CN103570721A - Triazolopyrazine(one) and isoxazolopiperidone compounds - Google Patents

Triazolopyrazine(one) and isoxazolopiperidone compounds Download PDF

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CN103570721A
CN103570721A CN201210250715.3A CN201210250715A CN103570721A CN 103570721 A CN103570721 A CN 103570721A CN 201210250715 A CN201210250715 A CN 201210250715A CN 103570721 A CN103570721 A CN 103570721A
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substituted
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俞晓明
陈晓光
刘迪
吕春婉
李永强
周玉美
马良
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Institute of Materia Medica of CAMS
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    • C—CHEMISTRY; METALLURGY
    • 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
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Abstract

The present invention discloses a class of triazolopyrazine(one) and isoxazolopiperidone compounds, preparation methods, drug compositions, and uses thereof. The three classes of the compounds can adopt intramolecular 3+2 cycloaddition reactions and other necessary steps to prepare heterocyclic compounds. The compounds provide inhibition effects for heat shock protein 90 (Hsp90) so as to be used for malignant tumor treatments, particularly for treatments of melanoma, gastric cancer, lung cancer, breast cancer, kidney cancer, liver cancer, oral epidermal carcinoma, cervical cancer, ovarian cancer, pancreatic cancer, prostate cancer, and colon cancer.

Description

Triazolopyrazine (ketone) and isoxazole piperidone compounds
Technical field
The present invention relates to the heterogeneous ring compound that three classes can utilize the interior 3+2 cycloaddition reaction of molecule and other necessary step to be prepared.These compounds are inhibited to heat shock protein 90 (Hsp90), thereby can be used for the treatment of malignant tumour, belong to medical technical field.
Background of invention
Tumour cell exists and is multiplely different from Normocellular carcinous feature (Hallmark traits of cancer), and there is specific former cancer signal path (oncogenic signaling pathways) corresponding (table 1) [1] with it the behind of each carcinous feature.The active of this class signal path in fact also formed the distinctive existence of tumour cell basis, so usings that they just may significantly reduce the impact of Chemotherapeutic Drugs On Normal cell and tissue as drug effect target.The successful listing of tyrosine kinase inhibitor series antineoplastic medicament and clinical application are exactly an example describing the problem very much [2].In the situation that suiting the medicine to the illness use, this class medicine is good effect not only, and toxic side effect is very little.
The carcinous feature of table 1 and former cancer signal path are for example
Figure BDA00001905040000011
Yet, in clinical practice, also found the some shortcomings of above-mentioned newtype drug, for example tumor suppression spectrum is narrower, and in drug effect, may occur obvious individual patient difference.There is viewpoint to think that this deficiency exactly comes from its target selectivity.Owing to having multiple parallel relation between former cancer signal path, in a lot of situations, can compensate mutually, replace, simply cut off the existence that a path is often not enough to jeopardize cancer cells.For remedy such and insufficient, people start to be conceived to the joint of these paths, hope is blocked many paths with a kind of medicine simultaneously, improve the action effect of medicine, improve tumor suppression spectrum and the individual patient universality of medicine, heat shock protein 90 (Heat Shock Protein90, Hsp90) is exactly wherein a kind of [3,4].
Hsp90 is extensively present in eukaryotic a kind of molecular chaperones (Molecular Chaperone), and under normal condition, in main helper cell, new synthetic client's protein polypeptide chain (Nascent peptide of Client protein) is folded into enzyme, acceptor or the signal factor etc. with various biochemical functions with correct quaternary structure.Unfavorable variation for antagonism cell internal and external environment; cell under stress situation need to start a kind of protective mechanism that is called heat shock response (Heat Shock Response); comprising raising fast the expression of Hsp90, to repair folding mistake, the prevention client protein coacervation of client's albumen.Otherwise the Hsp90 client's albumen that can not get safeguarding in time will be entered proteolytic degradation program by rapid ubiquitination (Ubiquitination), cell itself is apoptosis thereupon.
Tumour cell is exactly the cell of a class in stress situation in essence, and its heat shock response system is overactive.Correspondingly, the high 2-10 of the general compared with normal cell of its Hsp90 expression level doubly.More importantly, existing known have tens of kinds of former cancer signal proteins to belong to client's albumen of Hsp90 (comprising all kinds that table one is listed), and the molecular chaperones effect of Hsp90 is had to dependency.This dependence makes Hsp90 become an important former cancer signal network joint, as long as the Hsp90 molecular chaperone function in cancer cells is suppressed, just likely promote the degraded of multiple proto-protein matter and the apoptosis of tumour cell simultaneously, realize the object of oncotherapy.
The molecular weight of Hsp90 is about 90Kd, and known have Hsp90 α, Hsp90 β, GRP94 and tetra-kinds of hypotypes of TRAP, and first two is positioned endochylema, is the main object of existing research, and latter two is positioned respectively endoplasmic reticulum and plastosome.Unit molecule Hsp90 comprises nitrogen end, centre and three functional domains of carbon teminal, only with the connected Hsp90 homodimer of carbon teminal-carbon teminal, just has molecular chaperone function.The energy that needs hydrolysising ATP to obtain in Hsp90 mechanism, corresponding ATP-binding site is determined and is positioned at its nitrogen end functional domain.In addition, the molecular chaperone function of Hsp90 also relates to panimmunity avidin (Immunophilin) and accessory molecule companion's (co-chaperone) effect.Also have research to think that the carbon teminal territory of Hsp90 exists another ATP-binding site, but the ATP of combination herein and the direct relation between function are unclear later.
Figure BDA00001905040000021
Fig. 1 has Hsp90 and suppresses active natural product
About the discovery of heat-shocked mechanism and Hsp90 with before studying and can tracing back to 60 years.Because former viewpoint thinks that Hsp90 inhibitor must have strong toxicity, the drug target of this molecular chaperones is worth until nineteen ninety is just subject to extensive approval for the middle and later periods.The transformation of this attitude and understanding mainly comes from the result of geldanamycin (Geldanamycin, Fig. 1) and root shell Plant hormones regulators,gibberellins (Radicicol, Fig. 1 .1) antitumor mechanism research.These two natural products not only have very high anti tumor activity in vitro (IC 50~ 35,14nM), and normal cell has the selectivity of hundreds of times relatively.They can competitive occupy the nitrogen end ATP-binding site of Hsp90 follow-up study proof, suppress its chaperone activity and obviously promote the multiple proto-protein in tumour cell to degrade simultaneously.
If the whole molecular chaperones mechanism of Hsp90 of take is effective object, can predict in theory multiple different blocking-up method, for example can manage to disturb regulation and control and the expression of Hsp90, also the relay relationship between Hsp70 and Hsp90 can be cut off, formation stoping Hsp90 activated complex etc. can also be managed.But the main flow of Hsp90 inhibitor research at present remains ATPase inhibitor, existing nearly 20 small molecules Hsp90 inhibitor have entered the clinical study of different steps so far, and latest developments can be referring to the summary of delivering in the recent period [5-8].
Summary of the invention
The technical problem to be solved in the present invention be to provide three classes new, there is heat shock protein 90 (Hsp90) the inhibiting thick and heterocyclic compound that can be used for the treatment of malignant tumour.
Detailed Description Of The Invention
The invention provides three compounds shown in structural formula I, II, III or its salt:
Figure BDA00001905040000031
The R that structural formula I, II, III comprise 1group ties up to arbitrary position through ring carbon atom and the direct-connected substituting group of phenyl ring and substituting group combination, i.e. R 1be connected with any applicable position on phenyl ring, and represent one or more substituting groups, R 1be selected from H, substituted or non-substituted C1-6 straight or branched alkyl, hydroxyl, substituted or non-substituted C1-6 straight or branched alkoxyl group, sulfydryl, substituted or non-substituted C1-6 straight or branched alkylthio, C1-6 alcoxyl C1-6 alkyl, amino, substituted or non-substituted C1-6 straight or branched alkylamino, comprising single alkylamino and two alkylamino, aldehyde radical, substituted or non-substituted C1-6 straight or branched alkyloyl, substituted or non-substituted C1-6 straight or branched alkoxyl group acyl group, carboxyl, substituted or non-substituted C1-6 straight or branched alkanoyloxy, formamyl, substituted or non-substituted C1-6 straight or branched alkanamine acyl group, substituted or non-substituted C1-6 straight or branched alkyl amide, the alkene of C2-6, halogen, nitro, cyano group,
Substituting group on substituted or non-substituted C1-6 straight or branched alkyl is selected from: hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group;
Preferred R 1be selected from H, substituted or non-substituted C1-4 straight or branched alkyl, hydroxyl, substituted or non-substituted C1-4 straight or branched alkoxyl group, sulfydryl, substituted or non-substituted C1-4 straight or branched alkylthio, C1-4 alcoxyl C1-4 alkyl, amino, substituted or non-substituted C1-4 straight or branched alkylamino, comprising single alkylamino and two alkylamino, aldehyde radical, substituted or non-substituted C1-4 straight or branched alkyloyl, substituted or non-substituted C1-4 straight or branched alkoxyl group acyl group, carboxyl, substituted or non-substituted C1-4 straight or branched alkanoyloxy, formamyl, substituted or non-substituted C1-4 straight or branched alkanamine acyl group, substituted or non-substituted C1-4 straight or branched alkyl amide, the alkene of C2-4, halogen, nitro, cyano group,
Substituting group on substituted or non-substituted C1-4 straight or branched alkyl is selected from: hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group;
The X that structural formula I, II, III comprise is a Sauerstoffatom or a sulphur atom, is preferably Sauerstoffatom.
The natural number that the n span of the expression methylene radical number that structural formula I, II, III comprise is 1-4, wherein preferably n value is 1.
The R group that structural formula I, II, III comprise is a halogen atom, is preferably Cl; This substituting group can be also alkyl, C3-C6 cycloalkyl, C2-C6 thiazolinyl, C3-C6 cycloalkenyl group and the C2-C6 alkynyl of C1-C6, is preferably ethyl and sec.-propyl.
Term " C1-C6 alkyl " refers to the straight or branched alkyl with 1 to 6 carbon atom, comprises for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl, n-pentyl and n-hexyl.
Term " cycloalkyl " refers to the saturated carbon ring group with 3 to 6 carbon atoms, comprises for example cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
Term " C2-C6 thiazolinyl " refers to the straight or branched thiazolinyl that has 2 to 6 carbon atoms and contain at least one E or Z configured double bond, comprises for example vinyl, propylene-1-base, propylene-2-base and allyl group.
