) in contrast with normal cell, the colony of preparation tumor cell line, for example ovarian cancer cell line OVCAR-5 and SK-OV-3.In a test, by inoculation about 10 in each 15cm dish ⁶The described colony of individual cell preparation.By cultivating, can make the cell colony in these dishes develop into 80% fusion, be divided into 2 group with each colony this moment.After division, coating, wherein one group of The compounds of this invention with the subacute dosage of predetermined concentration was handled (for example between about 5 μ M and 20 μ M) 4-8 hour; Another group is control group (for example DMSO).

Every group is continued division, and all groups are divided equally (near merging) once more then.The cell of inoculating same quantity is so that its continued growth.Every four days, in sample, add compound or contrast with the concentration of initial adding.The cell that keeps is used for carrying out the analysis of Telomerase length.When undeterminate cell cultures merges to approaching, sample divides according to described once more.This a series of cells multiplication and division continue about 20-25 multiplication.Therefore, can obtain the funtcional relationship of Telomerase length and cell multiplication.

Telomerase length is measured by the DNA (TRF analysis) with the restriction enzyme peptic cell, and these enzymes are at removing repeated T in the human telomerase ₂AG ₃Sequence beyond the sequence.The DNA that is digested separates by size with the standard gel electrophoretic technique, to measure the length of Telomerase repeated fragment.After surveying with the Telomerase dna probe, the Telomerase repeated fragment in gel as the coating (approximately 2Kb-15Kb) of high-molecular-weight DNA.

The analytical results of telomere length will show the function as the multiplication of gradual cell, the not influence of speed that The compounds of this invention shortens for the length of control cells Telomerase.But, handle tumor cell line with The compounds of this invention, can measure shortening of telomere length.Keeping stable telomere length with the tumour cell that contrast is handled.Therefore, as the function of tumour cell division, compound of the present invention has restitution to normal shortening of Telomerase enzyme length.

In another experiment, use aforesaid method, extremely The compounds of this invention and the contrast of about 20 μ M are handled the HEK-293 cell at 1 μ M with concentration.In the coming weeks of administration test compounds of the present invention, cell enters crisis (being stopping of cell function).In addition, the application standard method, cell TRF analyzes and has shown that test compounds of the present invention is effective for the length that shortens Telomerase.Except above-mentioned HEK-293 cell, this analysis can be used for any Telomerase-positive cell line, for example the HeLa cell.

B. specificity

The method of compound application standard of the present invention filter out anti-Telomerase and have nucleic acid in conjunction with or other enzyme of repairing activity arranged for Telomerase.Screened enzyme comprises Telomerase, archaeal dna polymerase I, HeLa RNA polymerase II, T3 RNA polymerase, MMLV ThermoScript II, topoisomerase I, type, terminal enzyme (DNA) and single-stranded DNA binding protein (SSB).The compounds of this invention to the specificity of Telomerase by this compound relatively to the IC of Telomerase ₅₀Value and to the IC of other every kind screened enzyme ₅₀Value is measured.If IC to Telomerase ₅₀The IC of other every kind screened enzyme of value comparison ₅₀Be worth lowly, then this compound has high degree of specificity to Telomerase.

Another kind method is that the inhibition of telomerase of The compounds of this invention can be measured according to currently known methods (United States Patent (USP) 5,760,062).That is, the dimethyl sulfoxide (DMSO) of every kind of medicament (DMSO) solution mixes with the Telomerase of not exclusively purifying from the nuclear extracting solution of HEK293 cell, and is used as the oligodeoxynucleotide and the triphosphate deoxy-nucleotide processing of substrate.The reaction product that obtains (DNA with telomeric sequence) is absorbed on cytolemma, uses the oligodeoxynucleotide probe of supplying telomeric sequence that has that is labeled and carries out hydridization.The ratio that suppresses so that medicament to be arranged on cytolemma the signal of mark calculate with the ratio of the signal of no medicament (contrast) tense marker.Simultaneously, every kind is that the basis suppresses the drug concentration of 50% enzymic activity as IC with the contrast ₅₀Value is used.Table 7 is that selected compound suppresses active measurement result.

