CN102199152A - Heterocycle imidazoles phosphatide kinases inhibitor - Google Patents
Heterocycle imidazoles phosphatide kinases inhibitor Download PDFInfo
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Abstract
The invention discloses a heterocycle imidazoles phosphatide kinases inhibitor. The heterocycle imidazoles compound has a structural formula shown as formula I. X, Y, Z, Q are selected from C or N; R1 is selected from pyridyl or halogen, nitrile group, C1-C4 alkyl, C1-C4 alkyloxy substituted pyridyl, pyrimidinyl or C1-C4 alkyloxy substituted pyrimidinyl, quinoxalinyl, quinolyl or halogenated quinolyl, phenyl or C1-C4 alkyloxy substituted phenyl; R2 is selected from aromatic heterocycle which comprises pyridyl, naphthyl, phenyl, and disubstituted or monosubstituted pyridyl and phenyl, wherein the substituent is selected from a group of halogen, C1-C4 alkyl, or halogen, nitrile, imidazolyl or triazolyl substituted C1-C4 alkyl, C3-C10 cyclic hydrocarbon group, C1-C4 alkyl, C1-C4 sulfonyl, C1-C4 alkoxy, C1-C4 alcoxyl alkyl monosubstituted or disubstituted amido, or C1-C4 alkyl, C1-C4 sulfonyl substituted or non- substituted piperidino, 2- pyrrolidone group, C1-C4 alkoxyalkyl, imidazolyl, pyridyl, triazolyl; R3 is selected from O or S; R4 is selected from H, C1-C4 alkyl or C1-C4 alkyloxy; and R5 is selected from H or C1-C4 alkyl.
Description
Technical field
The present invention relates to the phosphatide kinase inhibitor, be specifically related to a kind of heterocycle imidazoles phosphatide kinase inhibitor.
Background technology
Phosphatidyl-inositol 3-kinase (PI3K) is one group of family's enzyme, can the phosphorylated phosphoinositide hydroxyl [D.Whiteman et al.1988, Nature, 332,664] of 3 of sugar.Its information transfering path can regulating cell a series of processes such as transfer of growth, propagation, survival and cell.
PI3K can be divided into three types according to its constitutional features and in external specificity to the Phospholipid hydrolase substrate.Wherein Ia class PI3K is a kind of enzyme [Vivanco and Sawyers that is generally involved in cancer, NatureReviews Cancer, 2002 (2): 489-501], be a kind of dimerization enzyme of hydridization, it contains a catalytic subunit p110 (α, β or δ) and another regulation and control subunit (p85 α or β).PI3K α participates in the generation and the insulin signaling of tumour, and is the closest with increment, death, metabolism and the survival of cell.PI3K β plays a part platelet aggregation, and PI3K δ is that immunocyte differentiation and function are requisite, and is relevant with anaphylaxis and hematologic cancers.
Ia class PI3K (α, β or δ) can be activated by receptor tyrosine kinase, comprises picture growth factor receptors VEGFR, EGF, PDGFR etc.And receptor tyrosine kinase can be by stimulus activation widely, as somatomedin, inflammation regulatory factor, hormone, neurotransmitter, immunoglobulin (Ig) and antigen etc.When in a single day PI3K is activated; it can shift by the catalysis phosphoryl; PIP2 is changed into PIP3, can build up to cytolemma containing the protein kinase of substrate homologous structure such as protein kinase B (Akt) and phosphatidylinositols dependant kinase 1 (PDK-1) then, thereby cause the transmission of PI3K information channel.
The activation of PI3K information channel is regulated and control by the inhibition of two phosphoinositide Phospholipid hydrolases effect again.Wherein a kind of enzyme is the phosphoinositide esterase (SHIP) that contains the SH2 structural domain, and it can be with 5 '-phosphinylidyne inositol P3[PtdIns (3,4,5) P3] change into phosphinylidyne inositol P2[PtdIns (3,4) P2].And another kind of enzyme, Phosphoric acid esterase is to come from the 10th homology of chromosome to lose acid phosphatase-tensin gene (PTEN), it can be hydrolyzed into PtdIns (3,4,5) P3 PtdIns (4,5) P2.PIP3 just loses the function that information is conducted after being hydrolyzed into PIP2, thereby inhibited to the growth of cancer cells.
The information transmission channels of PI3K is found in the multiple cancer and activates singularly.The activity of receptor tyrosine kinase increases, or the somatic mutation of the specific components of PI3K signal path, all can cause the activation of PI3K.At the cancer patient that surpasses 30%, comprise and all found P110a activation sudden change [Shayesteh in colorectal carcinoma, cancer of the stomach, the cancer of the brain, mammary cancer, ovarian cancer, lung cancer and the liver cancer patient, et al., NatureGenetics, 1999 (21): 99-102] and [Samuels, et al, Science, 2004,304-554], make the information channel of PI3K be in state of activation always.In addition, greater than 50% cancer patient, as finding that all variation has taken place PTEN among the cancer of the brain, pernicious black cystoma, prostate tumor, hysteroma and the oophoroma patient.In these cancerations, sudden change has often taken place in the PTEN gene, and deletion or active decline make PTEN lose the restraining effect to cancer cells, cause the information channel of PI3K to be in state of activation always.So the PI3K information transmission channels of abnormal activation is to the cancer cell growth and the outstanding effect of having survived.