Term " cycloalkenyl group " refers to have carbon ring group 3 to 6 carbon atoms and that contain at least one two key, comprises for example cyclopentenyl and cyclohexenyl.
Term " C2-C6 alkynyl " refers to and contains the straight or branched alkynyl of at least three key, comprises for example ethynyl, proyl, propargyl.
Term " salt " comprises base addition salt, acid salt and quaternary salt as used herein.Compound of the present invention can utilize its acidic-group comprising (as phenol) and alkali (for example alkali metal hydroxide is as sodium hydroxide and potassium hydroxide, and alkaline earth metal hydroxides is as calcium hydroxide, hydrated barta and magnesium hydroxide) and organic bases to form salt.Compound also can utilize its basic group comprising (as nitrogen heterocyclic ring) and mineral acid (such as haloid acid example hydrochloric acid or Hydrogen bromide, sulfuric acid, nitric acid or phosphoric acid) and organic acid (such as acetic acid, tartrate, succsinic acid, fumaric acid, toxilic acid, oxysuccinic acid, Whitfield's ointment, Citric Acid, methylsulfonic acid etc.) to form salt.
Particularly preferred compound of the present invention comprises those in embodiment, especially following compounds and salt thereof:
1) 5-(2-(2-(methylthio group) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-[1,2,3] triazolos [1,5-a] piperazine-6 (7H)-one
2) 5-(2-(4-(nitro) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-[1,2,3] triazolos [1,5-a] piperazine-6 (7H)-one
3) 5-(2-(4-(itrile group) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-[1,2,3] triazolos [1,5-a] piperazine-6 (7H)-one
4) 5-(2-(3-(itrile group) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-[1,2,3] triazolos [1,5-a] piperazine-6 (7H)-one
5) 4-(5-(2-(4-(methyl) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-chlorinated benzene-1,3-diphenol
6) 4-(5-(2-(3-(chlorine) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
7) 4-(5-(2-(3-(methoxyl group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
8) 4-(5-(2-(4-(itrile group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
9) 4-(5-(2-(4-(itrile group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-chloro-benzene-1,3-diphenol
10) 4-(5-(2-(4-(methylthio group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
11) 4-(5-(2-(3-(chlorine) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-chloro-benzene-1,3-diphenol
12) 4-(5-(2-(3-(itrile group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
13) 4-(5-(2-(4-(formamyl) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
14) 5-(2-(3-chlorophenoxy) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-isoxazoles are [4,3-c] piperidines-6 (7H)-one also
15) 5-(2-(3-chlorophenoxy) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-chloro-phenyl-)-isoxazoles are [4,3-c] piperidines-6 (7H)-one also
16) 5-(2-(4-chlorophenoxy) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-ethylphenyl)-isoxazoles are [4,3-c] piperidines-6 (7H)-one also
17) 5-(2-(4-(methylthio group) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-isoxazoles are [4,3-c] piperidines-6 (7H)-one also
18) 5-(2-(4-(methoxyl group) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-isoxazoles are [4,3-c] piperidines-6 (7H)-one also
Compound of the present invention can synthesize by following scheme:
(1) take the 3-phenyl propargyl alcohol suitably replacing is starting raw material, through bromination and N-alkylation synthesizing secondary amine intermediate:
Figure BDA00001905040000061
(2) the secondary amine intermediate and the chloro-acetyl chloride that with above-mentioned synthesis step, obtain are reacted into acid amides; in azide substitution and follow-up molecule, 3+2 cycloaddition reaction builds molecular skeleton again, last under acidic conditions deprotection base complete the synthetic of above-mentioned formula I compound:
Figure BDA00001905040000071
(3) the secondary amine intermediate obtaining with above-mentioned synthesis step equally reacts and obtains monoethanolamine intermediate with ethylene bromohyrin in tube sealing, changes hydroxyl into bromine subsequently, and with azide substitution; There is 3+2 cycloaddition reaction in triazo-compound, finally under acidic conditions, deprotection base completes the synthetic of above-mentioned formula II compound under heating condition:
Figure BDA00001905040000072
(4) the secondary amine intermediate still obtaining with above-mentioned synthesis step; under carboxylic acid activating agent's existence, react and obtain nitro acid amides with 3-nitropropionic acid; this compound generates nitrile oxide active intermediate the instant 3+2 of generation cycloaddition reaction under heating condition through dewatering, finally under acidic conditions, deprotection base completes the synthetic of above-mentioned formula III compound:
Figure BDA00001905040000073
Further aspect of the present invention also relates to usings the pharmaceutical composition of the compounds of this invention as active ingredient.This pharmaceutical composition can be according to method preparation well known in the art.Can be suitable for any formulation of human or animal's use by the pharmaceutically acceptable solid of the compounds of this invention and one or more or liquid excipient and/or assistant agent being combined, making.The content of the compounds of this invention in its pharmaceutical composition is generally 0.1-95 % by weight.
The compounds of this invention or the pharmaceutical composition that contains it can unit dosage form administrations, route of administration can be enteron aisle or non-enteron aisle, as oral, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, eye, lung and respiratory tract, skin, vagina, rectum etc.
Form of administration can be liquid dosage form, solid dosage or semisolid dosage form.Liquid dosage form can be solution (comprising true solution and colloidal solution), emulsion (comprising o/w type, w/o type and emulsion), suspensoid, injection (comprising aqueous injection, powder injection and transfusion), eye drops, nasal drop, lotion and liniment etc.; Solid dosage can be tablet (comprising ordinary tablet, enteric coated tablet, lozenge, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (comprising hard capsule, soft capsule, enteric coated capsule), granule, powder, micropill, dripping pill, suppository, film, paster, the agent of gas (powder) mist, sprays etc.; Semisolid dosage form can be ointment, gelifying agent, paste etc.
The compounds of this invention can be made ordinary preparation, also make is sustained release preparation, controlled release preparation, targeting preparation and various particulate delivery system.
For the compounds of this invention is made to tablet, can be widely used various vehicle well known in the art, comprise thinner, tamanori, wetting agent, disintegrating agent, lubricant, glidant.Thinner can be starch, dextrin, sucrose, glucose, lactose, N.F,USP MANNITOL, sorbyl alcohol, Xylitol, Microcrystalline Cellulose, calcium sulfate, secondary calcium phosphate, calcium carbonate etc.; Wetting agent can be water, ethanol, Virahol etc.; Tackiness agent can be starch slurry, dextrin, syrup, honey, glucose solution, Microcrystalline Cellulose, mucialga of arabic gummy, gelatine size, Xylo-Mucine, methylcellulose gum, Vltra tears, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyoxyethylene glycol etc.; Disintegrating agent can be dry starch, Microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, croscarmellose sodium, sodium starch glycolate, sodium bicarbonate and Citric Acid, polyoxyethylene sorbitol fatty acid ester, sodium laurylsulfonate etc.; Lubricant and glidant can be talcum powder, silicon-dioxide, stearate, tartrate, whiteruss, polyoxyethylene glycol etc.
Tablet further can also be made to coating tablet, for example sugar coated tablet, thin membrane coated tablet, ECT, or double-layer tablets and multilayer tablet.
For capsule is made in administration unit, effective constituent the compounds of this invention can be mixed with thinner, glidant, mixture is directly placed in to hard capsule or soft capsule.Also can by effective constituent the compounds of this invention first with thinner, tamanori, disintegrating agent granulation or micropill, then be placed in hard capsule or soft capsule.Also the capsule that can be used for preparing the compounds of this invention for the preparation of each thinner, tamanori, wetting agent, disintegrating agent, the glidant kind of the compounds of this invention tablet.
For the compounds of this invention is made to injection, can water, ethanol, Virahol, propylene glycol or their mixture as solvent and add the conventional solubilizing agent in appropriate this area, solubility promoter, pH to adjust agent, osmotic pressure regulator.Solubilizing agent or solubility promoter can be poloxamer, Yelkin TTS, hydroxypropyl-beta-cyclodextrin etc.; PH adjustment agent can be phosphoric acid salt, acetate, hydrochloric acid, sodium hydroxide etc.; Osmotic pressure regulator can be sodium-chlor, N.F,USP MANNITOL, glucose, phosphoric acid salt, acetate etc.As prepare lyophilized injectable powder, also can add N.F,USP MANNITOL, glucose etc. as propping agent.
In addition,, as needs, also can in pharmaceutical preparation, add tinting material, sanitas, spices, correctives or other additive.
For reaching medication object, strengthen result for the treatment of, medicine of the present invention or pharmaceutical composition can be with any known medication administrations.
The dosage of the compounds of this invention pharmaceutical composition is according to character and the severity that will prevent or treat disease, the individual instances of patient or animal, and route of administration and formulation etc. can have large-scale variation.In general, the appropriate dose scope of the every day of the compounds of this invention is 0.001-150mg/Kg body weight, is preferably 0.1-100mg/Kg body weight, and more preferably 1-60mg/Kg body weight, most preferably is 2-30mg/Kg body weight.Above-mentioned dosage can a dose unit or is divided into several dose unit administrations, and this depends on doctor's clinical experience and comprises the dosage regimen of using other treatment means.
Compound of the present invention or composition can be taken separately, or merge and use with other treatment medicine or symptomatic drugs.When compound of the present invention and other medicine existence synergy, should adjust according to practical situation its dosage.
As described in background of invention, Hsp90 be a kind of in tumour cell, have high expression level, with existence and the closely-related molecular chaperones of growing of tumour cell.Compound of the present invention proves Hsp90 inhibitor by activity research, can be used for the treatment of malignant tumour.
Therefore, the present invention also provides:
(1) in Mammals, particularly people, treatment is to the active method that suppresses to have the disease of response of Hsp90, and the method comprises above-mentioned formula I, the II of administration significant quantity or III compound;
(2) above-mentioned formula I, II or III compound, for people's medical science or veterinary science, suppress to have disease or the illness of response to Hsp90 activity especially for treatment; And
(3) above-mentioned formula I, II or III compound are suppressing to have the purposes in the disease of response or the medicine of illness for the preparation of controlling (meaning treatment or prevention) to Hsp90 activity.
