CN1064359C

CN1064359C - Diindole heterocyclic compounds, preparing method and use thereof

Info

Publication number: CN1064359C
Application number: CN98122896A
Authority: CN
Inventors: 姜标; 谷晓辉
Original assignee: Shanghai Institute of Organic Chemistry of CAS
Current assignee: Shanghai Institute of Organic Chemistry of CAS
Priority date: 1998-12-30
Filing date: 1998-12-30
Publication date: 2001-04-11
Anticipated expiration: 2018-12-30
Also published as: CN1224015A

Abstract

The present invention relates to a diindole heterocyclic compound, a preparation method and an antiinflammatory and antineoplastic medicament thereof. The compound has a molecular formula (1), wherein in a molecular formula (2) and a molecular formula (3), R< 1 >, R< 2 >, R< 3 > or R< 4 >=H, X, R< 8 >, CF3, CN, NO2, OR< 8 > and CO2 R< 8 > in a molecular formula (4), benzimidazolyl, benzofuranyl, thianaphthene radical, NHCO2 R< 8 > and NHSO2 R< 8 > in a molecular formula (6), a molecular formula (7) and a molecular formula (5); R< 5 > or R< 6 >=H, CH3, SO2 R< 10 > or COR< 8 > in a molecular formula (8) and a molecular formula (9); R< 7 >=H, CH3, SO2R< 10 >, CO2R< 8 > and C6H5 in a molecular formula (10). R< 8 >=H, C[1-5], un-substituted or substituted phenyl and benzyl; R< 9 >=H, X, CH3, CF3 or CO 2 R< 8 >; R< 10 >=R< 8 > or C6H4CH3, X=F or Cl or Br or I, and R=H or R< 8 >.

Description

Two indoles heterogeneous ring compounds, preparation method and its usage

The present invention relates to a class nitrogen-containing heterocycle compound, bionical two indoles heterogeneous ring compounds of a class specifically, as two indole thiazole compounds, two indoles pyrazine compounds, two indoles pyrazino ketone compounds and two indoles oxazoline compounds etc.To be that starting raw material is synthetic by benzazolyl compounds form in system.Compound of the present invention has multiple physiologically active, is a class potential medicine.

Over past ten years, scientists is separated to a series of bisindole alkaloids successively from the deep water sponge, as two indoles imidazoles topsentins (bartiK, K.etal, Can.J.Chem., 1987,65,2118-2121; Mc Connell, O.J.etal, U.S.P.5,290,777,1994), two indoles piperazine dragmacidins (Mc Connell, O.J.etal, J.Org.Chem., 1988,53,3116-3118; U.S.P.5,464,835,1995), nortopsentins (Sakemi, S.etal, J.Org.Chem., 1991,556,4304-4307; Capon, R.J.etal, J.Nat.Prod., 1998,61,660-662), Hamacanthins (Gunasekera, S.P.etal, J.Nat.Prod., 1994,57,1437-1441) wait alkaloid, that these marine natural products have is antibiotic, antiviral, anti-inflammatory, multiple physiologically active such as anticancer.Because the above-claimed cpd structure is special, content is extremely low in the marine organisms, and therefore, people are lead compound with this class double-indole Alkaloid, and its structure is transformed, and new medicine is sought in attempt.But because the complicacy of this compounds structure and the singularity of chemical property bring difficulty for complete synthesis work, report is very few so far.People such as Braekman were from the 3-acetyl indole in 1987, synthesized deoxytopsentin (Bull.Soc.Chim.Belg. through three-step reaction with 8.2% total recovery, 1987,96,809-812), people such as Rinehart comprise the mixture (J.Org.Chem. of the multiple cyclisation product of topsentin by two molecule 3-glyoxylyl indole derivativeses and ammonia condensation acquisition, 1998,53,5446-5453), S.Achab has synthesized topsentin first simultaneously by the catalytic three groups of coupling methods of palladium, deoxytopsentin and bromotopsentin (Tetrahedron Lett., 1996,37,5503-5506).1994, people such as M.P.Cava are with 1,4-lupetazin-2, the 5-diketone is a starting raw material, nucleophilic substitution and boron hydrogen reduction three-step reaction through bromination, indoles have synthesized better simply, symmetric (±)-dragmacidin B (Tetrahedron Lett., 1994,35,371-374), in the same year, people such as Jiang Biao are committed step with the Strecker reaction of 6-bromo indole-3-formaldehyde, finished the complete synthesis (J.Org.Chem. of (±)-Dragmacidin dexterously, 1994,59,6823-6827).People such as Ohta carry out continuous arylation by catalytic to imidazole ring 2,4 or 2,5 of palladium, have synthesized nortopsentins A-D first with better productive rate, (Chem.Phan.Bull.1996,44,1831-39.So far, the complete synthesis work of ocean bisindole alkaloid still is in the starting stage, but is just becoming the popular research topic of organic chemist and Pharmaceutical Chemist.

The object of the invention provides a class double-indole heterogeneous ring compound.

Another purpose of the present invention provides the method for the two indoles heterogeneous ring compounds of preparation.

The object of the invention also provides the purposes of this pair of indoles heterogeneous ring compound of the present invention.

The two compounds of two indoles that a class double-indole heterogeneous ring compound provided by the invention is a kind of and thiazole, oxazole, pyrazine, pyrazine-heterocycles such as 2-ketone are connected.

Of the present invention pair of indoles heterogeneous ring compound has following molecular formula:

Y is a heterocycle, can be R wherein ³Or R ⁴=H, X, R ⁸, CF ₃, CN, NO ₂,

Benzimidazolyl-, benzofuryl, benzothienyl, NHCO ₂R ⁸, NHSO ₂R ⁸Or NHR ⁸, R ⁵Or R ⁶=H, CH ₃, SO ₂R ¹⁰Or COR ⁸, R ⁷=H, SO ₂R ¹⁰, CO ₂R ⁸, C ₆H ₅R ⁸=H, CH ₃, C _1-5Alkyl, the phenyl or the benzyl that do not replace or replace.R ⁹=H, X, CH ₃, CF ₃Or CO ₂R ⁸, R ¹⁰=R ⁸Or C ₆H ₄CH ₃, X=F, Cl, Br or I, R=H or R ⁸In other words, of the present invention pair of indoles heterogeneous ring compound can be:

Above-mentioned pair of indoles heterogeneous ring compound of the present invention can prepare respectively by following several method:

Two indole thiazole compounds (1) can by 3-thioformamide benzazolyl compounds (7) and 3-(α-bromine or iodine is for ethanoyl)-indoles (8) in polar solvent and 60 ℃ to the reflux temperature reaction made in 0.1-5 hour.The temperature of reaction raising helps shortening the reaction times, recommends reflux temperature to react 0.1-1.5 hour down.The mol ratio of compound (7) and (8) is 1: 0.8-2, recommending mol ratio is 1: 1-1.5.Prolong the reaction times to not influence of reaction yield.During the reaction beginning, compound (7) and (8) are suspended in the solvent, become clarification behind the several minutes, then have solid to produce.Reaction finishes after-filtration and promptly obtains compound (1).Productive rate is greater than 95%.Available following reaction formula is represented:

In addition, work as R ⁵Or R ⁶For to Methyl benzenesulfonyl base (Ts) time, compound (1) and monovalence metal hydroxides mol ratio are 1: during 1-100, can remove the Methyl benzenesulfonyl base in backflow 0.5-5 hour, generate:

Compound (9), (10) or (11) can with haloalkane R ⁸X room temperature in solvent was reacted about 1-50 hour to reflux temperature and in the presence of monovalence metal carbonate or the alkaline earth metal hydride MH, can make alkylation on the nitrogen-atoms in the indyl.Compound (9), (10) or (11), the mol ratio of monovalence metal carbonate or alkaline earth metal hydride and haloalkane is 1: 1-20: 1-20.The amount that further increases monovalence metal carbonate or alkaline earth metal hydride and haloalkane also is favourable to reaction.Recommending mol ratio is 1: 2-10: 2-10.

