CN106279143A - Thiazole heterocycle compounds and its preparation method and application - Google Patents

Thiazole heterocycle compounds and its preparation method and application Download PDF

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CN106279143A
CN106279143A CN201510237794.8A CN201510237794A CN106279143A CN 106279143 A CN106279143 A CN 106279143A CN 201510237794 A CN201510237794 A CN 201510237794A CN 106279143 A CN106279143 A CN 106279143A
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base
compound
thiazole
chloro
heterocycle compounds
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饶子和
陈悦
杨诚
白翠改
何丁迪
王莹莹
郭宇
江银
管文豪
于建明
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TIANJIN INTERNATIONAL JOINT ACADEMY OF BIOMEDICINE
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TIANJIN INTERNATIONAL JOINT ACADEMY OF BIOMEDICINE
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention provides thiazole heterocycle compounds and its preparation method and application, wherein, thiazole heterocycle compounds has following general structure: found by cellular level experiment, the thiazole heterocycle compounds that the present invention provides all can suppress the propagation of K562, HL60, KG1a cell, particularly example 3 compound (compound 4c) is in the case of drug level is less than positive control medicine Dasatinib, can realize suppressing the effect of K562, HL60, KG1a cell proliferation, the thiazole heterocycle compounds that therefore present invention provides to may be used for treating leukemia equally.

Description

Thiazole heterocycle compounds and its preparation method and application
Technical field
The present invention relates to thiazole heterocycle compounds and its preparation method and application.
Background technology
Leukemia, also referred to as leukemia, be the Clonal malignant disease of a class hematopoietic stem cell exception.Leukaemia in its clone loses and is further differentiated into ripe ability and is stuck in cytocerastic different phase.In bone marrow and other hemopoietic tissue, other organs and tissue are gathered and infiltrated to a large amount of hypertrophy of leukaemia, makes normal hematopoiesis suppressed simultaneously, and clinical manifestation is anemia, hemorrhage, infection and each organ infiltration's symptom.
Leukemia is generally divided into: 1) acute lymphoblastic leukemia, and 2) acute non-leukemic lymphoblastoid (being called for short anxious non-pouring), 3) chronic leukemia, 4) specific type leukemia,
Wherein, chronic myelocytic leukemia (CML) be again chronic myelocytic leukemia, and it is the hematopoietic stem cell malignant clone proliferative disease of blood system, causes patient the symptom such as anemia, hemorrhage, infection occur.CML accounts for about the 20% of adult leukemia, and the most annual sickness rate is 50,000/, it is likely to morbidity at any age bracket, and especially in old people, sickness rate is higher, and male is higher than women sickness rate.Progression of disease situation and the order of severity according to CML patient are divided into chronic phase (CP), accelerated period (AP) and acute transformation phase (BP).The patients with chronic myelocytic leukemia of about 85%～90% is diagnosed discovery in chronic phase, this stage symptom inconspicuous or the most weak, arthralgia or abdominal distention, if Drug therapy is timely, chronic phase, will be elongated, and in the case of not treatment in time, disease can enter into accelerated period.The main cause that CML is formed is No. 9 and No. 22 a kind of fusion gene i.e. BCR-ABL fusion genes of chromosomes generation dystopy t (9:22) (q34:q11) (Philadelphia chromosome Ph) formation, this gene can encode BCR-ABL protein, is a kind of active tyrosine kinase.This BCR-ABL kinases can make some substrate phosphorylations in downstream, and then activates the signal transduction pathway relevant with cell proliferation, causes ripe granulocyte infinite multiplication to cause the generation of CML.
At present, Therapeutic Method to CML is mainly traditional Drug therapy, hematopoietic stem cell transplantation and emerging molecular targeted therapy clinically.Common Drug therapy includes alkylating agent busulfan, hydroxyurea, interferon (IFN-α), cytosine arabinoside and homoharringtonine.Wherein, owing to busulfan side reaction is bigger, stopped using；Although hydroxyurea is cheap, treatment cost is low, and toxic and side effects is little, but it is poor for the patient's CML action effect being in accelerated period, and the CML patient for acute transformation phase does not has effect substantially；Although alpha-interferon relatively the above two toxic and side effects have reduced, but it is very poor to the CML patient outcome of accelerated period and acute transformation phase.One drawback the biggest of this common drug treatment is also normal body cell to be produced damage while tumor cell is produced lethal effect.Hematopoietic stem cell transplantation is the method that the most uniquely can cure CML at present, it is by first being removed by CML tumor cell in the patient with Large dose chemoradiotherapy, again by the hematopoietic stem cell transplantation of autologous or allosome to patient so that it is re-establish normal hematolymphiod system.But this method gets up to there is a lot of difficulty in practical operation, there is certain requirement at the such as age to patient, operation complexity, success rate is low, expend height, and it is necessary to have suitable Marrow donation person, and transplant the later stage and be likely to occur infection, CML patient and household can be made to face the biggest risk, so hematopoietic stem cell transplantation is the most restricted in actual application.
Dasatinib is novel, oral, the small molecule tyrosine kinase inhibitors of Mutiple Targets, is second filial generation TKIs.Dasatinib is initially to be developed as SRC family (such as Fyn, Yes, Src and Lyk etc.) inhibitors of kinases, and it can also suppress BCR-ABL, EphA2, PDGF receptor and c-Kit.Although Dasatinib has certain therapeutic effect, but the shortcoming that there is also some clinical treatments.Dasatinib clinical test results shows, Dasatinib has the bone marrow transplantation phenomenon that existence is the most universal, modal untoward reaction includes fluid retention (including hydrothorax), suffers from diarrhoea, has a headache, feels sick, erythra, dyspnea, hemorrhage, tired, musculoskeletal pain, infects, vomits, coughs, suffers from abdominal pain and generate heat, visible heart failure once in a while.The incidence rate of the febrile neutropenic relevant to medicine is 5%.A kind of there are leukemic stem cells lethality and the relatively low compound of side effect extremely urgent so finding, and this also will open the new direction of CML treatment and change clinical assessment standard of anti-CML medicine.