Accompanying drawing explanation
Fig. 1. the impact of different concns LD053 on Hsp90, Hsp70 in BGC823 cell and downstream signal path protein expression
Fig. 2 .10 -5the impact of the LD053 effect BGC823 cell different time of M on Hsp90, Hsp70 and the expression of downstream signal pathway associated protein
The impact of Fig. 3 .LD053 on the growth of xenografts in nude mice cancer of the stomach BGC823 cell heteroplastic transplantation knurl
Embodiment
Below in conjunction with embodiment, invention is described further, but these embodiment do not limit the scope of the invention.
Compound preparation experiment
Embodiment 1:4-(5-(2-(4-(methylthio group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
Figure BDA00001905040000101
Room temperature is by compound 1-1(1.9g, 6.46mmol) be dissolved in the dry CH2Cl2 of 15ml, stirring adds triphenylphosphine (2.6g, 9.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (3.28g, 9.01mmol), reaction solution becomes brown in batches, there is solid to separate out, after 10min, react completely, stopped reaction, filters, solid washs with CH2Cl2, filtrate is concentrated, and silicagel column is separated fast, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 1-2 faint yellow solid 1.96g, yield 84.6%.
Step 2
Figure BDA00001905040000111
Under argon shield by 2-(4-methylthio group)-phenoxy ethylamine (2.9g, 15.8mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.8g; 5.8mmol), ice-water bath is cooling, slowly drips compound 1-2(1.9g; dry DMF solution 20ml 5.32mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 1-3 colorless oil 1.4g, yield 57.3%.1H?NMR(300MHz,CDCl3)δ7.23(s,2H),6.88-6.85(m,3H),5.20(s,2H),5.19(s,2H),4.10(t,J=4.8Hz,2H),3.76(s,2H),3.51(s,3H),3.48(s,3H),3.27-3.15(m,3H),2.94(s,2H),2.87(s,2H),2.43(s,3H),1.18(d,J=7.2Hz,6H).
Step 3
Figure BDA00001905040000112
Room temperature is by compound 1-3(568mg, 1.24mmol), be dissolved in 5ml acetone, add ethylene bromohyrin (1.1ml, 15.5mmol), Anhydrous potassium carbonate (187mg, 1.36mmol), room temperature tube sealing reaction 48h, reaction finishes, filter, solids washed with acetone, filtrate is concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=2:1, obtains compound 1-4, oily matter, 368mg, yield 59%.1H?NMR(300MHz,CDCl3)δ7.26-7.20(m,3H),6.87-6.84(m,3H),5.19(s,4H),4.08(t,J=6Hz,2H),3.76(s,2H),3.68(t,J=4.5Hz,2H),3.49-3.48(m,6H),3.24-3.20(m,1H),3.09(t,J=5.4Hz,2H),2.91(t,J=4.8Hz,2H),2.43(s,3H),1.19(d,J=6.9Hz,6H).
Step 4
Figure BDA00001905040000113
Room temperature is by compound 1-4(330mg, 0.66mmol) be dissolved in the dry CH2Cl2 of 3ml, stirring adds triphenylphosphine (240mg, 0.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (306mg in batches, 0.92mmol), after 60min, react completely, add 2ml to be dried DMF, then add sodiumazide (47mg, 0.72mmol), reaction is spent the night, stopped reaction, in impouring water, CH2Cl2 extraction, dry concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=7:1, obtain compound 1-5, oily matter 178mg, yield 51.4%.
Step 5
Figure BDA00001905040000121
By compound 1-5(178mg, 0.34mmol) be dissolved in 3ml toluene, reflux, after 5h, reaction finishes, and stopped reaction, removes solvent under reduced pressure, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 1-6,123mg, yield 69%.1H?NMR(300MHz,CDCl3)δ7.55(s,1H),7.24(d,J=8.7Hz,2H),6.94(s,1H),6.82(d,J=8.4Hz,2H),5.23(s,2H),5.08(s,2H),4.56(br,s,2H),4.18(br,s,2H),3.98(br,s,2H),3.51(s,3H),3.37(s,3H),3.32-3.25(m,3H),3.09(br,s,2H),2.44(s,3H),1.24(d,J=6.9Hz,6H).
Step 6
By compound 1-6(123mg, 0.23mmol) be dissolved in 2M hydrogen chloride methanol solution 3ml, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 40mg, yield 39%.1H?NMR(300MHz,DMSO)δ7.24(d,J=9Hz,3H),6.94(d,J=8.7Hz,2H),6.56(s,1H),4.81(s,2H),4.70(s,2H),4.47(s,2H),4.00(br,s,2H),3.68(s,2H),3.15-3.10(m,1H),2.42(s,3H),1.15(d,J=6.9Hz,6H).MS(ESI+)calcd.forC23H28N4O3S,440.1882,found441.1938.
Embodiment 2:5-(2-(4-(methylthio group) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-isoxazoles are [4,3-c] piperidines-6 (7H)-one also
Ice-water bath is by compound 1-4(300mg, 0.65mmol), 3-nitropropionic acid (117mg, 0.98mmol) is dissolved in 3ml dry methylene chloride, ice-water bath is cooling, and rapid stirring adds EDCI(188mg, 0.98mmol in batches), finish after 0.5h, reaction finishes, and adds 30ml methylene dichloride, washing, saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=2:1, obtain compound 2-1, oily matter 298mg, yield 81.3%.1H?NMR(300MHz,CDCl3)δ7.25-7.16(m,3H),6.69-6.83(m,3H),5.20(s,2H),5.16(s,2H),4.76-4.71(m,2H),4.64-4.59(m,2H),4.19(dt,J=24.9Hz,J=5.1Hz,2H),3.95(dt,J=29.7Hz,J=5.1Hz,2H),3.476(d,J=1.8Hz,6H),3.28-3.17(m,3H),2.42(s,3H),1.18(d,J=6.6Hz,6H).
Step 2
Under argon shield, by compound 2-1(298mg, 0.53mmol), be dissolved in 3ml dry toluene; stirring adds DMAP(13mg, 0.11mmol), be heated to 90 ℃, in 0.5h, drip the 3ml dry toluene solution of (Boc) 2O; finish, keep after 90 ℃ of reaction 4h, reaction finishes; remove solvent under reduced pressure, add dichloromethane extraction, anhydrous sodium sulfate drying; concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1; obtain compound 2-2,134mg, yield 46%.1H?NMR(300MHz,CDCl3)δ7.54(s,1H),7.21(d,J=8.7Hz,2H),6.99(s,1H),6.78(d,J=8.7Hz,2H),5.27(s,2H),5.19(s,2H),4.70(s,2H),4.22(t,J=5.1Hz,2H),3.86(t,J=5.1Hz,2H),3.77(s,2H),3.52(s,3H),3.44(s,3H),3.33-3.29(m,1H),2.43(s,3H),1.25(d,J=6.6Hz,6H).
Step 3
By compound 2-2(134mg, 0.25mmol) be dissolved in 2M hydrogen chloride methanol solution 4ml, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 62mg, yield 55.2%.1H?NMR(300MHz,DMSO)δ7.22(s,1H),7.19(d,J=8.7Hz,2H),6.87(d,J=8.7Hz,2H),6.58(s,1H),4.64(s,2H),4.12(t,J=5.1Hz,2H),3.76(t,J=4.5Hz,2H),3.67(s,2H),3.17-3.08(m,1H),2.40(s,3H),1.16(d,J=6.9Hz,6H).MS(ESI+)calcd?for?C24H26N2O5S,454.1562,found455.1619.
Embodiment 3:5-(2-(2-(methylthio group) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-[1,2,3] triazolos [1,5-a] piperazine-6 (7H)-one
Step 1
Figure BDA00001905040000142
Under argon shield by 2-(2-methylthio group)-phenoxy ethylamine (2.9g, 15.8mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.8g; 5.8mmol), ice-water bath is cooling, slowly drips compound 1-2(1.9g; dry DMF solution 20ml 5.32mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, concentrated; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 3-1 colorless oil 1.18g, yield 48.3%.1H?NMR(300MHz,CDCl3)δ7.24(s,1H),7.15-7.08(m,2H),6.98-6.93(m,1H),6.87(s,1H),6.84(s,1H),5.20(d,J=5.4Hz,4H),4.21(t,J=5.1Hz,2H),3.80(s,1H),3.50(d,J=8.7Hz,6H),3.24-3.20(m,3H),2.41(s,3H),1.18(d,J=7.2Hz,6H).
Step 2
Figure BDA00001905040000143
Ice-water bath, by compound 3-1(300mg, 0.66mmol) be dissolved in 3ml dry methylene chloride, stirring adds N, N-diisopropylethylamine (93mg, 0.72mmol), then slowly drip chloroacetyl chloride (81mg, 0.72mmol), drip and finish, 0 ℃ is stirred after 0.5h, add 2ml to be dried DMF, sodiumazide (50mg, 0.77mmol), naturally rise to room temperature reaction, stopped reaction after 48h, ethyl acetate extraction, anhydrous sodium sulfate drying, concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=4:1, obtain compound 3-2294mg, yield 85.2%.1H?NMR(300MHz,CDCl3)δ7.16-7.09(m,3H),6.98(s,1H),6.86-6.80(m,2H),5.20(s,4H),4.65(s,1H),4.56(s,1H),4.38(s,1H),4.25-4.22(m,3H),3.98-3.96(m,2H),3.48(s,6H),3.24-3.19(m,1H),2.44(s,3H),1.18(d,J=6.6Hz,6H).
Step 3
Figure BDA00001905040000151
By compound 3-2(294mg, 0.56mmol) be dissolved in 5ml toluene, reflux, after 4h, reaction finishes, and stopped reaction is concentrated, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 3-3,160mg, yield 53%.1H?NMR(300MHz,CDCl3)δ7.66(s,1H),7.08-7.03(m,1H),6.98-6.93(m,3H),6.75(d,J=8.4Hz,1H),5.25(s,2H),5.14(s,6H),4.26(b?r,s,2H),3.97(br,s,2H),3.33-3.29(m,1H),2.05(s,3H),1.26(d,J=6.6Hz,6H).
