CN105130995B - Pyrrolidone compound and its preparation method and application - Google Patents

Pyrrolidone compound and its preparation method and application Download PDF

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CN105130995B
CN105130995B CN201510569833.4A CN201510569833A CN105130995B CN 105130995 B CN105130995 B CN 105130995B CN 201510569833 A CN201510569833 A CN 201510569833A CN 105130995 B CN105130995 B CN 105130995B
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diketone
fluorophenyls
pyrazoles
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刘冠男
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Hangzhou Chengbang Pharmaceutical Co Ltd
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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 pyrrolidone compound and its preparation method and application, pyrrolidone compound includes its enantiomter, diastereoisomer, racemic modification and mixture, and its pharmaceutically acceptable salt or its solvate or hydrate, a kind of new pharmaceutical composition is also disclosed, pharmaceutical composition includes the pyrrolidone compound of therapeutically effective amount or the pharmaceutical composition of its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier.New pyrrole ketone compounds disclosed by the invention, to have no document report novel compounds, are that a class is the drug candidate of AntiHIV1 RT activity 1 with DEVELOPMENT PROSPECT.

Description

Pyrrolidone compound and its preparation method and application
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field, specifically, be one kind be related to pyrrolidone compound, Its preparation method, pharmaceutical composition and purposes containing such compound.
Background technology
The first acquired immunodeficiency caused by human immunodeficiency virus (HIV) virus was found in the U.S. from 1981 Since illness (acquired immunodeficiency syndrome, AIDS) patient, HIV is in the 180 Duo Ge states in the whole world Family and area are quickly spread.Existing 3,100,000 people in the whole world die from AIDS at present, and new infeetioa HIV number is about 4,900,000, and AIDS Patient and inhibition of HIV carrier sum reached 4, more than 200 ten thousand, among these China have nearly 1,000,000, the 2nd is occupied in Asia, complete Ball occupies the 14th.And China in Recent Years AIDS case load is with every year on average 30~40% speed rapid growth, As an increasingly serious public safety problem.HIV points are 1 type and 2 types, and wherein HIV-1 is the main of current Global prevalence Strain, HIV-2 is only popular in West Africa at present.
The mechanism of action of anti-HIV-1 medicines is by influenceing some link of HIV-1 replicative cycles, so as to suppress virus Replicate and infect.According to HIV-1 life cycle, current anti-AIDS drug is mainly for the several important of virus replication Link, i.e. HIV-1 depend on (Viral attachment), auxiliary acceptor interaction (Coreceptor to host cell ) and HIV-1 and cell merge (Fusion)-entry inhibitor (Entry inhibitor) interaction；Virus RNA reverse transcription (Reverse transcription)-efabirenz (Nucleoside reverse Transcriptase inhibitor, NRTIs) and non-nucleoside reverse transcriptase inhibitor (Nonnucleoside reverse transcriptase inhibitors,NNRTIs)；Integration (Integration)-integrase inhibitor of proviral DNA (Integrase inhibitors,INs)；DNA transcription (Transcription) and the expression of virus protein (Ttranslation), viral assembling (Viral assembly) and the germination of virion and maturation (Budding and Maturation of HIV-1virion)-protease inhibitors (Protease inhibitors, PIs).AIDS drugs The target of thing is main aiming at enzyme and acceptor involved in these links, such as HIV1-RT, HIV-1 albumen Enzyme, HIV-1 integrases etc., it is accordingly divided into：Entry inhibitor, CC chemokine receptor 5 (CCR5) antagonist, ucleosides are inverse Transcripting enzyme inhibitor and non-nucleoside reverse transcriptase inhibitor, integrase inhibitor, protease inhibitors etc..
At present, U.S. FDA ratifies mainly have five major classes for the medicine of HIV-1 the infected's clinical treatment：Ucleosides is reversed Transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitor, protease inhibitors, entry inhibitor and integrase inhibitor.And In a very long time, anti-HIV-1 medicines are mainly RTI and protease inhibitors.
Efabirenz Zidovudine (Zidovudine), zalcitabine (Zalcitabine) are used as The anti-AIDS drug of one class listing, occupies critically important status on the clinical treatment of AIDS, and is still joint now Therapy assembled unit.But efabirenz can cause host cell mitochondria to damage, toxic side effect is big, Er Qiechang Phase independent medication promotes virus to develop immunity to drugs rapidly.
Non-nucleoside reverse transcriptase inhibitor NVP (Nevimpine), delavirdine (Delavirdine) etc. are beautiful State FDA ratifies to be used for clinical treatment, as first-line treatment medicine.But this kind of medicine easily develops immunity to drugs, once form anti-medicine Property, the application of whole class medicine will be influenceed.In addition, especially in the case of having NRTI drug-fast, NNRTI drug resistance strains increase The difficulty for the treatment of.
Protease inhibitors is peptide analogues mostly, and high dosage, toxicity and drug resistance etc. generally occur when using The problem of aspect, representing medicine has inverase (Saquinavir).Non- peptide protease inhibitors tipranavir (Tipranavir) and DRV (Darunavir) respectively at 2005 and 2006 first the U.S. list although toxicity It is still this unavoidable problem of class medicine, but because they have brand-new molecular structure, can be conservative with protease Residue is combined, therefore can minimize virus drug resistance odds.
First entry inhibitor enfuirtide (Enfuvirtide) listing in 2003, changes anti-AIDS for a long time There was only the situation of RTI and protease inhibitors in medicine market.Pfizer's MVC in 2007 (maraviroc) ratified to list by FDA, it is specific CC chemokine receptor 5 (CCR5) antagonist, is that one kind has The medicine of brand-new mechanism of action.CCR5 is the main accessory receptor of HIV-1 invasion body cells, and HIV-1 is invaded by CCR5 Cell, and suppress CCR5, AIDS virus can be prevented to enter human body cell.
HAART (Highly active anti retroviral therapy, HAART) is mesh The effective means of preceding treatment AIDS.But because HIV-1 DNA replication dna lacks fidelity, easily undergo mutation and create antagonism The drug resistance of HIV-1 medicines, clinically in the urgent need to finding more anti-HIV-1 medicines for acting on different target spots.Just because of Action target spot is different, and integrase inhibitor is not by present because the drug resistance produced by chemotherapy is influenceed in recent years, and integrase presses down Preparation is concerned as the medicine of the promising treatment AIDS of a class, and the research to integrase inhibitor is extremely living Jump.
