CN108752351A - It is a kind of containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts and the preparation method and application thereof - Google Patents

It is a kind of containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts and the preparation method and application thereof Download PDF

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CN108752351A
CN108752351A CN201811065796.3A CN201811065796A CN108752351A CN 108752351 A CN108752351 A CN 108752351A CN 201811065796 A CN201811065796 A CN 201811065796A CN 108752351 A CN108752351 A CN 108752351A
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piperazine
pyrimidine
pyrazolos
bases
ethyl ketone
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杨德志
汪蓓蕾
袁泽利
令狐浪
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Zunyi Medical University
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    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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Abstract

The invention discloses a kind of containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts, which is characterized in that has following general formula Y：

Description

It is a kind of containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts and preparation method thereof With application
Technical field
The invention belongs to organic compound synthesis and pharmaceutical technology fields, and in particular to a kind of pyrazolopyrimidine containing piperazine Class compound or pharmaceutically acceptable salt thereof and the preparation method and application thereof.
Background technology
Phosphatidylinositol 3-kinase (PI3K)/AKT/mTOR signal paths be study at present it is active, swollen Oncocyte is mutated frequent access, in cellular signal transduction, promotes to play during cell Proliferation, existence, differentiation and apoptosis etc. Important function.This signal path excessive activation is in leukemia, and lymthoma, myeloma and oophoroma, prostate cancer etc. are swollen It is very common in tumor.The signal is usually by various ligands and a variety of receptors [mainly receptor tyrosine kinase (receptor Tyrosine kinases, RTKs) and g protein coupled receptor (G-protein-coupled receptors, GPCRs)] combine And it activates；Extracellular growth factors are combined activation RTKs with RTKs；The RTKs activated on cell membrane directly makes phosphatidylinositols 3- kinases (phosphatidylinositol 3-kinase, PI3K) is assembled and is activated, the 3- of the PI3K phosphorylations PIP2 of activation OH makes it be converted into PIP3；PIP3 is combined with the domains PH of AKT makes it be displaced to cell membrane, and AKT conformational changes expose threonine Two phosphorylation sites of Thr308 and serine Ser473, then respectively by phosphatidylinositols deopendent protein kinase 1 (phosphoinositide-dependent kinase 1, PDK1) and mTORC2 phosphorylations and so that AKT is activated completely；Activation AKT pass through a series of substrates of phosphorylation (including mTORC1, glycogen synthase kinase-3 (GSK3), cyclin dependent kinase Enzyme inhibitor p21Cip1 and p27Kip1, transcription factor family Forkhead/FOXO and pro apoptotic protein Bad) promote cell Proliferation and survival inhibit apoptosis (Fig.1).Therefore, AKT is the key kinases of this signal path, is adjusting cell survival, life Play the role of very important in long, proliferation, apoptosis, AKT is inhibited to be beneficial to the targeted therapy of tumour.
Currently, AKT has become one of important target spot of antitumor drug, up to the present there are many AKT inhibitor into Enter clinical or preclinical study.GSK690693 is first AKT inhibitor for entering clinical research in transplanting BT474 mammary gland GK690693 is injected intraperitoneally in the thin mouse of cancer and has slowed down tumor growth rate significantly, is injected intravenously GSK690693 treating cancers Patient causes drug-associated hyperglycemia and the medicine is made to terminate at clinical I phase；Other representativeness AKT inhibitor are such as GSK2110183 has completed the research of II phase of clinic in leukemia patient；AZD5363 has completed treatment metastatic prostate The I phase clinical researches of cancer；GDC0068 is just carrying out the II phase clinical research with paclitaxel plus medication treatment metastatic breast cancer, However there are still some critical problems not to be fully solved, such as toxic side effect, selectivity.Therefore, it develops new and effective Less toxic, highly selective AKT inhibitor shoulders heavy responsibilities.
Based on the above situation, the present invention propose it is a kind of containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts and its Preparation method and application.