Summary of the invention
Technical problem to be solved by this invention is to provide heterocycle glyoxaline compound or its pharmacy acceptable salt, is applied to the phosphatide kinase inhibitor.Compound among the present invention can effectively suppress PI3K kinases and m-TOR kinases, has the effect that treatment comprises cancer, immune inflammation and diabetes class disease, because these diseases are all relevant unusually with the PI3K conducting system.
Heterocycle glyoxaline compound of the present invention or its pharmacy acceptable salt, its structural formula is as shown in the formula shown in the I:
Wherein, X, Y, Z, Q all are selected from C or N.
R
1Be selected from: pyridyl or halogen, itrile group, C
1-C
4Alkyl, C
1-C
4The pyridyl that alkoxyl group replaces, pyrimidyl or C
1-C
4The pyrimidyl that alkoxyl group replaces, quinoxalinyl, quinolyl or halogenated quinoline base, phenyl or C
1-C
4The phenyl that alkoxyl group replaces.
R
2Be selected from: fragrant heterocycle, described fragrant heterocycle comprises pyridyl, naphthyl, phenyl, and two the replacement or mono-substituted pyridyl and phenyl, substituting group is selected from halogen, C
1-C
4Alkyl, or the C of halogen, itrile group, imidazolyl or triazol radical replacement
1-C
4Alkyl, C
3-C
10Cyclic hydrocarbon radical, C
1-C
4Alkyl, C
1-C
4Alkylsulfonyl, C
1-C
4Alkoxyl group, C
1-C
4The alkoxyalkyl list replaces or disubstituted amido, or C
1-C
4Alkyl, C
1-C
4Alkylsulfonyl replaces or unsubstituted piperidyl, 2-Pyrrolidone base, C
1-C
4Alkoxyalkyl, imidazolyl, pyridyl, triazol radical.
R
3Be selected from O or S.
R
4Be selected from H, C
1-C
4Alkyl or C
1-C
4Alkoxyl group.
R
5Be selected from H or C
1-C
4Alkyl.
Preferably, heterocycle glyoxaline compound of the present invention or its pharmacy acceptable salt can be following structural formula:
Shown in Ia, work as X=Y=Z=C, Q=N, R
3During=O, R
1Be selected from: pyridyl or halogen, itrile group, C
1-C
4Alkyl, C
1-C
4The pyridyl that alkoxyl group replaces, pyrimidyl or C
1-C
4The pyrimidyl that alkoxyl group replaces, quinoxalinyl, quinolyl or halogenated quinoline base, phenyl or C
1-C
4The phenyl that alkoxyl group replaces; R
2Be 2, the phenyl that 2-dimethyl acetonitrile replaces; R4 is selected from H, C
1-C
4Alkyl or C
1-C
4Alkoxyl group, preferable methyl; R
5Be selected from H or C
1-C
4Alkyl.
Shown in Ib, work as X=N, Y=Z=Q=C, R
3During=O, R
1Be selected from: pyridyl or halogen, itrile group, C
1-C
4Alkyl, C
1-C
4The pyridyl that alkoxyl group replaces, pyrimidyl or C
1-C
4The pyrimidyl that alkoxyl group replaces, quinoxalinyl, quinolyl or halogenated quinoline base, phenyl or C
1-C
4The phenyl that alkoxyl group replaces; R
2Be 2, the phenyl that 2-dimethyl acetonitrile replaces; R
4Be selected from H, C
1-C
4Alkyl or C
1-C
4Alkoxyl group, preferable methyl; R
5Be selected from H or C
1-C
4Alkyl.
Shown in Ic, work as Y=N, X=Z=Q=C, R
3During=O, R
1Be selected from: pyridyl or halogen, itrile group, C
1-C
4Alkyl, C
1-C
4The pyridyl that alkoxyl group replaces, pyrimidyl or C
1-C
4The pyrimidyl that alkoxyl group replaces, quinoxalinyl, quinolyl or halogenated quinoline base, phenyl or C
1-C
4The phenyl that alkoxyl group replaces; R
2Be 2, the phenyl that 2-dimethyl acetonitrile replaces; R
4Be selected from H, C
1-C
4Alkyl or C
1-C
4Alkoxyl group, preferable methyl; R
5Be selected from H or C
1-C
4Alkyl.
Shown in Id, work as Z=N, X=Y=Q=C, R
3During=O, R
1Be selected from: pyridyl or halogen, itrile group, C
1-C
4Alkyl, C
1-C
4The pyridyl that alkoxyl group replaces, pyrimidyl or C
1-C
4The pyrimidyl that alkoxyl group replaces, quinoxalinyl, quinolyl or halogenated quinoline base, phenyl or C
1-C
4The phenyl that alkoxyl group replaces; R
2Be 2, the phenyl that 2-dimethyl acetonitrile replaces; R
4Be selected from H, C
1-C
4Alkyl or C
1-C
4Alkoxyl group, preferable methyl.
Described halogen is F, Cl or Br.
Heterocycle glyoxaline compound of the present invention can adopt following operational path to be prepared from.Promptly set out by para-bromoaniline; obtain pyrroles's azo-compound through acetylize, diazotization reaction; after the condensation cyclization gets 1; the 2-naphthalene dinitrogen compound; and then after chlorination, amination, ester are hydrolyzed into acid; through curtis reset the imidazolone compound, after methylating, after the suzuki coupling gets target compound.
Heterocycle glyoxaline compound of the present invention can also adopt following operational path to be prepared from.Promptly set out, be hydrolyzed into acid through bromination, suzuki coupling and condensation, cyclization, chlorination, amination, ester by the 3-aminopyridine, through curtis reset intermediate imidazolone compound, promptly get target product through methylating again.