In the various HIV-1 integrase inhibitors reported, only diketoacids show effective cell Interior antiviral activity.Experiment shows that such compound is mainly by suppressing the chain tra nsfer mistake in two catalytic reactions of integrase Journey and obtain antiviral activity.Although the structure of current HIV-1 integrase inhibitors is a lot, enter the HIV- of clinical research 1 integrase inhibitor and the medicine of listing only have diketoacids.Diketone acids integrase inhibitor Merck (Raltegravir) ratify with angstrom listing that FDA was obtained respectively at 2007 and 2012 for lattice Wei (Elvitegravir), into The HIV-1 integrase inhibitor medicines listed for the first generation；Second generation diketone acids integrase inhibitor Du Lutewei (Dolutegravir) also examined and listed by FDA in 2013.As the anti-AIDS new drug with brand-new mechanism of action, it Significantly improve existing HIV-1 therapeutic effects, and as new therapy approach and selection.These integrase inhibitors it is upper City so that the research of integrase inhibitor obtains important breakthrough, promotes more strength to put into the research of this respect.
Problem present in the treatment to AIDS diseases is the poison of drug resistance and medicine caused by HIV-1 virus mutation at present Side effect profile is serious.Therefore, further the design effective AIDS medicines of synthesizing new have great ground-breaking meaning Justice.
The content of the invention
It is an object of the present invention to provide the new pyrrolidone compound with anti-HIV-1 virus function, and Its pharmaceutically acceptable salt, solvate or hydrate, and the anti-HIV-1 virus side for including pyrrolidone compound is provided The pharmaceutical composition of the application in face.
The present invention is achieved by the following technical solutions：
The invention discloses a kind of new pyrrole ketone compounds, shown in its formula for example following (I),
Wherein：
N is selected from 0 to 3 integer；
R1、R2And R3It is each independently selected from hydrogen, C1~C6The saturation or unsaturated alkyl of straight or branched, C3~C7Cyclic hydrocarbon Base, benzyl, aromatic radical Ar, 5~7 membered aromatic heterocycles (containing 1~3 selected from oxygen, sulphur, nitrogen hetero atom, can be by phenyl and fragrance Heterocycle is simultaneously closed, or is selected from halogen, C by one or more1~C6Straight or branched alkyl, cyano group, nitro, amino, hydroxyl, hydroxyl first Base, trifluoromethyl, trifluoromethoxy, carboxyl, C1~C4Alkoxy, sulfydryl, C1~C4Acyl group, aromatic radical Ar group are taken Generation)；
Aromatic radical Ar is substituted or unsubstituted phenyl, naphthyl, xenyl, heterocyclic aryl, and wherein substituent can be 1~4 It is individual to be selected from hydrogen, halogen, C1~C6Straight or branched saturation or unsaturated alkyl, cyano group, nitro, amino, hydroxyl, methylol, trifluoro Methyl, trifluoromethoxy, carboxyl, C1~C4Alkoxy, sulfydryl, C1~C4The group of acyl group；
As a further improvement, pyrrolidone compound of the present invention is different including its enantiomter, diastereomeric Structure body, racemic modification and mixture, and its pharmaceutically acceptable salt or its solvate or hydrate.
As a further improvement, pyrrolidone compound of the present invention pharmaceutically constitute acceptable salt or its Solvate or hydrate, including following compound：
1- (4- fluorophenyls) -3- (2,4- dihydroxy phenyls) -5- phenethyl -1,6a- pyrrolin simultaneously [3,4-c] pyrazoles - 4,6 (3aH, 5H)-diketone,
- 1,6a- pyrrolin is simultaneously by 1- (4- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (2- methoxy-benzyls) [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- methoxyphenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (2- methoxy-benzyls) -1,6a- dihydro pyrroles Cough up simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
- 1,6a- pyrrolin is simultaneously by 1- (4- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (3- methoxy-benzyls) [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- phenethyl -1,6a- pyrrolin is simultaneously [3,4-c] Pyrazoles -4,6 (3aH, 5H)-diketone,
- 1,6a- pyrrolin is simultaneously by 1- (4- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (3- fluorobenzene ethyl) [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
- 1,6a- pyrrolin is simultaneously by 1- (4- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (4- fluorobenzene ethyl) [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- methoxyphenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin And [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- methoxyphenyls) -3- phenyl -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxy phenyls) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4-c] pyrrole Azoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2,3- dihydroxy phenyls) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin is simultaneously [3,4-c] Pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- methoxyphenyls) -3- (pyridine -2- bases) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin is simultaneously [3,4-c] Pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- phenyl -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxyl-5-fluorines phenyl) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4- C] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2,3- Dimethoxyphenyls) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4- C] pyrazoles -4,6 (3aH, 5H)-diketone,
- 1,6a- pyrrolin is simultaneously by 1- (4- fluorophenyls) -3- (2- hydroxy-5-methyls phenyl) -5- (4- fluorobenzene ethyl) [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxy-3-methyls phenyl) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3, 4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (benzo [d] [1,3] dioxole -4- bases) -5- (4- fluorobenzene ethyl) -1,6a- Pyrrolin simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxyl -3- fluorophenyls) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4- C] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxyl -3- chlorphenyls) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4- C] pyrazoles -4,6 (3aH, 5H)-diketone,
- 1,6a- pyrrolin is simultaneously by 1- (4- aminomethyl phenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (4- fluorobenzene ethyl) [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- trifluoromethyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (4- fluorobenzene ethyl) -1,6a- dihydro pyrroles Cough up simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
- 1,6a- pyrrolin is simultaneously by 1- (3- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (4- fluorobenzene ethyl) [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone.
A kind of preparation method of new pyrrole ketone compounds, specific preparation process is as follows：
1), compound (II) and amine R3(CH2)nNH2Reacted in acid organic solvent, obtain compound (III)；
2), compound (IV) and aldehyde flow back in organic solvent solution, obtain compound (V)；
3), compound (III) and (V) react in organic solvent, obtain target compound (I)；
Wherein, n, R1、R2And R3It is defined as above.
As a further improvement, organic solvent of the present invention be benzene, tetrahydrofuran, ether, dimethylformamide, Glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, acetonitrile, ethanol, methanol or ethyl acetate；Described acid is organic base Or inorganic base, wherein organic acid is glacial acetic acid, silver acetate, silver trifluoromethanesulfonate or silver hexafluoroantimonate, and inorganic acid is zinc chloride, chlorine Change iron, silver nitrate, silver carbonate, hydrochloric acid or sulfuric acid.
As a further improvement, new pyrrole ketone compounds of the present invention, its enantiomter, diastereomeric is different Structure body, racemic modification and mixture, and its pharmaceutically acceptable salt or its solvate or hydrate, are preventing or are treating Application in the various diseases of the infection of HIV-1 viruses and its correlation.
A kind of new pharmaceutical composition, pharmaceutical composition includes pyrrolidone compound shown in the formula (I) of therapeutically effective amount Or the pharmaceutical composition of its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier.
As a further improvement, pharmaceutically acceptable carrier of the present invention include ion-exchanger, aluminum oxide, Aluminum stearate, lecithin, haemocyanin, buffer substance such as phosphate, glycerine, sorbic acid, potassium sorbate, saturated vegetable fatty acid Partial glyceride mixtures, water, salt or electrolyte, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, cabosil, Magnesium trisilicate, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, beeswax and Lanolin.