Invention content
One of the objects of the present invention is to provide a kind of containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts, such Compound has certain PC-3 cell growth inhibiting activities and AKT1 kinase inhibiting activities.The pyrazolo containing piperazine of the present invention Pyrimidines or its pharmaceutical salts, structure novel, as shown in general formula Y, the introducing of R3 groups (substituted-amino) is to improve chemical combination The active essential group of object has AKT1 kinase inhibiting activities, and to prostate gland cancer cell by this design improvement mode Strain (PC-3 cells) shows inhibitory activity.
The present invention is achieved through the following technical solutions：
It is a kind of containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts, there is following general formula Y：
Wherein, R1 is hydrogen, single halogen substitution, the substitution of double halogens, methoxyl group or alkane；R2 is hydrogen, chlorine or bromine；R3 be hydrogen, Amino, substituted-amino, substituted piperidine or substituted piperazinyl.
As a preferred embodiment, in the general formula Y, R1 is hydrogen, 4- chlorine, 4- bromines, 4- fluorine or 2,4- dichloros；R2 be hydrogen, Chlorine or bromine；R3 is hydrogen, amino, dimethylamino, N methyl piperazine, 4- hydroxy piperidines or Acetylpiperazine.
As a preferred embodiment, the general formula Y is one of following compounds：
1- (4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- bases) -2- Phenyl ethyl ketones,
1- (4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- bases) -2- (4- fluorophenyls) ethyl ketone,
1- (4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- bases) -2- (4- chlorphenyls) ethyl ketone,
1- (4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- bases) -2- (4- bromophenyls) ethyl ketone,
1- (4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- bases) -2- (2,4 dichloro benzene base) ethyl ketone,
1- (4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- Phenyl ethyl ketones,
1- (4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- fluorophenyls) ethyl ketone,
1- (4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) ethyl ketone,
1- (4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- bromophenyls) ethyl ketone,
1- (4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) -2- (4- first Base piperazine -1- bases) ethyl ketone,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- Phenyl ethyl ketones,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- fluorophenyls) ethyl ketone,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) ethyl ketone,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- bromophenyls) ethyl ketone,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (2,4 dichloro benzene base) ethyl ketone,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) -2- (4- first Base piperazine -1- bases) ethyl ketone,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) -2- amino second Ketone,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) -2- (diformazans Amino) ethyl ketone.
The second object of the present invention is to provide a kind of system containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts Preparation Method, with 3- substitution -1H- pyrazolos [3,4-d] pyrimidine be starting material, under microwave catalysis with 1- tertbutyloxycarbonyls-piperazine Piperazine occurs nucleophilic displacement of fluorine and obtains intermediate 2, sloughs Boc protecting groups in acid condition and obtains intermediate 3, intermediate 3 and substituted benzene Acetic acid progress is amide condensed, obtains target product Y.
The synthetic route of the preparation method is as follows：
Wherein, R1, R2, R3 are as described in general formula Y.
As a preferred embodiment, include the following steps：
1) replace -1H- pyrazolos [3,4-d] pyrimidine to be added in DMF 3-, sequentially add DIEA, 1- tertbutyloxycarbonyl Piperazine, microwave heating react 20~30min, reaction solution are poured into ice water, a large amount of solids, acetic acid second is precipitated to 85~95 DEG C Ester extracts, and organic phase successively using saturation ammonium chloride, saturated common salt water washing, filter, remove under reduced pressure molten by anhydrous sodium sulfate drying Agent is purified with petrol ether/ethyl acetate column chromatography, obtains intermediate 2；
2) by 2 solvent of intermediate in THF, concentrated hydrochloric acid is added, reacts at room temperature 4~5h, filters to obtain intermediate 3；
3) substituted phenylacetic acid is dissolved in DMF, sequentially adds HBTU, DIEA, 15~20min is stirred at room temperature, in addition Mesosome 3, room temperature reaction, reaction solution is poured into ice water, and a large amount of solids are precipitated, and ethyl acetate extraction merges organic phase, adopts successively With saturated ammonium chloride, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, filtering removes solvent afforded crude material under reduced pressure, uses Methylene chloride/methanol column chromatography purifies to obtain target product Y.