Step 4
By compound 3-3(160mg, 0.29mmol) be dissolved in 2M hydrogen chloride methanol solution 4ml, 30 ℃ of tube sealing reactions, 7d reacts end, stopped reaction, filters, and solid methanol wash is dry, methyl alcohol-methylene dichloride recrystallization, obtains title compound 35mg, yield 26.1%.1H?NMR(300MHz,DMSO)δ9.74(s,1H),9.41(s,1H),7.23(s,1H),7.06-7.00(m,2H),6.93-6.90(m,2H),6.49(s,1H),5.14(s,2H),5.08(s,2H),4.17(t,J=4.5，2H),3.86(t,J=4.5,2H),3.17-3.11(m,4H),2.00(s,3H),1.17(d,J=6.9,6H).
MS(ESI+)calcd?for?C23H26N4O4S,454.1765,found455.1797.
Embodiment 4:5-(2-(3-chlorophenoxy) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-chloro-phenyl-)-isoxazoles are [4,3-c] piperidines-6 (7H)-one also
Figure BDA00001905040000152
Step 1
Room temperature is by compound 4-1(1.9g, 6.46mmol) be dissolved in the dry CH2Cl2 of 15ml, stirring adds triphenylphosphine (2.6g, 9.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (3.28g, 9.01mmol), reaction solution becomes brown in batches, there is solid to separate out, after 10min, react completely, stopped reaction, filters, solid washs with CH2Cl2, filtrate is concentrated, and silicagel column is separated fast, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 4-2 faint yellow solid 1.96g, yield 83.6%.
Step 2
Figure BDA00001905040000161
Under argon shield by 2-(3-chlorine)-phenoxy ethylamine (2.7g, 15.7mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.8g; 5.8mmol), ice-water bath is cooling, slowly drips compound 4-2(1.9g; dry DMF solution 20ml 5.32mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 4-3 colorless oil 1.43g, yield 56.3%.1HNMR(400M?in?CDCl3)δ7.23(s,1H),7.20-7.16(m,1H),6.93-691(m,2H),6.85(s,1H),6.82-6.79(m,1H),5.20(s,2H),5.19(s,2H),4.11(t,J=5.2Hz,2H),3.77(s,2H),3.51(s,3H),3.48(s,3H),3.26-3.16(m,3H),1.19(s,3H),1.18(s,3H).
Step 3
Figure BDA00001905040000162
Bathe cooling lower to compound 4-3(400mg, 0.89mmol) and nitropropionic acid (160mg, 1.3mmol) be dissolved in DCM, add EDCI(256mg, 1.3mmol in batches), react after half an hour, TLC monitoring has been reacted, column chromatography, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 4-4 colorless oil 0.42g, yield 86%.1HNMR(300M?in?CDCl3)δ7.20-7.15(m,2H),6.94-6.90(m,2H),6.85-6.80(m,2H),5.20(s,2H),5.17(s,2H),4.76(m,2H),4.60(s,1H),4.50(s,1H),4.28-4.15(m,2H),4.04-3.89(m,2H),3.48(s,6H),3.29-3.19(m,2H),1.19(s,3H),1.16(s,3H).
Step 4
Figure BDA00001905040000163
by compound 4-4(450mg, 0.82mmol) and DMAP(20mg, 0.16mmol) be dissolved in toluene, the toluene solution of 90 degrees Celsius of lower Boc2O, adds in 30min.After 3 hours, TLC monitoring, raw material disappears.Evaporate to dryness toluene, residue dissolves with DCM, saturated NaHCO3 solution washing, DCM extraction 3 times for water, merges organic phase, anhydrous sodium sulfate drying.Column chromatography sherwood oil: ethyl acetate=2:1, obtains compound 4-5 colorless oil 205mg, productive rate 47%.1HNMR(300M?in?CDCl3)δ7.54(s,1H),7.17(t,J=8.1Hz,1H),6.99(s,1H),6.92(dd,J=2.1Hz,J=8.1Hz,1H),6.85(t,J=2.1Hz,1H),6.725(dd,J=2.1Hz,J=8.1Hz,1H),5.27(s,2H),5.20(s,2H),4.69(s,2H),4.23(t,J=4.8Hz,2H),3.87(t,J=4.8Hz,2H),3.77(s,2H),3.52(s,3H),3.46(s,3H),3.33-3.26(m,1H),1.26(s,3H),1.24(s,3H).
Step 5
By compound 4-5(205mg, 0.39mmol) be dissolved in 3M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 40mg, yield 39%.1HNMR(300M?in?DMSO)δ10.38(s,1H),9.91(s,1H),7.18(t,J=8.4Hz,1H),7.04(s,1H),6.90-6.74(m,3H),6.50(s,1H),4.11(s,2H),4.05(s,2H),3.98(s,2H),3.15(s,2H),3.02-2.92(m,1H),1.01(s,3H),0.99(s,3H).HRMS?calcld?forC23H24ClN2O5[M+H]+443.1374,found?443.1347.
Embodiment 5:4-(5-(2-(3-(chlorine) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
Figure BDA00001905040000172
Step 1
Room temperature is by compound 5-1(1.9g, 6.46mmol) be dissolved in the dry CH2Cl2 of 15ml, stirring adds triphenylphosphine (2.6g, 9.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (3.28g, 9.01mmol), reaction solution becomes brown in batches, there is solid to separate out, after 10min, react completely, stopped reaction, filters, solid washs with CH2Cl2, filtrate is concentrated, and silicagel column is separated fast, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 5-2 faint yellow solid 1.96g, yield 84.6%.
Step 2
Figure BDA00001905040000181
under argon shield by 2-(3-chlorine)-phenoxy ethylamine (2.7g, 15.7mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.8g; 5.8mmol), ice-water bath is cooling, slowly drips compound 5-2(1.9g; dry DMF solution 20ml 5.32mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 5-3 colorless oil 1.43g, yield 56.3%.1HNMR(400M?in?CDCl3)δ7.23(s,1H),7.20-7.16(m,1H),6.93-691(m,2H),6.85(s,1H),6.82-6.79(m,1H),5.204(s,2H),5.19(s,2H),4.11(t,J=5.2Hz,2H),3.77(s,2H),3.51(s,3H),3.48(s,3H),3.26-3.16(m,3H),1.19(s,3H),1.18(s,3H).
Step 3
Figure BDA00001905040000182
Room temperature is by compound 5-3(527mg, 1.18mmol), be dissolved in 5ml acetone, add ethylene bromohyrin (1.1ml, 15.5mmol), Anhydrous potassium carbonate (180mg, 1.3mmol), room temperature tube sealing reaction 48h, reaction finishes, filter, solids washed with acetone, filtrate is concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=2:1, obtains compound 5-4, oily matter, 440mg, yield 76%.1HNMR(400M?in?CDCl3)δ7.20-7.16(m,2H),6.94-6.92(m,2H),6.85(s,1H),6.82-6.80(m,1H),5.19(s,4H),4.09(t,J=5.6Hz,2H),3.76(s,2H),3.68-3.66(t,J=5.2Hz,2H),3.50(s,3H),3.48(s,3H),3.32-3.18(m,1H),3.10(t,J=5.6Hz,2H),2.89(t,J=5.6Hz,2H),1.20(s,3H),1.18(s,3H).
Step 4
Figure BDA00001905040000191
Room temperature is by compound 5-4(440mg, 0.89mmol) be dissolved in the dry CH2Cl2 of 3ml, stir and add triphenylphosphine (365mg, 1.34mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (444mg in batches, 1.34mmol), after 60min, react completely, add 2ml to be dried DMF, then add sodiumazide (70mg, 1.1mmol), reaction is spent the night, stopped reaction, in impouring water, CH2Cl2 extraction, dry concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=7:1, obtain compound 5-5, oily matter 280mg, yield 60%.1HNMR(400M?in?CDCl3)δ7.20-7.16(m,2H),6.94-6.91(m,2H),6.85(s,1H),6.82-6.79(m,1H),5.19(s,4H),4.12(t,J=5.6Hz,2H),3.78(s,2H),3.50(s,3H),3.48(s,3H),3.41(t,J=6Hz,2H),1.23(s,3H),1.20(s,3H).
Step 5
Figure BDA00001905040000192
By compound 5-5(280mg, 0.54mmol) be dissolved in 5ml toluene, reflux, after 5h, reaction finishes, and stopped reaction, removes solvent under reduced pressure, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 5-6,200mg, yield 71.4%.1HNMR(400M?in?CDCl3)δ7.54(s,1H),7.19(t,J=8Hz,1H),6.96-6.93(m,2H),6.89(t,J=2Hz,1H),6.78-6.76(m,1H),5.29(s,2H),5.08(s,2H),4.50(t,J=5.6Hz,2H),4.13(t,J=5.6Hz,2H),3.90(s,2H),3.5(s,3H),3.38(s,3H),3.33-3.20(m,1H),3.17(t,J=5.6Hz,2H),3.03(t,J=5.6Hz,2H),1.25(s,3H),1.23(s,3H).
Step 6
Figure BDA00001905040000193
By compound 5-6(200mg, 0.39mmol) be dissolved in 3M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 80mg, yield 48%.1HNMR(300M?in?DMSO):7.31(d,J=4.2Hz,1H),7.26(s,1H),7.13-7.04(m,2H),6.95(d,J=4.2Hz,1H),6.52(s,1H),4.79(s,2H),4.70(s,2H),4.50(s,2H),3.99(s,2H),3.77(s,2H),3.15-3.08(m,1H),1.16(s,3H),1.13(s,3H).HRMS?calcd?for?C22H26ClN4O3[M+H]+429.1693,found429.1674.
Embodiment 6:5-(2-(3-(methoxyl group) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-isoxazoles are [4,3-c] piperidines-6 (7H)-one also
Figure BDA00001905040000201
Step 1
Figure BDA00001905040000202
Room temperature is by compound 6-1(1.9g, 6.46mmol) be dissolved in the dry CH2Cl2 of 15ml, stirring adds triphenylphosphine (2.6g, 9.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (3.28g, 9.01mmol), reaction solution becomes brown in batches, there is solid to separate out, after 10min, react completely, stopped reaction, filters, solid washs with CH2Cl2, filtrate is concentrated, and silicagel column is separated fast, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 6-2 faint yellow solid 1.96g, yield 84.6%.
Step 2
Figure BDA00001905040000203
Under argon shield by 2-(3-methoxyl group)-phenoxy ethylamine (2.7g, 15.7mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.8g; 5.8mmol), ice-water bath is cooling, slowly drips compound 6-2(1.9g; dry DMF solution 20ml 5.32mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 6-3 colorless oil 1.43g, yield 56.3%.