Table 7: external inhibition of telomerase

Compound	???IC 50μM
		?????1	????21
?????4	????30
		?????5	????23
?????9	????8.3
		?????12	????5.8
?????13	????5.9
		?????14	????4.0
?????16	????26
		?????17	????10
?????18	????11
		?????19	????70
?????20	????9.0
		?????21	????4.3
?????23	????14
		?????24	????5.3
?????25	????4.2
		?????26	????4.2
?????31	????15
		?????32	????21
?????33	????5.5

???35	????3.9
		???36	????5.1
???37	????6.0
		???43	????2.6
???44	????1.9
		???47	????4.1
???48	????1.6
		???49	????4.4
???53	????0.77
		???54	????7.4
???55	????5.3
		???56	????7.9
???57	????5.4
		???58	???(56％)
???59	????2.1
		???60	????4.5
???61	????0.33
		???62	????7.8
???63	????6.5
		???64	????9.7
???65	????6.2
		???66	????3.7
???67	????1.0
		???68	????2.7
???69	????0.48
		???70	????4.8
???71	????2.7
		???72	????4.3
???73	????7.0
		???74	????3.7

???76	????3.9
		???78	????5.5
???79	????3.5
		???80	????5.5
???82	???(51％)
		???83	???(58％)
???84	????3.9
		???86	????8.0
???87	????6.9
		???89	???(56％)
???90	????3.7
		???91	???(61％)
???92	????5.6
		???93	???(55％)
???94	????7.8
		???96	???(62％)
???97	????5.6
		???99	????6.9
???100	????4.4
		???101	???(62％)
???104	???(61％)
		???106	????4.5
???108	????6.2
		???110	???(53％)
???113	???(68％)
		???115	????2.7
???120	????9.3
		???121	????4.0
???122	????7.7

?????123	????6.9
		?????124	???(54％)
?????125	????1.6
		?????126	????1.3
?????127	????5.7
		?????128	????2.6
?????129	????8.1
		?????132	????2.6
?????133	????9.1
		?????134	???(59％)
?????135	????4.5
		?????137	????5.5
?????138	????4.3
		?????139	????4.4
?????141	???(64％)
		?????143	???(62％)
?????153	???(53％)
		?????171	????7.2
Troglitazone	????16
		Pioglitazone	????83

Data in the bracket are the residual activity of compound concentration external Telomerase when being 10 μ M.

C. cytotoxicity

Carrying out Cytotoxic XTT with the HeLa cell analyzes.At 1 μ M to 1, handled 72 hours by the The compounds of this invention of 000 μ M with concentration for the clone of using in analysis.In this section period, the optical density(OD) of sample (OD) is measured under 540 nanometers (nm).There is not remarkable cytotoxicity influence under less than 5 μ M in concentration.Except the control cells system BJ cell as the normal people, other tumor cell lines for example uterus tumor clone OVCAR-5 and SK-OV-3 can be used for measuring cytotoxicity.Other for Cytotoxic analytical procedure for example MTT analyze (referring to people such as Berridge, 1996, biological chemistry 4:14-19) and alarmBlue ^TMAnalyzing (United States Patent (USP) 5,501,959) can well be used.

Some compound may cause G2 to suppress when being higher than 5 μ M (for example in 10-20 μ M concentration or higher).Preferably, the influence that the observation compound suppresses Telomerase under the cytotoxicity level should be lower than.Yet, because the chemotherapeutic validity of many cancers comes from Cytotoxic influence, within the scope of the invention, The compounds of this invention with any with the effective dosed administration of chemotherapy.In vitro study

But the heteroplastic transplantation model of application standard technology and material construction human tumor cells is wherein implanted nude mice with the OVCAR-5 cell.Mouse is divided into two groups.Wherein one group is carried out intraperitoneal with compound of the present invention and handles.Another group is handled with containing DMSO or ethanol, emulphor (oil) and phosphate buffer solution (PBS).After carrying out xenotransplantation with standard method, the average tumor of periodically measuring every group of mouse is heavy.

In the group with the The compounds of this invention processing, average tumor can increase after focusing on initial processing for some time, and after this, tumour is heavily stable to begin to descend then.By research, the tumour in the control group can increase.Therefore, compound expectation of the present invention can significantly slow down tumor propagation speed and finally cause tumour to reduce and the disappearance of tumour.

In another experiment, every kind of medicament is that ACHN contacts 3 days with people's kidney tumor cell, then by the activity of known method (United States Patent (USP) 5,629,154) preparation cell extract with the measurement enzyme.That is to say, prepare cell extract with the buffered soln that comprises 0.5%CHAPS.Use extracting solution, TRAP (telomere repetition amplification method) analyzes at the external (TRAP that carries out _EZE ^TMELISA Telomerase activity test kit is made by Intergen).The activity of the cell extract enzyme of calculating after chemicals treatment and the active ratio of undressed cell extract enzyme.The results are shown in the table 8.