Compound (9), (10) or (11) can with alkane acyl chlorides R ⁸COCl or SULPHURYL CHLORIDE R ¹⁰SO ₂Cl reacts, and contains the organic amine compound of lone-pair electron on organic solvent and nitrogen-atoms, and room temperature was reacted 1-20 hour to reflux conditions.Just can obtain compound (1), mol ratio is followed successively by 1: 0.8-1.2: 10.

3; two (3 '-indoles)-pyrazines of 5--2-ketone compounds (2); acylation reaction takes place with 3-(Norleucyl base)-benzazolyl compounds (14) in available 3-glyoxylyl chloro-indole compound (13); on polar solvent and nitrogen are former, contain in the presence of the organic amine compound of lone-pair electron; 0 ℃ was reacted 5-10 hour to room temperature; obtain closing ring precursor two keto-amides; promptly obtain 2-(3 '-indoles)-N-[2-(3 '-indoles)-2-oxygen ethyl]-2-oxygen-ethanamide (15), wherein compound (13); (14) and the mol ratio that contains the organic amine compound of lone-pair electron on the nitrogen-atoms be 1: 0.70-2: 1-10.Adopt the organic amine compound that contains lone-pair electron on the more nitrogen-atoms to not influence of reaction.

In solvent such as alcohol, compound (15) reacted 10-60 hour at 40-90 ℃ with liquefied ammonia, obtained 3-(3 '-indoles)-5-(3 '-indoles)-1, R then ⁷-pyrazine-2 ketone (2).Adopting excessive liquefied ammonia is favourable to reaction, and compound (15) is 1 with the liquefied ammonia mol ratio usually: 1-10000, recommending mol ratio is 1: 100-10000.Above-mentioned reaction can be represented by the formula:

3-(3 '-indoles)-6-(3 '-indoles)-N-R ⁷Synthesizing of-pyrazine-2 ketone (3), system is by compound (16) and (17), in solvent and on 1-124 Triazole oxygen three (dimethyl amine) phosphonic acids phosphofluoric acid ester (being called for short BOP) or bromo three (dimethyl amine) phosphonic acids phosphofluoric acid ester (being called for short BrOP) and the nitrogen-atoms, contain under the organic amine compound effect of lone-pair electron, at room temperature react 1-6 hour generation compound (18).Compound (16), compound (17), BOP or (BrOP) and the mol ratio of tertiary amine be 1: 0.8-1.5: 0.8-1.5: 1-10.

The available LiAlH of compound (18) ₄Be reduced into aldehyde, remove BOC then under acidic conditions, obtain ammonia hydrochloric acid salt, cyclization takes place in the latter in polar solvent, promptly obtains compound (3) through atmospheric oxidation.Specifically, compound (18) is when-25 ℃-0 ℃ of polar solvent neutralization, with LiAlH ₄Reacted 0.1-2 hour, and reacted 1-5 hour to room temperature and acidic conditions at-5 ℃ then, reaction product was stirred 1-5 days under the room temperature in polar solvent, promptly obtain compound (3).Wherein compound (18), LiAlH ₄Mol ratio be 1: 1-5.Reaction formula is as follows:

Under the described acidic conditions, promptly in reaction, can add inorganic or organic acidity material, make reaction solution be acid.As add mineral acids such as hydrochloric acid, sulfuric acid or comprise acetate, Acetyl Chloride 98Min., trifluoracetic acids etc. are at interior organic acidity material.Usually the mol ratio of compound (18) and acidic substance is 1: 1-5.

Two indoles pyrazine compounds (4) can make through catalytic hydrogenation from α-azido-ketone (19):

Specifically 3-(α-azido-ethanoyl) benzazolyl compounds (19) is in solvent and under the room temperature; feed hydrogen; under 1-5kg pressure; with content 5-15% palladium carbon (Pd/C) catalysis; reacted 5-36 hour; compound (19) is reduced into alpha-amino group ketone, and the latter self is condensed into the dihydro pyrazine immediately, is oxidised with air to two indoles pyrazine compounds (4) again.Described solvent can be sherwood oil, benzene, toluene, vinyl acetic monomer, acetate, acetonitrile, ether, methyl alcohol, ethanol, ethylene dichloride, chloroform etc.During reaction, help the carrying out that react under slightly acidic condition, preferably control PH=1-6.5, compound (19) is 1 with the catalyst weight ratio: 0.05-1.0.This preparation method can obtain higher yields. as work as R ¹, R ², R ³And R ⁴During=H, R ⁵And R ⁶Productive rate is 68% during=H, R ⁵And R ⁶=CH ₃The time, productive rate 74%.

Compound (7) can be by 3-chloracetyl benzazolyl compounds. (Bergman J.etal, Tetrahedron, 1973,29,971) or acetone-H of refluxing in room temperature and dimethyl sulfoxide (DMSO) ₂(Moody, C.T.etal, J.Chem.Perkin Trans, 1984,2903) use NaN among the O ₃Replace the chlorine atom, almost can quantitatively obtain corresponding compounds (19).

2,4-pair (preparation of 3 '-indoles) oxazole compound (5) can be represented by the formula:

(3 '-indoles) oxazole compound (20) and 3-tributyl tin benzazolyl compounds (21) are used the organic palladium catalyst to 2-bromo-4-in organic solvent, reacted 1-5 hour to reflux temperature at 60 ℃.The mol ratio of described compound (20), compound (21) and organic palladium catalyzer is 1: 0.8-2: 0.05-0.25.

2, two (3 '-indoles) pyrazine compounds (6) of 6-are by 3-tributyl tin indoles (20) and 3,5-dichloro or bromo-pyrazine (21), and in solvent under the organic palladium catalyst, in organic solvent reflux 1-5 hour and make.The mol ratio of compound (20), (21) and organic palladium catalyzer is followed successively by 1: 0.2-1.5: 0.05-0.50.Reaction can be represented by the formula:

Organic palladium catalyzer described in the present invention can be tetrakis triphenylphosphine palladium, four (tributylphosphine fertilizer), dichloro two (triphenylphosphine) palladium, dichloro two (acetonitrile-base) palladium, dichloro two (tri octyl phosphine) palladium.The organic amine compound that contains lone-pair electron on the described nitrogen-atoms can be C _1-24Tertiary amine, secondary amine or primary amine, also can be tetramethyl-two quadrols, as trioctylamine, triethylamine, Trimethylamine 99, diethylamine, dibutylamine etc.

Not only preparation process is simple for two indoles heterogeneous ring compounds described in the present invention, and productive rate is higher, and can be used as anti-inflammatory, anti-tumor drug.

As at external test 2,4-two (3 '-indoles) thiazole and 3, the anti-tumor activity of 6-two (3 '-indoles) pyrazine, their suppress 50% growth of cancer cells result and list in table 1 and table 2 respectively.

As can be seen from Table 1,2,4-two (3 '-indoles) thiazolium compounds 1-1 and 1-3～1-5 are in the external growth that can suppress multiple human body tumour cell.Do not have the ability of the compound 1-1 of bromine substituent and the compound 1-5 inhibition leukemia cell growth that two 6-bromine replaces basic identical, the GI50 value all is less than 10 μ M.When 2 of thiazole or 4 s' indole ring has bromine substituent, SR leukemia cell's restraining effect is weakened, when especially the indole ring 6-position of thiazole 2-position was replaced by bromine, activity reduced maximumly, GI ₅₀Become 12.2 μ M from 1.77 μ M.The ability that compound 1-1 suppresses other cancer cells such as chest cancer cells MCF7, MDA-MB-435, MDA-N and T-47D growth can not show a candle to 1-5.The ability that compound 1-1 suppresses breast cancer cell IGROV1 growth seldom is the twice of compound 1-5.When introducing bromine atoms on any one 6-position in two indole rings, a little less than energy the force rate that the single bromo compound 1-3 that obtains and 1-4 suppress leukemia cell's growth does not have the 6-position of the compound 1-1 of bromine substituent and two indole rings to have the compound of bromine substituent all to want simultaneously, suppress a little less than energy the force rate 1-5 of other growth of cancer cells but more eager to excel in whatever one does than 1-1.At these four kinds of compounds, compound 1-1 can optionally suppress leukemia cell growth, and two bromo compound 1-5 has the activity of the anticancer growth of wide spectrum.