Compound of the present invention can adopt following operational path to be prepared from again.Promptly be hydrolyzed into acid through suzuki coupling, condensation, cyclization, chlorination, amination, ester by 6-chloro-2-methyl-3 aminopyridine, through curtis reset the key intermediate imidazolone compounds, methylate again and promptly get target compound.
Wherein, in above-mentioned each synthesis technique, intermediate 2,2-dimethyl p-aminophenyl acetonitrile adopts following path of preparing to form:
Compound of the present invention can be prepared into acceptable salt on its pharmacology with any suitable acid.For example, mineral acid example hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid etc.; Organic acid such as formic acid, acetate, propionic acid, phenylformic acid, toxilic acid, fumaric acid, succsinic acid, tartrate, citric acid etc.; Alkylsulphonic acid such as methylsulphonic acid, ethylsulfonic acid etc.; Aryl sulfonic acid such as Phenylsulfonic acid, tosic acid etc. all can use.
Biological activity test:
1.MTT experiment:
1) sample preparation: after DMSO (Merck) dissolving, add solution or uniform suspension that PBS is made into 1000 μ g/ml, then with the PBS dilution that contains DMSO.
2) cell strain:
HL-60 (human leukemia cell), HCT116 (people's colon-cancer cell), MDA-MB-435 (human breast cancer cell), A549 (human lung carcinoma cell) is all available from Chinese Academy of Sciences's cell bank.
3) nutrient solution: RPMI 1640 substratum (available from Gibco company)+15%NBS (new-born calf serum is available from the Hangzhou four seasons clear biological engineering material company limited)+two anti-(penicillin, Streptomycin sulphate are available from Gibco companies).
4) instrument: full-automatic microplate reader, model: WellscanMK-2, production firm: Labsystems; Import 96 well culture plates.
5) concrete steps:
It is 4～5 * 10 that the every hole of 96 orifice plates adds concentration
4The cell suspension 100 μ l of individual/ml put 37 ℃, 5%CO
2In the incubator.Behind the 24h, add sample liquid, two multiple holes are established in 10 μ l/ holes, and 37 ℃, 5%CO
2Effect 72h.Every hole adds the MTT solution 20 μ l of 5mg/ml, adds lysate behind the effect 4h, and put in the incubator in 100 μ l/ holes, and 570nm OD value is surveyed with the full-automatic microplate reader of MK-2 in the dissolving back.
6) test-results sees Table 1.
Table 1
The sulphonyl rhodamine B (sulforhodamine B, SRB) protein staining experiment:
1) cell strain: PC-3 (human body prostate cancer cell) ATCC
2) action time: 72 hours
3) result: referring to table 2.
Judgement criteria: invalid 10
-5Mol/L＜50%; Effective 10
-5Mol/L＞50%.
Table 2
Wherein, the positive contrast of sample BEZ235 [F.Stauffer et al.l Bioorg.Med.Chem.Lett.18 (2008) 1027-1030].
From above-mentioned test as can be seen:
(1) The compounds of this invention has the obvious suppression effect to the in-vitro multiplication of human body lung cell A549, than positive control BEZ235 (PI3K﹠amp; The m-TOR double inhibitor) strong 15.6 times.
(2) The compounds of this invention has the obvious suppression effect to the in-vitro multiplication of human body prostate cancer cell strain PC-3, with positive control BEZ235 (PI3K﹠amp; The m-TOR double inhibitor) has similar or strong slightly activity.
Above-mentioned biological activity test result further specifies, and compound of the present invention or its pharmacy acceptable salt can be used for preparing antitumor drug, immune inflammation disease drug, diabetes medicament or phosphatide kinase inhibition agent medicine.
Embodiment
Below in conjunction with specific embodiment technical scheme of the present invention is described in further detail.
Reagent specification of the present invention and originate as follows:
| Title | Specification | Producer |
| The 3-aminopyridine | 99.5％(GC) | Splendid chemical Science and Technology Ltd. far away |
| The N-bromo-succinimide | AR | Chemical reagent purchase and supply 5-linked chemical plant, Shanghai |
| Diethyl ethoxymethylenemalonate | 98.4(GC) | Splendid chemical Science and Technology Ltd. far away |
| 3-quinoline boric acid | 97％ | Lark prestige chemical reagents corporation |
| Four (triphenyl phosphorus) palladium | Palladium content 9.1% | The Zhejiang Metallurgical Research Institute Co |
| Phenyl ether | 99％ | The lark waffle is learned reagent |
| Phosphorus oxychloride | CP | Jiangsu normal surplus chemical industry company limited |
| Diphenyl phosphate azide (DPPA) | 97.7％(GC) | Splendid chemical Science and Technology Ltd. far away |
| Sodium hydride | AR | The Long Huagongshijichang of Chengdu section |
| Methyl iodide | AR | Zhejiang Hai Chuan chemical company limited |
| 2-methyl-3-amino-6-chloropyridine | CP | River, sea, Fuxin, Liaoning chemistry company limited |
| The p-nitrophenyl acetonitrile | CP | Occasion chemical industry company limited is praised in Shanghai |
| Iron powder | AR | Gansu Province, west, Shantou, Guangdong chemical industry |
| The hexane solution of boron trichloride | 1mol/L | Beijing Ma Erdi Science and Technology Ltd. |
| The 4-bromaniline | CP | Sea, Shanghai Qu Huagong company limited |
| Aluminum chloride | AR | Shanghai Meixing Chemical Co., Ltd |
| Sodium Nitrite | AR | The Shanghai glad chemical reagent work of shaking |
| Diethyl carbonate | CP | Chemical Reagent Co., Ltd., Sinopharm Group |
| Trifluoroacetic acid (TFA) | CP | Chemical Reagent Co., Ltd., Sinopharm Group |
| Two (triphenyl phosphorus) palladium chloride | Palladium content＞14.8 % | Zhejiang Prov. Metallurgy Research Academy |
| The thin-layer silicon offset plate | GF254 | The biochemical plastic molding and processing plant of Taizhou, Zhejiang Province city road and bridge tetramethyl |
| Column layer chromatography silicone rubber | Granularity 200-300 order | Qingdao City Ji Yida silica gel chemical reagent work |
All the other reagent are commercially available analytical pure.
