CN105017254B - 4‑（4‑（（6 base of 9H purine）Sulphur）Phenyl）2 amine derivative of thiazolyl and its production and use - Google Patents
4‑（4‑（（6 base of 9H purine）Sulphur）Phenyl）2 amine derivative of thiazolyl and its production and use Download PDFInfo
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- CN105017254B CN105017254B CN201410175658.6A CN201410175658A CN105017254B CN 105017254 B CN105017254 B CN 105017254B CN 201410175658 A CN201410175658 A CN 201410175658A CN 105017254 B CN105017254 B CN 105017254B
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- 0 C*1CCOCC1 Chemical compound C*1CCOCC1 0.000 description 3
- SJRJJKPEHAURKC-UHFFFAOYSA-N CN1CCOCC1 Chemical compound CN1CCOCC1 SJRJJKPEHAURKC-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/26—Heterocyclic compounds containing purine ring systems with an oxygen, sulphur, or nitrogen atom directly attached in position 2 or 6, but not in both
- C07D473/36—Sulfur atom
- C07D473/38—Sulfur atom attached in position 6
Abstract
The invention belongs to chemical medicine, and in particular to 4 (4 ((6 base of 9H purine) sulphur) phenyl) 2 amine derivative of thiazolyl and its production and use.The invention provides a kind of 4 (4 ((6 base of 9H purine) sulphur) phenyl) 2 amine derivative of thiazolyl, its structure is shown in formula I.Present invention also offers the preparation method of above-mentioned 4 (4 ((6 base of 9H purine) sulphur) phenyl) 2 amine derivative of thiazolyl and its purposes in tumor is prepared.The synthetic route that the present invention is provided is shorter, and reaction condition is simple, and yield is high, easily derivative, and a series of compounds that the present invention is provided have preferable antitumor activity and relatively low toxicity.The present invention provides new selection to prepare antineoplastic.
Description
Technical field
The invention belongs to chemical medicine, more particularly to 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2-
Amine derivative and its production and use.
Background technology
Deteriorate with global environment, malignant tumour becomes the primary arch-criminal for threatening human health, latest data shows, currently
Chinese tumor incidence and the death rate are all in acceleration mode development, bring huge pressure to society and family.It is current main
Treatment means are operative treatment, radiotherapy and chemotherapy, wherein, substantial amounts of clinical practice and research confirm chemotherapeutics
Critical role, so finding new construction, the chemotherapeutics of novel targets is referred to as the task of top priority.
In antineoplastic, the medicine for cell cycle related proteins is it has been shown that good clinical efficacy and market
Prospect is such as：Taxol, vincristine etc..But there is big toxicity, poor selectivity, easily occur in such compound.
Therefore, such medicine further should be studied, is found potential GAP-associated protein GAP target spot, be controlling for tumour and drug-resistant tumor
Treat and thinking is provided.
The present invention by by area of computer aided pharmaceutical means, for mitosis check point GAP-associated protein GAP, by using
Pharmacophore technology, the related known compound storehouse of screening, and from the beginning the compound that screening is obtained is designed with reference to computer, send out
Existing new compound.Synthesize such compound by designing, screen through tumor cell in vitro proliferation inhibition test, find wherein
Some compounds have certain inhibitory activity in various kinds of cell strain, and its toxicity are commented by internal acute toxicity testing
Valency.
The content of the invention
First technical problem to be solved by this invention is to provide class 4- (4- ((9H- purine -6- bases) sulphur) phenyl)
Thiazolyl -2- amine derivatives, structure is as shown in formula I：
Wherein, R1～R4 is independently H, C1～C8 alkyl, C1～C8 alkoxy or halogens；
R5For
X1～X5 is independently N or C；
R6 is H or C1～C4 alkyl；
R7～R25 be independently-H, halogen, C1～C8 alkyl of halogen substiuted, C1～C8 alkyl, C1～C8 alkoxyls,
C3～C8 cycloalkyl, 3～8 circle heterocycles alkyl,C2～C8 thiazolinyls, C2～C8 alkynyls ,-CN ,-OH, C3～C8 rings
Thiazolinyl, 3～8 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Hetero atom in 3～8 described circle heterocycles alkyl or 3～8 circle heterocycles thiazolinyls
For N, O or S, heteroatomic number is 1～3.
Preferably, R1～R4 is independently H, C1～C4 alkyl, C1～C4 alkoxy or halogens；
R5For
X1～X5 is independently N or C；
R6 is H or C1～C4 alkyl；
R7～R25 be independently-H, halogen, C1～C4 alkyl of halogen substiuted, C1～C4 alkyl, C1～C4 alkoxyls,
C3～C6 cycloalkyl, 3～6 circle heterocycles alkyl,C2～C4 thiazolinyls, C2～C4 alkynyls ,-CN ,-OH, C3～C8 rings
Thiazolinyl, 3～6 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Hetero atom in 3～6 described circle heterocycles alkyl or 3～6 circle heterocycles thiazolinyls
For N, O or S, heteroatomic number is 1～3.
It is further preferred that
R1～R4 is independently H or C1～C4 alkyl；
R5For
X1～X5 is independently N or C；
R6 is H or C1～C4 alkyl；
R7～R25 is independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl, C1～C4 alkoxyls, C3～C6 cycloalkanes
Base, 6 circle heterocycles alkyl,-NO2Or-OCF3；Hetero atom in 6 described circle heterocycles alkyl be N, O or S, it is miscellaneous
The number of atom is 1～3.
Most preferably,
R1～R4 is independently H or methyl；
R5For
X1～X5 is independently N or C；
R6 is H；
R7～R25 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl, C1～C4 alkoxyls, cyclopropyl,-NO2Or-OCF3；.
Used as the preferred version of the present invention, above-mentioned 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derives
In thing, R5 isStructure is as shown in formula II：
Wherein, R1～R4 is independently H, C1～C8 alkyl, C1～C8 alkoxy or halogens；
X1～X5 is independently N or C；
R6 is H or C1～C4 alkyl；
R7～R10 be independently-H, halogen, C1～C8 alkyl of halogen substiuted, C1～C8 alkyl, C1～C8 alkoxyls,
C3～C8 cycloalkyl, 3～8 circle heterocycles alkyl,C2～C8 thiazolinyls, C2～C8 alkynyls ,-CN ,-OH, C3～C8
Cycloalkenyl group, 3～8 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Miscellaneous original in 3～8 described circle heterocycles alkyl or 3～8 circle heterocycles thiazolinyls
Son is N, O or S, and heteroatomic number is 1～3.
Preferably, R1～R4 is independently H, C1～C4 alkyl, C1～C4 alkoxy or halogens；
X1～X5 is independently N or C；
R6 is H or C1～C4 alkyl；
R7～R10 be independently-H, halogen, C1～C4 alkyl of halogen substiuted, C1～C4 alkyl, C1～C4 alkoxyls,
C3～C6 cycloalkyl, 3～6 circle heterocycles alkyl,C2～C4 thiazolinyls, C2～C4 alkynyls ,-CN ,-OH, C3～C8
Cycloalkenyl group, 3～6 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Miscellaneous original in 3～6 described circle heterocycles alkyl or 3～6 circle heterocycles thiazolinyls
Son is N, O or S, and heteroatomic number is 1～3.
It is further preferred that
R1～R4 is independently H or C1～C4 alkyl；
X1～X5 is independently N or C；
R6 is H or C1～C4 alkyl；
R7～R10 is independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl, C1～C4 alkoxyls, C3～C6 cycloalkanes
Base, 6 circle heterocycles alkyl,-NO2Or-OCF3；Hetero atom in 6 described circle heterocycles alkyl be N, O or S, it is miscellaneous
The number of atom is 1～3.
It is further preferred that
R1～R4 is independently H or methyl；
X1～X5 is independently N or C；
R6 is H；
R7～R10 is independently-H ,-F ,-Cl or-Br.
Used as the preferred version of the present invention, above-mentioned 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derives
In thing, R5 isStructural formula is as shown in formula III：
Wherein, R1～R4 is independently H, C1～C8 alkyl, C1～C8 alkoxy or halogens；
R6 is H or C1～C4 alkyl；
R11～R15 be independently-H, halogen, C1～C8 alkyl of halogen substiuted, C1～C8 alkyl, C1～C8 alkoxyls,
C3～C8 cycloalkyl, 3～8 circle heterocycles alkyl,C2～C8 thiazolinyls, C2～C8 alkynyls ,-CN ,-OH, C3～C8
Cycloalkenyl group, 3～8 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Miscellaneous original in 3～8 described circle heterocycles alkyl or 3～8 circle heterocycles thiazolinyls
Son is N, O or S, and heteroatomic number is 1～3.
Preferably, R1～R4 is independently H, C1～C4 alkyl, C1～C4 alkoxy or halogens；
R6 is H or C1～C4 alkyl；
R11～R15 be independently-H, halogen, C1～C4 alkyl of halogen substiuted, C1～C4 alkyl, C1～C4 alkoxyls,
C3～C6 cycloalkyl, 3～6 circle heterocycles alkyl,C2～C4 thiazolinyls, C2～C4 alkynyls ,-CN ,-OH, C3～C8
Cycloalkenyl group, 3～6 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Miscellaneous original in 3～6 described circle heterocycles alkyl or 3～6 circle heterocycles thiazolinyls
Son is N, O or S, and heteroatomic number is 1～3.