Table 8: inhibition of telomerase in the body

Compound	Concentration (μ M)	Residual enzyme activity (%)
			????1	??????30	???????11
????3	??????100	????????0
			????4	??????10	???????16
????5	??????10	???????16
			????11	??????100	???????50
????12	??????100	???????26
			????14	??????100	???????47
????16	??????100	????????0
			????21	??????30	???????35
????22	??????100	???????33
			????37	??????30	???????39
????38	??????30	???????36
			????54	??????30	???????50
????56	??????30	???????26
			????57	??????30	???????24
????66	??????30	????????0
			????68	??????10	???????18
????69	??????10	???????16
			????78	??????10	???????25
????82	???????3	???????23
			????83	??????10	???????32
????86	??????10	???????44
			????89	??????30	????????2
????92	??????30	???????41

???97	???30	???41
			??113	???30	???37
??120	???10	???40
			??133	???10	???11
??134	???10	????4
			??135	????3	???14
??141	???30	???26
			??143	???30	???36

Therefore, the invention provides the inhibition telomerase activation and have new compound, pharmaceutical composition and method, the especially cancer of the morbid state of harmful effect therein with the treatment telomerase activation.Compound of the present invention provides a kind of has high selectivity and effective methods of treatment for malignant cell, and these cells need telomerase activation to keep not dead; But this treatment does not influence non-malignant cell.

Although the preferred embodiments of the invention are illustrated and describe, it should be understood that do not breaking away under the spirit and scope of the present invention, can carry out various changes to the present invention.

Claims (49)

1, a kind of composition that suppresses Telomerase, it comprises and has 2, and 4-dioxy thiazolidine or 4-oxo-2-sulfo--thiazolidine skeleton also has the compound of inhibition of telomerase.

2, according to the composition of claim 1, wherein said compound has 2,4-dioxy thiazolidine skeleton.

3, according to the composition of claim 1, wherein said compound has 4-oxo-2-sulfo--thiazolidine skeleton.

4, a kind of anti-tumor compositions, it comprises having 2,4-dioxy thiazolidine or 4-oxo-2-sulfo--thiazolidine skeleton also has the compound that suppresses telomerase activation.

5, according to the composition of claim 4, wherein said compound has 2,4-dioxy thiazolidine skeleton.

6, according to the composition of claim 4, wherein said compound has 4-oxo-2-sulfo--thiazolidine skeleton.

7, a kind of composition that suppresses Telomerase comprises the compound or the acceptable salt of its medicine of formula I:

Wherein X is O or S; Be singly-bound or two key; A is aryl or heteroaryl; R ₁Be hydrogen or low alkyl group; R ₂, R ₃And R ₄From following group, select independently: hydrogen, halogen, alkyl, aryl, hydroxyl, alkoxyl group, aryloxy, aralkoxy, cyano group, nitro, the alkyl urea groups, the aromatic base urea groups, the dialkyl group urea groups, the diaryl urea groups, the alkylaryl urea groups, the alkyl sulfide urea groups, the aryl thiourea base, the dialkyl thiourea base, the diaryl thioureido, the alkylaryl thioureido, amino, alkylamino, arylamino, dialkyl amido, ammonia diaryl base, aryl-alkyl amino, aminocarboxyl, alkyl amino-carbonyl, aromatic yl aminocarbonyl, dialkyl amino carbonyl, the ammonia diaryl base carbonyl, the aryl-alkyl amino carbonyl, alkane carbonyl oxygen base, virtue carbonyl oxygen base, carboxyl, alkoxy carbonyl, aryloxycarbonyl, sulfo group, the alkane sulfonamido, the aryl-sulphonamidic base, alkyl sulphonyl, aryl sulfonyl, the alkyl sulfinyl, aryl sulfinyl and heteroaryl; L is a direct key or a linking group, and it has 1-3 atom, and is independently selected from carbon, nitrogen, oxygen or sulphur in non-replacement or replacement; And n equals 1 or 2.

8, according to the composition of claim 7, wherein X is O.

9, according to the composition of claim 7, wherein

It is a singly-bound.

10, according to the composition of claim 7, wherein

It is a two key.

11, according to the composition of claim 7, R wherein ₁Be hydrogen.

12, according to the composition of claim 7, wherein A is an aryl.

13, according to the composition of claim 12, wherein aryl is selected from following group: phenyl, xenyl, naphthyl and anthryl.

14, according to the composition of claim 13, wherein compound is the compound or the acceptable salt of its medicine of formula II:

Wherein X, R ₂, R ₃, R ₄, L and n as above limit.