3, the antitumour activity of two (3-indoles) the pyrazine 3-1 of 6-is lower, removes the GI to colon cancer cell HCT-116 and chest cancer cells MCF-7 ₅₀Be less than outside the 10 μ M, the GI of other cancer cells ₅₀All greater than 10 μ M.But its methylate 3, two (3 '-N-skatole) the pyrazine 3-1 of 6-have very strong antitumour activity, to the GI of tens kinds of cancer cells being surveyed ₅₀All be less than 10 μ M, wherein suppress the GI of leukemia cell CCRF-CEM growth ₅₀Be less than 10 ^-8M, TGI only are 0.0583 μ M.The GI that suppresses colon cancer cell KM-12 growth ₅₀Be 0.058 μ M.GI to other several cancer cells such as non-small cell lung cancer cell NCI-H322M, colon cancer cell HCT-15, melanoma cell SK-MEL-5 and chest cancer cells MCF-7 ₅₀All be less than 1 μ M.3, two (3 '-1H-indoles)-2 (1H) the pyrazine ketone 2-1 of 5-also have good antitumour activity to multiple human cancer cell, to leukemia cell K-562, SR, non-small cell lung cancer cell NCI-H522, colon cancer cell KM12, SW-620, CNS cancer cells SF-295, breast cancer cell IGROV1, OVCAR-4, the GI of kidney cancer cell RXF393, SN12C and chest cancer cells MDA-MB-435 and MDA-N ₅₀All be less than 10 μ M.

Table 1.2, two (3 '-indoles) thiazolium compoundss of 4-are in the result of vitro inhibition human cancer cell growth

Table 2.3, two (3 '-indoles) pyrazine compounds of 6-are in vitro inhibition

The result of human cancer cell's growth

ND: and do not measure

To help to understand the present invention by following embodiment, but not limit content of the present invention.

Embodiment 14[3 '-(N-p-toluenesulfonyl) indoles]-2-(3 '-indoles) thiazole (1-1) synthetic

(7176mg, 1mmol), (431mg, 1.1mmol), orange-red solution is 80-90 ℃ of following reflux for 25ml ethanol and N-p-toluenesulfonyl-3-(alpha-brominated ethanoyl) indoles to add 3-thioformamide indoles in the 25ml exsiccant reaction flask.It is muddy that reaction solution becomes at once, has orange-yellow precipitation to generate.The afterreaction mixture was chilled to room temperature in 1 hour, suction filtration, and (3 * 20ml), vacuum-drying weighs 455mg, productive rate 97% to filter cake with absolute ethanol washing.

Rf=0.77 (hexane hexane/ ethyl acetate EtOAc=2: 3)

¹HHMR(DMSO-d ₆，300MHz)：11．84(brs，1H，NH)，8．39-7．93(m，7H)，7．54-7．22(m，8H)，2．29(s，3H，CH ₃?of?Ts)．

EIMS(m／e，％)；469(M，39．17)，314(M-Ts，100．00)，172／173(26．79／23．01)，149(16．06)，128／129(22．39／15．89)．

HREIMS (molecular formula C ₂₆H ₁₉N ₃O ₂S ₂): calculated value 469.0919, measured value 469.0917.

IR(KBr，cm ^-1)：3070(NH)，1614，1577，1552，1449，1436，1380，1338，1238，1178，1150，1118，1090，1037，985，934，877，814，737，706，676，654，581，572，534．

Embodiment 22, two (3 '-indoles) thiazoles (1-2) of 4-synthetic.

(264mg 0.563mmol) is suspended in the 16ml methyl alcohol 4-(N-tolysulfonyl indoles-3)-2 (indoles-3) thiazoles (1-1), and (400mmg, 10mmol), solution becomes clarification (orange red) at once to add sodium hydrate solid.Reflux 3 hours, concentrating under reduced pressure, little residue quantity of fluid are distributed in 100ml water and the 100ml ether.Tell organic phase, water extracted with diethyl ether (3 * 50ml).Wash with water after the organic phase merging (2 * 60ml), anhydrous sodium sulfate drying, filtration concentrates, and obtains the 156mg faint yellow solid, productive rate 88.1%.

Rf=0．58(hexane／EtOAc=2∶3)，

¹HNMR(DMSO-d ₆，300Mhz)：11．74(brs，1H，NH)，11．39(brs，1H，NH)，8．37(m，1H)，8．22(m，1H)，8．14(m，1H)，7．6(m，1H)，7．53-7．47(m，2H)，7．26-7．16(m，4H)．

¹³CNMR(DMSO-d ₆)：161．76，150．54，136．65，136．5，126．39，126．22，124．66，124．39，122．36，121．55，120．71，120．45，120．18，119．7，112．16，111．35，110．84，105．95．

EIMS(m／e，％)：316(M+1，27．29)，315(M ⁺，100．00)，173(45．83)，172(14．13)，157(8．16)，146(8．15)，129(15．30)．

HREIMS (molecular formula C ₁₉H ₁₃N ₃S): calculated value 315.0831, measured value 315.0829.

IR(KBr，cm ^-1)：3388，3123，1675，1616，1575，1543，1475，1458，1427，1333，1259，1097，1022，939，842，739，709，622，582，532，427．

Embodiment 32,4-two (3-indoles) thiazolium compounds synthetic

Synthesizing with embodiment 1 and 2 of compound (1-3) to (1-12), the result is as follows.Compound R ¹R ³Two step overall yield (%) 1-3 6-Br H 821-4 H 6-Br 761-5 6-Br 6-Br 781-6 H 5-Br 801-7 5-Br H 841-8 5-Br 5-Br 721-9 6-OCH ₃6-Br 731-10 5-Br 6-Br 751-11 6-OCH ₃H 751-12 6-Br 5-Br 741-13 C ₂H ₅C ₂H ₅751-14 CF ₃CF ₃722-(3 '-indoles)-4-[3 '-(6-bromo indole)] thiazole (1-3):

¹HNMR(DMSO-d ₆，300MHz)：11．78(brs，1H，NH)，11．56(brs，1H，NH)，8．35(m，1H)，8．21(d，J=8．57Hz，1H)，8．16(d，J=2．5Hz，1H)，8．03(d，J=2．13Hz，1H)，7．67(d，J=1．64Hz，1H)，7．65(s，1H)，7．52(m，1H)，7．37(s，1H)，7．31(d，J=1．81Hz，1H)，7．28-7．22(m，2H)．

¹³CNMR(DMSO-d ₆)：162．06，149．78，137．51，136．63，126．57，125．73，124．90，124．52，122．42，122．03，120．79，120．38，114．46，114．33，112．24，111．47，110．66，106．63．

EIMS(m／e，％)：395／393(M，54．81／51．21)，253(25．30)，251(24．26)，172(23．54)，157(11．24)，142(100．00)，128(14．07)，115(46．51)．

HREIMS (molecular formula C ₁₉H ₁₂BrN ₃S): calculated value 393.9837, measured value 393.9799.

IR (KBr, cm ^-1): 3442,3215,1617,1578,1544,1474,1455,1243,1232,1134,1114,1098,1090,1022,939,883,831,801,793,767,742,710,576,554,498,421.2-[3 '-(6-bromo indole)]-4-(3 '-indoles) thiazole (1-4):

Rf=0．56(hexane／EtOAc=2∶3)

¹HNMR(DMSO-d ₆，300MHz)：11．87(brs，1H，NH)，11．42(brs，1H，NH)，8．34(d，J=8．56Hz，1H)，8．21-8．17(m，2H)，8．00(s，1H)，7．7(s，1H)，7．63(s，1H)，7．48(m，1H)，7．39(dd，1H)，7．20-7．16(m，2H)．

¹³CNMR(DMSO-d ₆)：161．11，150．59，137．41，136．62，127．23，124．81，124．64，123．53，122．24，121．48，120．03，119．65，114．97，114．67，111．82，111．19，110．95，106．22．

EIMS(m／e，％)：395／393(M，100／97．98)，314(M-Br，7．61)，173(90．26)，146(21．10)，129(41．25)，114(14．92)．

HREIMS (molecular formula C ₁₉H ₁₂BrN ₃S): calculated value 395.9993, measured value 395.9953.