It is further preferred that
R1～R4 is independently H or C1～C4 alkyl；
R6 is H or C1～C4 alkyl；
R11～R15 is independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl, C1～C4 alkoxyls, C3～C6 cycloalkanes
Base, 6 circle heterocycles alkyl,-NO2Or-OCF3；Hetero atom in 6 described circle heterocycles alkyl be N, O or S, it is miscellaneous
The number of atom is 1～3.
It is further preferred that
R1～R4 is independently H or methyl；
R6 is H；
R11～R15 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl, C1～C4 alkoxyls, cyclopropyl,Or-NO2。
Used as the preferred version of the present invention, above-mentioned 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derives
In thing, R5 isStructural formula is as shown in formula IV：
Wherein, R1～R4 is independently H, C1～C8 alkyl, C1～C8 alkoxy or halogens；
R6 is H or C1～C4 alkyl；
R16～R20 be independently-H, halogen, C1～C8 alkyl of halogen substiuted, C1～C8 alkyl, C1～C8 alkoxyls,
C3～C8 cycloalkyl, 3～8 circle heterocycles alkyl,C2～C8 thiazolinyls, C2～C8 alkynyls ,-CN ,-OH, C3～C8
Cycloalkenyl group, 3～8 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Miscellaneous original in 3～8 described circle heterocycles alkyl or 3～8 circle heterocycles thiazolinyls
Son is N, O or S, and heteroatomic number is 1～3.
Preferably, R1～R4 is independently H, C1～C4 alkyl, C1～C4 alkoxy or halogens；
R6 is H or C1～C4 alkyl；
R16～R20 be independently-H, halogen, C1～C4 alkyl of halogen substiuted, C1～C4 alkyl, C1～C4 alkoxyls,
C3～C6 cycloalkyl, 3～6 circle heterocycles alkyl,C2～C4 thiazolinyls, C2～C4 alkynyls ,-CN ,-OH, C3～C8
Cycloalkenyl group, 3～6 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Miscellaneous original in 3～6 described circle heterocycles alkyl or 3～6 circle heterocycles thiazolinyls
Son is N, O or S, and heteroatomic number is 1～3.
It is further preferred that
R1～R4 is independently H or C1～C4 alkyl；
R6 is H or C1～C4 alkyl；
R16～R20 is independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl, C1～C4 alkoxyls, C3～C6 cycloalkanes
Base, 6 circle heterocycles alkyl,-NO2Or-OCF3；Hetero atom in 6 described circle heterocycles alkyl be N, O or S, it is miscellaneous
The number of atom is 1～3.
It is further preferred that
R1～R4 is independently H or methyl；
R6 is H；
R11～R15 is independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl or C1～C4 alkoxyls.
Used as the preferred version of the present invention, above-mentioned 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derives
In thing, R5 isStructural formula is as shown in formula V：
Wherein, R1～R4It is independently H, C1～C8 alkyl, C1～C8 alkoxy or halogens；
R6For H or C1～C4 alkyl；
R21～R25Be independently-H, halogen, C1～C8 alkyl of halogen substiuted, C1～C8 alkyl, C1～C8 alkoxyls,
C3～C8 cycloalkyl, 3～8 circle heterocycles alkyl,C2～C8 thiazolinyls, C2～C8 alkynyls ,-CN ,-OH, C3～C8
Cycloalkenyl group, 3～8 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Miscellaneous original in 3～8 described circle heterocycles alkyl or 3～8 circle heterocycles thiazolinyls
Son is N, O or S, and heteroatomic number is 1～3.
Preferably, R1～R4It is independently H, C1～C4 alkyl, C1～C4 alkoxy or halogens；
R6For H or C1～C4 alkyl；
R21～R25Be independently-H, halogen, C1～C4 alkyl of halogen substiuted, C1～C4 alkyl, C1～C4 alkoxyls,
C3～C6 cycloalkyl, 3～6 circle heterocycles alkyl,C2～C4 thiazolinyls, C2～C4 alkynyls ,-CN ,-OH, C3～C8
Cycloalkenyl group, 3～6 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Miscellaneous original in 3～6 described circle heterocycles alkyl or 3～6 circle heterocycles thiazolinyls
Son is N, O or S, and heteroatomic number is 1～3.
It is further preferred that
R1～R4 is independently H or C1～C4 alkyl；
R6 is H or C1～C4 alkyl；
R21～R25 is independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl, C1～C4 alkoxyls, C3～C6 cycloalkanes
Base, 6 circle heterocycles alkyl,-NO2Or-OCF3；Hetero atom in 6 described circle heterocycles alkyl be N, O or S, it is miscellaneous
The number of atom is 1～3.
It is further preferred that
R1～R4 is independently H or methyl；
R6 is H；
R7～R25 is independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl or C1～C4 alkoxyls.
Most preferably, above-mentioned 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives, including followingization
Compound：
N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) Pyrazinamide, N- (4- (4-
((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -2- fluorine Pyrazinamides, N- (4- (4- ((9H- purine -
6- yls) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl)-pyrazine -2- acid amides, N- (4- (4- ((9H- purine -6- bases) sulphur) -2,
6- 3,5-dimethylphenyls) thiazol-2-yl)-pyrimidine -5- acid amides, N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- dimethyl benzenes
Base) thiazol-2-yl)-pyridazine -4- acid amides, 1- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazole -2-
Base) -3- (4- chloro- 3- (trifluoromethyl) phenyl) thiocarbamide, 1- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls)
Thiazol-2-yl) -3- (4- methyl) phenyl) thiocarbamide, 1- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiophenes
Azoles -2- bases) -3- (4- methoxyl groups) phenyl) thiocarbamide, 1- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiophenes
Azoles -2- bases) -3- (3- bromophenyls) thiocarbamide, 1- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazole -2-
Base) -3- (2- bromophenyls) thiocarbamide, (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazole -2-
Base) -3- (4- ethyoxyls) cinnamamide, (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazole -
2- yls) -3- (4- tert-butyl group bases) cinnamamide, (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiophenes
Azoles -2- bases) -3- (4- (trifluoromethyl) phenyl) cinnamamide, (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- diformazans
Base phenyl) thiazol-2-yl) -3- (4- (methoxyethoxy) phenyl) cinnamamide, (E)-N- (4- (4- ((9H- purine -6- bases)
Sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4- (cyclopropyl) phenyl) cinnamamide, ((((9H- is fast for 4- for 4- for (E)-N-
Purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4- (morpholinyl) phenyl) cinnamamide, (E)-N- (4- (4-
((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (3- fluoro-phenyls) cinnamamide, (E)-N- (4-
(4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (2- fluoro-phenyls) cinnamamide, 1- (4-
(4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- phenylthioureas, 1- (4- (4- ((9H- purine -
6- yls) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4- (trifluoromethyl) phenyl) thiocarbamide, ((((9H- is fast for 4- for 4- for 1-
Purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4- (methoxyl group) phenyl) thiocarbamide, ((((9H- is fast for 4- for 4- for 1-
Purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (2- bromophenyls) thiocarbamide, 1- (4- (4- ((9H- purine -6-
Base) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4- fluorophenyls) thiocarbamide, 1- (4- (4- ((9H- purine -6- bases) sulphur) -
2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4- chloro- 3- (trifluoromethyl) phenyl) thiocarbamide.
The corresponding chemical constitution of above-claimed cpd is respectively：
Second technical problem to be solved by this invention is to provide above-mentioned 4- (4- ((9H- purine -6- bases) sulphur) phenyl)
The preparation method of thiazolyl -2- amine derivatives.The method is comprised the following steps：
Wherein, R1～R4 is independently H, C1～C8 alkyl, C1～C8 alkoxy or halogens；
X1～X5 is independently N or C；
R5For
R6 is H or C1～C4 alkyl；
R7～R25 be independently-H, halogen, C1～C8 alkyl of halogen substiuted, C1～C8 alkyl, C1～C8 alkoxyls,
C3～C8 cycloalkyl, 3～8 circle heterocycles alkyl,C2～C8 thiazolinyls, C2～C8 alkynyls ,-CN ,-OH, C3～C8 rings
Thiazolinyl, 3～8 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Hetero atom in 3～8 described circle heterocycles alkyl or 3～8 circle heterocycles thiazolinyls
For N, O or S, heteroatomic number is 1～3；
Step A：Compound 1 is reacted with chloroacetic chloride in the basic conditions and prepares compound 2；Described alkali is carbonic acid
In potassium, sodium carbonate, potassium phosphate, cesium carbonate or potassium hydroxide any one；
Step B：Compound prepared and acylation reaction under Catalyzed by Anhydrous Aluminium Chloride with chloroacetic chloride in compound 2 there is
3；
Step C：Hydrolysis prepares compound 4 to compound 3 in acid condition；
Step D：Compound 4 is reacted in the concentrated hydrochloric acid of ice salt bath with natrium nitrosum and forms diazol, then iodine occurs with KI
Generation reaction prepares compound 5；
Step E：Compound 6 prepared and bromo-reaction with bromide reagent in compound 5 there is；Described bromide reagent is bromine
Change any one in cuprous, bromine or tetrabutyl tribromide ammonium；
Step F：Hantsch with thiocarbamide and compound 7 prepared into thiazole reaction in compound 6 there is；Reaction temperature is 72
～80 DEG C, the time is 4h～8h；
Step G：Preparing of 6～8h is reacted at compound 7 and Ismipur in the basic conditions 125～150 DEG C
Compound 8；Described alkalescence is any one in potassium hydroxide, potassium carbonate, potassium tert-butoxide, cesium carbonate or potassium phosphate；
Step H：Compound 8 is condensed with isonicotinic acid, substituted cinnamic acid is replaced respectively, or different with isocyanates, replacement is replaced
Thiocyanates prepare compound 9 into urea.