15, according to the composition of claim 13, wherein X is O, R ₁Be H, A is an anthryl, and L is S, R ₃Be the 4-halogen, R ₄Be H, and n is 1.

16, according to the composition of claim 7, wherein A is a heteroaryl.

17, according to the composition of claim 16, wherein heteroaryl is selected from following group: pyridine, quinoline, isoquinoline 99.9, thiophene, furans, imidazoles, benzoglyoxaline and pyrazoles.

18, according to the composition of claim 17, wherein compound is the compound or the acceptable salt of its medicine of formula III:

Wherein X, R ₁, R ₂, R ₃And R ₄As above limit with L.

19, according to the composition of claim 7, R wherein ₃And R ₄It is halogen.

20, according to the composition of claim 7, wherein n is 1 and R ₂Not hydrogen.

21, according to the composition of claim 7, wherein said compound is selected from following group:

5-(2-(3, the 4-dichlorophenyl) benzylidyne) thiazolidine-2, the 4-diketone,

5-(3-(3, the 4-dichlorophenyl) benzylidyne) thiazolidine-2, the 4-diketone,

5-(4-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2, the 4-diketone,

5-(2-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2, the 4-diketone,

5-(4-(3,4-dichloro-benzoyl amino) benzylidyne) thiazolidine-2, the 4-diketone,

5-(4-(N-3,4-dichlorophenyl urea groups) benzylidyne) thiazolidine-2, the 4-diketone,

5-(2-(N-3,4-dichlorophenyl urea groups) benzylidyne) thiazolidine-2, the 4-diketone,

5-(2-(N-3,4-dichlorophenyl carbamyl) benzylidyne) thiazolidine-2, the 4-diketone,

5-(3-(N-3,4-dichlorophenyl carbamyl) benzylidyne) thiazolidine-2, the 4-diketone,

5-(4-(N-3,4-dichlorophenyl carbamyl) benzylidyne) thiazolidine-2, the 4-diketone,

5-(4-(N-3,4-dichlorophenyl carbamoyloxy group) benzylidyne) thiazolidine-2, the 4-diketone,

5-(4-(3,4-dichlorophenoxy carbonyl) benzylidyne) thiazolidine-2, the 4-diketone,

5-(2-(3,4-dichlorophenoxy carbonyl) benzylidyne) thiazolidine-2, the 4-diketone,

5-(2-(3,4-dichlorophenylacetic acid base) benzylidyne) thiazolidine-2, the 4-diketone,

5-(3-(3,4-dichlorophenylacetic acid base) benzylidyne) thiazolidine-2, the 4-diketone,

5-(4-(3,4-dichlorophenylacetic acid base) benzylidyne) thiazolidine-2, the 4-diketone,

5-(2-(3,4-dichlorobenzoic acid base) benzylidyne) thiazolidine-2, the 4-diketone,

5-(3-(3,4-dichlorobenzoic acid base) benzylidyne) thiazolidine-2, the 4-diketone,

5-(4-(3,4-dichlorobenzoic acid base) benzylidyne) thiazolidine-2, the 4-diketone,

5-(3,4-two-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2, the 4-diketone,

5-(2-(3, the 4-dichlorophenoxy) benzylidyne) thiazolidine-2, the 4-diketone,

5-(4-(3, the 4-dichlorophenoxy) benzylidyne) thiazolidine-2, the 4-diketone,

5-(2,5-two-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2, the 4-diketone,

5-(2,4-two-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2, the 4-diketone,

5-(2-(3,4-benzyl dichloride sulfenyl)-3H-pyrimidin-4-one-6-base methyne) rhodanine,

5-(2-(3,4-benzyl dichloride sulfenyl) pyrimidine-4-base methyne) rhodanine,

5-(2-(3,4-benzyl dichloride sulfenyl) pyrimidine-4-base methyne) rhodanine,

5-(3-cyano group-2-(3,4-benzyl dichloride sulfenyl) pyridine-6-base methyne) thiazolidine-2, the 4-diketone,

5-(3-(3, the 4-dichloro-benzyloxy) benzylidyne) thiazolidine-2, the 4-diketone,

And acceptable salt on their pharmacology.

22, a kind of pharmaceutical composition that suppresses Telomerase, it comprises the compound or the acceptable salt of its medicine of formula IV: Wherein X is O or S;

Be a singly-bound or two key; R ₅Be H or low alkyl group; And Ar is aryl, heteroaryl, aralkyl, heteroaralkyl, aromatic yl alkenyl, heteroaryl alkenyl, aromatic yl polysulfide yl or the heteroaryl alkynyl of replacement or non-replacement.