IR (KBr, cm ^-1): 3390,3122,1670,1544,1475,1456,1423,1333,1292,1255,1235,1147,1096,1021,938,896,884,857,840,825,807,744,709,623,568,531,516,480,424.2, two [3 '-(6 '-bromo indole)] thiazoles (1-5) of 4-:

Rf=0．4(hexane／EtOAc=3∶2)．

¹HNMR(DMSO-d ₆，300MHz)：11．87(brs，1H，NH)，11．55(brs，1H，NH)，8．31(d，J=8．54Hz，1H)，8．18(m，2H)，8．03(s，1H)，7．68(m，2H)，7．40-7．27(m，3H)．

¹³CNMR(DMSO-d ₆)：162．40，150．94，138．43，134．55，130．27，128．64，128．41，126．73，124．64，124．37，123．52，123．23，122．93，116．02，115．72，115．41，112．39，111．85，107．91．

EIMS(m／e，％)：475／471(M，38．00／36．16)，392(7．26)，251(51．56)，253(51．49)，220(32．00)，207(18．44)，172(100．00)，145(32．11)，128(57．53)，114(48．46)，

HREIMS (molecular formula C ₁₉H ₁₁Br ₂N ₃S): calculated value 470.9041 (472.9020), measured value 470.9052 (472.9035).

IR(KBr，cm ^-1)：3539，3206，1615，1579，1543，1473，1451，1408，1331，1294，1251，1233，1120，1098，1055，1023，941，884，832，797，711，628，587，559，485，420。2-[3 '-(5 '-bromo indole)]-4-(3 '-indoles) thiazole (1-6):

¹HNMR(DMSO-d ₆，300MHz)：11．94(brs，1H，NH)，11．40(brs，1H，NH)，8．60(s，1H)，8．26(d，J=8．56Hz，1H)，8．21(d，J=2．4Hz，1H)，7．96(s，1H)，7．61(s，1H)，7．49(d，J=8．50Hz，1H)，7．37(dd，J=1．67Hz?and?8．57Hz，1H)，7．22-7．14(m，2H)．

¹³CNMR(DMSO-d ₆)：136．59，135．29，127．8，127．62，126．11，124．88，124．54，124．36，122．88，121．55，120．17，119．59，114．18，113．26，111．87，111．83，111．19，110．4，106．16．

EIMS(m／e，％)：395(M+1，22．8)，392／394(M，96．4／100．0)，393(M，31．7)，173(70．2)，172(24．9)，146(12．3)，129(26．9)，128(11．4)，114(5．4)．

HREIMS (molecular formula C ₁₉H ₁₂BrN ₃S): calculate position 391.9857, measured value 391.9853.

IR (KBr, cm ^-1): 3402,1558,1454,1421,1336,1241,1104,1018,883,797,743,581.2-(3 '-indoles)-4-[3 '-(5 '-smell indoles)] thiazole (1-7):

¹HNMR(DMSO-d ₆，300MHz)：11．73(brs，1H，NH)，11．60(brs，1H，NH)，8．52(d，J=1．71Hz，1H)，8．41(m，1H)，8．13(d，J=2．30Hz，1H)，8．05(d，J=1．91Hz，1H)，7．65(s，1H)，7．53(m，1H)，7．50(d，J=8．45Hz，1H)，7．33-7．23(m，2H)．

EIMS (m/e, %): 395 (M+1,23), 392/394 (M, 96.9/100.0), 393 (M, 31.1), 251/253 (39/39.3), 207/209 (8.4/8.0), 172 (28.5), 157 (11.3), 128 (11.9) .2, two [3 '-(5 '-bromo indole)] thiazoles (1-8) of 4-:

¹HNMR(DMSO-d ₆，300MHz)：11．85(brs，1H，NH)，11．57(brs，1H，NH)，8．57(d，J=1．88Hz，1H)，8．48(d，J=1．85Hz，1H)，8．35(d，J=2．43Hz，1H)，8．02(d，J=1．97Hz，1H)，7．67(s，1H)，7．50(d，J=8．66Hz，1H)，7．47(d，J=8．57Hz，1H)，7．38(dd，J=1．93Hz?and?8．62Hz，1H)，7，31(dd，J=1．90Hz?and?8．62Hz，1H)．

EIMS(m／e，％)：471／474(M，49．9／54．3)，473(M，100．0)，391／393(4．5／4．6)，251／253(45／45．2)，220／222(8．8／9)，207／209(11．6／11．1)，172(50．5)，145(14．3)，141(13．7)，128(23．1)，114(51)．

HREIMS (molecular formula C ₁₉H ₁₁Br ₂N ₃S): calculated value 470.9040, measured value 470.9036.2-[3 '-(6 '-bromo indole)]-and 4-[3 '-(6 '-methoxyl group) indoles] thiazole (1-9):

¹HNMR(DMSO-d ₆，300MHz)：11．84(brs，1H，NH)，11．18(brs，1H，NH)，8．33(d，J=8．75Hz，1H)，8．16(d，J=2．15Hz，1H)，8．06(d，J=8．76Hz，1H)，7．79(d，J=1．47Hz，1H)，7．72(d，J=1．51Hz，1H)，7．56(s，1H)，7．39(dd，J=1．78?and?8．54Hz，1H)，6．99(d，J=2．22Hz，1H)，6．83(dd，J=2．32Hz?and?8．72Hz，1H)，3．82(s，3H)．

EIMS(m／e，％)：423／425(M，83．2／84．4)，407／409(17．8／18．6)，343(6．1)，300(4．0)，220／222(14．7／13．6)，203(39．0)，188(100．0)，160(51．7)，141(23．3)，133(13)，128(17．4)，116(25．3)，115(15．4)，114(35．3)，89(30．5)．

HRMS (molecular formula C ₂₀H ₁₄BrN ₃OS): calculated value 423.0219, measured value 423.0206.

¹³CNMR(DMSO-d ₆)：161．09，155．69，150．69，137．44，137．27，127．22，127．05，123．56，123．34，122．23，120．67，119．04，115．00，114．71，111．21，110．99，106．01，94．87，55．16．

IR (KBr, cm ^-1): 3401,3120,1629,1567,1540,1503,1450,1404,1330,1294,1248,1199,1158,1088,1020,881,829,801,709.2-[3 '-(6 '-bromo indole)]-4-[3 '-(5 '-bromo indole)] thiazole (1-10):

¹HNMR(DMSO-d ₆，300MHz)：11．80(brs，1H，NH)，11．57(brs，1H，NH)，8．47(d，J=1．44Hz，1H)，8．35(d，J=8．51Hz，1H)，8．15(d，J=2．13Hz，1H)，8．04(d，J=1．77Hz，1H)，7．73(d，J=1．49Hz，1H)，7．66(s，1H)，7．47(d，J=8．60Hz，1H)，7．37(dd，J=1．75Hz?and?8．53Hz，1H)，7．32(dd，J=1．78Hz?and?8．60Hz，1H)．

EIMS(m／e，％)：471／475(M，49．7／52．7)，474(M，26．6)，473(M，100．0)，391／393(3．7／3．7)，251／253(39．1／40．5)，207／209(9．7／9．3)，172(33．5)，145(9．5)，128(15．2)．

HREIMS (molecular formula C ₁₉H ₁₁Br ₂N ₃S): calculated value 474.8999, measured value 474.8964.