Summary of the invention
In order to solve for treating the problem that leukemic curative effect of medication is the best in prior art, according to an aspect of the invention, it is provided a kind of thiazole heterocycle compounds, this thiazole heterocycle compounds has a following general structure:
In above-mentioned thiazole heterocycle compounds, in described formula, X is:
And wherein, R includes following group:
In above-mentioned thiazole heterocycle compounds, in described formula, X is:
And wherein, R includes following group:
In above-mentioned thiazole heterocycle compounds, in described formula, X is:
And wherein, R includes following group:
NullAccording to a further aspect in the invention, Additionally provide the preparation method of a kind of thiazole heterocycle compounds, comprise: make 2-((6-(4-(2-(t-butyldiphenylsilyl) oxygen) ethyl) piperazine-1-yl) 2-methylpyrimidine-4-yl) amino)-N '-(the chloro-6-toluyl of 2-) thiazole-5-carbonic acid hydrazine) and the tert-butyl group (2-(4-(6-((5-(2-(the chloro-6-toluyl of 2-) acyl group carbonyl) thiazol-2-yl) amino) 2-methylpyrimidine-4-yl) piperazine-1-yl) ethyl) carbamate there is respectively dehydrocyclization and react to prepare N-(6-(4-(2-(t-butyldiphenylsilyl) oxygen) ethyl) piperazine-1-yl) 2-methylpyrimidine-4-yl) 5-(5-(2-chlorine 6-tolyl) 1, 3, 4-oxadiazoles-2-base) thiazole-2-amine and the tert-butyl group (2-(4-(6-((5-(5-(2-chloro-6-toluene 1, 3, 4-oxadiazoles-2-base) thiazol-2-yl) amino) 2-methylpyrimidine-4-base) piperazine-1-base) ethyl) carbamate
Make described N-(6-(4-(2-(t-butyldiphenylsilyl) oxygen) ethyl) piperazine-1-base) 2-methylpyrimidine-4-base) 5-(5-(2-chlorine 6-tolyl) 1,3,4-oxadiazoles-2-base) thiazole-2-amine and the described tert-butyl group (2-(4-(6-((5-(5-(2-chloro-6-toluene 1,3,4-oxadiazoles-2-bases) thiazol-2-yl) amino) 2-methylpyrimidine-4-base) piperazine-1-base) ethyl) carbamate occurs substitution reaction to generate described thiazole heterocycle compounds respectively；
Wherein, the chemical structural formula of described thiazole heterocycle compounds is:
, wherein, R is:
According to a further aspect in the invention, additionally provide the preparation method of a kind of thiazole heterocycle compounds, including: make the tert-butyl group (5-acetylene thiazol-2-yl) carbamate and 1-nitrine-2-chlorobenzene react the generation tert-butyl group (5-(1-(2-chloro-6-tolyl)-1H-1,2,3-triazole-4-bases) thiazol-2-yl l) carbamate；
Make the described tert-butyl group (5-(1-(2-chloro-6-tolyl)-1H-1,2,3-triazole-4-base) thiazol-2-yl) carbamate and trifluoroacetic acid react generation 5-(1-(2-chloro-6-tolyl)-1H-1,2,3-triazole-4-base) thiazole-2-amine；
Make 5-(1-(2-chloro-6-tolyl)-1H-1,2,3-triazole-4-base) thiazole-2-amine and 4, the reaction of 6-bis-chloro-2-methylpyrimidine generates N-(6-chloro-2-methyl pyrimidine-4-yl)-5-(1-(2-chloro-6-tolyl)-1H-1,2,3-triazole-4-base) thiazole-2-amine；
Make described N-(6-chloro-2-methyl pyrimidine-4-yl)-5-(1-(2-chloro-6-tolyl)-1H-1,2,3-triazole-4-bases) thiazole-2-amine react with piperazine compounds, generate described thiazole heterocycle compounds；
Wherein, the chemical structural formula of described piperazine compounds is:
The chemical structural formula of described thiazole heterocycle compounds is:
And wherein, R at least includes
According to another aspect of the invention, above-mentioned thiazole heterocycle compounds is additionally provided for treating the application in leukemic medicine.
In above-mentioned application, described for treating leukemic pharmaceutical pack containing described thiazole heterocycle compounds, the described the most acceptable salt of thiazole heterocycle compounds, ester, hydrate or combinations thereof and adjuvant.
In above-mentioned application, the dosage form of the leukemic medicine of described treatment is selected from tablet, capsule, pill, suppository, aerosol, oral liquid, granule, powder, injection, syrup, medicated wine, tincture, distillate medicinal water, membrane or combinations thereof.
In above-mentioned application, the administering mode of the leukemic medicine of described treatment includes being administered orally, injects, implants, external, spray, suck or combinations thereof.
Thus, the invention provides new thiazole heterocycle compounds of a class and its preparation method and application, found by cellular level experiment, the thiazole heterocycle compounds that the present invention provides all can suppress the propagation of K562, HL60, KG1a cell, by measuring IC50And IC90Value finds, the thiazole heterocycle compounds that the present invention provides all can reach 90% to the inhibitory action of the propagation of K562, HL60, KG1a cell, and example 3 compound (compound 4c) that particularly present invention provides is in the case of drug level is less than positive control medicine Dasatinib, can realize suppressing the effect of K562, HL60, KG1a cell proliferation, the thiazole heterocycle compounds that therefore present invention provides to may be used for treating leukemia equally.
Accompanying drawing explanation
Fig. 1 shows the 1H NMR of compound 4a.
Fig. 2 shows compound 4a's13C NMR。
Fig. 3 shows compound 4b's1H NMR。
Fig. 4 shows compound 4b's13C NMR。
Fig. 5 shows compound 4c's1H NMR。
Fig. 6 shows compound 4c's13C NMR。
Fig. 7 shows compound 4d's1H NMR。
Fig. 8 shows compound 4d's13C NMR。
Fig. 9 shows compound 13a's1H NMR。
Figure 10 shows compound 13a's13C NMR。
Figure 11 shows compound 13b's1H NMR。
Figure 12 shows compound 13b's13C NMR。
Figure 13 shows compound 13c's1H NMR。
Figure 14 shows compound 13c's13C NMR。
Figure 15 shows compound 13d's1H NMR。
Figure 16 shows compound 13d's13C NMR。
Figure 17 shows compound 13e's1H NMR。
Figure 18 shows compound 13e's13C NMR。
Figure 19 shows compound 25a's1H NMR。
Figure 20 shows compound 25a's13C NMR。
Figure 21 shows compound 25c's1H NMR。
Figure 22 shows compound 25c's13C NMR。
Figure 23 shows compound 25d's1H NMR。
Figure 24 shows compound 25d's13C NMR。
Figure 25 shows compound 25e's1H NMR。
Figure 26 shows compound 25e's13C NMR。
Figure 27 shows compound 25f's1H NMR。
Figure 28 shows compound 25f's13C NMR。
Figure 29 shows Dasatinib, example 1 and example 4 compound inhibitory action to K562 cell.
Figure 30 shows example 2 compound inhibitory action to K562 cell.
Figure 31 shows example 3 compound inhibitory action to K562 cell.
Figure 32 shows example 5 compound, example 6 compound, example 7 compound, example 8 compound, example 9 compound inhibitory action to K562 cell.
Figure 33 shows example 10 compound, example 11 compound, example 12 compound, example 13 compound, example 14 compound inhibitory action to K562 cell.
Figure 34 shows Dasatinib, example 1 compound, example 4 compound inhibitory action to HL60 cell.
Figure 35 shows example 2 compound inhibitory action to HL60 cell.
Figure 36 shows example 3 compound inhibitory action to HL60 cell.
Figure 37 shows example 5 compound, example 6 compound, example 7 compound, example 8 compound, example 9 compound inhibitory action to HL60 cell.
Figure 38 shows example 10 compound, example 11 compound, example 12 compound, example 13 compound, example 14 compound inhibitory action to HL60 cell.
Figure 39 shows Dasatinib, example 1 compound, example 2 compound, example 3 compound, example 4 compound inhibitory action to KG1a cell.
Figure 40 shows example 5 compound, example 6 compound, example 7 compound, example 8 compound, example 9 compound inhibitory action to KG1a cell.
Figure 41 shows example 10 compound, example 11 compound, example 12 compound, example 13 compound, example 14 compound inhibitory action to KG1a cell.
Detailed description of the invention
Below in conjunction with the accompanying drawing in the embodiment of the present invention, the technical scheme in the embodiment of the present invention is clearly and completely described, it is clear that described embodiment is only a part of embodiment of the present invention rather than whole embodiments.Based on the embodiment in the present invention, the every other embodiment that those of ordinary skill in the art are obtained, broadly fall into the scope of protection of the invention.