As a further improvement, pharmaceutical composition of the present invention includes the pyrrolones chemical combination of therapeutically effective amount Thing, its enantiomter, racemic modification, pharmaceutically acceptable salt or their mixture, and pharmaceutically acceptable carrier, Excipient or sustained release agent, the form of described pharmaceutical composition is tablet, capsule, powder, syrup, solution shape, suspension or aerosol Agent.
As a further improvement, pyrrolidone compound of the present invention, its enantiomter, racemic modification, medicine Acceptable salt or their mixture account for the 0.1-90 weight % of described pharmaceutical composition gross weight on.
The pharmaceutical composition of the compounds of this invention can be following any-mode apply：Orally, spraying suction, rectum are used Medicine, nasal cavity applied medicine, cheek medication, local application, non-bowel medication, such as subcutaneous, vein, intramuscular, intraperitoneal, intrathecal, intra-ventricle, With intracranial injection or input in breastbone, or by a kind of explant reservoir medication.Wherein treat many diseases such as diabetes, mammary gland Preferred oral or intramuscular injection, intraperitoneal or intravenous administration mode when cancer and some neural class diseases etc..
The compound of structure formula (I) as described above be able to can pass through to mammal Clinical practice, including humans and animals The method of administration of mouth, nose, skin, lung or intestines and stomach etc..Optimal is preferably oral.Optimal preferably daily dose is 0.01~ 200mg/kg body weight, disposably takes, or 0.01~100mg/kg body weight part vics.Which kind of ineffective instructions of taking, it is personal Optimal dose should be according to specific treatment depending on.It is that since low dose, gradually incremental dose is until look under normal circumstances To most suitable dosage.
Beneficial effects of the present invention are as follows：
New pyrrole ketone compounds disclosed by the invention are to have no document report novel compounds.
The activity of the anti-HIV-1 virus of new pyrrole ketone compounds disclosed by the invention also has no document report.
New pyrrole ketone compounds disclosed by the invention have inhibitory activity to HIV-1 viruses, are that a class is that have to open The anti-HIV-1 drug candidate of hair prospect.
The therapeutic index (TI) for having 23 embodiments (I-1~I-23) in embodiment disclosed by the invention is more than 10, has Obvious external Anti-HIV-1 Active；Wherein embodiment I-7 and I-21 therapeutic index is more than 100, with more significant external Anti-HIV-1 Active, the two compounds not only inhibitory activity preferably (EC50About 4 μm of ol/L), while the smaller (CC of cytotoxicity50 It is all higher than 400 μm of ol/L), possess the researching value as potential anti-HIV-1 medicines.
Embodiment
Technical scheme is further described below by specific embodiment：
Part I：Compound synthesis embodiment
Illustrate the preparation of formula (I) compound with embodiment further below, but these embodiments are definitely not to the present invention's Any limitation.All parameters and related description in embodiment, are all using quality to illustrate foundation unless otherwise indicated.
In following preparation examples, nuclear magnetic resonance is surveyed by BrukerAMX-300/400 types and INVOA-600 types NMR Fixed, TMS is internal standard, and chemical shift unit is ppm；Mass spectrum is determined by MAT-711 types and MAT-95 types mass spectrograph；Column chromatography silicon The mesh of glue 200~300, Haiyang Chemical Plant, Qingdao's production；TLC silica gel plates are the HSGF-254 type thin-layer chromatographies that Yantai chemical plant is produced Prefabricated board；Petroleum ether boiling range is 60~90 DEG C；Developed the color using uviol lamp, iodine cylinder.
The preparation of the 1- of embodiment 1 (4- fluorobenzene ethyl) -1H- pyrrole-2,5-diones
0.68g (7.2mmol) maleic anhydride is dissolved in 25mL benzene, 1g (0.94mL, 7.2mmol) is added dropwise to fluorobenzene Ethamine, 0~50 DEG C is stirred 2 hours.0.98g (7.2mmol) zinc chloride is added, 30~120 DEG C of oil baths are moved to, 1.91g is added dropwise After (2.5mL, 11.8mmol) lithium hexamethyldisilazane amine (HMDS), it is heated to reflux 8 hours, is cooled to after room temperature, successively with dilute Hydrochloric acid, water, saturated sodium bicarbonate aqueous solution, saturated sodium-chloride water solution washing.Organic phase anhydrous sodium sulfate drying, filtering, It is evaporated to obtain pale yellow powder product.Yield 87%.LRMS(ESI,m/z)220[M+H]+
The preparation of the 1- of embodiment 2 (2,4- dihydroxy benzenes methylene) -2- phenyl hydrazines
By 0.69g (5.0mmol) 2,4- 4-dihydroxy benzaldehydes and 0.81g (5.0mmol) hydrazinobenzene hydrochloride salt dissolve in 25mL without In water-ethanol, 40~120 DEG C of stirrings, TLC is detected after completion of the reaction, is cooled to room temperature, is evaporated to obtain crude product.LRMS(ESI,m/ z)247[M+H]+
The 1- of embodiment 3 (4- fluorophenyls) -3- (2,4- dihydroxy phenyls) -5- phenethyl -1,6a- pyrrolin simultaneously [3,4- C] pyrazoles -4,6 (3aH, 5H)-diketone (I-1) preparation
By 0.4mmol 1- (4- fluorobenzene ethyl) -1H- pyrrole-2,5-diones and 0.4mmol 1-, (2,4- dihydroxy benzenes is sub- Methyl) -2- phenyl hydrazines are dissolved in 25mL absolute ethyl alcohols, are placed in closed container, and 60~120 DEG C of stirrings, TLC detection reactions are finished Afterwards, room temperature is cooled to, residue is evaporated to obtain, the quick preparative separation chromatograms of Isco (PE/EA=4/1, volume ratio) purify to obtain product 13.3mg, yield 7%.1H NMR(300MHz,CDCl3):δ7.32-7.20(m,4H),7.06-6.88(m,6H),6.48-6.46 (m, 1H), 6.42-6.38 (m, 1H), 4.43-4.41 (d, J=6.3Hz, 1H), 3.93-3.83 (m, 3H), 3.02-3.08 (t, J =7.5Hz, 2H) .MS (EI, m/z) 445 [M]+；HRMS(EI)m/z calcd C25H20FN3O4[M]+445.1438, found445.1430.
The 1- of embodiment 4 (4- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (2- methoxy-benzyls) -1,6a- two The preparation of hydrogen pyrrolo- [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-2)
2,4- 4-dihydroxy benzaldehydes are substituted for 2- hydroxy 3-methoxybenzene formaldehyde, fluorophenethylamine replaced with to fluorine benzyl Amine, hydrazinobenzene hydrochloride salt is substituted for O-methoxy hydrazinobenzene hydrochloride salt, remaining required raw material, reagent and the and of preparation method be the same as Example 2 Embodiment 3, obtains title compound.1H NMR(300MHz,CDCl3):δ7.59-7.56(m,1H),7.49-7.45(m,2H), 7.25-7.17 (m, 2H), 7.08-7.03 (t, J=8.1Hz, 2H), 6.98-6.97 (m, 2H), 6.91-6.79 (m, 2H), 5.07-4.99(m,2H),4.85-4.69(q,2H),3.94(s,3H),3.67(s,3H).MS(ESI,m/z)474[M-H]+； HRMS(ESI)m/z calcd C26H21FN3O5[M-H]+474.1465,found474.1476.