Step 3
Figure BDA00001905040000211
Ice bath is cooling lower to compound 6-3(483mg, 1.1mmol) and nitropropionic acid (194mg, 1.6mmol) be dissolved in DCM, add EDCI(312mg, 1.6mmol in batches), react after half an hour, TLC monitoring has been reacted, column chromatography, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 6-4 colorless oil 520mg, yield 87%.1HNMR(300M?in?CDCl3)δ7.19-7.14(m,2H),6.845(d,J=2.7Hz,1H),6.55-6.46(m,3H),5.19(s,2H),5.17(s,2H),4.78-4.72(m,2H),4.67-4.60(m,2H),4.26-4.15(m,2H),4.02-3.89(m,2H),3.77(d,J=3.9Hz,3H),3.48(s,6H),3.29-3.19(m,3H),1.19(s,3H),1.16(s,3H)。
Step 4
Figure BDA00001905040000212
by compound 6-4(520mg, 0.96mmol) and DMAP(23mg, 0.19mmol) be dissolved in toluene 90 degrees Celsius of lower droplet Boc2O(519mg, 2.4mmol) toluene solution, in 30min, add.After 3 hours, TLC monitoring, raw material disappears.Evaporate to dryness toluene, residue dissolves with DCM, saturated NaHCO3 solution washing, DCM extraction 3 times for water, merges organic phase, anhydrous sodium sulfate drying.Column chromatography sherwood oil: ethyl acetate=2:1, obtains compound 6-5 colorless oil 260mg, productive rate 50%.1HNMR(300M?in?CDCl3)δ7.55(s,1H),7.15(t,J=8.1Hz,1H),6.99(s,1H),6.52-6.40(m,3H),5.3(s,2H),5.19(s,2H),4.71(s,2H),4.23(t,J=4.8Hz,2H),3.87(t,J=4.8Hz,2H),3.81-3.72(m,5H),3.54(s,3H),3.42(s,2H),3.33-3.28(m,1H),1.29(s,3H),1.21(s,3H)。
Step 5
Figure BDA00001905040000213
by compound 6-5(260mg, 0.48mmol) be dissolved in 3M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 95mg, yield 41%.1HNMR(300M?in?DMSO)δ7.22(s,1H),7.13(t,J=8.1Hz,1H),6.56(s,1H),6.51-6.46(m,3H),4.66(s,2H),4.12(t,J=5.4Hz,2H),3.76(t,J=5.4Hz,2H),3.69(s,3H),3.67(s,3H),3.17-3.09(m,1H),1.16(s,3H),1.14(s,3H).HRMS?calcd?forC24H27N2O6[M+H]+439.1869,found439.1845.
Embodiment 7:4-(5-(2-(3-(methoxyl group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
Figure BDA00001905040000221
Step 1
Figure BDA00001905040000222
Room temperature is by compound 7-1(1.9g, 6.46mmol) be dissolved in the dry CH2Cl2 of 15ml, stirring adds triphenylphosphine (2.6g, 9.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (3.28g, 9.01mmol), reaction solution becomes brown in batches, there is solid to separate out, after 10min, react completely, stopped reaction, filters, solid washs with CH2Cl2, filtrate is concentrated, and silicagel column is separated fast, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 7-2 faint yellow solid 1.96g, yield 84.6%.
Step 2
Figure BDA00001905040000223
Under argon shield by 2-(3-methoxyl group)-phenoxy ethylamine (2.7g, 15.7mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.8g; 5.8mmol), ice-water bath is cooling, slowly drips compound 7-2(1.9g; dry DMF solution 20ml 5.32mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 7-3 colorless oil 1.43g, yield 56.3%.
Step 3
Figure BDA00001905040000231
Room temperature is by compound 7-3(500mg, 1.12mmol), be dissolved in 5ml acetone, add ethylene bromohyrin (1.1ml, 15.5mmol), Anhydrous potassium carbonate (170mg, 1.2mmol), room temperature tube sealing reaction 48h, reaction finishes, filter, solids washed with acetone, filtrate is concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=2:1, obtains compound 7-4, oily matter, 310mg, yield 58%.
Step 4
Figure BDA00001905040000232
Room temperature is by compound 7-4(310mg, 0.64mmol) be dissolved in the dry CH2Cl2 of 3ml, stir and add triphenylphosphine (260mg, 0.96mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (317mg in batches, 0.96mmol), after 60min, react completely, add 2ml to be dried DMF, then add sodiumazide (70mg, 1.1mmol), reaction is spent the night, stopped reaction, in impouring water, CH2Cl2 extraction, dry concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=7:1, obtain compound 7-5, oily matter 200mg, yield 61%.
Step 5
Figure BDA00001905040000233
By compound 7-5(200mg, 0.4mmol) be dissolved in 5ml toluene, reflux, after 5h, reaction finishes, and stopped reaction, removes solvent under reduced pressure, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 7-6,175mg, yield 88%.1HNMR(300M?in?CDCl3)δ7.54(s,1H),7.17(t,J=8.1Hz,1H),6.94(s,1H),6.54-6.44(m,3H),5.23(s,2H),5.08(s,2H),4.52(t,J=5.1Hz,2H),4.15(t,J=5.1Hz,2H),3.92(s,2H),3.77(s,3H),3.51(s,3H),3.38(s,3H),3.32-3.25(m,1H),3.19(t,J=4.8Hz,2H),3.06(t,J=4.8Hz,2H),1.25(s,3H),1.23(s,3H)。
Step 6
Figure BDA00001905040000241
By compound 7-6(175mg, 0.35mmol) be dissolved in 3M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 82mg, yield 56%.1HNMR(300M?in?DMSO)δ7.26(s,1H),7.20(t,J=8.4Hz,1H),6.58-6.54(m,4H),4.81(s,2H),4.72(s,2H),4.47(s,2H),3.77(s,2H),3.73(s,3H),3.14-3.08(m,1H),1.16(s,3H),1.13(s,3H).HRMS?calcd?for?C23H29N4O4[M+H]+425.2189,found425.2165.
Embodiment 8:5-(2-(4-chlorophenoxy) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-ethylphenyl)-isoxazoles are [4,3-c] piperidines-6 (7H)-one also
Step 1
Figure BDA00001905040000243
Room temperature is by compound 8-1(1.9g, 6.46mmol) be dissolved in the dry CH2Cl2 of 15ml, stirring adds triphenylphosphine (2.6g, 9.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (3.28g, 9.01mmol), reaction solution becomes brown in batches, there is solid to separate out, after 10min, react completely, stopped reaction, filters, solid washs with CH2Cl2, filtrate is concentrated, and silicagel column is separated fast, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 8-2 faint yellow solid 1.96g, yield 84.6%.
Step 2
Figure BDA00001905040000244
Under argon shield by 2-(4-chlorine)-phenoxy ethylamine (2.7g, 15.7mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.8g; 5.8mmol), ice-water bath is cooling, slowly drips compound 8-2(1.9g; dry DMF solution 20ml 5.32mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 8-3 colorless oil 1.43g, yield 56.3%.1HNMR(400M?in?CDCl3)δ7.23-7.19(m,2H),7.16(s,1H),6.85-6.82(m,3H),5.20(s,2H),5.19(s,2H),4.09(t,J=5.2Hz,2H),3.76(s,2H),3.53(s,3H),3.51(s,3H),3.16(t,J=5.2Hz,2H),2.56(q,J=5.7Hz,2H),1.16(t,J=5.7Hz,3H)。
Step 3
Figure BDA00001905040000251
Ice bath is cooling lower to compound 8-3(436mg, 1mmol) and nitropropionic acid (180mg, 1.5mmol) be dissolved in DCM, add EDCI(290mg, 1.5mmol in batches), react after half an hour, TLC monitoring has been reacted, column chromatography, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 8-4 colorless oil 419mg, yield 80%.1HNMR(300M?in?CDCl3)δ7.22-7.19(m,2H),7.07-7.04(m,1H),6.84-6.81(m,3H),5.19(s,2H),5.16(s,2H),4.78-4.72(m,2H),4.58(s,1H),4.48(s,1H),4.23(t,J=4.8Hz,1H),4.15(t,J=4.8Hz,1H),4.00(t,J=4.8Hz,1H),3.90(t,J=4.8Hz,1H),3.47(s,6H),3.28-3.26(m,2H),2.53(q,J=10Hz,2H),1.14(t,J=10Hz,3H)。
Step 4
Figure BDA00001905040000252
By compound 8-4(419mg, 0.78mmol) and DMAP(20mg, 0.16mmol) be dissolved in toluene 90 degrees Celsius of lower droplet Boc2O(430mg, 1.95mmol) toluene solution, in 30min, add.After 3 hours, TLC monitoring, raw material disappears.Evaporate to dryness toluene, residue dissolves with DCM, saturated NaHCO3 solution washing, DCM extraction 3 times for water, merges organic phase, anhydrous sodium sulfate drying.Column chromatography sherwood oil: ethyl acetate=2:1, obtains compound 8-5 colorless oil 190mg, productive rate 47%.1HNMR?(300M?in?CDCl3)δ7.50(s,1H),7.21-7.18(m,2H),6.98(s,1H),6.77-6.74(m,2H),5.27(s,2H),5.19(s,2H),4.69(s,2H),4.21(t,J=5.1Hz,2H),3.86(t,J=5.1Hz,2H),3.77(s,2H),3.52(s,3H),3.44(s,3H),2.66(q,J=7.5Hz,2H),1.22(t,J=7.5Hz,3H)。
Step 5
Figure BDA00001905040000261
By compound 8-6(190mg, 0.36mmol) be dissolved in 3M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 90mg, yield 59%.1HNMR(300M?in?DMSO)δ10.06(s,1H),9.85(s,1H),7.29(s,1H),7.26(s,1H),7.21(s,1H),6.94(s,1H),6.91(s,1H),6.53(s,1H),4.64(s,2H),4.14(t,J=5.4Hz,2H),3.76(t,J=5.4Hz,2H),3.67(s,2H),1.11(t,J=7.5Hz,3H).HRMS?calcd?for?C22H22ClN2O5[M+H]+429.1217,found429.1197.