MS instrument model: Themo Finnigan LCQ-Advantage.
NMR instrument model: Varian Mercury-Plus-400MHZ.
Embodiment 1
The preparation of compound 1
The hexane solution of adding boron trichloride in the stirring downhill reaction bottle (404ml, 404mmol).(45min drips off for 66.8g, acetonitrile 388mmol) (480ml) solution to wherein dripping the 4-bromaniline under 0 ℃ of the temperature control.Add in batches aluminum chloride (57g, 427mmol).Be heated to back flow reaction spend the night (about 17h).System is cooled to 0 ℃, adds 4M hydrochloric acid soln (600ml), back flow reaction 2h.Cooling, yellow soda ash adjust pH to 3, ethyl acetate extraction merges organic phase, and organic phase washes with water, anhydrous sodium sulfate drying.Filter, filtrate screws out solvent, obtains compound 1, light yellow solid, and 14g, yield 16.8%, not purified directly to next step reaction.
1HNMR(400MHz，CDCl
3)：δ(ppm)7.79(1H，d)，7.31(1H，dd)，6.55(1H，d)，2.56(3H，s)。
Embodiment 2
The preparation of compound 2
(14g 65.4mmol), finishes, and stirs 30min to add compound 1 under the stirring at room in 6M hydrochloric acid soln (60ml).(69g, frozen water solution (18ml) 65.4mmol) drip and finish, and obtain deep orange solution to splash into Sodium Nitrite under the condition of ice bath.System is filtered fast, and the ice filtrate that obtains splashes into the tetramethyleneimine of quick stirring, and (5.4ml is 65.4mmol) and in the red mixing solutions (t=0 ℃) of the potassium hydroxide solution (595ml) of 1.1M.System stirs 3h, filters, and filtration cakes torrefaction obtains compound 2, red solid, and 13.6g, yield 70%, not purified directly to next step reaction.
Embodiment 3
The preparation of compound 3
In system, add successively anhydrous tetrahydro furan (THF, 130ml), the Carbon Dioxide diethyl ester (111ml, 918mmol), (60%, 5.5g 137.7mol), is heated to backflow to sodium hydride.(30min drips complete for 13.6g, anhydrous THF (70ml) solution 45.9mmol) to splash into compound 2 under the reflux conditions.System is reduced to room temperature, acetate adjust pH to 7, and the 100ml water washing, water merges organic phase, anhydrous sodium sulfate drying with ethyl acetate extraction (100ml * 2).Filter, filtrate concentrating obtains compound 3, reddish-brown oily matter, and 17.4g, not purified directly to next step reaction.
Embodiment 4
The preparation of compound 4
In reaction flask, add successively compound 3 (17.4g, 47.2mmol), trifluoroacetic acid (TFA, 50ml), stirred overnight at room temperature (TLC monitoring).System is poured in the 200ml frozen water, stirred 20min, filter, filtration cakes torrefaction gets compound 4, red solid, 10.5g, yield 76%.
ES-MS：295.2(M-H)
-
1HNMR(400MHz，DMSO-d
6)δ(ppm)14.06(1H，s)，8.18(1H，d)，8.01(1H，m)，7.66(1H，d)，4.32(2H，q)，1.29(3H，t)
Embodiment 5
The preparation of compound 5
Stir in reaction flask, add successively down compound 4 (2g, 6.7mmol), phosphorus oxychloride (30ml).Heating reflux reaction 1h.Decompression screws out solvent, enriched material acetic acid ethyl dissolution, water, saturated sodium bicarbonate, salt solution washing respectively, anhydrous sodium sulfate drying.Filter, concentrate, cross post, get compound 5, green solid, 1.6g, yield 76%.
1HNMR(400MHz，DMSO-d
6)δ(ppm)8.54(1H，s)，8，31(1H，d)，8.20(1H，d)，4.55(2H，q)，1.41(3H，t)。
Embodiment 6
The preparation of compound 6
Stir in reaction flask, add successively down compound 5 (1.626g, 5.15mmol), 2, (0.915g, 5.71mmol), Virahol (20ml) is heated to back flow reaction 30min to 2-dimethyl p-aminophenyl acetonitrile.Reduce to room temperature, filter, filtration cakes torrefaction gets compound 6, yellow solid, and 2.1g, yield 93%, not purified directly to next step reaction.
Embodiment 7
The preparation of compound 7
Stir in reaction flask, add successively down compound 6 (2.1g, 4.78mmol), methyl alcohol (30ml), 4M sodium hydroxide solution (3ml).Be heated to back flow reaction 2h, reduce to room temperature, add 30ml water, acetate adjust pH to 3 filters, and water wash, filtration cakes torrefaction obtain compound 7, yellow solid, and 1.9g, yield 96.6%, not purified directly to next step reaction.