¹³CNMR (DMSO-d ₆): 164.44,149.94,137.45,135.24,127.33,126.53,126.06,125.88,124.00,123.44,123.38,122.58,122.17,115.03,114.78,113.82,112.39,110.91,110.86.2-(3 '-indoles)-4-[3 '-(6 '-methoxyl group indoles] thiazole (1-11):

¹HNMR(DMSO-d ₆，300MHz)：11．73(s，1H，NH)，11．18(s，1H，NH)，8．36(m，1H)，8．13(d，J=2．49Hz，1H)，8．04(d，J=8．85Hz，1H)，7．85(d，1H)，7．55(s，1H)，7．52(m，1H)，7．25(m，2H)，6．98(d，J=2．26Hz，1H)，6．82(dd，J=8．72Hz?and?2．32Hz，1H)．

EIMS(m／e，％)：345(M，28．8)，344(M-1，100．0)，329(16．6)，203(20．6)，188(43．4)，160(20．3)，116(10)，115(10．4)，89(11．2)．

HREIMS (molecular formula C ₂₀H ₁₅N ₃OS): calculated value 345.0936, measured value 345.0920.

IR (KBr, cm ^-1): 3388,3121,1633,1544,1507,1456,1301,1250,1161,1096,1019,828,798,739,707,530,427.2-[3 '-(5 '-bromo indole)]-4-[3 '-(6 '-bromo indole)] thiazole (1-12):

¹HNMR(DMSO-d ₆，300MHz)：11．89(brs，1H，NH)，11．48(brs，1H，NH)，8．56(d，J=1．89Hz，1H)，8．23(d，J=8．56Hz，1H)，8．18(d，J=2．33Hz，1H)，7．98(d，J=1．76Hz，1H)，7．69(d，J=1．72Hz，1H)，7．63(s，1H)，7．50(d，J=8．60Hz，1H)，7．37(dd，J=1．93Hz?and?8．62Hz，1H)，7．27(dd，J=1．81Hz?and?8．54Hz，1H)．

EIMS(m／e，％)：471／475(M，50／52．6)，473(M，100．0)，391／393(4．7／4．8)，251／253(42．3／42．5)，220(7．2)，207／209(9．6／8．9)，172(41．8)，145(11．5)，141(11．5)，141(10．1)，128(20)，114(11．6)．

HREIMS (molecular formula C ₁₉H ₁₁Br ₂N ₃S): calculated value 470.9040, measured value 470.9049.

¹³CNMR(DMSO-d ₆)：161．43，149．98，137．42，137．25，135．28，135．12，127．87，127．20，126．06，125．45，124．89，123．83，122．78，122．34，121．95，114．47，114．20，113．30，110．30．

IR (KBr, cm ^-1): 3429,3205,1616,1542,1451,1416,1329,1287,1242,1106,1054,1024,883,799,709,629,579,492.2, two [3 '-(6-the ethylindole)] thiazoles (1-13) of 4-:

¹H(DMSO-d ₆)：11．72(brs，1H)，11．58(brs，1H)，8．75(s，1H)，7．48(s，1H)，7．87(d，1H)，7．50(d，1H)，7．44(d，1H)，7．30(d，1H)，7．33(s，1H)，7．16(s，1H)，7．02(s，1H)，2．85(s，2H)，2．81(s，2H)，1．56(t，3H)，1．54(t，3H)．

MS (C ₂₃H ₂₁N ₃NS): 371 (100) .2, two [the 3 '-16-trifluoro methyl indole] thiazoles (1-14) of 4-:

¹H(DMSO-d ₆)：11．89(s，1H)，11．78(s，1H)，8．82(s，1H)，8．27(s，1H)，8．24(s，1H)，8．13(d，1H)，8．04(d，1H)，7．92(s，1H)，7．84(d，1H)，7．56(s，1H)，7．34(s，1H)．

MS(C ₂₁H ₁₁N ₃SF ₆)：45．1(100)．

Embodiment 42, two (N-methyl-3 '-indoles) thiazoles (1-15) of 4-synthetic:

Add 2 in the 50ml reaction flask, two (3 '-indoles) thiazole (149mg of 4-, 0.473mmol), make it to be dissolved in 10ml acetone, add the Anhydrous potassium carbonate solid (345mg, 2.5mmol) and methyl iodide (1.2ml), reaction solution reflux 16 hours, add into methyl iodide (2ml) and Anhydrous potassium carbonate solid (345mg, 2.5mmol).Continue heating 28 hours.Concentrating under reduced pressure, resistates are distributed in 50ml water and the 50ml ether.(3 * 50ml), extraction liquid merges the back and washs anhydrous sodium sulfate drying with saturated nacl aqueous solution water with extracted with diethyl ether.Filter, concentrate, resistates is through column chromatographic isolation and purification (SiO ₂, PE/EtOAc=3: 1), merge required fraction, concentrate, obtain the pale brown look solid of 135mg, productive rate 83%.

Mp．174．2℃-174．6℃

¹HNMR(DMSO-d ₆，300MHz)：8．39(m，1H)，8．22(d，1H)，8．16(s，1H)，7．8(s，1H)，7．58(s，1H)，7．57-7．51(m，2H)，7．34-7．18(m，4H)，3．90(s，3H)，3．89(s，3H)．

EIMS(m／e，％)：344(M+1，24．1)，343(M，100．0)，187(36．3)，172(19．9)，154(4．6)．

HREIMS (molecular formula C ₂₁H ₁₇N ₃S): calculated value 343.1144, measured value 343.1145.

IR (KBr, cm ^-1): 1612,1566,1544,1477,1462,1417,1330,1240,1209,1135,1076,1016,1001,877,817,732,706,420.2, two [3 '-(N-methyl-6-the cyanoindole)] thiophene (1-16) of 4-synthetic:

Operate the same, productive rate 90%.

¹H(DMSO-d ₆)：8．75(s，1H)，8．11(d，1H)，8．16(d，1H)，7．85(d，1H)，7．69(s，1H)，7．71(s，1H)，7．79(s，1H)，7．51(s，1H)，7．70(d，1H)，3．94(s，3H)，3．91(s，3H)．

MS(C ₂₃H ₁₅N ₅S)：393(70)．

Embodiment 52-(3 '-indoles)-N-[2-(3 '-indoles)-2-oxygen-ethyl]-2-oxygen-ethanamide (15-1) synthetic:

3-(2-ammonia ethanoyl) indole hydrochloride (14-1) (150mg, 0.71mmol), the anhydrous CH of 20ml ₂Cl ₂With anhydrous Et ₃N (0.4ml, 2.85mmol), reaction flask is inserted in the ice-water bath, and (190mg, 0.91mmol), mixture spends the night 0 ℃ of stirring disposable adding indoles-3-oxalyl chloride 13-1 solid.Add 50mlCH ₂Cl ₂Dilute reaction solution, and water (2 * 20ml), saturated NaCl solution (1 * 20ml) washing, anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure, crude product is through column chromatography (SiO ₂, CH ₂Cl ₂/ CH ₃OH=10: 1) separation and purification obtains the 165mg yellow solid, productive rate 67%. at last

¹HNMR (acetone-d ₆, 300Mhz): 8.47 (t, J=5.75 and 5.92Hz, 1H, NH), 8.38 (d, J=1.95Hz, 1H), 8.96 (d, J=2.37Hz, 1H), 7.82 (m, 1H), 7,73 (m, 1H), 7.12-7.04 (m, 2H0, and 6.85-6.81 (m, 2H), 6.79-6.75 (m, 2H), 4.19 (d, J=3.77Hz, 2H).