The 1- of embodiment 5 (4- methoxyphenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (2- methoxy-benzyls) -1, The preparation of 6a- pyrrolin simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-3)
4-Methoxybenzylamine will be substituted for fluorophenethylamine, 2,4- 4-dihydroxy benzaldehydes are substituted for 2- hydroxy-3-methoxies Benzaldehyde, hydrazinobenzene hydrochloride salt is substituted for O-methoxy hydrazinobenzene hydrochloride salt, remaining required raw material, reagent and preparation method be the same as Example 2 and embodiment 3, obtain title compound.1H NMR(300MHz,CDCl3):δ7.46-7.43(m,1H),7.39-7.37(m,1H), 7.24-7.21(m,4H),6.95-6.85(m,5H),5.00-4.76(m,4H),3.95(s,3H),3.86(s,3H),3.82(s, 3H).MS(EI,m/z)487[M]+；HRMS(EI)m/z calcd C27H25N3O6[M]+487.1743,found 487.1739.
The 1- of embodiment 6 (4- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (3- methoxy-benzyls) -1,6a- two The preparation of hydrogen pyrrolo- [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-4)
2,4- 4-dihydroxy benzaldehydes are substituted for 2- hydroxy 3-methoxybenzene formaldehyde, fluorophenethylamine replaced with to fluorine benzyl Amine, hydrazinobenzene hydrochloride salt is substituted for meta-methoxy hydrazinobenzene hydrochloride salt, remaining required raw material, reagent and the and of preparation method be the same as Example 2 Embodiment 3, obtains title compound.1H NMR(300MHz,CDCl3):δ 7.56-7.53 (t, J=5.4Hz, 1H), 7.49-7.45 (m, 2H), 7.24-7.21 (d, J=7.8Hz, 1H), 7.10-7.04 (t, J=9.0Hz, 2H), 6.99-6.93 (m, 4H), 6.86-6.83(m,1H),5.07-4.99(m,2H),4.69(s,2H),3.95(s,3H),3.78(s,3H).MS(ESI,m/z) 474[M-H]+；HRMS(ESI)m/z calcd C26H21FN3O5[M-H]+474.1465,found 474.1466.
The 1- of embodiment 7 (4- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- phenethyl -1,6a- pyrrolin is simultaneously The preparation of [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-5)
2,4- 4-dihydroxy benzaldehydes are substituted for 2- hydroxy 3-methoxybenzene formaldehyde, remaining required raw material, reagent and preparation Method be the same as Example 2 and embodiment 3, obtain title compound.1H NMR(300MHz,CDCl3):δ7.49-7.41(m,3H), 7.17-7.15 (d, J=6.6Hz, 2H), 7.11-7.04 (m, 5H), 6.98-6.96 (m, 2H), 4.98-4.90 (m, 2H), 3.96 (s, 3H), 3.86-3.82 (t, J=7.2Hz, 2H), 2.93-2.88 (t, J=8.1Hz, 2H) .MS (ESI, m/z) 458 [M-H ]+；HRMS(ESI)m/z calcd C26H21FN3O4[M-H]+458.1516,found 458.1517.
The 1- of embodiment 8 (4- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (3- fluorobenzene ethyl) -1,6a- dihydros The preparation of pyrrolo- [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-6)
2,4- 4-dihydroxy benzaldehydes are substituted for 2- hydroxy 3-methoxybenzene formaldehyde, hydrazinobenzene hydrochloride salt is substituted for a fluorobenzene Hydrazine hydrochloride, remaining required raw material, reagent and preparation method be the same as Example 2 and embodiment 3, obtain title compound.1H NMR (300MHz,CDCl3):δ7.49-7.40(m,3H),7.10-7.04(m,2H),6.98-6.96(m,3H),6.85-6.47(m, 3H), 4.99-4.92 (m, 2H), 3.96 (s, 3H), 3.85-3.80 (t, J=6.6Hz, 2H), 2.93-2.88 (t, J=7.5Hz, 2H).MS(ESI,m/z)476[M-H]+；HRMS(ESI)m/z calcd C26H20F2N3O4[M-H]+476.1422, found476.1424.
The 1- of embodiment 9 (4- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (4- fluorobenzene ethyl) -1,6a- dihydros The preparation of pyrrolo- [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-7)
2,4- 4-dihydroxy benzaldehydes are substituted for 2- hydroxy 3-methoxybenzene formaldehyde, hydrazinobenzene hydrochloride salt is substituted for fluorobenzene Hydrazine hydrochloride, remaining required raw material, reagent and preparation method be the same as Example 2 and embodiment 3, obtain title compound.1H NMR (300MHz,CDCl3):δ7.44-7.40(m,3H),7.11-6.96(m,6H),6.88-6.84(m,2H),4.96-4.94(m, 2H), 3.96 (s, 3H), 3.81-3.77 (t, J=7.5Hz, 2H), 2.89-2.85 (t, J=7.2Hz, 2H) .MS (EI, m/z) 477[M]+；HRMS(EI)m/z calcd C26H21F2N3O4[M]+477.1500,found477.1495.
The 1- of embodiment 10 (4- methoxyphenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (4- fluorobenzene ethyl) -1, The preparation of 6a- pyrrolin simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-8)
2,4- 4-dihydroxy benzaldehydes are substituted for 2- hydroxy 3-methoxybenzene formaldehyde, fluorophenethylamine is replaced with to methoxy Base phenyl ethylamine, hydrazinobenzene hydrochloride salt is substituted for fluorophenyl hydrazine hydrochloride, remaining required raw material, reagent and preparation method be the same as Example 2 With embodiment 3, title compound is obtained.1H NMR(300MHz,CDCl3):δ7.43-7.39(m,3H),7.02-6.85(m,8H), 4.93-4.92 (m, 2H), 3.96 (s, 3H), 3.83-3.78 (m, 5H), 2.89-2.85 (t, J=7.5Hz, 2H) .MS (EI, m/ z)489[M]+；HRMS(EI)m/z calcd C27H24FN3O5[M]+489.1700,found 489.1693.