ES-MS：409.1(M-H)
-
The preparation of embodiment 8 compounds 8
Stir in reaction flask, add successively down compound 7 (1.9g, 4.62mmol), toluene (55ml), triethylamine (1.42ml, 10.2mmol), DPPA (2.83g, 10.3mmol), oil bath is reacted 4h (TLC monitoring) down for 90 ℃, reduces to room temperature, filters, sherwood oil drip washing, filtration cakes torrefaction gets compound 8, light yellow solid, 1.1g, yield 58.5%, not purified directly to next step reaction.
ES-MS：406.5(M-H)
-
Embodiment 9
The preparation of compound 9
Condition of ice bath stirs down and add DMF (20ml) successively in reaction flask, and (1.1g 2.7mmol), adds sodium hydride (60% to compound 8 in batches, 130mg, 3.2mmol), temperature control stirs 30min for 0 ℃-5 ℃, (0.2ml 3.1mmol), stirs 20min to splash into methyl iodide.Remove ice bath, rise to stirring at room 2h (TLC monitoring).The methyl alcohol cancellation, the DCM dissolving, organic phase is water, salt solution washing respectively, anhydrous sodium sulfate drying.Filter, concentrate, cross post and obtain compound 9, yellow solid, 0.8g, yield 70.8%, not purified directly to next step reaction.
ES-MS：422.3(M+H)
+
Embodiment 10
The preparation of compound 10 (SC01095)
Stir and in reaction flask, add compound 9 (100mg down successively, 0.237mmol), three quinoline boric acid (61.5mg, 0.355mmol), two (triphenyl phosphorus) palladium chloride (6.1mg, 0.0087mmol), salt of wormwood (72mg, 0.524mmol), DMF (15ml), pour nitrogen after the system deoxidation three times, 90 ℃-100 ℃ of oil baths are heating 2.5h (TLC monitoring) down.Reduce to room temperature, add the DCM dissolving, organic phase is water, salt solution washing respectively, anhydrous sodium sulfate drying.Filter, concentrate, cross post and obtain compound 10, yellow solid, 75mg, yield 67.6%.
ES-MS：471.4(M+H)
+
1HNMR(400MHz，CDCl
3)：δ(ppm)8.92-8.93(1H，d)，8.59-8.61(1H，d)，8.14-8.18(1H，m)，8.00-8.03(2H，m)，7.87-7.89(1H，d)，7.76-7.83(3H，m)，7.62-7.69(3H，m)，7.40-7.41(1H，d)，3.90(3H，s)，1.84(6H，s)。
Embodiment 11
The preparation of compound 11
In reaction flask, add successively acetonitrile (250ml), 3-aminopyridine (20g, 0.212mol), stirring and dissolving.Slowly (38g 0.212mol), stirs 15min, removes ice bath, and the lucifuge reaction is spent the night under the room temperature to wherein adding the N-bromo-succinimide under the condition of ice bath.Decompression screws out solvent, and enriched material filters back extraction separatory with ethyl acetate and water dissolution, insolubles, after organic phase water and the salt solution washing, adds anhydrous sodium sulfate drying.Filter, screw out solvent, cross post and get compound 11, safran solid, 7.4g, yield 20.2%.
1HNMR(400Hz，CDCl
3)：δ(ppm)7.86-7.87(1H，d)，7.21-7.22(1H，d)，6.87-6.90(1H，m)。
Embodiment 12
The preparation of compound 12
In reaction flask, add toluene (200ml) under stirring successively, and compound 11 (6.8g, 39.3mmol), 3-quinoline boric acid (7.5g, 43.2mmol), salt of wormwood (12g, 86.4mmol), water (2ml), ethanol (20ml).Finish system deoxidation displacement nitrogen three times.15min is stirred in nitrogen protection down, and adding four (triphenyl phosphorus) palladium (937.5mg, 0.812mmol).80 ℃ are reacted spend the night (TLC monitoring) down.Concentrating under reduced pressure, enriched material extracts separatory with ethyl acetate and water dissolution, and organic phase is water, salt solution washing respectively, anhydrous sodium sulfate drying.Filter, cross post, get compound 12, yellow solid, 4g, yield 46%, not purified directly to next step reaction.
Embodiment 13
The preparation of compound 13
Stirring adds compound 12 successively in reaction flask (4g, 18mmol), (16g 72mmol), is heated to 130 ℃ of reaction 3h (TLC monitors to the raw material disappearance) to diethyl ethoxymethylenemalonate.Be cooled to 50 ℃, add petroleum ether and stirring, filter, filtration cakes torrefaction gets compound 13, light yellow solid, and 6.8g, yield 97.1%, not purified directly to next step reaction.
Embodiment 14
The preparation of compound 14
Stirring adds the 25ml phenyl ether in reaction flask, oil bath is heated to 240 ℃, and slowly (5.8g, 14.8mmol), temperature control reacts 2h (TLC monitors to the raw material disappearance) down for 240 ℃ to wherein adding compound 13.Be cooled to 50 ℃, add petroleum ether and stirring, filter, filtration cakes torrefaction gets compound 14, brown solid, and 3g, yield 58.8%, not purified directly to next step reaction.