EIMS(m／e，％)：345(M，3．48)，316(16．58)，302(3．09)，274(9．36)，201(13．20)，144(100．00)，130(4．78)，?116(17．01)．

IR(KBr，cm ^-1)：3386，3337，3273，3106，2927，1675，1645，1620，1583，1526，1507，1494，1432，1383，1336，1314，1242，1152，1010，935，878，797，749，656，422．

Embodiment 6

3, two (3 '-indoles)-1H-pyrazines of 5--2-ketone (2-1) synthetic:

Add 2-(3-indoles)-N-[2-(3-indoles)-2-oxygen-ethyl in the autoclave]-2-oxygen-ethanamide (150mg, 0.43mmol), the absolute methyl alcohol of 5ml and about 20g liquefied ammonia.Reaction mixture stirred three days down at 60-80 ℃.Decompression steams solvent, and resistates is distributed in water (30ml) and the ethyl acetate (50ml), and (2 * 30ml), organic phase merges the back, and (1 * 40ml), anhydrous sodium sulfate drying concentrates column chromatography (SiO to water with the saturated nacl aqueous solution washing with ethyl acetate extraction ₂, CH ₂Cl ₂/ CH ₃OH=25: 1), merge required fraction, concentrating under reduced pressure obtains 65mg brown solid, is recovered to the 40mg raw material simultaneously.Productive rate 62.5%.

Embodiment 73, two (3 '-indoles) pyrazines (4-1) of 6-synthetic:

(400mg 2mmol), 5%Pd/C (100mg) and 20ml methyl alcohol, adds several acetate again to add 3-(α-acetyl azide) indoles (19-1) in the reaction tubes.Reaction tubes is inserted in the autoclave, and hydrogenation 25 hours under 3 kilograms of pressure under the room temperature is filtered, and filtrate concentrates.Column chromatography (SiO ₂, CH ₂Cl ₂/ EtOAc=20: 1), merge required fraction, concentrating under reduced pressure.Obtain the 420mg pink solid.Productive rate 68%.

¹HNMR(DMSO-d ₆，400MHz)：11．21(s，1H)，8．33(s，1H)，8．19(d，J=7．5Hz，1H)，7．48(d，J=7．5Hz，1H)，7．23-7．17(m，3H)．

EIMS(m／e，％)：310(M，100．0)，245(12．7)，194(7．1)，155(15．7)，144(40．1)，141(35．1)，130(10)，117(47．7)，90(17．1)．

Embodiment 83, two [3 '-(N-the skatole)] pyrazines (4-2) of 6-synthetic:

The reaction, the operation the same, productive rate 74%.

¹HNMR(DMSO-d ₆，300MHz)：8．43(s，1H)，8．19(d，J=8．21Hz，1H)，7．64(d，J=8．18Hz，1H)，7．38-7．22(m，3H)，1．86(s，3H)．

EIMS(m／e，％)：338(M，100．0)，323(10．0)，184(9．8)，173(6．7)，169(10．6)，158(43)，144(8．2)，130(6．9)．

Embodiment 93, two (3 '-indoles) pyrazines of 6--2-ketone (3) synthetic:

(240mg 0.8mmol), makes it to be dissolved in the 15ml anhydrous methylene chloride to add 2-(3-indoles)-N-benzyl phosphinylidyne glycine (16-1) in the 50ml reaction flask.Add BOP (360mg, 0.8mmol) and anhydrous triethylamine (0.4ml, 2.85mmol).Add α-(3-indoles)-glycine-O after about 20 minutes, (the brown reaction solution that obtains at room temperature stirred 2 hours N-dimethyl hydroxylamine (17-1) for 190mg, anhydrous methylene chloride solution (5ml) 0.81mmol).TLC shows that reaction is complete.Reaction solution is with the dilution of 100ml methylene dichloride, then with saturated nacl aqueous solution washing, anhydrous sodium sulfate drying.Filter, concentrating under reduced pressure obtains red-brown thickness oily matter.Column chromatography (SiO ₂, CH ₂Cl ₂/ CH ₃OH=20: 1), merge required fraction, concentrate, obtain the solid dipeptides of 305mg spumescence.Productive rate 75%.

Above-mentioned dipeptides (0.8mmol) is dissolved among the anhydrous THF of 10ml.In this solution, add LiAlH under 0 ℃ ₄(46mg, 1.2mmol), the reaction solution that obtains stirred 50 minutes to room temperature at 0 ℃, added 5ml ethyl acetate and 2ml stopped reaction, with extracted with diethyl ether (3 * 30).Extraction liquid merges the back and washs anhydrous sodium sulfate drying with saturated nacl aqueous solution.Concentrate, obtain 350mg spumescence crude product.

The crude product that obtains is dissolved in the absolute methyl alcohol of 10ml, is added dropwise to Acetyl Chloride 98Min. (0.6ml) under 0 ℃.Reaction solution at room temperature stirred 4 hours after stirring 10 minutes under this temperature again.Circle round and steam solvent, resistates vacuum-drying adds the 20ml acetonitrile then, and the compound of reaction that obtains at room temperature stirred 2-3 days.Decompression steams solvent, and resistates is distributed in water and the ethyl acetate.Tell organic phase, the water ethyl acetate extraction.Extraction liquid washs with saturated sodium-chloride, anhydrous sodium sulfate drying.Concentrating under reduced pressure, post layer post (SiO ₂, PE/EtOAc=10: 1-5: 1).Merge required fraction, concentrate, obtain the yellow exceedingly beautiful solid of 60mg.Overall yield is 23%.

¹HNMR(DMSO-d ₆，300Mhz)12．31(brs，1H，NH)，11．86(brs，1H，NH)，11．63(brs，1H，NH)，8．85(s，1H)，8．80(d，J=7．8Hz，1H)，8．22(d，J=7，74Hz，1H)，8．08(m，2H)，7．64-7．57(m，2H)，7．43-7．09(m，4H)．

EIMS(m／e，％)327(M+1，32．6)，326(M，100．0)，298(M-28，17．2)，155(11．4)，144(17．1)，130(29．4)，117(16．5)．

HREIMS (molecular formula C ₂₀H ₁₄N ₄O): calculated value 326.1167, measured value 326.1172

IR(KBr，cm ^-1)3560，3412，1645，1620，1500，1455，1420，1334，1235，1160，1110，859，745，654，535，480．

Embodiment 102,4-pair (synthesizing of 3 '-indoles) oxazole (5-1):

2-bromo-4-[3 '-N-(p-toluenesulfonyl) indoles] oxazole (20-1) 0.1mol, 3-tributyl tin-N-(p-toluenesulfonyl) indoles (21-1) 0.11mol uses 0.008molPdCl in benzene ₂(PPh ₃) ₂Catalysis, reflux temperature reacted 3 hours down, the reaction after-filtration, filtrate is obtained (5-1) behind column chromatographic isolation and purification, productive rate 58%.

¹HNMR(DMSO-d ₆)，11．76(s，1H)，11．53(s，1H)，9．06(s，1H)，8．07(s，1H)，7．46(d，1H)，7．57(m，1H)，7．53(d，1H)，7．42(m，1H)，7．4-7．32(m，5H)．

MS(C ₁₉H ₁₃N ₃O)：299(100)．

Embodiment 112,4-pair [3 '-(synthesizing of N-(p-chlorobenzyl) indoles] oxazole (5-2):

Add (5-1) 1mmol and 10mlDMF in the reaction flask, 0 ℃ adds NaH2.4mmol down, stirs 30 minutes under the room temperature, adds and leads bromine chloride 2.4mmol, stirs under the room temperature and trembles 5 hours.Complete (5-2), productive rate 94% of behind column chromatographic isolation and purification, obtaining of reaction.

¹HNMR(DMSO-d ₆)：9．10(s，1H)，8．23(d，1H)，8．13(s，1H)，7．96(d，1H)，7．80(s，1H)，7．55-7．32(m，10H)，6．52-6．27(m，4H)，5．38(s，2H)，5．29(s，2H)．

MS(C ₃₃H ₂₃Cl ₂N ₃O)：548(100)．

Embodiment 122, and synthetic (5-3's) of two [3 '-(N-2, the 6-two fluoro-4-chlorobenzene formacyls) indoles] oxazoles of 4-is synthetic:

Compound (5-1) 1mmol is dissolved in 20mlCH ₂Cl ₂In, add diisopropyl ethyl amine 3mmol, add Benzoyl chloride 2.4mmol in the time of 0 ℃, stirred 8 hours under the room temperature, obtain (5-3) through column chromatographic isolation and purification, productive rate 82%.