As a kind of more preferable scheme, in step 1), 3- substitutions -1H- pyrazolos [3, the 4-d] pyrimidine, DIEA and 1- The molar ratio of tert-butoxycarbonyl-piperazine is 1：1.3：1.1.
As a kind of more preferable scheme, in step 2), the volume ratio 3 of the THF and dense HCl：1.
As a kind of more preferable scheme, in step 3), the intermediate 3, DIEA, HBTU and substituted phenylacetic acid molar ratio It is 1：1.5：1.05：1.
The third object of the present invention is to provide anti-in preparation containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts Application in tumour medicine.
As a preferred embodiment, the antitumor drug is the drug of the anti-prostate cancer and lymthoma that target AKT1.
Compared with prior art, the present invention haing the following advantages and advantageous effect：
The present invention containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts, structure novel, as shown in general formula Y, R3 The introducing of group (substituted-amino) is to improve the essential group of compound activity, by this design improvement mode, has AKT1 Kinase inhibiting activity, and inhibitory activity is shown to Prostatic cancer cell lines (PC-3 cells).
Specific implementation mode
The present invention is described in further detail with reference to embodiment, embodiments of the present invention are not limited thereto. The condition used in embodiment can do further adjustment according to existing appointed condition, and the implementation condition being not specified is usually normal Condition in rule experiment.
Heretofore described chemical reagent title is compareed with abbreviation：N,N-diisopropylethylamine (DIEA), N, N- dimethyl Formamide (DMF), hydrochloric acid (HCl), tetrahydrofuran (THF), O- benzotriazole-tetramethylurea hexafluorophosphoric acid ester (HBTU).
Room temperature of the present invention is 20~25 DEG C.
Embodiment 1：
The preparation of compound Y
1) preparation of intermediate 2：
Replace -1H- pyrazolos [3,4-d] pyrimidine (10mmol) to be dissolved in DMF (15mL) 3-, sequentially adds DIEA (15mmol, 2.5mL), 1- tert-butoxycarbonyl-piperazines (10.5mmol), 20~30min of microwave reaction at 90 DEG C, reaction finish, will Reaction is quenched with ice water (150mL) in reaction solution, is extracted using ethyl acetate (3 × 30mL), merges organic phase, successively using saturation Ammonium chloride (3 × 20mL), saturated salt solution (3 × 20mL) wash organic phase, anhydrous sodium sulfate drying, and filtering removes under reduced pressure molten Agent, column chromatography purify (petroleum ether：Ethyl acetate=1：3) intermediate 2 is obtained.
The intermediate 2 prepared is following several compounds：
4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- t-butyl formates (2a)
White solid, yield 89%,1H NMR (400MHz, DMSO) δ 8.94 (s, 1H), 8.60 (s, 1H), 4.32 (s, 4H), 3.35 (s, 4H), 1.39 (s, 9H)
4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- t-butyl formates (2b)
Faint yellow solid, yield 86%,1H NMR (400MHz, DMSO) δ 8.36 (s, 1H), 3.93-3.79 (m, 4H), 3.12-3.00 (m, 4H), 1.40 (s, 9H)
4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- t-butyl formates (2c)
White solid, yield 88%,1H NMR (400MHz, DMSO) δ 8.38 (s, 1H), 3.96-3.74 (m, 4H), 3.20-3.07 (m, 4H), 1.41 (s, 9H)
2) synthesis of intermediate 3:
Intermediate 2 (4.0g) is dissolved in tetrahydrofuran (12mL), concentrated hydrochloric acid (4mL) is added, reacts at room temperature 4-5h.Instead It should finish, a large amount of solids are precipitated, filter, obtain intermediate 3.
The intermediate 3 prepared is following several compounds：
4- (piperazine -1- bases) -1H- pyrazolos [3,4-d] pyrimidine dihydrochloride (3a)
Off-white powder, yield 84%,1H NMR(400MHz,DMSO)δ9.99(s,2H)8.97(s,1H),8.63(s, 1H),4.32(s,4H),3.35(s,4H).