The 1- of embodiment 11 (4- methoxyphenyls) -3- phenyl -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4- C] pyrazoles -4,6 (3aH, 5H)-diketone (I-9) preparation
2,4- 4-dihydroxy benzaldehydes are substituted for benzaldehyde, fluorophenethylamine replaced with to methoxyphenethylamine, phenylhydrazine salt Hydrochlorate is substituted for fluorophenyl hydrazine hydrochloride, remaining required raw material, reagent and preparation method be the same as Example 2 and embodiment 3, obtains title Compound.1H NMR(300MHz,CDCl3):δ8.02-7.95(m,1H),7.40-7.31(m,4H),7.25-7.16(m,2H), 7.04-6.87(m,6H),5.02-4.55(m,2H),3.89-3.77(m,5H),2.93-2.83(m,2H).MS(EI,m/z)443 [M]+；HRMS(EI)m/z calcd C26H22FN3O3[M]+443.1645,found 443.1654.
- 1,6a- pyrrolin is simultaneously by the 1- of embodiment 12 (4- fluorophenyls) -3- (2- hydroxy phenyls) -5- (4- fluorobenzene ethyl) The preparation of [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-10)
2,4- 4-dihydroxy benzaldehydes are substituted for Benzaldehyde,2-hydroxy, hydrazinobenzene hydrochloride salt is substituted for fluorophenyl hydrazine hydrochloride, Remaining required raw material, reagent and preparation method be the same as Example 2 and embodiment 3, obtain title compound.1H NMR(300MHz, CDCl3):δ 7.84-7.81 (m, 1H), 7.44-7.33 (m, 3H), 7.11-6.98 (m, 6H), 6.86-6.81 (t, J=8.4Hz, 2H), 4.98-4.89 (m, 2H), 3.83-3.79 (t, J=6.9Hz, 2H), 2.90-2.85 (t, J=7.2Hz, 2H) .MS (ESI, m/z)446[M-H]+；HRMS(ESI)m/z calcd C25H18F2N3O3[M-H]+446.1316,found 446.1327.
The 1- of embodiment 13 (4- fluorophenyls) -3- (2,3- dihydroxy phenyls) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin And the preparation of [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-11)
2,4- 4-dihydroxy benzaldehydes are substituted for 2,3- 4-dihydroxy benzaldehydes, hydrazinobenzene hydrochloride salt is substituted for fluorine phenylhydrazine hydrochloric acid Salt, remaining required raw material, reagent and preparation method be the same as Example 2 and embodiment 3, obtain title compound.1HNMR(300MHz, CDCl3):δ 7.44-7.38 (m, 3H), 7.13-6.99 (m, 5H), 6.96-6.91 (t, J=7.5Hz, 1H), 6.86-6.80 (t, J=8.4Hz, 2H), 4.99-4.88 (m, 2H), 3.85-3.80 (t, J=6.9Hz, 2H), 2.91-2.86 (t, J=7.2Hz, 2H).MS(EI,m/z)463[M]+；HRMS(EI)m/z calcd C25H19F2N3O4[M]+463.1344,found 463.1341.
The 1- of embodiment 14 (4- methoxyphenyls) -3- (pyridine -2- bases) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin And the preparation of [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-12)
2,4- 4-dihydroxy benzaldehydes are substituted for pyridine -2- aldehyde, fluorophenethylamine replaced with to methoxyphenethylamine, phenylhydrazine Hydrochloride is substituted for fluorophenyl hydrazine hydrochloride, remaining required raw material, reagent and preparation method be the same as Example 2 and embodiment 3, must be marked Inscribe compound.1H NMR(300MHz,CDCl3):δ8.72-8.69(m,1H),8.00-7.97(m,1H),7.75-7.73(m, 1H),7.54-7.51(m,2H),7.29-7.24(m,1H),7.06-7.02(m,2H),6.95-6.83(m,4H),5.23-5.05 (m, 2H), 3.82-3.74 (m, 5H), 2.89-2.84 (t, J=7.5Hz, 2H) .MS (ESI, m/z) 445 [M+H]+；HRMS (ESI)m/z calcd C25H21FN4O3Na[M+Na]+467.1495,found 467.1497.
The 1- of embodiment 15 (4- fluorophenyls) -3- phenyl -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4-c] pyrrole The preparation of azoles -4,6 (3aH, 5H)-diketone (I-13)
2,4- 4-dihydroxy benzaldehydes are substituted for benzaldehyde, hydrazinobenzene hydrochloride salt is substituted for fluorophenyl hydrazine hydrochloride, remaining institute Raw material, reagent and preparation method be the same as Example 2 and embodiment 3 are needed, title compound is obtained.1HNMR(300MHz,CDCl3):δ 8.02-7.98 (m, 1H), 7.54-7.43 (m, 5H), 7.09-7.00 (m, 4H), 6.87-6.81 (t, J=8.7Hz, 2H), 5.07-5.03 (d, J=7.5Hz, 1H), 4.84-4.81 (d, J=7.8Hz, 1H), 3.81-3.76 (t, J=6.9Hz, 2H), 2.89-2.84 (t, J=8.1Hz, 2H) .MS (ESI, m/z) 430 [M-H]+；HRMS(ESI)m/z calcd C25H18F2N3O2[M- H]+430.1367,found 430.1369.
The 1- of embodiment 16 (4- fluorophenyls) -3- (2- hydroxyl-5-fluorines phenyl) -5- (4- fluorobenzene ethyl) -1,6a- dihydro pyrroles Cough up the preparation of simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-14)
2,4- 4-dihydroxy benzaldehydes are substituted for 2- hydroxyl-5-fluorine benzaldehydes, hydrazinobenzene hydrochloride salt is substituted for fluorobenzene hydrazonium salt Hydrochlorate, remaining required raw material, reagent and preparation method be the same as Example 2 and embodiment 3, obtain title compound.1H NMR (300MHz,CDCl3):δ7.69-7.65(m,1H),7.22-7.19(m,1H),7.06-6.92(m,7H),6.87-6.81(m, 2H), 5.43-5.39 (d, J=10.5Hz, 1H), 4.78-4.74 (d, J=9.9Hz, 1H), 3.78-3.73 (t, J=7.5Hz, 2H), 2.89-2.84 (t, J=6.9Hz, 2H) .MS (ESI, m/z) 464 [M-H]+；HRMS(ESI)m/z calcd C25H17F3N3O3[M-H]+464.1222,found 464.1228.
The 1- of embodiment 17 (4- fluorophenyls) -3- (2,3- Dimethoxyphenyls) -5- (4- fluorobenzene ethyl) -1,6a- dihydro pyrroles Cough up the preparation of simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-15)
2,4- 4-dihydroxy benzaldehydes are substituted for 2,3- dimethoxy benzaldehydes, hydrazinobenzene hydrochloride salt is substituted for fluorobenzene hydrazonium salt Hydrochlorate, remaining required raw material, reagent and preparation method be the same as Example 2 and embodiment 3, obtain title compound.1H NMR (300MHz,CDCl3):δ7.52-7.47(m,2H),7.26-7.23(m,1H),7.12-6.98(m,6H),6.93-6.87(t,J =8.7Hz, 2H), 5.25-5.22 (d, J=10.8Hz, 1H), 4.99-4.95 (d, J=10.8Hz, 1H), 3.99 (s, 3H), 3.91 (s, 3H), 3.77-3.71 (m, 2H), 2.88-2.83 (t, J=7.2Hz, 2H) .MS (ESI, m/z) 490 [M-H]+；HRMS (ESI)m/z calcd C27H22F2N3O4[M-H]+490.1578,found 490.1586.