¹HNMR(DMSO-d ₆)：9．35(s，1H)，8．74(s，1H)，8．34(m，1H)，8．28(s，1H)，8．23(d，1H)，7．91-7．26(m，10H)．

MS (C ₃₃H ₁₅Cl ₂F ₄N ₃O ₃): 648 (100) .2,4-pair [synthesizing of 3 '-(N-methyl-6-trifluoromethyl) indoles] oxazole (5-4):

With 2,4-two [3 '-(6-trifluoromethyl) indoles] oxazole is a raw material, operate the same, productive rate 87%.

¹HNMR(DMSO-d ₆)：9．02(s，1H)，8．30(d，1H)，8．14(d，1H)，7．89(d，1H)，7．81(d，1H)，7，71(d，1H)，7．66(s，1H)，7．57(s，1H)，7．4(s，1H)，3．62(s，3H)，3．58(s，3H)．

MS(C ₂₃H ₁₅F ₆N ₃O)：463(100)．

Embodiment 132, two [3 '-(N-is to the trifluoromethyl benzoyl) indoles] oxazoles (5-5) of 4-synthetic:

Add 2 in the reaction flask, 4-two [3 '-indoles) oxazole (5-1) 1mmol, CH ₂Cl ₂10ml and triethylamine 3.0mmol add below 0 ℃ trifluoromethyl benzoyl chloride 2, and 4mmol stirs under the room temperature and spends the night, column chromatographic isolation and purification, and the productive rate with 95% obtains (5-5).

¹HNMR(DMSO-d ₆)：9．31(s，1H)，8．99(s，1H)，8．79-8．70(m，2H)，8．53-8．51(m，2H)，8．35(d，1H)，8．29-8．14(m，4H)，7．85-7．78(m，3H)，8．05-7．93(m，5H)．

MS(C ₃₃H ₁₁F ₆N ₃O ₅S ₂)：716(100)．

Embodiment 142, two [3 '-(N-the skatole)] pyrazines (6-1) of 6-synthetic:

N-methyl-3-tributyl tin-indoles (20-1) 1mmol, 3,5-dichloropyrazine (21-1) 1mmol in 20ml dimethyl sulfoxide (DMSO) or dioxane solvent, PdCl ₂(PPh ₃) ₂, 0.1mmol reacted 2 hours under reflux temperature, obtained (6-1) compound, productive rate 65%.

¹HNMR(DMSO-d ₆)：8．?52(s，2H)，8．05(d，2H)，7．55(s，2H)，7．52(m，2H)，7．41(d，2H)，7．27(m，2H)，3．79(s，3H)．

MS(C ₂₂H ₁₈N ₄)：338(100)．

Embodiment 152, two [3 '-(N-benzyl-5-methoxyl group) indoles] pyrazines (6-2) of 6-synthetic:

With 2, two [3 '-(5-methyl) indoles] the pyrazine 0.1mol of 6-, bromotoluene 0.2mol, reaction is 3 hours under NaHO.1mmol and the 50ml dimethyl sulfoxide (DMSO) room temperature, and column chromatographic isolation and purification obtains (6-2) compound with 84% productive rate.

¹HNMR(DMSO-d ₆)：8．47(s，2H)，8．23(s，2H)，7．12-7．01(m，14H)，6．68(d，2H)，5．37(s，4H)，3．83(s，6H)．

Embodiment 162, two [3 '-(N-methyl-6-amidino groups) indoles] thiazoles (1-17) of 4-synthetic:

5mmol compound (1-16) is suspended in the 50ml ethanol, feeds exsiccant HCl gas and continue 2-3hr in this solution, stirs 2-4 days under the solution that the obtains sealing room temperature, circles round and steams solvent, and the crude product that obtains is dissolved in the ethanol again, feeds exsiccant MH ₃The about 1hr of gas stirred 1 day under the reaction mixture room temperature, steamed solvent, obtained (1.17) of red solid, productive rate 87%.

¹HNMR(DMSO-d ₆)：8．75(s，1H)，8．44(s，1H)，8．24(s，1H)，7．86(d，1H)，7．82(d，1H)．7．71(d．1H)，7．66(d．1H)．7．46(s．1H0，7．20(s．1H)，5．45(s，6H)，3．99(s，3H)，3．86(s，3H)．

MS(C ₂₃H ₂₁N ₇S)：428(100)．

Synthesizing of two [3 '-(N-methyl-6 '-(5 '-tetrazolium) indoles)] thiazoles (1-17) of embodiment 172,4-:

Compound (1-16) 5-5mmol and TMSN ₃11mmol is dissolved in the 20ml toluene, adds dimethyl tin oxide 0.55mmol, 10mol% then, reaction mixture reflux 1-2 days, concentrating under reduced pressure reaction solution, resistates CH ₃OH dissolving and then concentrated, resistates is distributed in ethyl acetate and 10%NaHCO ₃In the molten ring, organic phase 10%NaHCO ₃Washing, water merge the back and are neutralized to PH=2 with 10%HCl, and then extract the organic phase anhydrous Na after the merging with acetic acid second vinegar ₂SO ₄Drying concentrates, and the productive rate with 73% obtains compound (1-17).

¹HNMR(DMSO-d ₆)：9．27(d，1H)，8．75(s，1H)，8．62(s，1H)，7．85(s，1H)，7．75(s，1H)，7．69(d，1H)，7．67(d，1H)，7．2(dd，1H)，7．15(s，1H)，6．91(s，1H)，6．87(s，1H)，3．85(s，3H)，3．87(s，3H)．

MS(C ₂₃H ₁₇N ₁₁S)：480(68)．

Embodiment 182, two [3 '-(N-(2, the 6-trifluorophenyl)-6 '-benzoglyoxaline)] thiazoles (1-18) of 4-synthetic:

Phenylenediamine and 2 with equivalent, two [3 '-(the N-2 of 4-, the 6-difluorophenyl)-6 '-formaldehyde)] thiazole is dissolved in the oil of mirbane, 45 ℃～50 ℃ following heated and stirred 10 hours, remove solvent under reduced pressure, silica gel column chromatography with vinyl acetic monomer/sherwood oil=5: 1 wash-outs, obtains (1-18) compound with 68% productive rate at last.

¹HNMR(DMSO-d ₆)：9．01(d，1H)，8．89(s，1H)，8．87(s，1H)，8．84(s，1H)，8．38(s，1H)，8．81(d，1H)，8．18(s，1H)，7．92(s，1H)，7．94(s，1H0，7．59(d，1H)，6．8-7．5(m，14H)，5．32(s，2H)，5．30(s，2H)。

MS(C ₄₇H ₂₉F ₄N ₇S)：799．

Embodiment 19

With embodiment 3 and 4 operations, 2, (1-21) the compound result is as follows: compound R for 1-19,1-20 for two (3 '-indoles) thiazoles of 4- ¹R ²R ³R ⁴R ⁵R ⁶Productive rate:

1-21 H 5-Br 5-Br 6-OCH ₃CH ₃CH ₃81 compounds (1-19):

¹H(DMSO-d ₆)：8．51(s，1H)，7．91(s，1H)，7．79(s，1H)，7．69(s，1H)，7．49(s，1H)，7．38-7．00(m，15H)，6．27-6．23(m，5H)，5．06(s，2H)，4．98(s，2H)。

MS(C ₄₉H ₂₉Cl ₂F ₂N ₃O ₂S)：833(M，100)。Compound (1-20):

¹HNMR(DMSO-d ₆)：9．08(s，1H)，8．87(s，1H)，8．73(s，1H)，8．61(s，1H)，8．40(s，1H)，7．75(s，1H)，7．58(s，1H)，4．16(s，3H)，4．13(s，3H)，3．64(s，3H)，3．52(s，3H)。

MS(C ₂₇H ₁₉H ₆N ₁₁S)：644(M，89)。Compound (1-21):