The chloro- 4- of 3- (piperazine -1- bases) -1H- pyrazolos [3,4-d] pyrimidine dihydrochloride (3b)
Pale solid, yield 68%,1H NMR (400MHz, DMSO) δ 8.36 (d, J=5.7Hz, 1H), 3.93-3.79 (m,4H),3.12–3.00(m,4H).
The bromo- 4- of 3- (piperazine -1- bases) -1H- pyrazolos [3,4-d] pyrimidine dihydrochloride (3c)
Off-white powder, yield 88%,1H NMR(400MHz,DMSO)δ8.38(s,1H),3.96–3.74(m,4H), 3.20–3.07(m,4H).
3) prepared by target compound Y：
It is dissolved in substituted phenylacetic acid (1mmol) in DMF (5mL), sequentially adds HBTU (1.05mmol), DIEA Intermediate 3 (1mmol) is added in (2.0mmol), stirring at normal temperature 15 minutes, reacts at room temperature 6h.Reaction finishes, with ice water (50mL) It is quenched, ethyl acetate extracts (3 × 20mL), merges organic phase, uses saturated ammonium chloride (3 × 20mL), saturated salt solution (3 successively × 20mL) washing organic phase, it removes solvent under reduced pressure, obtains crude product, column chromatographic isolation and purification obtains target product Y, eluting solvent two Chloromethanes/methanol=50：1.
The target product Y prepared is following several compounds：
1- (4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- bases) -2- Phenyl ethyl ketones (Y1)
White solid,1H NMR(400MHz,MeOD)δ8.25(s,1H),8.19(s,1H),7.36–7.22(m,5H), 4.07–4.01(m,2H),3.98–3.90(m,2H),3.85(s,2H),3.84–3.80(m,2H),3.80–3.75(m,2H).
1- (4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- bases) -2- (4- fluorophenyls) ethyl ketone (Y2)
White solid,1H NMR (400MHz, DMSO) δ 13.58 (s, 1H), 8.27 (d, J=2.6Hz, 2H), 7.33- 7.25 (m, 2H), 7.20-7.09 (m, 2H), 3.98 (t, J=14.7Hz, 4H), 3.78 (s, 2H), 3.76-3.65 (m, 4H)13C NMR(101MHz,DMSO)δ169.69(s),160.24(s),156.95(s),155.99(s),155.12(s),134.15(s), 132.39(s),131.55(2C),115.51(2C),99.93(s),46.33(2C),44.95(s),42.27(s),41.78 (s).
1- (4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- bases) -2- (4- chlorphenyls) ethyl ketone (Y3)
White solid,1H NMR (400MHz, MeOD) δ 8.26 (s, 1H), 8.22 (s, 1H), 7.30 (dd, J=23.2, 8.4Hz, 4H), 4.10-3.98 (m, 4H), 3.84 (s, 2H), 3.81 (dd, J=9.8,4.7Hz, 4H)13C NMR(101MHz, DMSO)δ169.46(s),156.95(s),155.92(s),155.12(s),135.30(s),134.16(s),131.59(3C), 128.55(2C),99.99(s),54.09(s),44.95(2C),41.19(s),39.07(s).
1- (4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- bases) -2- (4- bromophenyls) ethyl ketone (Y4)
White solid,1H NMR (400MHz, DMSO) δ 13.57 (s, 1H), 8.26 (s, 2H), 7.50 (d, J=8.3Hz, 2H), 7.22 (d, J=8.3Hz, 2H), 4.01-3.91 (m, 4H), 3.78 (s, 2H), 3.75-3.63 (m, 4H)13C NMR (101MHz,DMSO)δ169.39(s),156.89(s),155.99(s),155.13(s),135.62(s),134.16(s), 132.04(2C),131.55(2C),120.11(s),100.05(s),44.95(2C),41.19(s),39.14(2C).