Embodiment 9:4-(5-(2-(4-(formamyl) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-ethylbenzene-1,3-diphenol
Figure BDA00001905040000262
Step 1
Figure BDA00001905040000263
Room temperature is by compound 9-1(1.9g, 6.46mmol) be dissolved in the dry CH2Cl2 of 15ml, stirring adds triphenylphosphine (2.6g, 9.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (3.28g, 9.01mmol), reaction solution becomes brown in batches, there is solid to separate out, after 10min, react completely, stopped reaction, filters, solid washs with CH2Cl2, filtrate is concentrated, and silicagel column is separated fast, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 9-2 faint yellow solid 1.96g, yield 84.6%.
Step 2
Figure BDA00001905040000271
Under argon shield by 2-(4-formamyl)-phenoxy ethylamine (2.7g, 15.7mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.8g; 5.8mmol), ice-water bath is cooling, slowly drips compound 9-2(1.9g; dry DMF solution 20ml 5.32mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 9-3 colorless oil 600mg, yield 25%.1HNMR(300M?in?CDCl3)δ7.76(d,J=8.7Hz,2H),6.94(d,J=9.0Hz,2H),6.85(s,1H),5.21(s,2H),5.19(s,2H),4.17(t,J=5.1Hz,2H),3.78(s,2H),3.51(s,3H),3.48(s,3H),3.21(t,J=5.1Hz,2H),2.56(q,J=7.5Hz,2H),1.16(t,J=7.5Hz,3H)。
Step 3
Figure BDA00001905040000272
Room temperature is by compound 9-3(214mg, 0.48mmol), be dissolved in 5ml acetone, add ethylene bromohyrin (1.1ml, 15.5mmol), Anhydrous potassium carbonate (170mg, 1.2mmol), room temperature tube sealing reaction 48h, reaction finishes, filter, solids washed with acetone, filtrate is concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=2:1, obtains compound 9-4, oily matter, 140mg, yield 60%.1HNMR(300M?in?CDCl3)δ7.76(d,J=8.4Hz,2H),7.15(s,1H),6.94(d,J=8.7Hz,2H),6.85(s,1H),5.98(s,2H),5.19(s,4H),4.16(t,J=5.7Hz,2H),3.77(s,2H),3.68(m,2H),3.50(s,3H),3.48(s,3H),3.13(t,J=5.4Hz,2H),2.91(t,J=5.1Hz,2H),2.56(q,J=7.5Hz,2H),1.16(t,J=7.5Hz,3H)。
Step 4
Figure BDA00001905040000273
Room temperature is by compound 9-4(140mg, 0.29mmol) be dissolved in the dry CH2Cl2 of 3ml, stir and add triphenylphosphine (118mg, 0.43mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (142mg in batches, 0.43mmol), after 60min, react completely, add 2ml to be dried DMF, then add sodiumazide (70mg, 1.1mmol), reaction is spent the night, stopped reaction, in impouring water, CH2Cl2 extraction, dry concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=7:1, obtain compound 9-5, oily matter 50mg, yield 34%.1HNMR(300M?in?CDCl3)δ7.57(d,J=8.7Hz,2H),7.13(s,1H),6.97(d,J=8.7Hz,2H),6.85(s,1H),5.19(s,4H),4.18(t,J=5.4Hz,2H),3.78(s,2H),3.50(s,3H),3.48(s,3H),3.40(t,J=5.7Hz,2H),3.12(t,J=5.4Hz,2H),2.96(t,J=5.7Hz,2H),2.56(q,J=7.5Hz,2H),1.16(t,J=7.5Hz,3H)。
Step 5
Figure BDA00001905040000281
By compound 9-5(50mg, 0.1mmol) be dissolved in 5ml toluene, reflux, after 5h, reaction finishes, and stopped reaction, removes solvent under reduced pressure, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 9-6,25mg, yield 50%.1HNMR(300M?in?CDCl3)δ7.58(d,J=8.4Hz,2H),7.50(s,1H),6.93(m,3H),5.23(s,2H),5.08(s,2H),4.51(t,J=5.4Hz,2H),4.19(t,J=5.1Hz,2H),3.92(s,2H),3.51(s,3H),3.37(s,3H),3.19(t,J=5.4Hz,2H),3.07(t,J=5.1Hz,2H),3.07(t,J=5.1Hz,2H),2.64(q,J=7.5Hz,2H),1.21(t,J=7.5Hz,3H)。
Step 6
By compound 9-6(25mg, 0.05mmol) be dissolved in 3M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 17mg, yield 75%.1HNMR(400M?in?DMSO)δ9.79(s,1H),9.47(s,1H),7.86(dd,J=8.4,50.4Hz,2H),7.20(s,1H),7.11(dd,J=8.8,28.4Hz,2H),6.51(s,1H),4.75(s,2H),4.55(s,2H),4.54(s,2H),3.82(s,2H),3.75(s,2H),1.10(t,J=7.2Hz,3H).HRMS?calcd?forC22H26N5O4[M+H]+424.1985,found429.1197.
Embodiment 10:4-(5-(2-(4-(formamyl) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-chlorinated benzene-1,3-diphenol
Step 1
Figure BDA00001905040000292
Room temperature is by compound 10-1(1.9g, 6.46mmol) be dissolved in the dry CH2Cl2 of 15ml, stirring adds triphenylphosphine (2.6g, 9.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (3.28g, 9.01mmol), reaction solution becomes brown in batches, there is solid to separate out, after 10min, react completely, stopped reaction, filters, solid washs with CH2Cl2, filtrate is concentrated, and silicagel column is separated fast, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 10-2 faint yellow solid 1.96g, yield 84.6%.
Step 2
Figure BDA00001905040000293
Under argon shield by 2-(4-formamyl)-phenoxy ethylamine (730mg, 4.1mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (205mg; 1.5mmol), ice-water bath is cooling, slowly drips compound 10-2(471m g; dry DMF solution 20ml 1.4mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 10-3 colorless oil 285mg, yield 45%.1HNMR(300M?in?CDCl3)δ7.78-7.74(m,2H),7.36(m,1H),6.97-6.92(m,3H),5.86(s,2H),5.24-5.19(m,4H),4.17(m,2H),3.76(s,2H),3.50(m,6H),3.19(m,2H)。
Step 3
Figure BDA00001905040000301
Room temperature is by compound 10-3(285mg, 0.64mmol), be dissolved in 5ml acetone, add ethylene bromohyrin (1.1ml, 15.5mmol), Anhydrous potassium carbonate (97mg, 0.7mmol), room temperature tube sealing reaction 48h, reaction finishes, filter, solids washed with acetone, filtrate is concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=2:1, obtains compound 10-4, oily matter, 230mg, yield 73%.1HNMR(300M?in?CDCl3)δ7.80-7.74(m,2H),7.41(s,1H),6.96-6.91(m,3H),6,06(s,2H),5.21(m,4H),4.24(m,2H),3.91(s,2H),3.76(m,2H),3.49(m,6H),3.25(m,2H),3.03(m,2H)。
Step 4
Figure BDA00001905040000302
Room temperature is by compound 10-4(230mg, 0.47mmol) be dissolved in the dry CH2Cl2 of 3ml, stir and add triphenylphosphine (191mg, 0.7mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (232mg in batches, 0.7mmol), after 60min, react completely, add 2ml to be dried DMF, then add sodiumazide (70mg, 1.1mmol), reaction is spent the night, stopped reaction, in impouring water, CH2Cl2 extraction, dry concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=7:1, obtain compound 10-5, oily matter 120mg, yield 34%.1HNMR(300M?in?CDCl3)δ7.58(d,J=8.7Hz,2H),7.33(s,1H),6.98-6.95(m,3H),5.24(s,2H),5.19(s,2H),4.17(t,J=5.7Hz,2H),3.78(s,2H),3.52(s,3H),3.49(s,3H),3.40(t,J=6.0Hz,2H),3.10(t,J=6.0Hz,2H),2.95(t,J=6.0Hz,2H)。
Step 5
Figure BDA00001905040000303
By compound 10-5(120mg, 0.23mmol) be dissolved in 5ml toluene, reflux, after 5h, reaction finishes, and stopped reaction, removes solvent under reduced pressure, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 10-6,78mg, yield 65%.1HNMR(300M?in?CDCl3)δ7.72(s,1H),7.59(d,J=8.7Hz,2H),7.06(s,1H),6.93(d,J=8.7Hz,2H),5.27(s,2H),5.11(s,2H),4.51(t,J=5.7Hz,2H),4.20(t,J=5.7Hz,2H),3.91(s,2H),3.55(s,3H),3.39(s,3H),3.20(t,J=5.4Hz,2H),3.08(t,J=5.1Hz,2H)。
Step 6
Figure BDA00001905040000311
By compound 10-6(78mg, 0.15mmol) be dissolved in 3M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 45mg, yield 70%.1HNMR(300M?in?DMSO)δ10.35(s,1H),10.30(s,1H),7.87(dd,J=8.7,38.4Hz,2H),7.41(s,1H),7.12(dd,J=8.7,20.4Hz,2H),6.70(s,1H),4.71(s,2H),4.58(s,2H),4.50(s,2H),3.82(s,2H),3.65(s,2H).HRMS?calcd?for?C20H21ClN5O4[M+H]+430.1282,found430.1255.
Embodiment 11:4-(5-(2-(2-(formamyl) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
Step 1
Figure BDA00001905040000313
Room temperature is by compound 11-1(1.9g, 6.46mmol) be dissolved in the dry CH2Cl2 of 15ml, stirring adds triphenylphosphine (2.6g, 9.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (3.28g, 9.01mmol), reaction solution becomes brown in batches, there is solid to separate out, after 10min, react completely, stopped reaction, filters, solid washs with CH2Cl2, filtrate is concentrated, and silicagel column is separated fast, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 11-2 faint yellow solid 1.96g, yield 84.6%.
Step 2
Under argon shield by 2-(2-formamyl)-phenoxy ethylamine (3g, 15.8mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.85g; 5.8mmol), ice-water bath is cooling, slowly drips compound 11-2(1.85g; dry DMF solution 20ml 5.32mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 11-3 colorless oil 1.4g, yield 57.3%.