In above-mentioned preparation method step A, reaction solvent used is in dichloromethane, tetrahydrofuran, chloroform or toluene
Meaning is a kind of, 0.5～3h of reaction time.
In above-mentioned preparation method step B, reaction temperature is 15～30 DEG C, and the reaction time is 1～3h, reacts solvent used
For in dichloromethane, tetrahydrofuran, chloroform or toluene any one.
In above-mentioned preparation method step C, under conditions of described acid condition is hydrochloric acid, reaction temperature is 80～100 DEG C,
Hydrolysis time is 1～2h.
In above-mentioned preparation method step D, iodide reaction temperature is 15～30 DEG C, and the iodide reaction time is 6～7h.
In above-mentioned preparation method step E, the reaction temperature of cuprous bromide bromo is adopted for 70 DEG C；Using bromine or the tetrabutyl
The reaction temperature of tribromide ammonium bromo is 15～30 DEG C；Reaction time is 7～9h.
3rd technical problem to be solved by this invention is to provide above-mentioned 4- (4- ((9H- purine -6- bases) sulphur) phenyl)
Purposes of the thiazolyl -2- amine derivatives in antineoplastic is prepared.
Present invention also offers the prodrug of above-mentioned 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives
Or hydrate.Described prodrug is the derivative of above-claimed cpd, their own may have weaker activity or even without
Activity, but upon administration, (such as by metabolism, solvolysis or other mode) is converted to accordingly in physiological conditions
Biologically active form.
Present invention also offers such pharmaceutical composition, is by above-mentioned 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazole
Base -2- amine derivatives add other pharmaceutically acceptable complementary compositions and are prepared.
4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives of the present invention are the bases in a large amount of screenings
Obtain on plinth, with antitumor activity, the development and application for antineoplastic provides new selection and thinking.
Specific embodiment
1 I A N- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) different nicotinoyl
Amine
Step 1
3,5- dimethylanilines (0.082mol) are weighed in 40mL dichloromethane, anhydrous K is added2CO3(0.164mol),
Ice bath cools down 30min, and chloroacetic chloride (0.164mol) is added dropwise with constant pressure funnel, and reaction 2h, TLC are warmed to room temperature naturally after dripping off
(PE:EA=1:1) detection reaction, question response add 20mL water quenchings to go out completely, are dissolved with dichloromethane, wash repeatedly organic phase 2 with water
Secondary, watery hydrochloric acid is washed 2 times, collects organic phase, and concentrate drying obtains N- (3,5- 3,5-dimethylphenyl) acetamide 13.30g, is greyish white color chips
Shape crystalline product；
1H NMR:(DMSO-d6,400MHz):2.01(s,3H),2.22(s,6H),6.66(s,1H),7.19(s,2H),
9.74 (s, 1H) step 2
Weigh in aluminum trichloride (anhydrous) (369.09mmol) and dry dichloromethane solution, under ice-water bath, chloroacetic chloride is added dropwise
(246.06 mmol), adds N- (3,5- 3,5-dimethylphenyl) acetamide (82.02mmol) afterwards, is warming up to room temperature, react 3h,
TLC(PE:EA=1:1) detection reaction, question response terminate, and by reactant liquor punching analysis in 600mL water+20mL concentrated hydrochloric acids, add
Dichloromethane dissolves, extraction, collects organic phase, and concentrate drying directly throws next step；
1H NMR:(DMSO-d6,400MHz):2.03(s,3H),2.14(s,6H),2.42(s,3H),7.26(s,2H),
9.88(s,1H)
Step 3
60mL2N HCl and 60mL water is added in the solid that will be obtained after concentration, 80～100 DEG C of hydrolysis 2h, TLC are heated to
(PE:EA=1:1) detect reaction end.Question response terminates, and adds saturated sodium bicarbonate to be quenched, modulates pH=8～9, has a large amount of
Solids of sedimentation is separated out, and suction filtration solid, dried in vacuum overnight obtain 13.04g pale yellow powder solids, are 1- (4- amino -2,6-
3,5-dimethylphenyl) acetophenone；
1H NMR:(DMSO-d6,400MHz):2.06(s,6H),2.34(s,3H),5.17(s,2H),6.21(s,2H)
Step 4
1- (4- amino -2,6- 3,5-dimethylphenyls) acetophenone (82.1mmol) is weighed in 120mL concentrated hydrochloric acids and 40mL water,
Temperature is cooled under ice salt bath<5 DEG C, NaNO2 (98.52mmol) solution is added dropwise, process keeping temperature is added dropwise and is less than 5 DEG C, be added dropwise
20min is reacted after finishing, KI (123.15mmol) solution is added dropwise afterwards, after adding, be warmed to room temperature naturally reaction 7h, TLC (PE:EA
=4:1) reaction process is detected, question response terminates, is quenched with saturated sodium bicarbonate, is extracted with ethyl acetate 4 times, merges organic
Phase, column chromatographic isolation and purification obtain 1- (iodo- 2, the 6- 3,5-dimethylphenyls of the 4-) acetophenone of 14.35g brown oil liquid.
1H NMR:(DMSO-d6,400MHz):2.14(s,6H),2.44(s,3H),7.48(s,2H)
Step 5
1- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) acetophenone (52.17mmol) is weighed in ethyl acetate/chloroform (30mL：
10mL) mixed solution, adds CuBr2 (102.98mmol), 65～70 DEG C of backflows 8h, TLC (PE:EA=30:1) detection react into
Journey, question response terminate, and are extracted with saturated sodium bicarbonate and ethyl acetate, collect organic phase, obtain brown-red solid 18.6g2-
Bromo- 1- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) ethyl ketone.Next step is thrown directly.
Step 6
The bromo- 1- of 2- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) ethyl ketones (52mmol) and thiocarbamide (52mmol) are weighed in 80mL ethanol
In, it is stirred overnight at 72～80 DEG C, produces a large amount of white opacities, reaction terminates suction filtration, washs filter cake with ethanol, dry
22g white solids.
1H NMR:(DMSO-d6,400MHz):2.14(s,6H),6.46(s,1H),6.96(s,2H),7.32(s,2H).
Step 7
Weigh 4- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) thiazolyl -2- amine (0.515mmol), Ismipur
(1.03mmol), Cu2O (0.026mmol), and KOH (1.03mmol) in DMF (40mL) and water (10mL), 125～130 DEG C
Lower reaction is overnight.TLC monitoring reactions, question response terminate, and add aqueous hydrochloric acid solution to be quenched, are extracted with ethyl acetate and water repeatedly,
Organic phase is collected, concentrate drying obtains yellow solid product.
1H NMR:(DMSO-d6,400MHz):2.15(s,6H),6.47(s,1H),6.95(s,2H),7.34(s,2H),
8.49(s,1H),8.58(s,1H),13.57(s,1H)
Step 8
Weigh 4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazolyl -2- amine (2.29mmol), different cigarette
, in THF, overnight, question response terminates stirring at normal temperature, instead for sour (2.29mmol), HATU (2.29mmol) and TEA (11.45mmol)
Multiplexing ethyl acetate and water extraction, collect organic phase, column chromatography (PE:EA=4:1) sterling, yellow solid, yield 65% are obtained.
1H NMR:(DMSO-d6,400MHz):2.15(s,6H),7.31(s,1H),7.42(s,2H),8.00(d,2H),
8.52(s,1H),8.60(s,1H),8.82(d,2H),13.33(s,2H)
MS-ESI(m/z)：482.09(M+Na+)
2 I B N- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -2- fluorine is different
Niacinamide
Method is with embodiment 1.
1H NMR:(DMSO-d6,400MHz):2.15(s,6H),7.28(s,1H),7.25(s,2H),7.75(d,1H),
7.86(s,2H),8.60(s,1H),8.82(d,2H),8.62(d,1H),11.03(s,1H),13.13(s,1H)
MS-ESI(m/z)：477.09(M+H+)
3 I C N- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl)-pyrazine -
2- acid amides
Method is with embodiment 1.