1- (4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- bases) -2- (2,4 dichloro benzene base) ethyl ketone (Y5)
White solid,1H NMR(400MHz,DMSO)δ13.59(s,1H),8.29(s,1H),8.28(s,1H),7.60 (d, J=1.8Hz, 1H), 7.39-7.36 (m, 2H), 4.11-4.03 (m, 2H), 4.03-3.94 (m, 2H), 3.89 (s, 2H), 3.82–3.74(m,2H),3.71-3.68(m,2H).13C NMR(101MHz,DMSO)δ168.18(s),156.95(s), 155.85(s),155.15(s),135.27(s),134.15(2C),133.78(s),132.48(s),128.83(s),127.55 (s),99.93(s),46.33(2C),44.81(s),41.27(s),37.32(s).
1- (4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- Phenyl ethyl ketones (Y6)
White solid,1H NMR(400MHz,CDCl3)δ8.42(s,1H),7.97(s,1H),7.37–7.31(m,2H), 7.30-7.25 (m, 3H), 3.93 (d, J=5.9Hz, 2H), 3.90-3.83 (m, 4H), 3.80 (s, 2H), 3.71-3.62 (m, 2H).13C NMR(101MHz,CDCl3)δ169.97(s),160.31(s),158.12(s),155.33(s),134.24(s), 128.85(2C),128.59(2C),126.75(s),119.71(s),100.88(s),60.21(s),44.88(s),43.75 (s),40.89(s),29.86(s).
1- (4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- fluorophenyls) ethyl ketone (Y7)
White solid,1H NMR(400MHz,CDCl3) δ 8.43 (s, 1H), 7.97 (s, 1H), 7.24 (dd, J=8.4, 5.4Hz, 2H), 7.03 (t, J=8.6Hz, 2H), 3.96-3.84 (m, 4H), 3.87-3.73 (m, 2H), 3.76 (s, 2H), 3.72–3.64(m,2H).13C NMR(101MHz,CDCl3)δ169.59(s),162.97(s),160.80(s),157.70(s), 154.85(s),130.27(3C),119.91(s),115.84(s),115.56(s),100.59(s),61.31(s),45.33 (s),41.16(s),39.62(s),29.07(s).
1- (4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) ethyl ketone (Y8)
White solid,1H NMR(400MHz,CDCl3)δ8.44(s,1H),7.96(s,1H),3.98–3.90(m,4H), 3.87-3.75(m,2H),3.75(s,2H),3.71–3.63(m,2H).13C NMR(101MHz,CDCl3)δ169.37(s), 160.80(s),157.49(s),155.53(s),132.97,130.04(2C),128.45(2C),119.29(s),100.38 (s),60.48(s),45.10(s),41.15(s),39.84(s),30.35(s).
1- (4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- bromophenyls) ethyl ketone (Y9)
White solid,1H NMR(400MHz,CDCl3) δ 8.44 (s, 1H), 7.97 (s, 1H), 7.46 (d, J=8.4Hz, 2H), 7.15 (d, J=8.3Hz, 2H), 4.09-3.84 (m, 4H), 3.90-3.83 (m, 2H), 3.73 (s, 2H), 3.70-3.61 (m,2H).13C NMR(101MHz,CDCl3)δ169.58(s),160.80(s),157.28(s),155.32(s),133.35 (s),131.95(2C),130.24(2C),121.04(s),119.28(s),101.50(s),60.71(s),45.10(s), 40.89(s),38.71(s),30.62(s).
1- (4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) -2- (4- first Base piperazine -1- bases) ethyl ketone (Y10)
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- Phenyl ethyl ketones (Y11)
White solid,1H NMR(400MHz,CDCl3)δ13.86(s,1H),8.43(s,1H),7.37–7.31(m,2H), 7.27 (dd, J=8.2,4.6Hz, 3H), 3.89 (dd, J=13.4,5.6Hz, 4H), 3.83 (s, 2H), 3.69 (dd, J= 19.0,5.7Hz,4H).13C NMR(101MHz,CDCl3)δ169.95(s),158.83(s),156.81(s),154.63(s), 134.62(s),128.96(2C),128.53(2C),127.08(s),119.75(s),101.92(s),49.33(s),48.68 (s),45.82(s),41.71(s),41.20(s).