Step 3
Figure BDA00001905040000322
Room temperature is by compound 11-3(522mg, 1.14mmol), be dissolved in 5ml acetone, add ethylene bromohyrin (1.1ml, 15.5mmol), Anhydrous potassium carbonate (180mg, 1.3mmol), room temperature tube sealing reaction 48h, reaction finishes, filter, solids washed with acetone, filtrate is concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=2:1, obtains compound 11-4, oily matter, 310mg, yield 54%.1HNMR(300M?in?CDCl3)δ8.18(d,J=7.8Hz,1H),7.44(t,J=7.5Hz,1H),7.20(s,1H),7.08(t,J=7.5Hz,1H),6.98(d,J=8.1Hz,1H),6.87(s,1H),6.1(s,1H),5.22(s,2H),5.19(s,2H),4.27(t,J=4.8Hz,2H),3.77-3.70(m,4H),3.51(s,3H),3.48(s,3H),3.25-3.16(m,3H),2.89(t,J=4.5Hz,2H),1.21(s,3H),1.18(s,3H)。
Step 4
Figure BDA00001905040000323
Room temperature is by compound 11-4(310mg, 0.62mmol) be dissolved in the dry CH2Cl2 of 3ml, stirring adds triphenylphosphine (260mg, 0.93mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (308mg in batches, 0.93mmol), after 60min, react completely, add 2ml to be dried DMF, then add sodiumazide (70mg, 1.1mmol), reaction is spent the night, stopped reaction, in impouring water, CH2Cl2 extraction, dry concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=7:1, obtain compound 11-5, oily matter 230mg, yield 71%.1HNMR(300M?in?CDCl3)δ7.57-7.50(m,2H),7.20(s,1H),7.02-6.97(m,2H),6.84(s,1H),5.20(s,4H),4.25(t,J=6.0Hz,2H),3.81(s,2H),3.50-3.43(m,8H),3.22-3.17(m,3H),3.04(t,J=6.0Hz,2H),1.19(d,J=7.2Hz,6H)
Step 5
Figure BDA00001905040000331
By compound 11-5(230mg, 0.43mmol) be dissolved in 5ml toluene, reflux, after 5h, reaction finishes, and stopped reaction, removes solvent under reduced pressure, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 11-6,150mg, yield 65%.1HNMR(300M?in?CDCl3)δ7.59-7.51(m,3H),7.07-6.93(m,3H),5.23(s,2H),5.10(s,2H),4.52(t,J=5.4Hz,2H),4.25(t,J=5.4Hz,2H),3.91(s,2H),3.51(s,3H),3.39(s,3H),3.30(t,J=6.0Hz),3.12(t,J=5.4Hz,2H),1.25(s,3H),1.23(s,3H)。
Step 6
Figure BDA00001905040000332
By compound 11-6(150mg, 0.3mmol) be dissolved in 3M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 80mg, yield 64%.1HNMR(300M?in?DMSO)δ7.79-7.68(m,2H),7.33(d,J=8.4Hz,1H),7.25(s,1H),7.16(t,J=7.5Hz,1H),6.55(s,1H),4.86-4.69(m,6H),4.09(s,2H),3.86(s,2H),3.15-3.06(m,1H),1.16(s,3H),1.14(s,3H).HRMS?calcd?for?C23H24N4O4[M-NH3]+420.1798,found?420.2013.
Embodiment 12:4-(5-(2-(2-(formamyl) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-chlorinated benzene-1,3-diphenol
Figure BDA00001905040000341
Step 1
Room temperature is by compound 12-1(1.9g, 6.46mmol) be dissolved in the dry CH2Cl2 of 15ml, stirring adds triphenylphosphine (2.6g, 9.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (3.28g, 9.01mmol), reaction solution becomes brown in batches, there is solid to separate out, after 10min, react completely, stopped reaction, filters, solid washs with CH2Cl2, filtrate is concentrated, and silicagel column is separated fast, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 12-2 faint yellow solid 1.96g, yield 84.6%.
Step 2
Figure BDA00001905040000343
Under argon shield by 2-(2-formamyl)-phenoxy ethylamine (3g, 15.8mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.85g; 5.8mmol), ice-water bath is cooling, slowly drips compound 12-2(1.85g; dry DMF solution 20ml 5.32mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 12-3 colorless oil 1.4g, yield 57.3%.1HNMR(300M?in?CDCl3)δ8.20-8.15(m,2H),7.44(t,J=7.5Hz,1H),7.35(s,1H),7.08(t,J=7.5Hz,1H),6.99(s,1H),6.97(s,1H),5.24(s,2H),5.22(s,2H),4.27(t,J=5.1Hz,2H),3.75(s,2H),3.51(s,3H),3.50(s,3H),3.27(t,J=5.1Hz,2H)。
Step 3
Figure BDA00001905040000344
Room temperature is by compound 12-3(453mg, 1mmol), be dissolved in 5ml acetone, add ethylene bromohyrin (1.1ml, 15.5mmol), Anhydrous potassium carbonate (154mg, 1.1mmol), room temperature tube sealing reaction 48h, reaction finishes, filter, solids washed with acetone, filtrate is concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=2:1, obtains compound 12-4, oily matter, 230mg, yield 47%.1HNMR(300M?in?CDCl3)δ8.19-8.14(m,2H),7.45(t,J=7.5Hz,1H),7.36(s,1H),7.09(t,J=7.5Hz,1H),6.99(s,1H),6.97(s,1H),5.25(s,2H),5.23(s,2H),4.30(t,J=4.8Hz,2H),3.81(s,2H),3.73(t,J=4.8Hz,2H),5.52(s,3H),5.50(s,3H),3.20(t,J=4.5Hz,2H),2.92(t,J=4.5Hz,2H)。
Step 4
Figure BDA00001905040000351
Room temperature is by compound 12-4(860mg, 1.74mmol) be dissolved in the dry CH2Cl2 of 3ml, stirring adds triphenylphosphine (717mg, 2.6mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (868mg in batches, 2.6mmol), after 60min, react completely, add 2ml to be dried DMF, then add sodiumazide (100mg, 1.5mmol), reaction is spent the night, stopped reaction, in impouring water, CH2Cl2 extraction, dry concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=7:1, obtain compound 12-5, oily matter 550mg, yield 60%.1HNMR(300M?in?CDCl3)δ7.57-7.51(m,2H),7.32(s,1H),7.03-6.97(m,3H),5.24(s,2H),5.20(s,2H),4.25(t,J=6Hz,2H),3.81(s,2H),3.51(s,3H),3.5(s,3H),3.44(t,J=6Hz,2H),3.18(t,J=6Hz,2H),3.03(t,J=6Hz,2H)。
Step 5
Figure BDA00001905040000352
by compound 12-5(550mg, 1.06mmol) be dissolved in 5ml toluene, reflux, after 5h, reaction finishes, and stopped reaction, removes solvent under reduced pressure, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 12-6,260mg, yield 47%.1HNMR(300M?in?CDCl3)δ7.72(s,1H),7.58-7.51(m,2H),7.56-6.95(m,2H),5.27(s,2H),5.13(s,2H),4.53(t,J=5.4Hz,2H),4.27(t,J=5.1Hz,2H),3.93(s,2H),3.55(s,3H),3.40(s,3H),3.31(t,J=5.1Hz,2H),3.14(t,J=5.1Hz,2H)。
Step 6
Figure BDA00001905040000361
By compound 12-6(260mg, 0.5mmol) be dissolved in 3M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 150mg, yield 61%.1HNMR(300M?in?DMSO)7.79-7.68(m,2H),7.43(s,1H),7.32(d,J=8.4Hz,1H),7.16(t,J=7.5Hz,1H),6.76(s,1H),4.86(s,2H),4.77(s,2H),4.68(s,2H),4.072(s,2H),3.86(s,2H),2.51(t,J=1.8Hz,2H).HRMS?calcd?for?C20H17ClN4O4[M-NH3]+412.0938,found?412.1158.
Embodiment 13:4-(5-(2-(3-chloro phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-ethylbenzene-1,3-diphenol
Figure BDA00001905040000362
Step 1
Figure BDA00001905040000363
Room temperature is by compound 13-1(1.9g, 6.46mmol) be dissolved in the dry CH2Cl2 of 15ml, stirring adds triphenylphosphine (2.6g, 9.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (3.28g, 9.01mmol), reaction solution becomes brown in batches, there is solid to separate out, after 10min, react completely, stopped reaction, filters, solid washs with CH2Cl2, filtrate is concentrated, and silicagel column is separated fast, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 13-2 faint yellow solid 1.96g, yield 84.6%.
Step 2
Figure BDA00001905040000364
argon gas
Under protection by 2-(3-chlorine)-phenoxy ethylamine (3g, 15.7mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.8g; 5.8mmol), ice-water bath is cooling, slowly drips compound 13-2(2g; dry DMF solution 20ml 5.32mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 13-3 colorless oil 1.6g, yield 59%.1HNMR(300M?in?CDCl3)δ7.21-7.15(m,2H),6.93-6.79(m,4H),5.21(s,2H),5.19(s,2H),4.12(t,J=5.1Hz,2H),3.8(s,2H),3.51(s,3H),3.45(s,3H),3.18(t,J=5.1Hz,2H),2.56(q,J=7.5Hz,2H),1.16(d,J=7.5Hz,3H)。
Step 3
Figure BDA00001905040000371
Room temperature is by compound 13-3(550mg, 1.3mmol), be dissolved in 5ml acetone, add ethylene bromohyrin (1.1ml, 15.5mmol), Anhydrous potassium carbonate (190mg, 1.4mmol), room temperature tube sealing reaction 48h, reaction finishes, filter, solids washed with acetone, filtrate is concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=2:1, obtains compound 13-4, oily matter, 230mg, yield 40%.1HNMR(300M?in?CDCl3)δ7.21-7.15(m,2H),6.94-6.79(m,4H),5.19(s,4H),4.11(t,J=5.7Hz,2H)3.78(s,2H),3.68(t,J=5.1Hz,2H),3.50(s,3H),3.48(s,3H),3.12(t,J=5.4Hz,2H),2.91(t,J=5.1Hz,2H),2.56(q,J=7.5Hz,2H),1.17(t,J=7.5?Hz,3H)。
Step 4
Figure BDA00001905040000372
room temperature is by compound 13-4(135mg, 0.3mmol) be dissolved in the dry CH2Cl2 of 3ml, stirring adds triphenylphosphine (115mg, 0.42mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (140mg in batches, 0.42mmol), after 60min, react completely, add 2ml to be dried DMF, then add sodiumazide (100mg, 1.5mmol), reaction is spent the night, stopped reaction, in impouring water, CH2Cl2 extraction, dry concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=7:1, obtain compound 13-5, oily matter 118mg, yield 80%.1HNMR(300M?in?CDCl3)δ7.21-7.14(m,2H),6.93-6.79(m,4H),5.19(s,4H),4.12(t,J=5.7Hz,2H),3.79(s,2H),3.50(s,3H),3.47(s,3H),3.40(t,J=5.7Hz,2H),3.10(t,J=5.4Hz,2H),2.96(t,J=5.7Hz,2H),2.55(q,J=7.5Hz,2H),1.16(t,J=7.5Hz,3H)。
Step 5
Figure BDA00001905040000381
By compound 13-5(100mg, 0.2mmol) be dissolved in 5ml toluene, reflux, after 5h, reaction finishes, and stopped reaction, removes solvent under reduced pressure, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 13-6,80mg, yield 80%.1HNMR(300M?in?CDCl3)δ7.51(d,J=2.4Hz,1H),7.18(m,1H),6.95-6.76(m,4H),5.23(d,J=3.0Hz,2H),5.08(d,J=2.4Hz,2H),4.51(s,2H),4.14(m,2H),3.92(s,2H),3.51(d,J=3.0Hz,3H),3.38(d,J=2.7Hz,3H),3.18(s,2H),3.05(m,2H),2.64(q,J=7.5Hz,2H),1.21(m,3H).