The general structure of the thiazole heterocycle compounds provided in the present invention is:
Wherein, in formula
That is, above-mentioned formula can be:
Embodiment 1 has chemosynthesis and the Structural Identification of the thiazole heterocycle compounds of formula one
In above-mentioned formula one:
The experiment of synthetic chemistry step (the Compound of Example experimental procedure that formula one is comprised) with the thiazole heterocycle compounds of formula one is as follows:
1. general synthetic routes
2. concrete synthesis step:
The synthesis of 2.1: compound 3:N-(2-chloro-6-aminomethyl phenyl)-2-((6-(4-(2-(1,3-dioxoisoindolin) ethyl) piperazine)-2-methylpyrimidine) amino) thiazole-5-Methanamide
At 0 DEG C, by compound 1 (500mg, 1.02mmol), triphenyl phosphorus PPh3(349mg, 1.33mmol), phthalimide 2 (195.7mg, 1.33mg) join in the anhydrous tetrahydro furan that 10mL heavily steams, add diisopropyl azodiformate DIAD (226.4mg the most under agitation, 1.33mmol), after low temperature stirring 10min, move to room temperature reaction, until raw material 1 reacts completely (reaction sometimes can not be carried through to the end).After reaction terminates, low pressure concentrates and removes reaction dissolvent, and then column chromatography purification i.e. can get compound 3 (white solid, 555mg).Productivity is 87.8%.1H NMR (400MHz, CDCl3) δ ppm 8.04 (br, 1H), 7.83-7.85 (m, 2H), 7.70-7.72 (m, 2H), 7.45 (s, 1H), 7.30 (dd, J=0.8,7.2Hz, 1H), 7.14-7.20 (m, 2H), 5.78 (s, 1H), 3.85 (t, J=6.4Hz, 2H), 3.56 (br, 4H), (2.68 t, J=6.4Hz, 2H), 2.60 (br, 4H), 2.50 (s, 3H), 2.35 (s, 3H).
The example 1 compound 4a:N-(synthesis of 2-chloro-(6-aminomethyl phenyl)-2-[[6-[4-(2-aminoethyl)-1-piperazinyl]-2-methyl-4-pyrimidine radicals] amino]-5-thiazole carboxamides
By compound 3 (606mg, 0.98mmol) join in the round-bottomed flask of 10mL ethanol, it is subsequently adding 5mL hydrazine hydrate, being heated to 78 DEG C of backflows and within two hours, can react complete, concentrating under reduced pressure removes reaction dissolvent, then adds sodium chloride saturated solution, extract 3 times with oxolane, organic facies anhydrous sodium sulfate is dried, and filters, and concentrates.Column chromatography is further purified to obtain compound 4a (white solid).1HNMR (400MHz, DMSO-d6) δ ppm9.88 (br, 1H), 8.23 (s, 1H), 7.40 (dd, J=7.2Hz, 1H), 7.24-7.30 (m, 2H), 6.06 (s, 1H), 3.52 (br, 4H), 2.68 (t, J=6.4Hz, 2H), 2.44 (t, J=4.4Hz, 4H), 2.41 (s, 3H), 2.36 (t, J=6.4Hz, 2H), 2.24 (s, 3H)；13CNMR (100MHz, DMSO-d6) δ 165.61,163.11,162.84,160.42,157.47,141.32,139.29,134.02,132.92,129.48,128.62,127.47,126.11,83.14,60.63,52.89,44.09,38.72,26.05,18.77；
HRMS-ESI (+): C22H28ClN8OS value of calculation 487.1759, detects 487.1805 [M+H]+。
The example 2 compound 4b:N-(synthesis of 2-chloro-(6-aminomethyl phenyl)-2-[[6-[4-(2-isothiocyanate)-1-piperazinyl]-2-methyl-4-pyrimidine radicals] amino]-5-thiazole carboxamides
At 0 DEG C, compound 4a (100mg, 0.21mmol) is joined in 3mL dichloromethane round-bottomed flask, be subsequently adding dicyclohexylcarbodiimide DCC (1.1eq), then under stirring condition, be slowly added dropwise Carbon bisulfide CS2(15eq), after dripping, at low temperatures after stirring 5min, removing ice-water bath, then stirring at normal temperature is to reaction completely.Concentrating under reduced pressure removes reaction dissolvent, and silica gel column chromatography purification i.e. can get compound 4b (white solid).This compound1HNMR (400MHz, DMSO-d6) δ ppm11.47 (s, 1H), 9.88 (s, 1H), 8.23 (s, 1H), 7.40 (dd, J=1.2,7.2Hz, 1H), 7.24-7.30 (m, 2H), 6.07 (s, 1H), 3.80 (t, J=6.0Hz, 2H), 3.54 (br, 4H), 2.66 (t, J=6.0Hz, 2H), 2.54 (br, 4H), 2.42 (s, 3H), 2.24 (s, 3H)；13CNMR (100MHz, DMSO-d6) δ 165.67,163.02,162.81,160.39,157.44,141.30,139.29,134.00,132.91,130.09,129.49,128.63,127.47,126.19,83.17,56.80,52.24,44.11,43.07,26.05,18.77；
HRMS-ESI (+): C23H26ClN8OS2Value of calculation, 529.1359；529.1356. [M+H] detected+。
The example 3 compound 4c:N-(synthesis of 2-chloro-(6-aminomethyl phenyl)-2-[[6-[4-(2-acrylamide)-1-piperazinyl]-2-methyl-4-pyrimidine radicals] amino]-5-thiazole carboxamides
At 0 DEG C, compound 4a (150mg, 0.31mmol) is joined in the round-bottomed flask of 3mL dichloromethane, then under stirring condition, add acryloyl chloride (3mL, 0.35mmol) and the Et of above-mentioned preparation3N (47mg, 0.46mmol), finishes, and at low temperatures after stirring 5min, removes ice-water bath, and then stirring at normal temperature is to reaction completely.Reactant liquor saturated aqueous common salt washs 2 times, organic facies anhydrous Na2SO4Being dried, filter, concentrate, silica gel column chromatography purification i.e. can get compound 4c (white solid).This compound1HNMR (400MHz, DMSO-d6) δ ppm11.48 (s, 1H), 9.89 (s, 1H), 8.23 (s, 1H), 8.08 (s, 1H), 7.40 (dd, J=1.2,7.2Hz, 1H), 7.24-7.31 (m, 2H), 7.25 (dd, J=10,16.8Hz, 1H), 6.11 (d, J=1.2Hz, 1H), 6.07 (s, 1H), 5.59 (dd, J=0.4,9.6Hz, 1H), 3.52 (br, 4H), 3.31 (s, 2H), 2.50-2.51 (m, 9H), 2.42 (s, 1H)；13CNMR (100MHz, DMSO-d6) δ 165.64,165.07,163.02,162.82,160.41,157.44,141.34,139.29,134.02,133.03,132.29,129.47,128.61,127.46,126.19,125.43,83.16,57.30,52.67,43.93,36.51,26.04,18.78；HRMS-ESI (+): C25H30ClN8O2S value of calculation 541.1901；541.1879 [M+H] detected+。
The example 4 compound 4d:N-(synthesis of 2-chloro-(6-aminomethyl phenyl)-2-[[6-[4-(2-chloroacetamide)-1-piperazinyl]-2-methyl-4-pyrimidine radicals] amino]-5-thiazole carboxamides
At 0 DEG C, compound 4a (100mg, 0.20mmol) is joined in the round-bottomed flask of 2mL dichloromethane, then under stirring condition, add chloracetyl chloride (44mg, 0.39mmol) and Et3N (45.5mg, 0.45mmol), finishes, and at low temperatures after stirring 5min, removes ice-water bath, and then stirring at normal temperature is to reaction completely.Reactant liquor saturated aqueous common salt washs 2 times, organic facies anhydrous Na2SO4Being dried, filter, concentrate, silica gel column chromatography purification i.e. can get compound 4d (beige solid).This compound1HNMR (400MHz, DMSO-d6) δ ppm9.95 (s, 1H), 8.27 (s, 2H), 7.40 (d, J=7.2Hz, 1H), 7.23-7.30 (m, 2H), 6.09 (s, 1H), 4.08 (s, 2H), 3.52 (br, 4H), 3.25 (q, J=6,12Hz, 1H), 2.41-2.48 (m, 9H), 2.24 (s, 3H)；13CNMR (100MHz, DMSO-d6) δ 165.86,162.79,162.44,161.47,160.37,157.78,141.42,139.30,134.05,132.96,129.47,128.60,127.46,126.51,84.03,59.44,58.19,53.07,43.16,37.88,26.01,18.81；HRMS-ESI (+): C24H29Cl2N8O2S value of calculation 563.1511；563.1542 [M+H] detected+。
Embodiment 2 has chemosynthesis and the Structural Identification of the thiazole heterocycle compounds of formula two
The experiment of synthetic chemistry step (the Compound of Example experimental procedure that formula two is comprised) with the thiazole heterocycle compounds of formula two is as follows:
1. general routes outlined
2. concrete synthesis step:
The preparation of 2.1 compound 9a-9b
By compound 7 (5.67g, 18.98mmol), the piperazine (2-5eq) of different R group and DIPEA (4.91g, 37.99mmol) join in the Isosorbide-5-Nitrae-dioxane (95mL) of stirring, be then heated to 100-105 DEG C of backflow 3-12h, it is cooled to room temperature (the most overnight) after reaction completely, a large amount of solid is had to separate out, sucking filtration, then obtain compound 9 (white solid) with distilled water wash filter cake.Productivity about 90%.