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- fluorophenyls) ethyl ketone (Y12)
White solid,1H NMR(400MHz,CDCl3) δ 8.44 (s, 1H), 7.26 (d, J=4.2Hz, 2H), 7.04 (t, J =8.6Hz, 2H), 3.92-3.86 (m, 4H), 3.78 (s, 4H), 3.69 (s, 2H)13C NMR(101MHz,CDCl3)δ169.77 (s),163.12(s),160.68(s),158.87(s),156.80(s),154.67(s),130.25(2C),119.76(s), 115.89(s),115.68(s),101.98(s),49.40(s),48.68(s),45.75(s),41.73(s),40.08(s).
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) ethyl ketone (Y13)
White solid,1H NMR(400MHz,CDCl3) δ 13.70 (s, 1H), 8.45 (s, 1H), 7.31 (d, J=8.4Hz, 2H), 7.22 (d, J=8.4Hz, 2H), 3.92-3.86 (m, 4H), 3.78 (s, 4H), 3.68-3.65 (m, 2H)13C NMR (101MHz,MeOD)δ170.23(s),159.67(s),157.91(s),156.03(s),136.12(s),132.38(3C), 129.45(2C),120.00(s),102.35(s),50.01,49.70,46.23(s),42.36(s),39.84(s).
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- bromophenyls) ethyl ketone (Y14)
White solid,1H NMR(400MHz,CDCl3) δ 13.48 (s, 1H), 8.45 (s, 1H), 7.47 (d, J=8.3Hz, 2H), 7.16 (d, J=8.2Hz, 2H), 3.92-3.87 (m, 4H), 3.76 (s, 4H), 3.67-3.65 (m, 2H)13C NMR (101MHz,DMSO)δ169.36(s),158.79(s),157.05(s),155.06(s),135.73(s),132.01(2C), 131.57(2C),119.92(s),119.22(s),101.60(s),49.32(s),49.10(s),45.43(s),41.55(s), 39.11(s).
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (2,4 dichloro benzene base) ethyl ketone (Y15)
White solid,1H NMR(400MHz,DMSO-d6)δ14.09(s,1H),8.38(s,1H),7.59(s,1H),7.37 (d, J=3.8Hz, 2H), 3.90 (s, 2H), 3.86 (s, 2H), 3.80 (s, 4H), 3.69 (s, 2H)13C NMR(101MHz, DMSO-d6)δ168.15(s),158.87(s),157.07(s),155.24(s),135.24(s),134.15(s),133.77 (s),132.45(s),128.81(s),127.54(s),119.25(s),101.61(s),49.34(s),49.16(s),45.27 (s),41.67(s),37.32(s).
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) -2- (4- first Base piperazine -1- bases) ethyl ketone (Y16)
White solid,1H NMR(400MHz,DMSO-d6) δ 8.34 (s, 1H), 7.44 (q, J=8.5Hz, 4H), 4.65 (s, 1H),3.57-3.75(m,8H),2.42(s,4H),2.29(s,4H),2.12(s,3H).13C NMR(101MHz,DMSO-d6)δ 169.00(s),158.84(s),157.14(s),155.12(s),135.62(s),132.77(s),131.46(2C),128.63 (2C),119.09(s),101.60(s),68.17(s),63.07(s),55.35(s),52.50(s),50.23(s),46.17 (s),46.09(s),45.24(s),41.86(s).
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) -2- amino second Ketone (Y17)
White solid,1H NMR(400MHz,DMSO)δ8.34(s,1H),7.40(s,4H),5.01(s,1H),3.84– 3.60(m,6H),3.54–3.40(m,2H).13C NMR(101MHz,DMSO)δ167.36(s),158.85(s),157.06(s), 155.18(s),146.69(s),134.41(s),130.72(2C),129.65(2C),119.11(s),101.67(s),53.54 (s),49.18(s),48.97(s),46.00(s),44.81(s),42.23(s).
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) -2- (diformazans Amino) ethyl ketone (Y18)
White solid,1H NMR(400MHz,DMSO-d6)δ14.01(s,1H),8.34(s,1H),7.45(s,4H),4.72 (s,1H),3.89-3.85(m,1H),3.78–3.59(m,6H),3.57–3.47(m,1H),2.24(s,6H).13C NMR (101MHz,DMSO-d6)δ168.97(s),158.83(s),157.06(s),155.18(s),140.22(s),133.10(s), 131.42(2C),128.85(2C),119.16(s),101.61(s),68.46(s),52.49(s),49.26(s),45.18 (s),42.77(s),41.82(s).