1H NMR:(DMSO-d6,400MHz):2.14(s,6H),7.25(s,2H),7.28(s,1H),8.53(s,1H),
8.57(s,1H),8.89(d,1H),9.02(d,2H),9.96(s,1H),10.03(s,1H),13.43(s,1H)
MS-ESI(m/z)：460.20(M+H+)
4 I D N- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl)-pyrimidine -
5- acid amides
Method is with embodiment 1.
1H NMR:(DMSO-d6,400MHz):2.15(s,6H),7.22(s,2H),7.26(s,1H),8.53(s,1H),
8.57(s,1H),9.36(s,2H),9.51(s,1H),10.03(s,1H),12.03(s,1H)
MS-ESI(m/z)：460.20(M+H+)
5 I E N- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl)-pyridazine -
4- acid amides
Method is with embodiment 1.
1H NMR:(DMSO-d6,400MHz):2.16(s,6H),7.22(s,2H),7.26(s,1H),8.12(d,1H),
8.53(s,1H),8.57(s,1H),9.51(d,1H),9.79(s,1H),10.03(s,1H),11.02(s,1H)
MS-ESI(m/z)：460.20(M+H+)
6 I F1- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4-
Chloro- 3- (trifluoromethyl) phenyl) thiocarbamide
Step 1
Appropriate 3,5- dimethylanilines (0.082mol) are weighed in 40mLDCM, anhydrous K 2CO3 is added
(0.164mol), ice bath cooling 30min, is added dropwise chloroacetic chloride (0.164mol) with constant pressure funnel, rises to naturally room after dripping off
Temperature reaction 2h, TLC (PE:EA=2:1) detection reaction, question response add 20mL water quenchings to go out completely, are dissolved with DCM, are washed with water repeatedly
Organic phase 2 times, watery hydrochloric acid are washed 2 times, collect organic phase, and concentrate drying obtains N- (3,5- 3,5-dimethylphenyl) acetamide 13.30g, is
Canescence flat crystal product；
1H NMR:(DMSO-d6,400MHz):2.01(s,3H),2.22(s,6H),6.66(s,1H),7.19(s,2H),
9.74(s,1H)
Step 2
Weigh in appropriate aluminum trichloride (anhydrous) (369.09mmol) and dry dichloromethane solution, be added dropwise under ice-water bath
Chloroacetic chloride (246.06mmol), adds N- (3,5- 3,5-dimethylphenyl) acetamide (82.02mmol) afterwards, is warming up to room temperature, instead
Answer 3h, TLC (PE:EA=1:1) detection reaction, question response terminate, by reactant liquor punching analysis in 600mL water+20mL concentrated hydrochloric acids, then
DCM dissolvings, extraction is added to collect organic phase, concentrate drying directly throws next step；
1H NMR:(DMSO-d6,400MHz):2.03(s,3H),2.14(s,6H),2.42(s,3H),7.26(s,2H),
9.88 (s, 1H) step 3
60mL2N HCl and 60mL water is added in the solid that will be obtained after concentration, 80～100 DEG C of hydrolysis 2h, TLC are heated to
(PE:EA=1:1) detect reaction end.Question response terminates, and adds saturated sodium bicarbonate to be quenched, modulates pH=8～9, has a large amount of
Solids of sedimentation is separated out, and suction filtration solid, dried in vacuum overnight obtain 13.04g pale yellow powder solids, are 1- (4- amino -2,6-
3,5-dimethylphenyl) acetophenone.
1H NMR:(DMSO-d6,400MHz):2.06(s,6H),2.34(s,3H),5.17(s,2H),6.21(s,2H)
Step 4
1- (4- amino -2,6- 3,5-dimethylphenyls) acetophenone (82.1mmol) is weighed in 120mL concentrated hydrochloric acids and 40mL water,
Temperature is cooled under ice salt bath<5 DEG C, NaNO2 solution is added dropwise, process keeping temperature is added dropwise and is less than 5 DEG C, react after completion of dropping
20min, is added dropwise KI solution afterwards, and reaction 7h, TLC (PE are warmed to room temperature naturally after adding:EA=4:1) reaction process is detected, is treated
Reaction terminates, and is quenched with saturated sodium bicarbonate, is extracted with ethyl acetate 4 times, merges organic phase, and column chromatographic isolation and purification is obtained
1- (iodo- 2, the 6- 3,5-dimethylphenyls of the 4-) acetophenone of 14.35g brown oil liquid.
1H NMR:(DMSO-d6,400MHz):2.14(s,6H),2.44(s,3H),7.48(s,2H)
Step 5
1- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) acetophenone (52.17mmol) is weighed in ethyl acetate/chloroform (30mL：
10mL) mixed solution, adds CuBr2 (102.98mmol), 65～70 DEG C of backflows 8h, TLC (PE:EA=30:1) detection react into
Journey, question response terminate, and are extracted with saturated sodium bicarbonate and ethyl acetate, collect organic phase, obtain brown-red solid 18.6g2-
Bromo- 1- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) ethyl ketone.Next step is thrown directly.
Step 6
The bromo- 1- of 2- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) ethyl ketones (52mmol) and thiocarbamide (52mmol) are weighed in 80mL ethanol
In, it is stirred overnight at 72～80 DEG C, produces a large amount of white opacities, reaction terminates suction filtration, washs filter cake with ethanol, dry
22g white solids.
1H NMR:(DMSO-d6,400MHz):2.14(s,6H),6.46(s,1H),6.96(s,2H),7.32(s,2H).
Step 7
Weigh 4- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) thiazolyl -2- amine (0.515mmol), Ismipur
(1.03mmol), Cu2O (0.026mmol), and KOH (1.03mmol) in DMF (40mL) and water (10mL), 125～130 DEG C
Lower reaction is overnight.TLC monitoring reactions, question response terminate, and add aqueous hydrochloric acid solution to be quenched, are extracted with ethyl acetate and water repeatedly,
Organic phase is collected, concentrate drying obtains yellow solid product.
1H NMR:(DMSO-d6,400MHz):2.15(s,6H),6.47(s,1H),6.95(s,2H),7.34(s,2H),
8.49(s,1H),8.58(s,1H),13.57(s,1H)
Step 8
Weigh 4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazolyl -2- amine (1.51mmol), 4-
Chloro- 3- (trifluoromethyl)-isocyanates (3.02mmol), DIPEA (4.53mmol) in DCM, stirring at normal temperature overnight, question response
Terminate, extracted with ethyl acetate and water repeatedly, collect organic phase, column chromatography (PE:EA=15:1) obtain sterling, white powder,
Yield 45%.
1H NMR:(DMSO-d6,400MHz):2.15(s,6H),7.12(s,1H),7.41(s,2H),7.67(d,1H),
7.72(d,1H),8.13(s,1H),8.51(s,1H),8.60(s,1H),9.45(s,1H),10.83(s,1H),13.60(s,
1H)
MS-ESI(m/z)：598.06(M+Na+)
7 I G1- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4- first
Base) phenyl) thiocarbamide
Method is with embodiment 6.
1H NMR:(DMSO-d6,400MHz):2.15(s,6H),2.32(s,3H),7.12(s,1H),7.41(s,2H),
7.67(d,2H),7.72(d,2H),8.51(s,1H),8.60(s,1H),9.02(s,1H),10.57(s,1H),13.71(s,
1H)
MS-ESI(m/z)：510.60(M+Na+)
8 I H1- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4- first
Epoxide) phenyl) thiocarbamide
Method is with embodiment 6.
1H NMR:(DMSO-d6,400MHz):2.14(s,6H),3.83(s,3H),6.92(d,2H),7.12(s,1H),
7.39(s, 2H),7.57(d,2H),8.51(s,1H),8.60(s,1H),9.02(s,1H),10.57(s,1H),13.71(s,
1H)
MS-ESI(m/z)：526.60(M+Na+)
9 I I1- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (3- bromines
Phenyl) thiocarbamide
Method is with embodiment 6.
1H NMR:(DMSO-d6,400MHz):2.12 (s, 6H), 7.12 (s, 1H), 7.17 (t, 1H), 7.32～7.55
(m,4H),7.86(s,1H),8.51(s,1H),8.60(s,1H),9.01(s,1H),10.55(s,1H),11.71(s,1H)
MS-ESI(m/z)：553.47(M+H+)
10 I J1- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (2-
Bromophenyl) thiocarbamide
Method is with embodiment 6.