The nuclear magnetic data of compound 9a is as follows:1HNMR (400MHz, CDCl3) δ ppm8.01 (s, 1H), 7.71 (dd, J=1.2,7.6Hz, 4H), 7.35-7.46 (m, 6H), 5.74 (s, 1H), 4.33 (q, J=7.2Hz, 2H), 3.84 (t, J=6.0Hz, 2H), 3.59 (br, 4H), (2.63 t, J=6.0Hz, 2H), 2.57 (br, 4H), 2.54 (s, 3H), 1.35 (t, J=7.2Hz, 3H), 1.071 (s, 9H)；13CNMR (100MHz, CDCl3) δ 166.31,165.51,162.94,162.30,156.567,143.36,135.63,133.68,129.73,127.73,121.44,82.93,62.09,60.86,60.32,53.34,44.09,26.89,25.80,19.21,14.45.
The nuclear magnetic data of compound 9b is as follows:1HNMR (400MHz, DMSO-d6): δ ppm10.72 (s, 1H), 8.05 (s, 1H), 5.79 (s, 1H), 5.02 (br, 1H), 4.36 (q, J=7.2Hz, 2H), 3.64 (s, 4H), 3.28 (br, 2H), 2.54 (s, 9H), 1.46 (s, 9H), 1.38 (t, J=7.2Hz, 3H)；13CNMR (100MHz, DMSO-d6): δ 165.62,164.22,162.85,162.30,157.23,156.03,145.98,120.59,83.32,78.01,60.89,57.75,52.71,44.06,37.83,28.73,26.03,14.78.
1.2. the preparation of compound 10a-10b
Compound 9 is added in two mouthfuls of round-bottomed flasks, add 213mL ethanol, the hydrazine hydrate 106.5mL of the lower addition 80% of stirring, it is heated to 78 DEG C of back flow reaction 2h.After reaction, it is cooled to room temperature, has a large amount of solid to separate out.Then sucking filtration, filter cake massive laundering is washed, and is vacuum dried to obtain compound 10 (white solid).
The nuclear magnetic data of compound 10b is as follows:1HNMR (400MHz, DMSO-d6): δ ppm11.33 (s, 1H), 9.56 (s, 1H), 7.92 (s, 1H), 6.69 (t, J=4.8Hz, 1H), 6.03 (s, 1H), 4.51 (s, 1H), 3.49 (br, 1H), 3.07 (q, J=6.0Hz, 2H), 2.45 (br, 4H), 2.41 (s, 3H), 2.36 (t, J=6.8Hz, 2H), 1.38 (s, 9H)；13CNMR (100MHz, DMSO-d6): δ 165.60,162.84,162.26,161.94,157.48,156.03,139.41,125.39,82.95,78.01,57.74,52.71,44.06,37.81,28.72,26.05.
Bishydrazide compound 11a-11b is prepared in 2.3 acid ammonium condensations
At 0 DEG C, compound 10 (1.0eq) and triethylamine (8.7g, 8.60mmol) are slowly added in the dichloromethane solution of 29 in batches, after about 4h, react complete.In reaction system, directly add 20mL distilled water, sucking filtration, filter cake distilled water wash, be dried to obtain compound 11 (white solid).Productivity 50%-80%.
Compound 11a:2-((6-(4-(2-(t-butyldiphenylsilyl) oxygen) ethyl) piperazine-1-base) 2-methylpyrimidine-4-base) amino)-N '-(2-chloro-6-toluyl) thiazole-5-carbonic acid hydrazine) structural formula as follows:
The nuclear magnetic data of compound 11a is as follows:1HNMR (400MHz, DMSO-d6null): δ ppm11.64 (s，1H)，10.49(s，1H)，10.40(s，1H)，8.18(s，1H)，7.66(dd，J=1.2，7.2Hz，4H)，7.45-7.53(m，6H)，7.33-7.38(m，2H)，7.27(dd，J=2.4，6.4Hz，1H)，6.20(s，1H)，4.36(dd，J=0.8，12.4Hz，2H)，4.07(br，2H)，3.64(d，J=10.8Hz，2H)，3.47(t，J=12.4Hz，2H)，3.38(s，2H)，3.22(d，J=9.6Hz，2H)，2.48(s，3H)，2.46(s，3H)，1.02(s，9H)；
The structural formula of compound 11b: the tert-butyl group (2-(4-(6-((5-(2-(2-chloro-6-toluyl) acyl carbonyl) thiazol-2-yl) amino) 2-methylpyrimidine-4-base) piperazine-1-base) ethyl) carbamate is as follows:
The nuclear magnetic data of compound 11b is as follows:1HNMR (400MHz, DMSO-d6): δ ppm11.45 (s, 1H), 10.44 (s, 1H), 10.38 (s, 1H), 8.14 (s, 1H), 7.33-7.38 (m, 2H), 7.27 (dd, J=6.4HZ, 1H), 6.69 (t, J=1.2Hz, 1H), 6.06 (s, 1H), 3.51 (br, 4H), (3.08 q, J=6.4Hz, 2H), 2.46 (s, 7H), 2.433 (s, 3H), 2.37 (t, J=6.4Hz, 2H), 1.39 (s, 9H)；13CNMR (100MHz, DMSO-d6): δ 166.01,165.61,163.04,162.87,161.32,157.39,156.04,141.29,138.34,135.79,130.67,130.51,129.16,126.85,124.49,83.17,78.02,57.72,52.70,45.99,44.07,37.80,28.73,26.00,19.54.
Diazole compounds 12a-12b is prepared in 2.4 dehydrocyclization reactions
Compound 11 (5.78mmol) is dissolved in 30mL dichloromethane, it is subsequently adding the DIPEA (2.24g of 3eq, 17.34mmol) and the TsCl (1.65g of 1.5eq, 8.68mmol), stirring at normal temperature reacts complete to compound 11, about 3h, reaction system is become yellow clear solution from suspension.The aqueous solution adding ammonia after reaction completely removes the TSCl of excess, organic facies anhydrous Na2SO4Being dried, filter, concentrate, crude product is crossed column purification and is obtained compound 12 (white solid).Productivity 76.3%-79%.
Compound 12a:N-(6-(4-(2-(t-butyldiphenylsilyl) oxygen) ethyl) piperazine-1-base) 2-methylpyrimidine-4-base) 5-(5-(2-chlorine 6-tolyl) 1,3,4-oxadiazoles-2-bases) structural formula of thiazole-2-amine is as follows:
Compound 12a's1HNMR (400MHz, DMSO-d6): δ ppm10.13 (br, 1H), 8.10 (s, 1H), 7.68 (d, J=6.4Hz, 4H), 7.32-7.45 (m, 8H), 7.22-7.25 (m, 1H), 5.81 (s, 1H), 3.83 (t, J=5.2Hz, 2H), 3.60 (br, 4H), 2.55-2.60 (m, 9H), 1.05 (s, 9H)；13CNMR (100MHz, DMSO-d6): δ 166.34,164.14,162.88,160.65,160.45,156.30,141.48,140.14,135.56,134.91,133.59,132.04,129.69,128.86,127.69,127.35,123.72,113.31,82.85,61.90,60.19,53.20,44.00,26.81,25.61,20.59,19.15.