Embodiment 2：
Determination experiment of the compound to the antiproliferative activity of AKT1 kinase inhibiting activities, PC-3 cells
The target compound Y1 to Y18 prepared in example 1 is subjected to biological activity determination by the following method, the results are shown in Table 1 In.
Compound carries out the antiproliferative activity of AKT1 kinase inhibiting activities, PC-3 cells using the method for document report, Referring specifically to：LIu Y,Yin Y,Zhang J,NomIe K,Zhang L,Yang D,Wang ML,Zhao G.2016.DIscovery of 4-(PIperazIn-1-yl)-7H-pyrrolo[2,3-d]pyrImIdIne DerIvatIves as Akt InhIbItors.Arch Pharm(WeInheIm)349:356-362.LIu Y,Yin Y, Zhang Z,LI C.J,Zhang H,Zhang D,JIang C,NomIe K,Zhang L,Wang M.L,Zhao G.2017.Structural optImIzatIon elaborates novel potent Akt InhIbItors wIth promIsIng antIcancer actIvIty.Eur J Med Chem 138:543-551.
1. target compound Y1 to Y18 of table is to AKT1 kinase inhibiting activities and PC-3 cellular antiproliferative activity
aHalf-inhibition concentration (IC of the compound to AKT1 kinases50)
bND=not detected
The experimental results showed that majority of compounds has certain inhibitory activity under 1 μM of concentration to AKT1 kinases, In, compound Y10 and Y16 shows strongest inhibition living respectively 94.3% and 99.7% to AKT1 kinases, they are to AKT1 The half-inhibition concentration of kinases is 31.8nM and 23.5nM.Y10 and Y16 is to the growth inhibitory activity of Human Prostate Cancer PC-3 Cell Line 11.5 μM and 6.4 μM of half-inhibition concentration, therefore, the compound of the present invention can be as the medicines of the anti-prostate cancer of targeting AKT1 Object.
The above is only presently preferred embodiments of the present invention, not does limitation in any form to the present invention, it is every according to According to the technical spirit of the present invention to any simple modification, equivalent variations made by above example, the protection of the present invention is each fallen within Within the scope of.

Claims (10)

1. a kind of containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts, which is characterized in that have following general formula Y：
Wherein, R1 is hydrogen, single halogen substitution, the substitution of double halogens, methoxyl group or alkane；R2 is hydrogen, chlorine or bromine；R3 be hydrogen, amino, Substituted-amino, substituted piperidine or substituted piperazinyl.
2. according to claim 1 containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts, which is characterized in that described In general formula Y, R1 is hydrogen, 4- chlorine, 4- bromines, 4- fluorine or 2,4- dichloros；R2 is hydrogen, chlorine or bromine；R3 is hydrogen, amino, dimethylamino, N- Methyl piperazine, 4- hydroxy piperidines or Acetylpiperazine.
3. according to claim 1 containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts, which is characterized in that described General formula Y is one of following compounds：
1- (4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- bases) -2- Phenyl ethyl ketones,
1- (4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- bases) -2- (4- fluorophenyls) ethyl ketone,
1- (4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- bases) -2- (4- chlorphenyls) ethyl ketone,
1- (4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- bases) -2- (4- bromophenyls) ethyl ketone,
1- (4- (1H- pyrazolos [3,4-d] pyrimidine-4-yl) piperazine -1- bases) -2- (2,4 dichloro benzene base) ethyl ketone,
1- (4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- Phenyl ethyl ketones,
1- (4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- fluorophenyls) ethyl ketone,
1- (4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) ethyl ketone,
1- (4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- bromophenyls) ethyl ketone,
1- (4- (chloro- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) -2- (4- methyl piperazines Piperazine -1- bases) ethyl ketone,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- Phenyl ethyl ketones,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- fluorophenyls) ethyl ketone,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) ethyl ketone,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- bromophenyls) ethyl ketone,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (2,4 dichloro benzene base) ethyl ketone,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) -2- (4- methyl piperazines Piperazine -1- bases) ethyl ketone,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) -2- amino ethyl ketone,
1- (4- (bromo- 1H- pyrazolos [3,4-d] pyrimidine-4-yls of 3-) piperazine -1- bases) -2- (4- chlorphenyls) -2- (dimethylamino) Ethyl ketone.