1H NMR:(DMSO-d6,400MHz):2.12 (s, 6H), 7.08 (s, 1H), 7.28～7.37 (m, 4H), 7.78
(d,1H),8.06(d,1H),8.51(s,1H),8.60(s,1H),8.82(s,1H),9.55(s,1H),12.71(s,1H)
MS-ESI(m/z)：553.50(M+H+)
Embodiment 11 I K (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3-
(4- ethyoxyls) cinnamamide
Step 1
Appropriate 3,5- dimethylanilines (0.082mol) are weighed in 40mLDCM, anhydrous K 2CO3 is added
(0.164mol), ice bath cooling 30min, is added dropwise chloroacetic chloride (0.164mol) with constant pressure funnel, rises to naturally room after dripping off
Temperature reaction 2h, TLC (PE:EA=2:1) detection reaction, question response add 20mL water quenchings to go out completely, are dissolved with DCM, are washed with water repeatedly
Organic phase 2 times, watery hydrochloric acid are washed 2 times, collect organic phase, and concentrate drying obtains N- (3,5- 3,5-dimethylphenyl) acetamide 13.30g, is
Canescence flat crystal product；
1H NMR:(DMSO-d6,400MHz):2.01(s,3H),2.22(s,6H),6.66(s,1H),7.19(s,2H),
9.74 (s, 1H) step 2
Weigh in appropriate aluminum trichloride (anhydrous) (369.09mmol) and dry dichloromethane solution, be added dropwise under ice-water bath
Chloroacetic chloride (246.06mmol), adds N- (3,5- 3,5-dimethylphenyl) acetamide (82.02mmol) afterwards, is warming up to room temperature, instead
Answer 3h, TLC (PE:EA=1:1) detection reaction, question response terminate, by reactant liquor punching analysis in 600mL water+20mL concentrated hydrochloric acids, then
DCM dissolvings, extraction is added to collect organic phase, concentrate drying directly throws next step；
1H NMR:(DMSO-d6,400MHz):2.03(s,3H),2.14(s,6H),2.42(s,3H),7.26(s,2H),
9.88 (s, 1H) step 3
60mL2N HCl and 60mL water is added in the solid that will be obtained after concentration, 100 DEG C of hydrolysis 2h, TLC (PE are heated to:
EA=1:1) detect reaction end.Question response terminates, and adds saturated sodium bicarbonate to be quenched, modulates pH=8～9, have a large amount of solids
Precipitation, suction filtration solid, dried in vacuum overnight obtain 13.04g pale yellow powder solids, are 1- (4- amino -2,6- diformazans
Base phenyl) acetophenone.
1H NMR:(DMSO-d6,400MHz):2.06(s,6H),2.34(s,3H),5.17(s,2H),6.21(s,2H)
Step 4
1- (4- amino -2,6- 3,5-dimethylphenyls) acetophenone (82.1mmol) is weighed in 120mL concentrated hydrochloric acids and 40mL water,
Temperature is cooled under ice salt bath<5 DEG C, NaNO2 solution is added dropwise, process keeping temperature is added dropwise and is less than 5 DEG C, react after completion of dropping
20min, is added dropwise KI solution afterwards, and reaction 7h, TLC (PE are warmed to room temperature naturally after adding:EA=4:1) reaction process is detected, is treated
Reaction terminates, and is quenched with saturated sodium bicarbonate, is extracted with ethyl acetate 4 times, merges organic phase, and column chromatographic isolation and purification is obtained
1- (iodo- 2, the 6- 3,5-dimethylphenyls of the 4-) acetophenone of 14.35g brown oil liquid.
1H NMR:(DMSO-d6,400MHz):2.14(s,6H),2.44(s,3H),7.48(s,2H)
Step 5
1- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) acetophenone (52.17mmol) is weighed in ethyl acetate/chloroform (30mL：
10mL) mixed solution, adds CuBr2 (102.98mmol), 65～70 DEG C of backflows 8h, TLC (PE:EA=30:1) detection react into
Journey, question response terminate, and are extracted with saturated sodium bicarbonate and ethyl acetate, collect organic phase, brown-red solid 18.6g2- it is bromo-
1- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) ethyl ketone.Next step is thrown directly.
The bromo- 1- of 2- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) ethyl ketones (52mmol) and thiocarbamide (52mmol) are weighed in 80mL ethanol
In, it is stirred overnight at 80 DEG C, produces a large amount of white opacities, reaction terminates suction filtration, filter cake is washed with ethanol, dry that 22g is white
Color solid.
1H NMR:(DMSO-d6,400MHz):2.14(s,6H),6.46(s,1H),6.96(s,2H),7.32(s,2H).
Step 6
Weigh 4- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) thiazolyl -2- amine (0.515mmol), Ismipur
(1.03mmol), Cu2O (0.026mmol), and KOH (1.03mmol) in DMF (40mL) and water (10mL), 125～130 DEG C
Lower reaction is overnight.TLC monitoring reactions, question response terminate, and add aqueous hydrochloric acid solution to be quenched, are extracted with ethyl acetate and water repeatedly,
Organic phase is collected, concentrate drying obtains yellow solid product.
1H NMR:(DMSO-d6,400MHz):2.15(s,6H),6.47(s,1H),6.95(s,2H),7.34(s,2H),
8.49(s,1H),8.58(s,1H),13.57(s,1H)
Step 7
Weigh 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine (2.29mmol), 4- ethoxy-cinnamic acids
(2.29mmol), in THF, overnight, question response terminates stirring at normal temperature, repeatedly for HATU (2.29mmol) and TEA (11.45mmol)
Extracted with ethyl acetate and water, collect organic phase, column chromatography (DCM:MeOH=10:1) sterling, off-white powder, yield are obtained
50%.
1H NMR:(DMSO-d6,400MHz):1.34(t,2H),2.12(s,6H),4.08(q,3H),6.79(d,1H),
7.01(d,2H),7.16(s,1H),7.37(s,2H),7.60(d,2H),7.69(s,1H),8.32(s,1H),8.48(S,1H),
12.39(s,1H),13.52(s,1H)
MS-ESI(m/z)：551.14(M+Na+)
Embodiment 12 I L (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3-
(4- tert-butyl group bases) cinnamamide
Method is with embodiment 11.
1H NMR:(DMSO-d6,400MHz):1.30(s,9H),2.15(s,6H),6.92(d,1H),7.22(s,1H),
7.41(s,2H),7.50(d,2H),7.58(d,2H),7.74(d,1H),8.53(S,1H),8.62(s,1H),12.41(s,
1H),13.62(s,1H)
MS-ESI(m/z)：563.18(M+Na+)
Embodiment 13 I M (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3-
(4- (trifluoromethyl) phenyl) cinnamamide
Method is with embodiment 11.
1H NMR:(DMSO-d6,400MHz):2.15(s,6H),7.08(d,1H),7.25(s,1H),7.41(s,2H),
7.82～7.89 (m, 5H), 8.51 (s, 1H), 8.61 (s, 1H), 12.53 (s, 1H), 13.59 (s, 1H)
MS-ESI(m/z)：575.10(M+Na+)
Embodiment 14 I N (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3-
(4- (nitro) phenyl) cinnamamide
Method is with embodiment 11.
1H NMR:(DMSO-d6,400MHz):2.14(s,6H),7.12(d,1H),7.26(s,1H),7.41(s,2H),
7.87(d,1H),7.92(d,2H),8.32(d,2H),8.52(s,1H),8.61(s,1H),12.58(s,1H),13.59(s,
1H)
MS-ESI(m/z)：552.1(M+Na+)
Embodiment 15 I O (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3-
(4- (methoxyethoxy) phenyl) cinnamamide
Method is with embodiment 11.
1H NMR:(DMSO-d6,400MHz):2.15(s,6H),3.31(s,3H),3.80(t,2H),4.30(t,3H),
6.89(d,1H),7.32(s,1H),7.41(s,2H),7.51(d,2H),7.58(d,2H),7.37(d,1H),8.53(s,1H),
8.62(s,1H),12.39(s,1H),13.60(s,1H)
MS-ESI(m/z)：559.67(M+H+)
Embodiment 16 I P (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3-
(4- (cyclopropyl) phenyl) cinnamamide
Method is with embodiment 11.
MS-ESI(m/z)：547.67(M+Na+)
Embodiment 17 I Q (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3-
(4- (morpholinyl) phenyl) cinnamamide
Method is with embodiment 11.
MS-ESI(m/z)：570.70(M+H+)
Embodiment 18 I R (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3-
(3- fluoro-phenyls) cinnamamide
Method is with embodiment 11.
MS-ESI(m/z)：525.60(M+H+)
Embodiment 19 I S (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3-
(2- fluoro-phenyls) cinnamamide
Method is with embodiment 11.