Compound 12b: the tert-butyl group (2-(4-(6-((5-(5-(2-chloro-6-toluene 1,3,4-oxadiazoles-2-base) thiazol-2-yl) amino) 2-methylpyrimidine-4-base) piperazine-1-base) ethyl) structural formula of carbamate is as follows:
The preparation method of compound 12b is ibid.Its nuclear magnetic data is as follows:1HNMR (400MHz, CDCl3): δ ppm10.87 (br, 1H), 8.07 (s, 1H), 7.38-7.42 (m, 2H), 7.28 (d, J=4Hz, 1H), 5.84 (s, 1H), 4.99 (br, 1H), 3.63 (br, 4H), 3.26 (d, J=3.2Hz, 2H), 2.51 (s, 9H), 2.40 (s, 3H), 1.47 (s, 9H)；13CNMR (100MHz, CDCl3): δ 166.39,164.04,162.85,160.56,160.51,156.33,156.00,141.57,139.98,134.92,132.14,128.98,127.46,123.76,113.42,82.82,79.31,57.30,52.49,43.94,37.04,29.69,28.48,25.57,20.64.
The synthesis of 2.5 diazole compounds 13a-13e
Example 5 compound: the synthesis of 13a
Compound 12a (3.00g, 4.00mmol) is joined in the round-bottomed flask of 40mL oxolane, be subsequently adding solid TBAF (3.14g, 12.01mmol), stirring at normal temperature 3h, washs 3 times with 120mL saturated aqueous common salt after reaction completely, organic facies anhydrous Na2SO4Being dried, filter, concentrate, crude product further column chromatography purification obtains compound 13a (white solid, 1.974g).Productivity is 96.3%.Compound1HNMR (400MHz, DMSO-d6): δ ppm11.77 (s, 1H), 8.17 (s, 1H), 7.55-7.61 (m, 2H), 7.46 (d, J=7.2Hz, 1H), 6.07 (s, 1H), 4.45 (t, J=5.2Hz, 1H), 3.53 (br, 6H), 3.33 (s, 6H), 2.42-2.45 (m, 9H), 2.30 (s, 3H)；13CNMR (100MHz, DMSO-d6): 165.53,162.97,162.82,160.83,160.14,156.97,142.50,141.84,134.15,133.40,129.85,127.79,123.64,112.04,83.24,60.63,58.94,53.16,44.06,25.94,20.30；HRMS-ESI (+): C23H26ClN8O2S, value of calculation 513.1588；513.1607 [M+H] detected+。
The synthesis of example 6 compound 13b:N-(6-(4-(2-amino-ethyl) piperazinyl)-2-methylpyrimidine base)-2-(5-(2-chloro-6-aminomethyl phenyl)-1,3,4-di azolies) aminothiazole
Compound 12b (173mg, 0.28mmol) is dissolved in 2.5mL dichloromethane, under stirring at normal temperature, adds CF3COOH, room temperature reaction is wholly absent to compound 12b.Low pressure concentrates the solvent removed in reaction, is subsequently adding saturated aqueous common salt, with saturated NaHCO3Regulation pH9～10, extracts three times with oxolane, merges organic facies, organic facies anhydrous Na2SO4Being dried, filter, concentrate, crude product further column chromatography purification obtains compound 13b (white solid, 144.5mg).Productivity is 83%.This compound1HNMR (400MHz, DMSO-d6): δ ppm8.17 (s, 1H), 7.55-7.61 (s, 1H), 7.45 (d, J=6.4Hz, 1H), 6.15 (s, 1H), 3.56 (br, 4H), 2.92 (t, J=6.4Hz, 2H), 2.56 (t, J=6.4Hz, 2H), 2.50 (s, 4H), 2.45 (s, 3H), 2.30 (s, 3H)；13CNMR (100MHz, DMSO-d6): 165.54,162.97,162.80,160.84,160.15,157.06,142.53,141.85,134.15,133.41,129.86,127.80,123.65,112.01,83.37,55.06,52.47,43.98,36.34,25.95,20.29；HRMS-ESI (+): C23H27ClN9OS, value of calculation 512.1748；512.1733 [M+H] detected+。
Other derivant 13c-13e (example 7-9 compound) is synthesized further: concrete synthetic method is shown in above-mentioned 4b-4d from compound 13b.
Example 7 compound
The productivity of synthesis compound 13c is 37%.This compound1HNMR (400MHz, DMSO-d6): δ ppm11.77 (s, 1H), 8.18 (s, 1H), 7.61-7.55 (m, 2H), 7.48-7.46 (dd, J=7.2,0.8Hz, 1H), 6.10 (s, 1H), 3.80 (t, J=6.4Hz, 2H), 3.56 (br, 4H), 2.66 (t, J=6.4Hz, 2H), 2.54 (br, 4H), 2.46 (s, 3H), 2.30 (s, 3H)；13CNMR (100MHz, DMSO-d6): δ 165.57,162.97,162.80,160.84,160.16,157.02,142.49,141.85,134.17,133.39,129.85,127.80,123.66,112.08,88.33,56.80,52.23,44.13,43.08,25.95,20.30；HRMS-ESI (+): C24H25ClN9OS2, value of calculation 554.1311；554.1332 [M+H] detected+。
Example 8 compound
Compound 13d's1HNMR (400MHz, CDCl3): δ ppm10.09 (br, 1H), 8.10 (s, 1H), 7.39 (m, 2H), 7.30 (d, J=2Hz, 1H), 6.34 (dd, J=1.2,17.2Hz, 1H), 6.14-6.21 (m, 2H), 6.88 (dd, J=1.2,10Hz, 1H), 33.68 (br, 4H), 3.51 (q, J=5.6,11.2Hz, 2H), 2.56-2.61 (m, 9H), 2.41 (s, 3H)；13CNMR (100MHz, DMSO-d6): δ 165.57,165.05,162.98,162.82,160.84,160.16,157.00,142.51,141.85,134.17,133.40,132.30,129.85,127.80,125.43,123.66,112.07,83.29,57.33,52.70,44.01,36.54,25.95,20.30；HRMS-ESI (+): C26H29ClN9O2S, value of calculation 566.1848；566.1868 [M+H] detected+。
Embodiment 9 compound
Compound 13e's1HNMR (400MHz, CDCl3): δ 9.62 (br, 1H), 8.10 (s, 1H), 7.40-7.44 (m, 2H), 7.22 (d, J=0.8Hz, 1H), 5.82 (s, 1H), 4.10 (s, 2H), 3.68 (br, 4H), 3.46 (q, J=5.6,11.2Hz, 2H), 2.55-2.62 (m, 9H), 2.40 (s, 3H)；13C-NMR (100MHz, DMSO-d6): 166.54,165.61,162.92,162.70,160.82,160.16,157.09,142.51,141.84,134.16,133.40,129.85,127.80,123.64,112.11,83.54,58.24,56.61,52.21,43.15,37.89,25.93,20.30；HRMS-ESI (+): C25H28Cl2N9O2S, value of calculation 588.1459；588.1359 [M+H] detected+。
Embodiment 3 has chemosynthesis and the Structural Identification of the thiazole heterocycle compounds of formula three
The experiment of synthetic chemistry step (the Compound of Example experimental procedure that formula three is comprised) with the thiazole heterocycle compounds of formula three is as follows:
1. general routes outlined
2. concrete synthesis step:
The synthesis of 2.1 compounds 15
Take two mouthfuls of flasks of 100mL, add compound 14 (5.00g, 49.93mmol), THF (50mL), stir at 0 DEG C, be then respectively adding triethylamine (10.10g, 99.81mmol) and DMAP (30mg, 0.25mmol).After 10min, in flask, drip (Boc)2O (13.08g, 59.93mmol).Drip complete, remove ice bath, be warmed to room temperature, continue stirring 3h, TLC detection reaction completely, drip distilled water cancellation.Sucking filtration, filtrate is spin-dried for, it is merged together with filter cake, add 100mL dchloromethane, washing organic facies 3-5 time with saturated citric acid solution (100mL), then wash organic facies 1-2 time with saturated nacl aqueous solution (100mL), anhydrous sodium sulfate is dried, it is concentrated to give compound 15 (white solid, 7.65g).Productivity is 76.4%.This compound1HNMR (400MHz, CDCl3): δ ppm12.71 (bs, 1H), 7.41 (d, J=3.5Hz, 1H), 6.90 (d, J=3.5Hz, 1H), 1.61 (s, 9H)；13CNMR (100MHz, CDCl3) δ 162.17,153,13,136.67,111.94,81.73,28.33；MS:[M+H]+201.01。