The 1- of embodiment 18 (4- fluorophenyls) -3- (2- hydroxy-5-methyls phenyl) -5- (4- fluorobenzene ethyl) -1,6a- two The preparation of hydrogen pyrrolo- [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-16)
2,4- 4-dihydroxy benzaldehydes are substituted for 2- hydroxy-5-methyl epoxide benzaldehydes, hydrazinobenzene hydrochloride salt is substituted for fluorobenzene Hydrazine hydrochloride, remaining required raw material, reagent and preparation method be the same as Example 2 and embodiment 3, obtain title compound.1H NMR (300MHz,CDCl3):δ7.44-7.39(m,3H),7.09-6.96(m,6H),6.84-6.81(m,2H),5.01-4.97(d,J =11.1Hz, 1H), 4.92-4.88 (d, J=10.8Hz, 1H), 3.86-3.79 (m, 5H), 2.90-2.85 (t, J=7.5Hz, 2H).MS(ESI,m/z)476[M-H]+；HRMS(ESI)m/z calcd C26H20F2N3O4[M-H]+476.1422,found 476.1406.
The 1- of embodiment 19 (4- fluorophenyls) -3- (2- hydroxy-3-methyls phenyl) -5- (4- fluorobenzene ethyl) -1,6a- dihydros The preparation of pyrrolo- [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-17)
2,4- 4-dihydroxy benzaldehydes are substituted for 2- hydroxy-3-methyl benzaldehydes, hydrazinobenzene hydrochloride salt is substituted for fluorine phenylhydrazine Hydrochloride, remaining required raw material, reagent and preparation method be the same as Example 2 and embodiment 3, obtain title compound.1H NMR (300MHz,CDCl3):δ7.69-7.66(m,1H),7.46-7.41(m,2H),7.25-7.22(m,1H),7.11-6.99(m, 4H), 6.95-6.90 (t, J=7.5Hz, 1H), 6.86-6.80 (t, J=8.7Hz, 2H), 4.98-4.90 (m, 2H), 3.83- (s, the 3H) .MS (ESI, m/z) 460 [M-H] of 3.79 (t, J=7.2Hz, 2H), 2.89-2.85 (t, J=7.5Hz, 2H), 2.35+； HRMS(ESI)m/z calcd C26H20F2N3O3[M-H]+460.1473,found 460.1476.
The 1- of embodiment 20 (4- fluorophenyls) -3- (benzo [d] [1,3] dioxole -4- bases) -5- (4- fluorophenethyls Base) -1,6a- pyrrolin simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-18) preparation
2,4- 4-dihydroxy benzaldehydes are substituted for benzo [d] [1,3] dioxole -4- aldehyde, hydrazinobenzene hydrochloride salt is replaced Change into fluorophenyl hydrazine hydrochloride, remaining required raw material, reagent and preparation method be the same as Example 2 and embodiment 3 obtain title compound Thing.1H NMR(300MHz,CDCl3):δ7.53-7.49(m,2H),7.36-7.34(m,1H),7.08-7.01(m,4H),6.92- 6.85 (m, 4H), 6.09 (s, 2H), 5.02-4.94 (m, 2H), 3.78-3.73 (t, J=6.9Hz, 2H), 2.88-2.83 (t, J =7.5Hz, 2H) .MS (ESI, m/z) 474 [M-H]+；HRMS(ESI)m/z calcd C26H18F2N3O4[M-H]+474.1265, found474.1259.
The 1- of embodiment 21 (4- fluorophenyls) -3- (2- hydroxyl -3- fluorophenyls) -5- (4- fluorobenzene ethyl) -1,6a- dihydro pyrroles Cough up the preparation of simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-19)
2,4- 4-dihydroxy benzaldehydes are substituted for 2- hydroxyl -3- fluorobenzaldehydes, hydrazinobenzene hydrochloride salt is substituted for fluorobenzene hydrazonium salt Hydrochlorate, remaining required raw material, reagent and preparation method be the same as Example 2 and embodiment 3, obtain title compound.1H NMR (300MHz,CDCl3):δ 7.62-7.59 (d, J=8.9Hz, 1H), 7.45-7.40 (m, 2H), 7.09-6.95 (m, 6H), 6.87-6.81 (t, J=8.7Hz, 4H), 5.02-4.99 (d, J=10.5Hz, 1H), 4.93-4.89 (d, J=11.1Hz, 1H), 3.86-3.81 (t, J=7.2Hz, 2H), 2.91-2.86 (t, J=6.9Hz, 2H) .MS (ESI, m/z) 464 [M-H]+；HRMS (ESI)m/z calcd C25H17F3N3O3[M-H]+464.1222,found 464.1217.
The 1- of embodiment 22 (4- fluorophenyls) -3- (2- hydroxyl -3- chlorphenyls) -5- (4- fluorobenzene ethyl) -1,6a- dihydro pyrroles Cough up the preparation of simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-20)
2,4- 4-dihydroxy benzaldehydes are substituted for 2- hydroxyl -3- chlorobenzaldehydes, hydrazinobenzene hydrochloride salt is substituted for fluorobenzene hydrazonium salt Hydrochlorate, remaining required raw material, reagent and preparation method be the same as Example 2 and embodiment 3, obtain title compound.1H NMR (300MHz,CDCl3):δ7.78-7.75(m,1H),7.46-7.41(m,3H),7.12-6.94(m,6H),6.86-6.81(t,J =8.7Hz, 2H), 5.04-4.99 (d, J=10.8Hz, 1H), 4.93-4.89 (d, J=10.8Hz, 1H), 3.85-3.81 (t, J =6.9Hz, 2H), 2.91-2.86 (t, J=6.9Hz, 2H) .MS (EI, m/z) 481 [M]+；HRMS(EI)m/z calcd C25H18ClF2N3O3[M]+481.1005,found481.1016.
The 1- of embodiment 23 (4- aminomethyl phenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (4- fluorobenzene ethyl) -1,6a- The preparation of pyrrolin simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-21)
2,4- 4-dihydroxy benzaldehydes are substituted for 2- hydroxy 3-methoxybenzene formaldehyde, fluorophenethylamine is replaced with to methyl Phenyl ethylamine, hydrazinobenzene hydrochloride salt is substituted for fluorophenyl hydrazine hydrochloride, remaining required raw material, reagent and the and of preparation method be the same as Example 2 Embodiment 3, obtains title compound.1H NMR(300MHz,CDCl3):δ 7.48-7.45 (m, 1H), 7.38-7.35 (d, J= 8.4Hz, 2H), 7.20-7.17 (d, J=8.4Hz, 2H), 7.05-6.95 (m, 4H), 6.88-6.82 (t, J=9.0Hz, 2H), 5.03-4.99 (d, J=11.8Hz, 1H), 4.93-4.89 (d, J=10.5Hz, 1H), 3.96 (s, 3H), 3.83-3.78 (t, J =7.2Hz, 2H), 2.89-2.85 (t, J=7.5Hz, 2H), 2.34 (s, 3H) .MS (ESI, m/z) 472 [M-H]+；HRMS (ESI)m/z calcd C27H23FN3O4[M-H]+472.1673,found 472.1680.