MS-ESI(m/z)：525.60(M+H+)
20 I T1- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- phenyl
Thiocarbamide
Step 1
Appropriate 3,5- dimethylanilines (0.082mol) are weighed in 40mLDCM, anhydrous K 2CO3 is added
(0.164mol), ice bath cooling 30min, is added dropwise chloroacetic chloride (0.164mol) with constant pressure funnel, rises to naturally room after dripping off
Temperature reaction 2h, TLC (PE:EA=2:1) detection reaction, question response add 20mL water quenchings to go out completely, are dissolved with DCM, are washed with water repeatedly
Organic phase 2 times, watery hydrochloric acid are washed 2 times, collect organic phase, and concentrate drying obtains N- (3,5- 3,5-dimethylphenyl) acetamide 13.30g, is
Canescence flat crystal product；
1H NMR:(DMSO-d6,400MHz):2.01(s,3H),2.22(s,6H),6.66(s,1H),7.19(s,2H),
9.74(s,1H)
Step 2
Weigh in appropriate aluminum trichloride (anhydrous) (369.09mmol) and dry dichloromethane solution, be added dropwise under ice-water bath
Chloroacetic chloride (246.06mmol), adds N- (3,5- 3,5-dimethylphenyl) acetamide (82.02mmol) afterwards, is warming up to room temperature, instead
Answer 3h, TLC (PE:EA=1:1) detection reaction, question response terminate, by reactant liquor punching analysis in 600mL water+20mL concentrated hydrochloric acids, then
DCM dissolvings, extraction is added to collect organic phase, concentrate drying directly throws next step；
1H NMR:(DMSO-d6,400MHz):2.03(s,3H),2.14(s,6H),2.42(s,3H),7.26(s,2H),
9.88(s,1H)
Step 3
60mL2N HCl and 60mL water is added in the solid that will be obtained after concentration, 95～100 DEG C of hydrolysis 2h, TLC are heated to
(PE:EA=1:1) detect reaction end.Question response terminates, and adds saturated sodium bicarbonate to be quenched, modulates pH=8～9, has a large amount of
Solids of sedimentation is separated out, and suction filtration solid, dried in vacuum overnight obtain 13.04g pale yellow powder solids, are 1- (4- amino -2,6-
3,5-dimethylphenyl) acetophenone.
1H NMR:(DMSO-d6,400MHz):2.06(s,6H),2.34(s,3H),5.17(s,2H),6.21(s,2H)
Step 4
1- (4- amino -2,6- 3,5-dimethylphenyls) acetophenone (82.1mmol) is weighed in 120mL concentrated hydrochloric acids and 40mL water,
Temperature is cooled under ice salt bath<5 DEG C, NaNO2 solution is added dropwise, process keeping temperature is added dropwise and is less than 5 DEG C, react after completion of dropping
20min, is added dropwise KI solution afterwards, and reaction 7h, TLC (PE are warmed to room temperature naturally after adding:EA=4:1) reaction process is detected, is treated
Reaction terminates, and is quenched with saturated sodium bicarbonate, is extracted with ethyl acetate 4 times, merges organic phase, and column chromatographic isolation and purification is obtained
1- (iodo- 2, the 6- 3,5-dimethylphenyls of the 4-) acetophenone of 14.35g brown oil liquid.
1H NMR:(DMSO-d6,400MHz):2.14(s,6H),2.44(s,3H),7.48(s,2H)
Step 5
1- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) acetophenone (52.17mmol) is weighed in ethyl acetate/chloroform (30mL：
10mL) mixed solution, adds CuBr2 (102.98mmol), 65～70 DEG C of backflows 8h, TLC (PE:EA=30:1) detection react into
Journey, question response terminate, and are extracted with saturated sodium bicarbonate and ethyl acetate, collect organic phase, obtain brown-red solid 18.6g2-
Bromo- 1- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) ethyl ketone.Next step is thrown directly.
Step 6
The bromo- 1- of 2- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) ethyl ketones (52mmol) and thiocarbamide (52mmol) are weighed in 80mL ethanol
In, it is stirred overnight at 72～80 DEG C, produces a large amount of white opacities, reaction terminates suction filtration, washs filter cake with ethanol, dry
22g white solids.
1H NMR:(DMSO-d6,400MHz):2.14(s,6H),6.46(s,1H),6.96(s,2H),7.32(s,2H).
Step 7
Weigh 4- (iodo- 2, the 6- 3,5-dimethylphenyls of 4-) thiazolyl -2- amine (0.515mmol), Ismipur
(1.03mmol), Cu2O (0.026mmol), and KOH (1.03mmol) in DMF (40mL) and water (10mL), 125～130 DEG C
Lower reaction is overnight.TLC monitoring reactions, question response terminate, and add aqueous hydrochloric acid solution to be quenched, are extracted with ethyl acetate and water repeatedly,
Organic phase is collected, concentrate drying obtains yellow solid product.
1H NMR:(DMSO-d6,400MHz):2.15(s,6H),6.47(s,1H),6.95(s,2H),7.34(s,2H),
8.49(s,1H),8.58(s,1H),13.57(s,1H)
Step 8
Weigh 4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazolyl -2- amine (2mmol), phenyl different
In pyridine (20ml), 100～110 DEG C are stirred overnight thiocyanates (2mmol), and question response terminates, repeatedly with ethyl acetate and
Water is extracted, and collects organic phase, column chromatography (DCM:MeOH=20:1) sterling, yellow solid, yield 62% are obtained.
1H NMR:(DMSO-d6,400MHz):2.19 (s, 6H), 7.15～7.90 (m, 8H), 8.51 (s, 1H), 8.59
(s,1H),10.39(s,1H),11.81(s,1H),13.60(s,1H)
MS-ESI(m/z)：512.1(M+Na+)
21 I U1- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4-
(trifluoromethyl) phenyl) thiocarbamide
Method is with embodiment 20.
1H NMR:(DMSO-d6,400MHz):2.21(s,6H),6.97(s,1H),7.50(s,2H),7.56(d,2H),
7.96(d,2H),8.52(s,1H),8.59(s,1H),10.37(s,1H),13.43(s,1H),13.62(s,1H)
MS-ESI(m/z)：580.64(M+Na+)
22 I V1- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4-
(methoxyl group) phenyl) thiocarbamide
Method is with embodiment 20.
1H NMR:(DMSO-d6,400MHz):2.18(s,6H),3.74(s,3H),6.98(d,3H),7.28(d,2H),
7.37(s,2H),8.49(s,1H),8.57(s,1H),9.60(s,1H),13.563(s,1H),13.623(s,1H)
MS-ESI(m/z)：542.10(M+Na+)
23 I W1- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (2-
Bromophenyl) thiocarbamide
Method is with embodiment 20.
1H NMR:(DMSO-d6,400MHz):2.17(s,6H),7.19(m,2H),7.42(s,3H),7.69(d,1H),
7.83(d,1H),8.50(s,1H),8.59(s,1H),12,14(s,1H),13.11(s,1H),13.59(s,1H)
MS-ESI(m/z)：591.53(M+Na+)
24 I X1- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4-
Fluorophenyl) thiocarbamide
Method is with embodiment 20.
1H NMR:(DMSO-d6,400MHz):2.17(s,6H),6.97(s,1H),7.17(t,4H),7.40(t,4H),
8.51(s,1H),8.59(s,1H),9.84(s,2H),13.54(s,1H)
MS-ESI(m/z)：530.63(M+Na+)
25 I Y1- of embodiment (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4-
Chloro- 3- (trifluoromethyl) phenyl) thiocarbamide
Method is with embodiment 20.
1H NMR:(DMSO-d6,400MHz):2.20(s,6H),6.98(s,1H),7.49(s,2H),7.54(s,1H),
8.14(s,1H),8.3(s,1H),8.52(s,1H),8.58(s,1H),10.4(s,1H),13.34(s,1H),13.61(s,1H)
MS-ESI(m/z)：615.08(M+Na+)
Pharmacodynamic experiment part
First, cell growth inhibition assay
1st, experiment reagent
Methyl thiazoly tetrazolium assay (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenylte trazoliumb
Romide, MTT), dimethyl sulfoxide (DMSO) (DMSO), EL be purchased from Sigma Co., USA (St.Louis, MO).DMEM、RPMI-1640、
Hyclone and pancreatin are bought certainly in Gibco companies (Auckland, N.Z).The noval chemical compound being related in the present invention is by me
Laboratory voluntarily synthesizes gained, the storing solution of 90mmol/L is configured to DMSO, and lucifuge is stored in 20 DEG C of ﹣ in testing in vitro
Refrigerator is standby, when experiment is used, is diluted to desired concn with complete medium.
Clone and its culture：Breast cancer lines (MDA-MB-231 and MDA-MB-468) that this laboratory uses,
Human cervical carcinoma cell lines (Hela) and human chronic myeloblastic leukemia cell line (K562) are bought in American Type Culture Collection
The heart (ATCC).
Breast cancer lines (MDA-MB-231 and MDA-MB-468), human cervical carcinoma cell lines (Hela) are used containing 10%
Hyclone and antibiotic (penicillin 100U/mL, streptomysin 100U/mL) DMEM complete medium cultures, be placed in 37
DEG C, 5%CO2, incubator under the conditions of saturated humidity.
Human chronic myeloblastic leukemia cell line (K562) is using containing 10% hyclone and antibiotic (penicillin 100U/
ML, streptomysin 100U/mL) RPMI-1640 complete medium cultures, be placed in 37 DEG C, 5%CO2, under the conditions of saturated humidity
Incubator.