ES-MS：344.4(M-H)
-
Embodiment 15
The preparation of compound 15
In reaction flask, add phosphorus oxychloride (25ml) under stirring successively, and compound 14 (3.0g, 8.6mmol).Be heated to back flow reaction 3h (TLC monitors to the raw material disappearance).Reduce to room temperature, system is slowly poured in the frozen water, stir 0.5h, methylene dichloride (DCM) extraction, organic phase is water, sodium bicarbonate, salt solution washing respectively, anhydrous sodium sulfate drying.Filter, filtrate screws out solvent and obtains compound 15, yellow solid, and 1g, yield 32.2%, not purified directly to next step reaction.
ES-MS：364.2(M+H)
+
Embodiment 16
The preparation of compound 16
Stir and in reaction flask, to add Virahol (30ml), compound 15 down successively (1g, 2.7mmol), 2, (1.3g 8.1mmol), is heated to back flow reaction 1h (TLC monitor to raw material disappear) to 2-dimethyl p-aminophenyl acetonitrile.Screw out solvent, enriched material is crossed post and is got compound 16, yellow solid, 120mg, yield 8.9%.
ES-MS：488.6(M+H)
+
1HNMR(400MHz，CDCl
3)：δ(ppm)10.48(1H，s)，9.22(1H，s)，8.94(1H，s)，8.42-8.45(1H，d)，8.33-8.34(1H，d)，8.23-8.25(1H，d)，8.07-8.09(1H，d)，7.82-7.84(1H，d)，7.73-7.76(1H，t)，7.58-7.62(1H，t)，7.46-7.48(2H，d)，7.25-7.27(2H，m)，4.36(3H，q)，1.69(6H，s)，1.39(3H，t)。
Embodiment 17
The preparation of compound 17
(100mg, 0.2mmol), methyl alcohol 10ml slowly adds 4M sodium hydroxide solution (4ml) to add compound 16 under stirring successively in reaction flask.Heating reflux reaction 2h (the TLC monitoring is reacted to the raw material disappearance).Decompression screws out solvent.Add entry (10ml) and methyl alcohol (1ml) in enriched material, stir, the hydrochloric acid adjust pH stirs 0.5h to 2-3, filters, and filtration cakes torrefaction gets compound 17, yellow solid, and 50mg, yield 53.2%, not purified directly to next step reaction.
ES-MS：460.4(M+H)
+
Embodiment 18
The preparation of compound 18
Stir and in reaction flask, to add toluene (10ml) down successively, compound 17 (50mg, 0.108mmol), DMF (0.5ml), triethylamine (0.5ml, 3.67mmol) and DPPA (201mg, 0.73mmol).Oil bath is reacted 7h down for 85 ℃-95 ℃, pressurization screws out solvent, and enriched material extracts separatory with DCM and water dissolution, organic phase is washed with salt solution, anhydrous sodium sulfate drying filters, and screws out solvent, obtain the crude product that enriched material is a compound 18, yellow solid, 125mg, the not purified the next step that is directly used in.
ES-MS：457.5(M+H)
+
Embodiment 19
The preparation of compound 19 (SC01096)
Under the condition of ice bath, in reaction flask, add successively compound 18 (125mg, 0.108mmol), exsiccant DMF (10ml), slowly add sodium hydride (60%, 78mg, 1.9mmol), temperature control stirs 0.5h for 0 ℃.Slowly add methyl iodide (0.5ml), stir 20min.System is put in reacts 2h (TLC monitors to the raw material disappearance) under the room temperature.Slowly in system, add the small amount of methanol cancellation, add DCM and water dissolution, extraction separatory, organic phase water and salt solution washing, anhydrous sodium sulfate drying.Filter, filtrate screws out solvent, and enriched material is crossed post and got compound 19, light yellow solid, 10mg, yield 20%.
ES-MS：471.4(M+H)
+
1HNMR(400MHz，CDCl
3)：δ(ppm)9.06(1H，s)，8.89(1H，s)，8.57-8.59(1H，d)，8.53(1H，s)，8.16-8.18(2H，d)，7.90-7.92(1H，d)，7.76-7.82(3H，m)，7.63-7.68(3H，m)，3.76(3H，s)，1.90(6H，s)。
Embodiment 20
The preparation of compound 20
In reaction flask, add toluene (60ml) under stirring successively, and 2-methyl-3-amino-6-chloropyridine (3g, 21mmol), 3-quinoline boric acid (4g, 23.1mmol), salt of wormwood (6.4g, 46.3mmol), water (0.75ml), ethanol (7.5ml).Finish system deoxidation displacement nitrogen three times.15min is stirred in nitrogen protection down, and adding four (triphenyl phosphorus) palladium (500mg, 0.43mmol).80 ℃ are reacted spend the night (TLC monitoring) down.Concentrating under reduced pressure, enriched material extracts separatory with ethyl acetate and water dissolution, and organic phase is water, salt solution washing respectively, anhydrous sodium sulfate drying.Filter, cross post, get compound 20, yellow solid, 2.5g, yield 50%.
Embodiment 21
The preparation of compound 21
Stirring adds compound 20 successively in reaction flask (2.5g, 10.6mmol), diethyl ethoxymethylenemalonate (15ml) is heated to 130 ℃ of reaction 3h (TLC monitors to the raw material disappearance).Be cooled to 50 ℃, add petroleum ether and stirring, filter, filtration cakes torrefaction gets compound 21, light yellow solid, and 4g, yield 93%, not purified directly to next step reaction.
Embodiment 22
The preparation of compound 22
Stirring adds the 50ml phenyl ether in reaction flask, oil bath is heated to 240 ℃, and slowly (4g, 9.8mmol), temperature control reacts 2h (TLC monitors to the raw material disappearance) down for 240 ℃ to wherein adding compound 21.Be cooled to 50 ℃, add petroleum ether and stirring, filter, filtration cakes torrefaction gets compound 22, brown solid, and 3g, yield 85.7%, not purified directly to next step reaction.