¹HNMR(DMSO-d ₆)：8．76(s，1H)，7．96(s，1H)，7．90(s，1H)，7．70(s，1H)，7．47(d，J=7．5Hz，1H)，7．42(s，1H)，7．26(d，J=7．5Hz，1H)，7．10(s，1H)，4．03(s，3H)，3．79(s，3H)，3．64(s，3H)。

MS(C ₂₂H ₁₇Br ₂N ₃OS)：5．33(M，89)，531(M，100)，5．29(M，87)。

Embodiment 20

At U.S. NCI is extracorporeal anti-tumor screening system (Rubinstein, L.V.etal, J.Natl.Cancer Inst., 1990,82,1113 of guiding with the disease; Monks, A.etal., the same, 1991,93,757-766), measured four kind 2, two (3 '-indoles) thiazoles of 4-and three kind 3, the anti-tumor activity of two (3 '-indoles) pyrazine compounds of 6-.This test relates to determines that a kind of testing compound is the influence of the growth parameter(s) of about 60 clock human body tumour cells.These tumour cell major parts are solid tumor cell such as nonsmall-cell lung cancer, colorectal carcinoma, mammary cancer, kidney, prostate cancer, prostate cancer, malignant melanoma, chest cancer and some leukemia cells.The cellular toxicity of each compound is done in order to GI ₅₀, TGI and LC ₅₀Expression.They are represented respectively and suppress 50% cell growth, suppress the growth of cell and cause the volumetric molar concentration of the required medicine of 50% necrocytosis fully.This method for expressing can make us determine the effect of a kind of given medicine to the specific tumors cell fast, and the growth of cancer cells result of their inhibition 50% lists in table 1 and the table 2 respectively

Claims

1. two indoles heterogeneous ring compound is characterized in that having following molecular formula: Wherein,

R ¹, R ², R ³Or R ⁴=H, X, R ⁸, CF ₃, CN, NO ₂,

Benzimidazolyl-, benzofuryl, benzothienyl, NHCO ₂R ⁸, NHSO ₂R ⁸Or NHR ⁸, R ¹, R ², R ³Or R ⁴Be above-mentioned identical or different group,

R ⁵Or R ⁶=H, CH ₃,

SO ₂R ¹⁰Or COR ⁸,

R ⁷=H、CH ₃、SO ₂R ¹⁰、CO ₂R ⁸、

C ₆H ₅，

R ⁸=H, C _1-5Alkyl, the phenyl and the benzyl that do not replace or replace,

R ⁹=H, X, CH ₃, CF ₃Or CO ₂R ₈,

R ¹⁰=R ⁸Or C ₆H ₄CH ₃,

X=F, Cl, Br or I,

R=H or R ⁸

2. as claimed in claim 1 pair of indoles heterogeneous ring compound, wherein [Y]=

3. as claimed in claim 1 pair of indoles heterogeneous ring compound, wherein [Y]=

4. as claimed in claim 1 pair of indoles heterogeneous ring compound, wherein [Y]=

5. as claimed in claim 1 pair of indoles heterogeneous ring compound, wherein [Y]=

6. as claimed in claim 1 pair of indoles heterogeneous ring compound, wherein [Y]=

7. as claimed in claim 1 pair of indoles heterogeneous ring compound, wherein [Y]=

8. the preparation method of an as claimed in claim 1 pair of indoles heterogeneous ring compound is characterized in that being made respectively by following method:

(1), in polar solvent, molecular formula is

3-thioformamide benzazolyl compounds and molecular formula be

3-(α-bromine or chloro ethanoyl)-the indoles mol ratio is 1: during 0.8-2,, generate molecular formula and be 60 ℃ of reactions 0.1-5 hour to the reflux temperature

Two indoles thiophene compounds;

(2), work as R ⁵Or/and R ⁶During for the Methyl benzenesulfonyl base, be 1 as (1) described pair of indoles thiophene compound and monovalence metal hydroxides mol ratio: during 1-100, backflow 0.5-5 hour, remove the Methyl benzenesulfonyl base, generate R ⁵Or/and R ⁶Two indoles thiophene compounds for H;

(3), work as R ⁵Or/and R ⁶During for H, as (1) described pair of indoles thiophene compound, monovalence metal carbonate or alkaline earth metal hydride MH and idoalkane R ⁸The mol ratio of I is 1: 1-20: 1-20, in solvent, under refluxing, reacted 1-50 hour with room temperature, and generate R ⁵Or/and R ⁶Be R ⁸Two indoles thiophene compounds; Perhaps as (1) described R ⁵Or/and R ⁶Two indoles thiophene compounds and R during for H ⁸COCl or R ¹⁰SO ₂The organic amine compound mol ratio 1 that contains lone-pair electron on Cl, the nitrogen-atoms: 0.8-1.2: during 1-10, in solvent, to reflux temperature, reacted 1-20 hour, generate R with room temperature ⁵Or/and R ⁶=R ⁸CO is or/and R ¹⁰SO ₂Two indoles thiophene compounds;

(4), molecular formula is 3-glyoxylyl chloro-indoles, molecular formula is

3-(2-glycyl)-indoles, the organic amine compound mol ratio that contains lone-pair electron on the nitrogen-atoms is 1: 0.70-2: 1-10, in polar solvent, 0 ℃ of reaction 5-10 hour to the room temperature obtains the diketone amide product; Two keto-amides and liquefied ammonia mol ratio are 1: during 1-10000, with 40-90 ℃ of reaction 10-60 hour, generate 3 in solvent, two indoles pyrazine-2 ketone compounds of 5-;

With the organic amine compound mol ratio that contains lone-pair electron on 1-124 Triazole oxygen three (dimethyl amine) phosphonic acids phosphofluoric acid ester or bromo three (dimethyl amine) phosphonic acids phosphofluoric acid ester and the nitrogen-atoms be 1: 0.8-1.5: 0.8-1.5: 1-10, in solvent, reacted 1-6 hour under the room temperature, generate dipeptide compound, this dipeptide compound is when-25 ℃ to 0 ℃ of solvent neutralizations and LiAlH ₄Reacted 0.1-2 hour, and reacted 1-5 hour to room temperature and acidic conditions at-5 ℃ then, in polar solvent, stirred 1-5 days under the room temperature again, generate 3, the two indoles pyrazines of 6--2-ketone compound, wherein dipeptide compound and LiAlH ₄Mol ratio is 1: 1-5;

(6), molecular formula is

α-azido-ethanoyl indoles, in solvent and under the room temperature, feed hydrogen, keep under the 1-5kg pressure, use content 5-15%Pd/C, catalyst weight is than being 5-100%, catalysis 5-36 hour, product self condensation and oxidation generate 3, the two indoles pyrazine compounds of 6-;

(7), molecular formula is Compound and molecular formula be

3-tributyl tin benzazolyl compounds, use the organic palladium catalyst, mol ratio is followed successively by 1: 0.8-2: 0.05-0.25,60 ℃ to reflux temperature, reaction is 1-5 hour in polar solvent, generates 2, two (3 '-indoles) oxazoline compounds of 4-;

(8), molecular formula is 3-tributyl tin indoles and 3,5-dichloro or bromo-pyrazine, under the organic palladium catalyst, mol ratio is followed successively by 1: 0.2-1.5: 0.05-0.50; In polar solvent backflow 1-5 hour, generate 2, two (3 '-indoles) pyrazine compounds of 6-;

The organic amine compound that contains lone-pair electron on the aforesaid nitrogen-atoms is the C that comprises trioctylamine, triethylamine, Trimethylamine 99, diethylamine, dibutylamine _1-24Tertiary amine, secondary amine, primary amine or tetramethyl-two quadrols, described the valency palladium catalyst is arranged is four (tri octyl phosphine) palladium, four (trioctylphosphine) phosphorus palladium, dichloro two (acetonitrile-base) palladium, dichloro two (diphenylphosphine) palladium, R ^1-6With claim 1.

9. one kind as claim 1, and 2,3,4,5,6 or the purposes of 7 described pairs of indoles heterogeneous ring compounds, it is characterized in that being used to prepare anti-inflammatory or cancer therapy drug.