2nd, mtt assay
The cell of exponential phase is collected, and concentration of cell suspension is adjusted according to the speed of cell growth, with 2500～
The density of 4000 cells/wells is inoculated into 96 orifice plates, per 100 μ L of pore volume；96 orifice plates are placed in into 37 DEG C, 5%CO2 cell culture
Overnight incubation in incubator；Next day by 3 times dilution in the way of by diluted chemical compound into corresponding concentration, and respectively use variable concentrations
I a～I l (final concentration be respectively 90,30,10,3,1,0.3 μm of ol/L) process cell, each concentration gradient set 3～5 it is multiple
Hole, and arrange isopyknic solvent control group, the content of the DMSO per hole are required to below 0.1% that (0.1% DMSO is to thin
Born of the same parents' propagation has not significant impact)；Put 37 DEG C, culture 96 hours, drug-treated group and control group in 5%CO2 cell culture incubator
20 μ L MTT solution (5mg/mL) are added per hole, is continued to be incubated 2～4 hours in incubator, is terminated culture after first a ceremonial jade-ladle, used in libation is formed, incline
Supernatant is removed, adds per hole 150 μ L DMSO (for suspension cell, after culture is terminated, to add per hole the 20%SDS of 50 μ L molten
Liquid, overnight incubation treat that first a ceremonial jade-ladle, used in libation is complete molten)；15-20 minutes are shaken on shaking table, each Kong Guang are determined on ELIASA (λ=570nm)
Absorption value (OD570), takes its mean value and records result.Cell proliferation inhibition rate=(control group OD570- experimental groups OD570)/
Control group OD570 × 100%.Experiment is at least repeated 3 times, and is asked with GraphPad Prism softwares according to the inhibiting rate of variable concentrations
Calculate IC50。
3rd, experimental result
In I A～I W, extracorporeal anti-tumor proliferation function of the part of compounds on four different tumor cell lines is shown in Table 1.
Table 1
The present invention has carried out Breast cancer lines (MDA-MB-231, MDA-MB-468), people palace to the compound for preparing
The cell in vitro proliferation inhibition test research of neck cancer cell line (Hela) and human chronic myeloblastic leukemia cell line (K562), as a result
The compound for representing prepared has good inhibitory action to above-mentioned cell, and partial data sees the above table 1.
Claims (24)
1.4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives, its structure is shown in formula I：
Wherein, R1～R4 is independently H, C1～C8 alkyl, C1～C8 alkoxy or halogens；
R5For
X1～X5 is independently N or C；
R6 is H or C1～C4 alkyl；
R7～R25 be independently-H, halogen, C1～C8 alkyl of halogen substiuted, C1～C8 alkyl, C1～C8 alkoxyls, C3～
C8 cycloalkyl, 3～8 circle heterocycles alkyl,C2～C8 thiazolinyls, C2～C8 alkynyls ,-CN ,-OH, C3～C8 cyclenes
Base, 3～8 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Hetero atom in 3～8 described circle heterocycles alkyl or 3～8 circle heterocycles thiazolinyls is
N, O or S, heteroatomic number are 1～3.
2. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 1, its feature
It is：
R1～R4 is independently H, C1～C4 alkyl, C1～C4 alkoxy or halogens；
X1～X5 is independently N or C；
R6 is H or C1～C4 alkyl；
R7～R25 be independently-H, halogen, C1～C4 alkyl of halogen substiuted, C1～C4 alkyl, C1～C4 alkoxyls, C3～
C6 cycloalkyl, 3～6 circle heterocycles alkyl,C2～C4 thiazolinyls, C2～C4 alkynyls ,-CN ,-OH, C3～C8 cyclenes
Base, 3～6 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Hetero atom in 3～6 described circle heterocycles alkyl or 3～6 circle heterocycles thiazolinyls is
N, O or S, heteroatomic number are 1～3.
3. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 2, its feature
It is：
R1～R4 is independently H or C1～C4 alkyl；
X1～X5 is independently N or C；
R6 is H or C1～C4 alkyl；
R7～R25 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl, C1～C4 alkoxyls, C3～C6 cycloalkyl, 6
Circle heterocycles alkyl,-NO2Or-OCF3；Hetero atom in 6 described circle heterocycles alkyl be N, O or S, hetero atom
Number be 1～3.
4. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 3, its feature
It is：
R1～R4 is independently H or methyl；
X1～X5 is independently N or C；
R6 is H；
R7～R25 is independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl, C1～C4 alkoxyls, cyclopropyl,-NO2Or-OCF3。
5. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 1, its feature
It is：R5 isStructure is as shown in formula II：
Wherein, R1～R4 is independently H, C1～C8 alkyl, C1～C8 alkoxy or halogens；
X1～X5 is independently N or C；
R6 is H or C1～C4 alkyl；
R7～R10 be independently-H, halogen, C1～C8 alkyl of halogen substiuted, C1～C8 alkyl, C1～C8 alkoxyls, C3～
C8 cycloalkyl, 3～8 circle heterocycles alkyl,C2～C8 thiazolinyls, C2～C8 alkynyls ,-CN ,-OH, C3～C8 cyclenes
Base, 3～8 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Hetero atom in 3～8 described circle heterocycles alkyl or 3～8 circle heterocycles thiazolinyls is
N, O or S, heteroatomic number are 1～3.
6. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 5, its feature
It is：
R1～R4 is independently H, C1～C4 alkyl, C1～C4 alkoxy or halogens；
X1～X5 is independently N or C；
R6 is H or C1～C4 alkyl；
R7～R10 be independently-H, halogen, C1～C4 alkyl of halogen substiuted, C1～C4 alkyl, C1～C4 alkoxyls, C3～
C6 cycloalkyl, 3～6 circle heterocycles alkyl,C2～C4 thiazolinyls, C2～C4 alkynyls ,-CN ,-OH, C3～C8 cyclenes
Base, 3～6 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Hetero atom in 3～6 described circle heterocycles alkyl or 3～6 circle heterocycles thiazolinyls is
N, O or S, heteroatomic number are 1～3.
7. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 6, its feature
It is：
R1～R4 is independently H or C1～C4 alkyl；
X1～X5 is independently N or C；
R6 is H or C1～C4 alkyl；
R7～R10 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl, C1～C4 alkoxyls, C3～C6 cycloalkyl, 6
Circle heterocycles alkyl,-NO2Or-OCF3；Hetero atom in 6 described circle heterocycles alkyl be N, O or S, hetero atom
Number be 1～3.
8. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 7, its feature
It is：
R1～R4 is independently H or methyl；
X1～X5 is independently N or C；
R6 is H；
R7～R10 is independently-H ,-F ,-Cl or-Br.
9. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 1, its feature
It is：R5 isStructural formula is as shown in formula III：
Wherein, R1～R4 is independently H, C1～C8 alkyl, C1～C8 alkoxy or halogens；
R6 is H or C1～C4 alkyl；
R11～R15 be independently-H, halogen, C1～C8 alkyl of halogen substiuted, C1～C8 alkyl, C1～C8 alkoxyls, C3～
C8 cycloalkyl, 3～8 circle heterocycles alkyl,C2～C8 thiazolinyls, C2～C8 alkynyls ,-CN ,-OH, C3～C8 cyclenes
Base, 3～8 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Hetero atom in 3～8 described circle heterocycles alkyl or 3～8 circle heterocycles thiazolinyls is
N, O or S, heteroatomic number are 1～3.
10. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 9, which is special
Levy and be：
R1～R4 is independently H, C1～C4 alkyl, C1～C4 alkoxy or halogens；
R6 is H or C1～C4 alkyl；
R11～R15 be independently-H, halogen, C1～C4 alkyl of halogen substiuted, C1～C4 alkyl, C1～C4 alkoxyls, C3～
C6 cycloalkyl, 3～6 circle heterocycles alkyl,C2～C4 thiazolinyls, C2～C4 alkynyls ,-CN ,-OH, C3～C8 cyclenes
Base, 3～6 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Hetero atom in 3～6 described circle heterocycles alkyl or 3～6 circle heterocycles thiazolinyls is
N, O or S, heteroatomic number are 1～3.
11. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 10, which is special
Levy and be：
R1～R4 is independently H or C1～C4 alkyl；
R6 is H or C1～C4 alkyl；
R11～R15 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl, C1～C4 alkoxyls, C3～C6 cycloalkyl, 6
Circle heterocycles alkyl,-NO2Or-OCF3；Hetero atom in 6 described circle heterocycles alkyl be N, O or S, hetero atom
Number be 1～3.
12. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 11, which is special
Levy and be：
R1～R4 is independently H or methyl；
R6 is H；
R11～R15 is independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl, C1～C4 alkoxyls, cyclopropyl,Or-NO2。
13. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 1, which is special
Levy and be：R5 isStructural formula is as shown in formula IV：
Wherein, R1～R4 is independently H, C1～C8 alkyl, C1～C8 alkoxy or halogens；
R6 is H or C1～C4 alkyl；
R16～R20 be independently-H, halogen, C1～C8 alkyl of halogen substiuted, C1～C8 alkyl, C1～C8 alkoxyls, C3～
C8 cycloalkyl, 3～8 circle heterocycles alkyl,C2～C8 thiazolinyls, C2～C8 alkynyls ,-CN ,-OH, C3～C8 cyclenes
Base, 3～8 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Hetero atom in 3～8 described circle heterocycles alkyl or 3～8 circle heterocycles thiazolinyls is
N, O or S, heteroatomic number are 1～3.
14. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 13, which is special
Levy and be：
R1～R4 is independently H, C1～C4 alkyl, C1～C4 alkoxy or halogens；
R6 is H or C1～C4 alkyl；
R16～R20 be independently-H, halogen, C1～C4 alkyl of halogen substiuted, C1～C4 alkyl, C1～C4 alkoxyls, C3～
C6 cycloalkyl, 3～6 circle heterocycles alkyl,C2～C4 thiazolinyls, C2～C4 alkynyls ,-CN ,-OH, C3～C8 cyclenes
Base, 3～6 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Hetero atom in 3～6 described circle heterocycles alkyl or 3～6 circle heterocycles thiazolinyls is
N, O or S, heteroatomic number are 1～3.
15. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 14, which is special
Levy and be：
R1～R4 is independently H or C1～C4 alkyl；
R6 is H or C1～C4 alkyl；
R16～R20 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl, C1～C4 alkoxyls, C3～C6 cycloalkyl, 6
Circle heterocycles alkyl,-NO2Or-OCF3；Hetero atom in 6 described circle heterocycles alkyl be N, O or S, hetero atom
Number be 1～3.
16. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 15, which is special
Levy and be：
R1～R4 is independently H or methyl；
R6 is H；
R11～R15 is independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl or C1～C4 alkoxyls.
17. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 1, which is special
Levy and be：R5 isStructural formula is as shown in formula V：
Wherein, R1～R4It is independently H, C1～C8 alkyl, C1～C8 alkoxy or halogens；
R6For H or C1～C4 alkyl；
R21～R25It is independently-H, halogen, C1～C8 alkyl of halogen substiuted, C1～C8 alkyl, C1～C8 alkoxyls, C3～C8
Cycloalkyl, 3～8 circle heterocycles alkyl,C2～C8 thiazolinyls, C2～C8 alkynyls ,-CN ,-OH, C3～C8 cycloalkenyl groups,
3～8 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Hetero atom in 3～8 described circle heterocycles alkyl or 3～8 circle heterocycles thiazolinyls is N, O
Or S, heteroatomic number is 1～3.
18. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 17, which is special
Levy and be：
R1～R4It is independently H, C1～C4 alkyl, C1～C4 alkoxy or halogens；
R6For H or C1～C4 alkyl；
R21～R25It is independently-H, halogen, C1～C4 alkyl of halogen substiuted, C1～C4 alkyl, C1～C4 alkoxyls, C3～C6
Cycloalkyl, 3～6 circle heterocycles alkyl,C2～C4 thiazolinyls, C2～C4 alkynyls ,-CN ,-OH, C3～C8 cycloalkenyl groups,
3～6 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Hetero atom in 3～6 described circle heterocycles alkyl or 3～6 circle heterocycles thiazolinyls is N, O
Or S, heteroatomic number is 1～3.
19. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 18, which is special
Levy and be：R1～R4 is independently H or C1～C4 alkyl；
R6 is H or C1～C4 alkyl；
R21～R25 be independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl, C1～C4 alkoxyls, C3～C6 cycloalkyl, 6
Circle heterocycles alkyl,-NO2Or-OCF3；Hetero atom in 6 described circle heterocycles alkyl be N, O or S, hetero atom
Number be 1～3.
20. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives according to claim 19, which is special
Levy and be：
R1～R4 is independently H or methyl；
R6 is H；
R7～R25 is independently-H ,-F ,-Cl ,-Br ,-CF3, C1～C4 alkyl or C1～C4 alkoxyls.
21. 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine according to any one of Claims 1 to 4 spread out
It is biological, it is characterised in that：Including following compound：
N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) Pyrazinamide, N- (4- (4-
((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -2- fluorine Pyrazinamides, N- (4- (4- ((9H- purine -
6- yls) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl)-pyrazine -2- acid amides, N- (4- (4- ((9H- purine -6- bases) sulphur) -2,
6- 3,5-dimethylphenyls) thiazol-2-yl)-pyrimidine -5- acid amides, N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- dimethyl benzenes
Base) thiazol-2-yl)-pyridazine -4- acid amides, 1- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazole -2-
Base) -3- (4- chloro- 3- (trifluoromethyl) phenyl) thiocarbamide, 1- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls)
Thiazol-2-yl) -3- (4- methyl) phenyl) thiocarbamide, 1- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiophenes
Azoles -2- bases) -3- (4- methoxyl groups) phenyl) thiocarbamide, 1- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiophenes
Azoles -2- bases) -3- (3- bromophenyls) thiocarbamide, 1- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazole -2-
Base) -3- (2- bromophenyls) thiocarbamide, (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazole -2-
Base) -3- (4- ethyoxyls) cinnamamide, (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazole -
2- yls) -3- (4- tert-butyl group bases) cinnamamide, (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiophenes
Azoles -2- bases) -3- (4- (trifluoromethyl) phenyl) cinnamamide, (E)-N- (4- (4- ((9H- purine -6- bases) sulphur) -2,6- diformazans
Base phenyl) thiazol-2-yl) -3- (4- (methoxyethoxy) phenyl) cinnamamide, (E)-N- (4- (4- ((9H- purine -6- bases)
Sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4- (cyclopropyl) phenyl) cinnamamide, ((((9H- is fast for 4- for 4- for (E)-N-
Purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4- (morpholinyl) phenyl) cinnamamide, (E)-N- (4- (4-
((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (3- fluoro-phenyls) cinnamamide, (E)-N- (4-
(4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (2- fluoro-phenyls) cinnamamide, 1- (4-
(4- ((9H- purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- phenylthioureas, 1- (4- (4- ((9H- purine -
6- yls) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4- (trifluoromethyl) phenyl) thiocarbamide, ((((9H- is fast for 4- for 4- for 1-
Purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4- (methoxyl group) phenyl) thiocarbamide, ((((9H- is fast for 4- for 4- for 1-
Purine -6- bases) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (2- bromophenyls) thiocarbamide, 1- (4- (4- ((9H- purine -6-
Base) sulphur) -2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4- fluorophenyls) thiocarbamide, 1- (4- (4- ((9H- purine -6- bases) sulphur) -
2,6- 3,5-dimethylphenyls) thiazol-2-yl) -3- (4- chloro- 3- (trifluoromethyl) phenyl) thiocarbamide.
4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives described in 22. any one of claim 1～21
Preparation method, it is characterised in that：Comprise the following steps：
R1～R4 is independently H, C1～C8 alkyl, C1～C8 alkoxy or halogens；
X1～X5 is independently N or C；
R5For
R6 is H or C1～C4 alkyl；
R7～R25 be independently-H, halogen, C1～C8 alkyl of halogen substiuted, C1～C8 alkyl, C1～C8 alkoxyls, C3～
C8 cycloalkyl, 3～8 circle heterocycles alkyl,C2～C8 thiazolinyls, C2～C8 alkynyls ,-CN ,-OH, C3～C8 cyclenes
Base, 3～8 circle heterocycles thiazolinyls ,-NO2Or-OCF3；Hetero atom in 3～8 described circle heterocycles alkyl or 3～8 circle heterocycles thiazolinyls is
N, O or S, heteroatomic number are 1～3；
Step A：Compound 1 is reacted with chloroacetic chloride in the basic conditions and prepares compound 2；Described alkali is potassium carbonate, carbon
In sour sodium, potassium phosphate, cesium carbonate or potassium hydroxide any one；
Step B：Compound 3 prepared and acylation reaction under Catalyzed by Anhydrous Aluminium Chloride with chloroacetic chloride in compound 2 there is；
Step C：Hydrolysis prepares compound 4 to compound 3 in acid condition；
Step D：Compound 4 is reacted in the concentrated hydrochloric acid of ice salt bath with natrium nitrosum and forms diazol, then anti-with KI generation iodos
Compound 5 should be prepared；
Step E：Compound 6 prepared and bromo-reaction with bromide reagent in compound 5 there is；Described bromide reagent is protobromide
In copper, bromine or tetrabutyl tribromide ammonium any one；
Step F：Hantsch with thiocarbamide and compound 7 prepared into thiazole reaction in compound 6 there is；Reaction temperature is 72～80
DEG C, the time is 4h～8h；
Step G：Compound 7 prepares compound with 6～8h of reaction at Ismipur in the basic conditions 125～150 DEG C
8；Described alkali is any one in potassium hydroxide, potassium carbonate, potassium tert-butoxide, cesium carbonate or potassium phosphate；
Step H：Compound 8 respectively with replace isonicotinic acid, substituted cinnamic acid condensation, or with replace isocyanates, replace different sulphur cyanogen
Acid esters prepares compound 9 into urea.
4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiazolyl -2- amine derivatives described in 23. any one of claim 1～21
Purposes in tumor is prepared.
24. pharmaceutical compositions, are 4- (4- ((9H- purine -6- bases) sulphur) phenyl) thiophenes by described in any one of claim 1～21
Oxazolyl -2- amine derivatives add what the pharmaceutically complementary composition of acceptable was prepared from.
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