Embodiment 23
The preparation of compound 23
In reaction flask, add phosphorus oxychloride (25ml) under stirring successively, and compound 22 (3g, 8.3mmol).Be heated to back flow reaction 3h (TLC monitors to the raw material disappearance).Reduce to room temperature, system is slowly poured in the frozen water, stir 0.5h, the DCM extraction, organic phase is water, sodium bicarbonate, salt solution washing respectively, anhydrous sodium sulfate drying.Filter, filtrate screws out solvent and obtains compound 23, and is light yellow, 1g, and yield 32%, not purified directly to next step reaction.
Embodiment 24
The preparation of compound 24
Stir and in reaction flask, to add Virahol (30ml), compound 23 down successively (1g, 2.6mmol), 2, (1.3g 7.9mmol), is heated to back flow reaction 2h (TLC monitor to raw material disappear) to 2-dimethyl p-aminophenyl acetonitrile.Screw out solvent, enriched material is crossed post and is got compound 24, yellow solid, 80mg, yield 6%.
ES-MS：502.3(M+H)
+
1HNMR(400MHz，CDCl
3)：δ(ppm)10.58(1H，s)，9.35(1H，s)，8.93-8.94(1H，d)，8.54-8.55(1H，d)，8.07-8.09(1H，d)，7.84-7.86(1H，d)，7.68-7.73(2H，m)，7.51-7.58(3H，m)，7.19-7.21(2H，m)，4.46-4.52(2H，q)，3.16(3H，s)，1.79(6H，s)，1.49(3H，t)。
Embodiment 25
The preparation of compound 25
(76mg, 0.15mmol), methyl alcohol 20ml slowly adds 4M sodium hydroxide solution (8ml) to add compound 24 under stirring successively in reaction flask.Heating reflux reaction 2h (the TLC monitoring is reacted to the raw material disappearance).Decompression screws out solvent.Add entry (10ml) and methyl alcohol (1ml) in enriched material, stir, the hydrochloric acid adjust pH stirs 0.5h to 2-3, filters, and filtration cakes torrefaction gets compound 25, yellow solid, and 60mg, yield 83.3%, not purified directly to next step reaction.
Embodiment 26
The preparation of compound 26
In reaction flask, add toluene (10ml) under stirring successively, and compound 25 (60mg, 0.126mmol), DMF (0.5ml), triethylamine (0.5ml) and DPPA (250mg, 0.9mmol).Oil bath is reacted 7h down for 85 ℃-95 ℃, pressurization screws out solvent, and enriched material extracts separatory with DCM and water dissolution, organic phase is washed with salt solution, anhydrous sodium sulfate drying filters, and screws out solvent, obtain the crude product that enriched material is a compound 26, light yellow solid, 217mg, the not purified the next step that is directly used in.
ES-MS：471.5(M+H)
+
Embodiment 27
The preparation of compound 27 (SC01097)
Under the condition of ice bath, in reaction flask, add successively compound 26 (217mg, 0.126mmol), exsiccant DMF (15ml), slowly add sodium hydride (60%, 300mg, 7.5mmol), temperature control stirs 0.5h for 0 ℃.(0.5ml 8.0mmol), stirs 20min slowly to add methyl iodide.System is put in reacts 2h (TLC monitors to the raw material disappearance) under the room temperature.Slowly in system, add the small amount of methanol cancellation, add DCM and water dissolution, extraction separatory, organic phase water and salt solution washing, anhydrous sodium sulfate drying.Filter, filtrate screws out solvent, and enriched material is crossed post and got compound 27, light yellow solid, 10mg, yield 16.4%.
ES-MS：485.3(M+H)
+
1HNMR(400MHz，CDCl
3)：δ(ppm)8.89(1H，s)，8.64(1H，m)，7.40-7.95(1H，m)，7.85-7.87(2H，m)，7.78(1H，brs)，7.64-7.66(3H，m)，7.35(1H，brs)，7.26(2H，m)，3.74(3H，s)，3.19(3H，s)，1.91(6H，s)。
Embodiment 28
The preparation of compound 28
(24g, 148mmol), DMF (120ml), 0 ℃ of temperature control add potassium hydroxide down (24g, 429mmol) 50min are stirred in the back to add the p-nitrophenyl acetonitrile successively in reaction flask.Temperature control slowly drips methyl iodide (20ml, 320mmol) back stirring 30min down for 0 ℃.Stir under the room temperature spend the night (TLC monitoring).Slowly in system, drip the 400ml frozen water, ethyl acetate extraction, organic phase is water, aqueous ammonium chloride solution, salt solution washing respectively, anhydrous sodium sulfate drying.Filter, filtrate concentrating obtains compound 28, green solid, 28.3g.
Embodiment 29
The preparation of compound 29
In reaction flask, add successively compound 28 (28.3g, 149mmol), ethanol (500ml), iron powder (75g, 1.34mol), water (40ml), heating reflux reaction 3h.Reduce to room temperature, add 80ml water, stir 40min, filter, filtrate concentrates.Enriched material 200ml acetic acid ethyl dissolution, organic phase water washing, anhydrous sodium sulfate drying.Filter, concentrate compound 29, brown oil, 25.3g.