4. a kind of system as described in any one of claims 1 to 3 containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts Preparation Method, which is characterized in that with 3- substitution -1H- pyrazolos [3,4-d] pyrimidine be starting material, under microwave catalysis with uncle 1- Butoxy carbonyl-piperazine occurs nucleophilic displacement of fluorine and obtains intermediate 2, sloughs Boc protecting groups in acid condition and obtains intermediate 3, intermediate Body 3 and substituted phenylacetic acid progress are amide condensed, obtain target product Y.
5. the preparation method according to claim 4 containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts, special Sign is, includes the following steps：
1) preparation of intermediate 2：
Replace -1H- pyrazolos [3,4-d] pyrimidine to be added in DMF 3-, sequentially adds DIEA, 1- tert-butoxycarbonyl-piperazine, it is micro- Wave heating reacts 20~30min, reaction solution is poured into ice water to 85~95 DEG C, and a large amount of solids are precipitated, and ethyl acetate extracts, Organic phase successively using saturation ammonium chloride, saturated common salt water washing, filter, remove solvent under reduced pressure, use stone by anhydrous sodium sulfate drying Oily ether/ethyl acetate column chromatography purifying, obtains intermediate 2；
2) synthesis of intermediate 3:
By 2 solvent of intermediate in THF, concentrated hydrochloric acid is added, reacts at room temperature 4~5h, filters to obtain intermediate 3；
3) prepared by target compound Y：
Substituted phenylacetic acid is dissolved in DMF, HBTU, DIEA are sequentially added, 15~20min is stirred at room temperature, intermediate 3 is added, Room temperature reaction, reaction solution is poured into ice water, and a large amount of solids are precipitated, and ethyl acetate extraction merges organic phase, successively using saturation Ammonium chloride, saturated common salt water washing organic phase, anhydrous sodium sulfate drying, filtering remove solvent afforded crude material under reduced pressure, using dichloromethane Alkane/methanol column chromatography purifies to obtain target product Y.
6. the preparation method according to claim 5 containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts, special Sign is, in step 1), 3- substitutions -1H- pyrazolos [3, the 4-d] pyrimidine, DIEA and 1- tert-butoxycarbonyl-piperazines mole Than being 1：1.3：1.1.
7. the preparation method according to claim 5 containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts, special Sign is, in step 2), the volume ratio 3 of the THF and dense HCl：1.
8. the preparation method according to claim 5 containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts, special Sign is, in step 3), the molar ratio of the intermediate 3, DIEA, HBTU and substituted phenylacetic acid is 1：1.5：1.05：1.
9. claims 1 to 3 any one of them is preparing anti-swell containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts Application in tumor medicine.
10. the preparation method according to claim 9 containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts, special Sign is that the antitumor drug is the drug of the anti-prostate cancer and lymthoma that target AKT1.
CN201811065796.3A 2018-09-13 2018-09-13 It is a kind of containing the Pyrazolopyrimidines of piperazine or its pharmaceutical salts and the preparation method and application thereof Pending CN108752351A (en)

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CN112441970A (en) * 2019-09-04 2021-03-05 天津医科大学 2, 5-disubstituted-3-aminopyridine compound and preparation method and application thereof

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CN112441970A (en) * 2019-09-04 2021-03-05 天津医科大学 2, 5-disubstituted-3-aminopyridine compound and preparation method and application thereof
CN111646996A (en) * 2020-06-12 2020-09-11 山东大学 Pyrazolopyrimidine piperazinone compound as well as preparation method and application thereof

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