The synthesis of 2.2 compounds 16
Compound 15 (7.65g, 38.20mmol), dichloromethane (76mL) is placed in flask, being dividedly in some parts NIS (8.6g, 38.22mmol) under stirring, solution is become darkviolet from colourless rapidly, finish, 2h, TLC detection reaction is stirred at room temperature completely.Mixed liquor addition dchloromethane, to 100mL, uses Na2S2O3Saturated solution (100mL/ time) washing organic facies 2-3 time, isolates organic facies, then organic facies anhydrous Na2SO4It is dried, is concentrated to give crude product, yellow solid 11.42g；Compound 16 (white solid powder, 8.32g) is obtained the most further through silica gel column chromatography purification.Productivity is 66.8%.This compound1HNMR (400MHz, CDCl3) δ ppm12.19 (bs, 1H), 7.38 (s, 1H), 1.60 (s, 9H)；13CNMR (100MHz, CDCl3) δ 165.77,152.96,143.94,82.49,62.56,28.26；MS:[M+H]+326.85。
The synthesis of 2.3 compounds 17
Compound 16 (2.00g, 6.13mmol) is placed in one and is dried two mouthfuls of flasks, adds CuI (116.7mg, 0.61mmol), PdCl in glove box2(PPh3)2(215mg, 0.31mmol), then evacuation, inflated with nitrogen (repeats 2-3 time)；Being separately added into dry triethylamine (1.86g, 18.38mmol) with syringe, heavily steam THF (20mL) and trimethyl silicane ethyl-acetylene (1.20g, 12.26mmol), solution quickly becomes black, and 12h is stirred at room temperature.After reaction terminates, use distilled water cancellation.Sand core funnel one layer of kieselguhr of paving, the solid being filtered to remove in reaction mixture, pressurization concentrates and removes organic solvent, dissolve with dichloromethane, respectively with distilled water, saturated nacl aqueous solution washing organic facies 2-3 time, anhydrous sodium sulfate is dried, and concentrates, silica gel column chromatography separating purification.2.5%EtOAc/PE affords compound 17 (yellow solid powder, 2.02g).Productivity is 55.5%.This compound1HNMR (400MHz, CDCl3) δ ppm12.11 (bs, 1H), δ 7.46 (s, 1H), δ 1.60 (s, 9H), 0.26 (s, 9H)；13CNMR (100MHz, CDCl3) δ 161.44,152.63,141.83,111.78,101.17,94.33,82.53,53.42,28.27；MS:[M+H]+297.02。
2.4 compounds 18: the synthesis of the tert-butyl group (5-acetylene thiazol-2-yl) carbamate
Compound 17 (2.22g, 7.49mmol) is suspended in solvent methanol (70mL), adds Anhydrous potassium carbonate (2.07g, 15.00mmol) while stirring, and after 30min, reaction terminates, and is spin-dried for by solvent.Adding dichloromethane to dissolve, by distilled water wash organic facies 3 times, saturated nacl aqueous solution washing organic facies 1-2 time, anhydrous sodium sulfate is dried, and is concentrated to give compound 18 (yellow powder, 1.64g).Productivity is 97.6%.This compound1HNMR (400MHz, CDCl3) δ ppm11.84 (bs, 1H), 7.53 (s, 1H), 3.39 (s, 1H), 1.61 (s, 9H)；13CNMR (100MHz, CDCl3) δ 161.94,152.75,142.42,110.49,83.27,82.59,73.96,28.26.
2.5 compounds 21: the synthesis of the tert-butyl group (5-(1-(2-chloro-6-tolyl)-1H-1,2,3-triazole-4-base) thiazol-2-yl) carbamate
At 0 DEG C, compound 19 (425mg, 3.00mmol), NaNO2(414mg, 6.00mmol) and 5mLH2O adds in round-bottomed flask, is slowly added dropwise 3N hydrochloric acid (3mL, 9.00mmol) while stirring, finishes, and continues stirring 1h.Weigh NaN3(214.5mg, 3.30mmol), is dissolved in 2mLH2In O, being slowly added dropwise to above-mentioned flask, continue stirring 1.5h, TLC detection, raw material disappears, and reaction is completely.With dichloromethane extractive reaction mixed liquor, merging organic facies, rotate and remove partial solvent, add acetonitrile solution, continue to be spin-dried for dichloromethane, obtain the mixture of 20, product is dissolved in acetonitrile, directly throws next step；
Take another flask, add compound 18, evacuation, inflated with nitrogen, nitrogen stream adds acetonitrile solution and nanometer Cu of catalytic amount of compound 20 (1-nitrine-2-chlorobenzene)2O (is suspended in H2In O), under nitrogen protection, reaction is stirred at room temperature overnight.After reaction terminates, column chromatographic isolation and purification product, first remove the miscellaneous point of part with P:E=5:1 eluting, 2% ethanol/methylene affords product, i.e. compound 21 (751mg, 85.8%).This compound1HNMR (400MHz, CDCl3) δ ppm10.91 (bs, 1H), 7.86 (s, 1H), 7.77 (s, 1H), 7.32-7.46 (m, 3H), 2.17 (s, 3H), 1.64 (s, 9H)；13CNMR (100MHz, CDCl3) δ 161.260,152.824,140.00,138.18,134.16,133.97,131.80,131.15,129.54,127.90,121.35,82.49,28.34,17.92；MS:[M+H]+391.78。
The synthesis of 2.6 compound 22:5-(1-(2-chloro-6-tolyl)-1H-1,2,3-triazole-4-base) thiazole-2-amine
Compound 21 (2.3g, 5.88mmol) is dissolved in CH2Cl2(30mL), in, CF under room temperature, is added while stirring3COOH (6mL), room temperature continues stirring 3h, TLC detection reaction completely, and rotation is evaporated off solvent and part CF3COOH, addition saturated sodium bicarbonate solution to pH8～9.Dichloromethane extracts 2-3 time, merges organic facies, and organic facies anhydrous sodium sulfate is dried, and filters, and low pressure is concentrated to give product, i.e. compound 22 (yellow-brown solid, 1.67g).Productivity is 97.6%.This compound1HNMR (400MHz, CDCl3) δ ppm7.77 (s, 1H), 7.40-7.45 (m, 3H), 7.32 (s, 1H), 5.33 (bs, 2H), 2.14 (s, 3H)；13CNMR (100MHz, CDCl3) δ 140.43,138.20,135.85,133.99,131.83,131.15,129.49,127.85,120.78,17.88.