23, according to the composition of claim 22, wherein

It is a two key.

24, a kind of pharmaceutical composition that suppresses Telomerase, it comprises the compound or the acceptable salt of its medicine of formula (V):

Wherein X is S or O; W be CH=CH, S or-N=C-; R ₆Be H or low alkyl group; R ₇Be OH, halogen, sulfydryl, nitro, cyano group, lower alkylthio, low alkyl group, lower alkoxy, lower alkanoyloxy, NR ₁₁R ₁₂(R wherein ₁₁And R ₁₂Be independently selected from following group: hydrogen, low alkyl group, low-grade alkane acidyl, aryl, heteroaryl, heteroaralkyl, or R ₁₁And R ₁₂Form to replace or non-substituted heterocycle), CO ₂R ₁₃(R wherein ₁₃Be selected from following group: hydrogen, low alkyl group, aralkyl and heteroaralkyl), CONR ₁₁R ₁₂, replacement or non-replacement aryl, replacement or non-substituted heteroaryl, aryloxy, heteroaryloxy, aralkoxy, assorted aralkoxy, low-grade alkane acidyl, aroyl, low-grade alkenyl, arylthio or low-grade alkynyl; And when W represents S, R ₇Also can be hydrogen; L is O, S, SO, SO ₂, OCH ₂, SCH ₂, SOCH ₂, SO ₂CH ₂Or N (R ₁₀) (CH ₂) _m(R wherein ₁₀Be to replace or non-substituted aryl, heteroaryl, aralkyl or heteroaralkyl, m is 0 or 1), (CH ₂) N (R ₁₀) (CH ₂) _mOr CR ₁₃R ₁₄(R wherein ₁₃And R ₁₄Be independently selected from hydrogen, hydroxyl, aryl and heteroaryl); And A ₁Be cycloalkyl with following formula (A1): Z wherein ₁To Z ₅Be independently selected from following group: hydrogen, low alkyl group, low-grade alkenyl, lower alkanoyloxy, sulfydryl, alkylthio, NR ₁₁R ₁₂, nitro, cyano group, CO ₂R ₁₃, CONR ₁₁R ₁₂, aryl, heteroaryl, aryloxy, heteroaryloxy, aralkoxy, assorted aralkoxy, halogen and low-grade alkane acidyl, condition is when W is CH=CH, A also can be a pyridyl.

25, according to the composition of claim 24, wherein W is S.

26, according to the composition of claim 24, wherein W is CH=CH.

27, according to the composition of claim 24, wherein L is OCH ₂

28, according to the composition of claim 24, wherein L is N (R ₁₀) (CH ₂).

29, according to the composition of claim 24, wherein L is S.

30, according to the composition of claim 24, wherein L is SO.

31, according to the composition of claim 24, wherein L is SO ₂

32, according to the composition of claim 26, wherein L is SO.

33, according to the composition of claim 26, wherein L is SO ₂

34, according to the composition of claim 24, R wherein ₇It is nitro.

35, according to the composition of claim 24, A wherein ₁It is the 4-aminomethyl phenyl.

36, according to the composition of claim 26, A wherein ₁It is the 4-aminomethyl phenyl.

37, a kind of method that suppresses Telomerase, it comprises makes the Telomerase contact as the described composition of each claim among the claim 1-35.

38, a kind of method that suppresses Telomerase positive cell propagation, it comprises makes the described composition of each claim among cells contacting such as the claim 1-35.

39, according to the method for claim 38, wherein said cell is mammiferous cell.

40, according to the method for claim 39, wherein said cell is people's a cell.

41, according to the method in the claim 40, wherein said cell is a cancer cells.

42, a kind of method for the treatment of tumour, it comprises makes the tumour contact as the described composition of each claim among the claim 1-35.

43, a kind of pharmaceutical composition, it comprise medicine effective quantity as described compound of each claim and medicine acceptable carrier among the claim 1-35.

44, the application of the described composition of each claim aspect the inhibition telomerase activation among the claim 1-35.

45, the application of the described composition of each claim aspect inhibition Telomerase positive cell propagation among the claim 1-35.

46, the application of the described composition of each claim aspect the medicine of preparation inhibition telomerase activation among the claim 1-35.

47, the application aspect the medicine of the telomerase activation of the described composition of each claim in preparation inhibition cell among the claim 1-35.

48, according to the medicine of claim 47, wherein said disease is a cancer.

49, the application aspect the medicine of the telomerase activation of the described composition of each claim in preparation inhibition cell among the claim 1-35.