The 1- of embodiment 24 (4- trifluoromethyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (4- fluorobenzene ethyl) -1, The preparation of 6a- pyrrolin simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-22)
2,4- 4-dihydroxy benzaldehydes are substituted for 2- hydroxy 3-methoxybenzene formaldehyde, fluorophenethylamine is replaced with to trifluoro Methylphenethylamine, hydrazinobenzene hydrochloride salt is substituted for fluorophenyl hydrazine hydrochloride, remaining required raw material, reagent and preparation method be the same as Example 2 and embodiment 3, obtain title compound.1H NMR(300MHz,CDCl3):δ 7.64-7.61 (d, J=9.0Hz, 2H), 7.53- 7.46 (m, 3H), 7.03-6.98 (m, 4H), 6.86-6.80 (t, J=8.7Hz, 2H), 5.13-5.09 (d, J=10.8Hz, 1H), 4.99-4.96 (d, J=10.5Hz, 2H), 3.97 (s, 3H), 3.85-3.80 (t, J=7.2Hz, 2H), 2.90-2.85 (t, J=6.9Hz, 2H) .MS (ESI, m/z) 526 [M-H]+；HRMS(ESI)m/z calcd C27H20F4N3O4[M-H]+ 526.1390,found 526.1401.
The 1- of embodiment 25 (3- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (4- fluorobenzene ethyl) -1,6a- two The preparation of hydrogen pyrrolo- [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone (I-23)
2,4- 4-dihydroxy benzaldehydes are substituted for 2- hydroxy 3-methoxybenzene formaldehyde, a fluorobenzene is replaced with to fluorophenethylamine Ethamine, hydrazinobenzene hydrochloride salt is substituted for fluorophenyl hydrazine hydrochloride, remaining required raw material, reagent and preparation method be the same as Example 2 and reality Example 3 is applied, title compound is obtained.1H NMR(300MHz,CDCl3):δ7.48-7.45(m,1H),7.34-7.13(m,4H),7.04- 6.94 (m, 3H), 6.87-6.81 (m, 2H), 6.78-6.72 (m, 1H), 5.05-5.01 (d, J=10.8Hz, 1H), 4.96- 4.93 (d, J=10.5Hz, 2H), 3.96 (s, 3H), 3.84-3.79 (t, J=7.5Hz, 2H), 2.90-2.85 (t, J= 7.2Hz,2H).MS(ESI,m/z)464[M-H]+；HRMS(ESI)m/z calcd C26H20F2N3O4[M-H]+464.1422, found 464.1431.
Part II：Biological activity test test example
23 Compound ira vitro Anti-HIV-1 Actives of biological activity test test example：
1. material and method
(1) medicine and compound
Positive reference compound retrovir (3 '-Azido-3 '-deoxythymidine, AZT) is purchased from Sigma companies. 70 samples are dissolved in DMSO, and storage liquid concentration is 25mg/ml, and condition of storage is：-20℃；AZT is dissolved in RPMI- In 1640 complete mediums, 0.22 μm of membrane filtration is degerming, -20 DEG C of preservations after packing.
(2) reagent and solution
A. reagent
HEPES(N-2-(2-Hydroxyothyl)-piperazine-N'-(2-ethanesufonic acid)、MTT (3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide)、DMF(N,N’- Dimethyl formamine), penicillin (Penicillin), streptomycin sulphate (Streptomycin sulfate), paddy ammonia Acid amides (Glutamine) is purchased from Sigma companies；2 mercapto ethanol (2-ME, 2-Mercaptoethanol) is Bio-Rad Products.RPMI-1640 and hyclone are Gibco Products.
B. culture medium
RPMI-1640 complete mediums, contain 10% inactivated fetal bovine serum, 2mM Glus, 10MmHEPES, 50 μ M 2 mercapto ethanols, 100,000IU penicillin, 100 μ g/ml streptomysins.
(3) cell and virus
Human T lymphocyte system C8166, MT4 cell and HIV-1 experiment strains HIV-1IIIBBy Britain Medical Research Council, AIDS Reagent Project give.All cells and virus are with containing 10% hyclone RPMI-1640 complete mediums are cultivated.HIV-1 is prepared according to a conventional methodIIIB, titrate and calculate the TCID of virus50.Disease After poison storage liquid packing, -70 DEG C of preservations are put.Cell and virus freeze and recovered according to a conventional method.
(4) toxicity test of the compound to C8166 cells
4×105/ ml C8166 cell suspensions 100uL are mixed from different testing compound solutions, if three repeating holes. AZT is positive drug control.Control wells and blank control wells without compound, 37 DEG C, 5%CO are set simultaneously2Culture 3 days, Using MTT colorimetric determination cytotoxicities.ELx800 ELIASAs determine OD values, and measure wavelength is 595nm, and reference wavelength is 630nm.Calculating obtains CC50It is worth (50%Cytotoxic concentration), i.e. the normal T-lymphocytes system to 50% C8166 produces compound concentration during toxicity.
(5) compound HIV-1IIIBThe Inhibition test of cytopathogenic effect (CPE)
By 8 × 105/ ml C8166 cell 50ul/ holes are inoculated into 96 containing 100 μ L/ gradient pores doubling dilution compounds In porocyte culture plates, 50 μ L HIV-1 is then addedIIIBDilute supernatant, 1300TCID50/ hole.If 3 repeating holes.Set simultaneously Put the normal cell controls hole without compound.AZT is positive drug control.37 DEG C, 5%CO2Culture 3 days, inverted microscope Under (100 ×) count plasomidum formation.Calculating obtains EC50(50%Effective concentration), that is, suppress 50% Compound concentration during Syncytium formation.
(6) calculation formula
Dose-effect response curve is drawn according to experimental result, calculating compound by Reed＆Muench methods suppresses virus 50% valid density (EC50), 50% suppresses cell growth concentration (CC50) and Anti-HIV-1 Active therapeutic index (Therapeutic index, TI) is：TI=CC50/EC50。
Biological activity test result-table 1
Above-mentioned biological test result shows：The TI values of 23 embodiments are all higher than 10, are lived with certain external anti-HIV-1 Property.Wherein, substantially, TI values are respectively I-7 and I-21 activity>105.26 and>103.09.
Exemplified as above is only the preferred embodiment of the present invention, and the present invention is not limited to above example, this area skill The oher improvements and changes that art personnel directly export or associated without departing from the spirit and concept in the present invention, all should Think comprising within the scope of the present invention.