The synthesis of 2.7 compound 24:N-(6-chloro-2-methyl pyrimidine-4-yl)-5-(1-(2-chloro-6-tolyl)-1H-1,2,3-triazole-4-base) thiazole-2-amine
At 0 DEG C, by compound 22 (1.67g, 5.74mmol) join the NaH (1148mg of 60%, 28.70mmol use before by petroleum ether 3 times) tetrahydrofuran solution (57mL) in, under stirring, compound 23 (1.12g, 6.89mmol) is dividedly in some parts in above-mentioned suspension, finish, after low temperature stirring 30min, move to room temperature reaction overnight.Rotation is evaporated off tetrahydrofuran solution, adds 60mL distilled water, regulates pH5～6.5 with citric acid, and dichloromethane extracts 3 times, merges organic facies, is dried with anhydrous sodium sulfate, filters, and concentrates.Column chromatography is further purified to obtain compound 24 (Off-white solid, 1.8g).Productivity is 75.3%.This compound1HNMR (400MHz, DMSO-d6) δ ppm12.06 (br, 1H), 8.86 (s, 1H), 7.88 (s, 1H), 7.57-7.64 (m, 2H), 7.52 (d, J=7.2Hz, 1H), 6.94 (s, 1H), 2.61 (s, 3H), 2.07 (s, 3H)；13CNMR (100MHz, DMSO-d6) δ 167.86,158.79,158.22,158.08,140.20,138.37,135.62,134.10,132.24,131.13,130.37,128.22,123.50,121.50,103.51,25.64,17.66；MS:[M+H]+418.03。
Example 10 to example 11 compound: the synthesis of 25a-25b
By compound 24 (1.8g, 4.30mmol), piperazine compounds (21.51mmol), DIPEA (1.11g, 8.59mmol) all joins in round-bottomed flask, is subsequently adding reaction dissolvent 1,4-dioxane 43mL, heats 103 DEG C of return stirring 3h, reacts complete.It is cooled to room temperature (the most overnight), has solid to separate out, sucking filtration, wash respectively 2 times by water and ethyl acetate, the most i.e. can get compound 25 (white solid), productivity is 73-88%.Note: the response time depends primarily on the amount of piperazine, the response time increases with piperazine amount and reduces, probably can float at 3-20h.
Example 10 compound
This compound1HNMR (400MHz, DMSO-d6) δ ppm11.26 (s, 1H), 8.78 (s, 1H), 7.76 (s, 1H), 7.50-7.63 (m, 3H), 6.05 (s, 1H), 4.47 (bs, 1H), 3.54 (t, J=5.6Hz, 6H), 2.43-2.50 (m, 9H), 2.06 (s, H)；13CNMR (100MHz, DMSO-d6) δ 165.58,162.84,159.56,157.60,140.64,138.37,135.34,134.16,132.18,131.13,130.34,128.20,123.04,119.99,82.65,60.61,58.89,53.15,44.01,26.05,17.64；HRMS-ESI (+): C23H27ClN9OS, value of calculation 512.1748；512.1744 [M+H] detected+。
This compound1HNMR (400MHz, DMSO-d6) δ ppm9.89 (br, 1H), 7.86 (s, 1H), 7.84 (s, 1H), 7.40-7.47 (m, 2H), 7.33 (dd, J=0.8,7.2Hz, 1H), 5.87 (s, 1H), 5.03 (br, 1H), 3.66 (br, 4H), 3.29 (d, J=5.2Hz, 2H), 2.51-2.56 (m, 9H), 2.18 (s, 3H), 1.48 (s, 9H)；13CNMR (100MHz, DMSO-d6) δ 165.59,162.86,159.59,157.62,156.04,140.64,138.38,135.35,134.18,132.18,131.15,130.34,128.20,123.04,120.01,82.67,78.02,66.83,57.76,52.74,44.11,37.84,28.73,26.05,17.65；MS:[M+H]+611.16。
The synthesis of 2.9 compound 25c-25f
Example 11 compound: the synthesis of 25c
Compound 25b (500mg, 0.82mmol) is joined in the round-bottomed flask containing 8mL dichloromethane, under stirring, adds 2mLCF3COOH, finishes room temperature reaction 3h, TLC monitoring reaction completely.Low pressure concentrates and removes dichloromethane, then adds 5mL methanol in system, adds solid sodium carbonate regulation pH9～10, is filtered to remove insoluble solid, and filtrate concentrates, and obtains compound 25c (334mg, white solid) by column chromatography purification further.Productivity is 80%.This compound1HNMR (400MHz, DMSO-d6) δ ppm8.78 (s, 1H), 7.76 (s, 1H), 7.56-7.64 (m, 2H), 7.51 (dd, J=0.4,7.2Hz, 1H), 6.06 (s, 1H), 3.52 (br, 4H), 2.69 (t, J=6.4Hz, 2H), 2.44-2.45 (m, 7H), 2.37 (t, J=6.4Hz, 2H), 2.07 (s, 3H), 1.83 (s, 1H)；13CNMR (100MHz, DMSO-d6) δ 165.58,162.85,159.61,157.63,140.66,138.37,135.36,134.17,132.18,131.14,130.34,128.20,123.04,119.99,82.67,60.41,52.89,44.11,38.60,26.06,17.64；HRMS-ESI (+): C23H28ClN10S, value of calculation 511.1908；511.1905 [M+H] detected+。
Example 12-14 compound: the synthesis of 25d-25f
The method as 4b-4d is used to synthesize a series of derivant, as shown below on the basis of compound 25c:
Compound 25d:
Example 12 compound
1HNMR (400MHz, DMSO-d6) δ ppm11.25 (s, 1H), 8.79 (s, 1H), 7.76 (s, 1H), 7.64-7.56 (m, 2H), 7.51 (d, J=7.2Hz, 1H), 6.06 (s, 1H), 3.80 (t, J=5.6Hz, 2H), 3.54 (br, 4H), 2.66 (t, J=5.6Hz, 2H), 2.54 (t, J=4.4Hz, 4H), 2.44 (s, 3H), 2.07 (s, 3H)；13CNMR (100MHz, DMSO-d6) δ 165.62,162.82,159.59,157.65,140.65,138.37,135.36,134.18,132.16,131.15,130.33,130.19,128.19,123.04,120.03,82.75,56.83,52.26,44.14,43.09,26.06,17.65；HRMS-ESI (+): C24H26ClN10S2, value of calculation 553.1472；553.1387 [M+H] detected+。
Compound 25e:
Example 13 compound
1HNMR (400MHz, DMSO-d6) δ ppm9.95 (s, 1H), 8.27 (s, 2H), 7.40 (d, J=7.2Hz, 1H), 7.23-7.30 (m, 2H), 6.09 (s, 1H), 4.08 (s, 2H), 3.52 (br, 4H), 3.25 (q, J=6,12Hz, 2H), 2.41-2.48 (m, 9H), 2.24 (s, 3H)；13CNMR (100MHz, DMSO-d6) δ 172.39,165.55,165.12,162.77,159.53,157.70,140.67,138.35,135.41,134.16,132.37,132.17,131.12,130.34,128.19,125.33,123.10,119.98,82.88,57.17,52.55,43.77,36.30,26.05,17.64；HRMS-ESI (+): C26H30ClN10OS, value of calculation 565.2014；565.1992 [M+H] detected+。
Compound 25f:
Example 14 compound
1HNMR (400MHz, DMSO-d6) δ ppm11.26 (s, 1H), 8.79 (s, 1H), 8.18 (t, J=5.2Hz, 1H), 7.76 (s, 1H), 7.51-7.64 (m, 1H), 6.05 (s, 1H), 4.08 (s, 2H), 3.52 (br, 1H), 3.263 (q, J=6.4Hz, 2H), 2.42-2.49 (m, 9H), 2.07 (s, 3H)；13CNMR (100MHz, DMSO-d6) δ 165.82,162.40,161.48,159.35,157.94,140.58,138.36,135.43,134.15,132.21,131.13,130.36,128.21,123.17,120.27,83.59,59.45,58.20,53.05,43.15,37.89,26.02,17.65；HRMS-ESI (+): C26H30ClN10OS, value of calculation 587.1624；587.1640 [M+H] detected+。
The active testing of example 1 to example 14 compound that embodiment 4 is prepared by embodiment 1 to embodiment 3
MTT powder is bought in Sigma company, is configured to, with phosphate buffer (PBS), the solution that concentration is 5 mg/ml, chooses 0.22 μm filter membrane and filters, then keeps in Dark Place at 4 DEG C.K562 cell (chronic myeloid leukemia cell line) is purchased from from gold amethyst bio tech ltd, Beijing.Cell culture medium used in experiment is modified form RPMI-1640 (Hyclone) basal medium, adds the hyclone (Hyclone) of 10%.