Should be noted that at last, above embodiment is only unrestricted in order to technical scheme of the present invention to be described, although the present invention is had been described in detail with reference to preferred embodiment, those of ordinary skill in the art is to be understood that, can make amendment or be equal to replacement the technical scheme of invention, and not breaking away from the spirit and scope of technical solution of the present invention, it all should be encompassed in the claim scope of the present invention.
Claims (10)
1. heterocycle glyoxaline compound or its pharmacy acceptable salt as shown in the formula an I structure,
Wherein, X, Y, Z, Q all are selected from C or N;
R
1Be selected from: pyridyl or halogen, itrile group, C
1-C
4Alkyl, C
1-C
4The pyridyl that alkoxyl group replaces, pyrimidyl or C
1-C
4The pyrimidyl that alkoxyl group replaces, quinoxalinyl, quinolyl or halogenated quinoline base, phenyl or C
1-C
4The phenyl that alkoxyl group replaces;
R
2Be selected from: fragrant heterocycle, described fragrant heterocycle comprises pyridyl, naphthyl, phenyl, and two the replacement or mono-substituted pyridyl and phenyl, substituting group is selected from halogen, C
1-C
4Alkyl, or the C of halogen, itrile group, imidazolyl or triazol radical replacement
1-C
4Alkyl, C
3-C
10Cyclic hydrocarbon radical, C
1-C
4Alkyl, C
1-C
4Alkylsulfonyl, C
1-C
4Alkoxyl group, C
1-C
4The alkoxyalkyl list replaces or disubstituted amido, or C
1-C
4Alkyl, C
1-C
4Alkylsulfonyl replaces or unsubstituted piperidyl, 2-Pyrrolidone base, C
1-C
4Alkoxyalkyl, imidazolyl, pyridyl, triazol radical;
R
3Be selected from O or S;
R
4Be selected from H, C
1-C
4Alkyl or C
1-C
4Alkoxyl group;
R
5Be selected from H or C
1-C
4Alkyl.
2. compound as claimed in claim 1 or its pharmacy acceptable salt is characterized in that,
Work as X=Y=Z=C, Q=N, R
3During=O,
R
1Be selected from: pyridyl or halogen, itrile group, C
1-C
4Alkyl, C
1-C
4The pyridyl that alkoxyl group replaces, pyrimidyl or C
1-C
4The pyrimidyl that alkoxyl group replaces, quinoxalinyl, quinolyl or halogenated quinoline base, phenyl or C
1-C
4The phenyl that alkoxyl group replaces;
R
2Be 2, the phenyl that 2-dimethyl acetonitrile replaces;
R
4Be selected from H, C
1-C
4Alkyl or C
1-C
4Alkoxyl group;
R
5Be selected from and be H or C
1-C
4Alkyl.
3. compound as claimed in claim 1 or its pharmacy acceptable salt is characterized in that,
Work as X=N, Y=Z=Q=C, R
3During=O,
R
1Be selected from: pyridyl or halogen, itrile group, C
1-C
4Alkyl, C
1-C
4The pyridyl that alkoxyl group replaces, pyrimidyl or C
1-C
4The pyrimidyl that alkoxyl group replaces, quinoxalinyl, quinolyl or halogenated quinoline base, phenyl or C
1-C
4The phenyl that alkoxyl group replaces;
R
2Be 2, the phenyl that 2-dimethyl acetonitrile replaces;
R
4Be selected from H, C
1-C
4Alkyl or C
1-C
4Alkoxyl group;
R
5Be selected from and be H or C
1-C
4Alkyl.
4. compound as claimed in claim 1 or its pharmacy acceptable salt is characterized in that,
Work as Y=N, X=Z=Q=C, R
3During=O,
R
1Be selected from: pyridyl or halogen, itrile group, C
1-C
4Alkyl, C
1-C
4The pyridyl that alkoxyl group replaces, pyrimidyl or C
1-C
4The pyrimidyl that alkoxyl group replaces, quinoxalinyl, quinolyl or halogenated quinoline base, phenyl or C
1-C
4The phenyl that alkoxyl group replaces;
R
2Be 2, the phenyl that 2-dimethyl acetonitrile replaces;
R
4Be selected from H, C
1-C
4Alkyl or C
1-C
4Alkoxyl group;
R
5Be selected from and be H or C
1-C
4Alkyl.
5. compound as claimed in claim 1 or its pharmacy acceptable salt is characterized in that,
Work as Z=N, X=Y=Q=C, R
3During=O,
R
1Be selected from: pyridyl or halogen, itrile group, C
1-C
4Alkyl, C
1-C
4The pyridyl that alkoxyl group replaces, pyrimidyl or C
1-C
4The pyrimidyl that alkoxyl group replaces, quinoxalinyl, quinolyl or halogenated quinoline base, phenyl or C
1-C
4The phenyl that alkoxyl group replaces;
R
2Be 2, the phenyl that 2-dimethyl acetonitrile replaces;
R
4Be selected from H, C
1-C
4Alkyl or C
1-C
4Alkoxyl group.
6. as each described compound of claim 1-5 or its pharmacy acceptable salt, it is characterized in that described halogen is F, Cl or Br.
7. the described compound of claim 1 or its pharmacy acceptable salt application in the preparation antitumor drug.
8. the described compound of claim 1 or its pharmacy acceptable salt application in preparation immune inflammation disease drug.
9. the described compound of claim 1 or its pharmacy acceptable salt application in the preparation diabetes medicament.
10. the described compound of claim 1 or its pharmacy acceptable salt application in preparation phosphatide kinase inhibition agent medicine.
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