Industrial applicibility
The pyrrolidone compound of the present invention has stronger inhibitory activity in anti-HIV-1 virus test, can be used as acquisition Property acquired immunodeficiency syndrome medicine.
Therefore, compound of the invention can be used for the medicine for preparing treatment Immune Deficiency Syndrome.
Exemplified as above is only the preferred embodiment of the present invention, and the present invention is not limited to above example, this area skill The oher improvements and changes that art personnel directly export or associated without departing from the spirit and concept in the present invention, all should Think comprising within the scope of the present invention.

Claims (11)

1. a kind of pyrrolidone compound or its salt, it is characterised in that shown in its formula for example following (I),
Wherein：
R1It is selected from：2,4- dihydroxy phenyls, 2- hydroxy 3-methoxybenzenes base, phenyl, 2- hydroxy phenyls, 2,3- dihydroxy phenyls, Pyridine -2- bases, 2- hydroxyl-5-fluorines-phenyl, 2,3- Dimethoxyphenyls, 2- hydroxy-5-methyls phenyl, 2- hydroxy-3-methyls Phenyl, benzo [d] [1,3] dioxole -4- bases, 2- hydroxyl -3- fluorophenyls, 2- hydroxyl -3- fluorophenyls；
R2It is selected from：4- fluorophenyls, 4- methoxyphenyls, 4- aminomethyl phenyls, 4- trifluoromethyls, 3- fluorophenyls；
R3It is selected from：Phenyl, 2- methoxyphenyls, 3- methoxyphenyls, 3- fluorophenyls, 4- fluorophenyls；
N takes 1 or 2.
2. pyrrolidone compound according to claim 1 or its salt, it is characterised in that described pyrrolidone compound Or its salt is following compound or its salt：
1- (4- fluorophenyls) -3- (2,4- dihydroxy phenyls) -5- phenethyl -1,6a- pyrrolin simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (2- methoxy-benzyls) -1,6a- pyrrolin simultaneously [3, 4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
- 1,6a- pyrrolin is simultaneously by 1- (4- methoxyphenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (2- methoxy-benzyls) [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (3- methoxy-benzyls) -1,6a- pyrrolin simultaneously [3, 4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- phenethyl -1,6a- pyrrolin simultaneously [3,4-c] pyrazoles - 4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (3- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4- C] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4- C] pyrazoles -4,6 (3aH, 5H)-diketone,
- 1,6a- pyrrolin is simultaneously by 1- (4- methoxyphenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (4- fluorobenzene ethyl) [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- methoxyphenyls) -3- phenyl -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxy phenyls) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2,3- dihydroxy phenyls) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4-c] pyrrole Azoles -4,6 (3aH, 5H)-diketone,
1- (4- methoxyphenyls) -3- (pyridine -2- bases) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4-c] pyrazoles - 4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- phenyl -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxyl-5-fluorines phenyl) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4-c] pyrrole Azoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2,3- Dimethoxyphenyls) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4-c] pyrrole Azoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxy-5-methyls phenyl) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4- C] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxy-3-methyls phenyl) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin is simultaneously [3,4-c] Pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (benzo [d] [1,3] dioxole -4- bases) -5- (4- fluorobenzene ethyl) -1,6a- dihydros Pyrrolo- [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxyl -3- fluorophenyls) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4-c] pyrrole Azoles -4,6 (3aH, 5H)-diketone,
1- (4- fluorophenyls) -3- (2- hydroxyl -3- chlorphenyls) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4-c] pyrrole Azoles -4,6 (3aH, 5H)-diketone,
1- (4- aminomethyl phenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3, 4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
- 1,6a- pyrrolin is simultaneously by 1- (4- trifluoromethyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (4- fluorobenzene ethyl) [3,4-c] pyrazoles -4,6 (3aH, 5H)-diketone,
1- (3- fluorophenyls) -3- (2- hydroxy 3-methoxybenzenes base) -5- (4- fluorobenzene ethyl) -1,6a- pyrrolin simultaneously [3,4- C] pyrazoles -4,6 (3aH, 5H)-diketone.
3. a kind of preparation method of pyrrolidone compound as claimed in claim 1, it is characterised in that specific preparation process is such as Under：
1), compound (II) and amine R3(CH2)nNH2In the presence of acid, react in organic solvent, obtain compound (III)；
2), compound (IV) and aldehyde flow back in organic solvent solution, obtain compound (V)；
3), compound (III) and (V) react in organic solvent, obtain target compound (I)；
Wherein, n, R1、R2And R3Definition with claim 1.
4. the preparation method of pyrrolidone compound according to claim 3, it is characterised in that described organic solvent is Benzene, tetrahydrofuran, ether, dimethylformamide, glycol dimethyl ether, ethylene glycol diethyl ether, dioxane, acetonitrile, ethanol, first Alcohol or ethyl acetate；Described acid is glacial acetic acid, silver acetate, silver trifluoromethanesulfonate, silver hexafluoroantimonate, zinc chloride, iron chloride, nitre Sour silver, silver carbonate, hydrochloric acid or sulfuric acid.
5. a kind of pharmaceutical composition, it is characterised in that described pharmaceutical composition is included described in the claim 1 of therapeutically effective amount Formula (I) shown in pyrrolidone compound or its pharmaceutically acceptable salt and at least one pharmaceutically acceptable carrier.
6. pharmaceutical composition according to claim 5, it is characterised in that described pharmaceutically acceptable carrier include from Sub- exchanger, aluminum oxide, lecithin, haemocyanin, buffer substance, glycerine, sorbic acid, potassium sorbate, saturated vegetable fatty acid Partial glyceride mixtures, water, electrolyte, cabosil, polyvinylpyrrolidone, cellulosic material, polyethylene glycol, poly- Acrylate, beeswax and lanolin.
7. pharmaceutical composition according to claim 6, it is characterised in that described buffer substance is phosphate.
8. pharmaceutical composition according to claim 6, it is characterised in that described electrolyte is salt.
9. pharmaceutical composition according to claim 8, it is characterised in that described salt be disodium hydrogen phosphate, potassium hydrogen phosphate, Any one in sodium chloride, zinc salt, magnesium trisilicate, sodium carboxymethylcellulose, aluminum stearate.
10. the pharmaceutical composition according to claim 5 or 6 or 7 or 8 or 9, it is characterised in that described pharmaceutical composition Compound, its pharmaceutically acceptable salt or their mixture described in claim 1 including therapeutically effective amount, and pharmacy Upper acceptable carrier, excipient or sustained release agent, the form of described pharmaceutical composition is tablet, capsule, powder, syrup, solution Shape, suspension or aerosol.
11. pharmaceutical composition according to claim 10, it is characterised in that compound described in described claim 1, Its pharmaceutically acceptable salt or their mixture account for the 0.1-90 weight % of described pharmaceutical composition gross weight.
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