MTT colorimetric method for determining cytoactive includes following several step (as a example by the method for testing of K562 cell, the method for testing of KG1aHL60 cell is consistent with the method for K562 cell):
(1) choose and be in the K562 cell of exponential phase, by every hole 3 × 103It is inoculated in 96 orifice plates, 5%CO2, hatch overnight incubation for 37 DEG C.
(2) being provided with 9 Concentraton gradient in dosing, this experiment, system Chinese medicine final concentration gradient is: 30 μMs, 15 μMs, 7.5 μMs, 3.7 μMs, 1.8 μMs, 0.9 μM, 0.5 μM, 0.2 μM, 0.1 μM.The multiple hole of each concentration 5, arranges matched group (not dosing only inoculating cell) and blank well (non-inoculating cell only adds culture medium), 5%CO simultaneously2, 37 DEG C of incubators hatch 72 hours.
(3) every hole adds 20 μ LMTT solution (5mg/ml, i.e. 0.5%MTT), continues to cultivate 4 hours.If medicine can react with MTT, can first be centrifuged and discard culture fluid afterwards, after carefully rinsing 2-3 time with PBS, add the culture fluid containing MTT.
Terminate after (4) 4 hours cultivating, suck the liquid in hole carefully.And the dimethyl sulfoxide of 150 μ L is added to every hole.It is subsequently placed in low-speed oscillation about 15 minutes on shaking table, makes crystal fully dissolve.Enzyme-linked immunosorbent assay instrument MULTISKANFC (Thermoscientific) is used to measure at 490nm and the absorbance in each hole of 570nm, using blank well as zeroing hole during measurement.
(5) data are processed.With drug level as abscissa, cell number is vertical coordinate, carries out probit weighted regression method (Bliss method) with data processing software SPSS software (IBM Corporation) and carries out data process, mapping, obtains IC50And IC90Value, is shown in Table 1.
Table 1 example 1 to example 14 compound is to K562, the inhibitory action of KG1a, HL60 cell
By table 1, can be seen that example 1 to example 14 compound prepared in an embodiment (corresponds respectively to compound 4a-4d, 13a-13e, 25a and 25c-25f) all can effectively suppress K562, HL60, the propagation of KG1a cell, particularly example 3 compound (compound 4c) is in the case of drug level is less than positive control medicine Dasatinib, still can realize effectively suppressing K562 equally, HL60, the effect of KG1a cell proliferation, therefore, example 1 to example 14 compound that the present invention provides may be used for treating leukemia.
The foregoing is only presently preferred embodiments of the present invention, not in order to limit the present invention, all within the spirit and principles in the present invention, any amendment made, equivalent, improvement etc., should be included within the scope of the present invention.

Claims (10)

1. a thiazole heterocycle compounds, it is characterised in that there is following general structure:
Thiazole heterocycle compounds the most according to claim 1, it is characterised in that described formula Middle X is:
And wherein, R includes following group:
Thiazole heterocycle compounds the most according to claim 1, it is characterised in that described formula Middle X is:
And wherein, R includes following group:
Thiazole heterocycle compounds the most according to claim 1, it is characterised in that described formula Middle X is:
And wherein, R includes following group:
5. the preparation method of a thiazole heterocycle compounds, it is characterised in that including:
Make 2-((6-(4-(2-(t-butyldiphenylsilyl) oxygen) ethyl) piperazine-1-base) 2-methylpyrimidine -4-base) amino)-N '-(2-chloro-6-toluyl) thiazole-5-carbonic acid hydrazine) and the tert-butyl group (2-(4-(6-((5-(2-(2-chloro-6-toluyl) acyl carbonyl) thiazol-2-yl) amino) 2-methylpyrimidine-4-base) Piperazine-1-base) ethyl) carbamate occur respectively dehydrocyclization reaction prepare N-(6-(4-(2-(tertiary fourth Base diphenylsilyl group) oxygen) ethyl) piperazine-1-base) 2-methylpyrimidine-4-base) 5-(5-(2-chlorine 6-toluene Base) 1,3,4-oxadiazoles-2-bases) thiazole-2-amine and the tert-butyl group (2-(4-(6-((5-(5-(2-chloro-6-toluene 1,3,4- Oxadiazoles-2-base) thiazol-2-yl) amino) 2-methylpyrimidine-4-base) piperazine-1-base) ethyl) carbamate
Make described N-(6-(4-(2-(t-butyldiphenylsilyl) oxygen) ethyl) piperazine-1-base) 2-methyl Pyrimidine-4-yl) 5-(5-(2-chlorine 6-tolyl) 1,3,4-oxadiazoles-2-bases) thiazole-2-amine and the described tert-butyl group (2-(4-(6-((5-(5-(2-chloro-6-toluene 1,3,4-oxadiazoles-2-base) thiazol-2-yl) amino) 2-methylpyrimidine -4-base) piperazine-1-base) ethyl) carbamate generation substitution reaction to be to generate described thiazole heterocycle class Compound；
Wherein, the chemical structural formula of described thiazole heterocycle compounds is:
, wherein, R is :-OH or-NH2。
6. the preparation method of a thiazole heterocycle compounds, it is characterised in that including:
The tert-butyl group (5-acetylene thiazol-2-yl) carbamate and 1-nitrine-2-chlorobenzene is made to react the tertiary fourth of generation Base (5-(1-(2-chloro-6-tolyl)-1H-1,2,3-triazole-4-base) thiazol-2-yl) carbamate；
Make the described tert-butyl group (5-(1-(2-chloro-6-tolyl)-1H-1,2,3-triazole-4-base) thiazol-2-yl) Carbamate and trifluoroacetic acid react generation 5-(1-(2-chloro-6-tolyl)-1H-1,2,3-triazole-4- Base) thiazole-2-amine；
Make 5-(1-(2-chloro-6-tolyl)-1H-1,2,3-triazole-4-base) thiazole-2-amine and the chloro-2-of 4,6-bis- Methylpyrimidine reaction generates N-(6-chloro-2-methyl pyrimidine-4-yl)-5-(1-(2-chloro-6-toluene Base)-1H-1,2,3-triazole-4-base) thiazole-2-amine；
Make described N-(6-chloro-2-methyl pyrimidine-4-yl)-5-(1-(2-chloro-6-tolyl)-1H-1,2,3-three nitrogen Azoles-4-base) thiazole-2-amine reacts with piperazine compounds, generates described thiazole heterocycle compounds；
Wherein, the chemical structural formula of described piperazine compounds is:
The chemical structural formula of described thiazole heterocycle compounds is:
And wherein, R at least includes-OH.
7. according to the thiazole heterocycle compounds according to any one of claim 1-6 be used for treating white Application in the medicine of disorders of blood.
Application the most according to claim 7, it is characterised in that described leukemic for treating Pharmaceutical pack pharmaceutically can accept containing described thiazole heterocycle compounds, described thiazole heterocycle compounds Salt, ester, hydrate or combinations thereof and adjuvant.
Application the most according to claim 7, it is characterised in that the leukemic medicine of described treatment Dosage form selected from tablet, capsule, pill, suppository, aerosol, oral liquid, granule, Powder, injection, syrup, medicated wine, tincture, distillate medicinal water, membrane or combinations thereof.
Application the most according to claim 7, it is characterised in that the leukemic medicine of described treatment The administering mode of thing includes being administered orally, injects, implants, external, spray, suck or combinations thereof.
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