Step 6
Figure BDA00001905040000382
By compound 13-6(80mg, 0.15mmol) be dissolved in 3M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 50mg, yield 63%.1HNMR(300M?in?DMSO)δ9.80(s,1H),9.50(s,1H),7.33(t,J=8.1Hz,1H),7.21(s,1H),7.07(m,2H),6.96(d,J=8.1Hz,1H),6.52(s,1H),4.78(s,2H),4.70(s,2H),4.49(m,2H),3.97(s,2H),3.76(s,2H),2.44(m,2H),1.10(t,J=7.5Hz,3H).HRMS?calcd?for?C21H24ClN4O3[M+1]+415.1537,found?415.1516.
Embodiment 14:5-(2-(3-chloro phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-ethylphenyl)-[1,2,3] triazolos [1,5-a] piperazine-6 (7H)-one
Figure BDA00001905040000383
Step 1
Figure BDA00001905040000391
Room temperature is by compound 14-1(1.9g, 6.46mmol) be dissolved in the dry CH2Cl2 of 15ml, stirring adds triphenylphosphine (2.6g, 9.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (3.28g, 9.01mmol), reaction solution becomes brown in batches, there is solid to separate out, after 10min, react completely, stopped reaction, filters, solid washs with CH2Cl2, filtrate is concentrated, and silicagel column is separated fast, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 14-2 faint yellow solid 1.96g, yield 84.6%.
Step 2
Under argon shield by 2-(3-chlorine)-phenoxy ethylamine (3g, 15.7mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.8g; 5.8mmol), ice-water bath is cooling, slowly drips compound 14-2(2g; dry DMF solution 20ml 5.32mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 14-3 colorless oil 1.6g, yield 59%.1HNMR(300M?in?CDCl3)δ7.21-7.15(m,2H),6.93-6.79(m,4H),5.21(s,2H),5.19(s,2H),4.12(t,J=5.1Hz,2H),3.8(s,2H),3.51(s,3H),3.45(s,3H),3.18(t,J=5.1Hz,2H),2.56(q,J=7.5Hz,2H),1.16(d,J=7.5Hz,3H)。
Step 3
Figure BDA00001905040000393
Argon shield, under ice bath by compound 14-3(290mg, 0.67mmol) and DIPEA(87mg, 0.67mmol) be dissolved in 5mlDCM, slowly splash into wherein chloroacetyl chloride (91mg, 0.8mmol).After reaction 2h, TLC monitoring, raw material disappears.Add wherein 2mlDMF, sodiumazide (110mg, 1.7mmol), reacts TLC monitoring after 3 days, reacts completely, and is spin-dried for solvent, DCM dissolution residual substance, and washing, DCM extraction 3 times for water, merges organic phase.Be spin-dried for solvent, column chromatography.Eluent is sherwood oil: ethyl acetate=7:1, obtains compound 14-4, oily matter 203mg, yield 59%.1HNMR(300M?in?CDCl3)δ7.21-6.78(m,6H),5.19(s,2H),5.17(s,2H),4.61(s,1H),4.39(s,1H),4.22-4.15(m,4H),3.94-3.91(m,2H),3.49(s,3H),2.54(q,J=7.2Hz,2H),1.45(t,J=7.2Hz,3H)。
Step 4
Figure BDA00001905040000401
By compound 14-4(203mg, 0.4mmol) be dissolved in 5ml toluene, reflux, after 5h, reaction finishes, and stopped reaction, removes solvent under reduced pressure, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 14-5,120mg, yield 60%.1HNMR(300M?in?CDCl3)δ7.28-7.16(m,2H),6.98-6.95(m,2H),6.85(s,1H),6.72(s,1H),5.27(s,2H),5.15(s,4H),4.92(s,2H),2.72-2.67(m,2H),1.26-1.22(m,3H)。
Step 5
By compound 14-5(120mg, 0.23mmol) be dissolved in 3M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 80mg, yield 69%.1HNMR(300M?in?DMSO):9.77(s,1H),9.41(s,1H),7.27(t,J=6.0Hz,1H),7.20(s,1H),7.00(s,1H),6.98(s,1H),6.88(d,J=6Hz,1H),6.49(s,1H),5.13(s,2H),4.90(s,2H),4.20(t,J=3.9Hz,2H),3.85(t,J=3.9Hz,2H),3.32(s,2H),1.12(t,J=5.4Hz,3H).HRMS?calcd?for?C21H22ClN4O4,429.1330,found?429.1302.
Embodiment 15:4-(5-(2-(3-(methoxyl group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-chlorinated benzene-1,3-diphenol
Figure BDA00001905040000403
Step 1
Room temperature is by compound 15-1(1.9g, 6.46mmol) be dissolved in the dry CH2Cl2 of 15ml, stirring adds triphenylphosphine (2.6g, 9.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (3.28g, 9.01mmol), reaction solution becomes brown in batches, there is solid to separate out, after 10min, react completely, stopped reaction, filters, solid washs with CH2Cl2, filtrate is concentrated, and silicagel column is separated fast, and eluent is sherwood oil: ethyl acetate=3:1, obtain compound 15-2 faint yellow solid 1.96g, yield 84.6%.
Step 2
Figure BDA00001905040000412
Under argon shield by 2-(3-methoxyl group)-phenoxy ethylamine (2.7g, 15.7mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.8g; 5.8mmol), ice-water bath is cooling, slowly drips compound 15-2(1.9g; dry DMF solution 20ml 5.32mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 15-3 colorless oil 1.5g, yield 58%.
Step 3
Figure BDA00001905040000413
Room temperature is by compound 15-3(550mg, 1.3mmol), be dissolved in 5ml acetone, add ethylene bromohyrin (1.1ml, 15.5mmol), Anhydrous potassium carbonate (210mg, 1.4mmol), room temperature tube sealing reaction 48h, reaction finishes, filter, solids washed with acetone, filtrate is concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=2:1, obtains compound 15-4, oily matter, 370mg, yield 58%.1HNMR(300M?in?CDCl3)δ7.73-7.70(m,1H),7.54-7.5(m,1H),7.36(s,1H),7.20-7.14(m,2H),6.97(s,1H),5.24(s,2H),5.20(s,2H),4.31(t,J=5.7Hz,2H),4.12-4.03(m,4H),3.70-3.65(m,3H),3.51(s,3H),3.49(s,3H),3.09(t,J=5.4Hz,2H),2.89(t,J=5.4Hz,2H)。
Step 4
Figure BDA00001905040000421
Room temperature is by compound 15-4(360mg, 0.76mmol) be dissolved in the dry CH2Cl2 of 3ml, stirring adds triphenylphosphine (310mg, 1.1mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (380mg in batches, 1.1mmol), after 60min, react completely, add 2ml to be dried DMF, then add sodiumazide (100mg, 1.5mmol), reaction is spent the night, stopped reaction, in impouring water, CH2Cl2 extraction, dry concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=7:1, obtain compound 15-5, oily matter 170mg, yield 46%.1HNMR(300M?in?CDCl3)δ7.3(s,1H),7.17(t,J=8.4Hz,1H),6.97(s,1H),6.53-6.50(m,3H),5.24(s,2H),5.19(s,2H),4.14(s,2H),3.78(m,5H),3.52(s,3H),3.49(s,3H),3.42-3.39(m,2H),3.09(m,2H),2.97(m,2H)。
Step 5
Figure BDA00001905040000422
By compound 15-5(170mg, 0.33mmol) be dissolved in 5ml toluene, reflux, after 5h, reaction finishes, and stopped reaction, removes solvent under reduced pressure, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 15-6,90mg, yield 53%.1HNMR(300M?in?CDCl3)δ7.73(s,1H),7.18(t,J=8.4Hz,1H),7.01(s,1H),6.55-6.44(m,3H),5.27(s,2H),5.10(s,2H),4.53(m,2H),4.18(m,2H),3.93(s,2H),3.78(s,3H),3.55(s,3H),3.39(s,3H),3.21(m,2H),3.06(m,2H)。
Step 6
Figure BDA00001905040000423
By compound 15-6(90mg, 0.17mmol) be dissolved in 3M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 60mg, yield 73%.1HNMR(300M?in?DMSO)δ7.45(s,1H),7.21(t,J=8.1Hz,1H),6.75(s,1H),6.58-6.54(m,3H),4.81-4.75(m,4H),4.47(s,2H),4.00(s,2H),3.77-3.73(m,5H).HRMS?calcd?for?C20H22ClN4O4,417.1330,found?417.1308.
Embodiment 16:4-(5-(2-(4-(itrile group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
Figure BDA00001905040000431
Step 1
Room temperature is by compound 16-1(1.9g, 6.46mmol) be dissolved in the dry CH2Cl2 of 15ml, stir and add triphenylphosphine (2.6g, 9.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (3.28g, 9.01mmol), reaction solution becomes brown in batches, have solid to separate out, after 30min, TLC detection reaction is complete, stopped reaction, silicagel column is separated fast, eluent is sherwood oil: ethyl acetate=8:1, obtains compound 16-2 faint yellow solid 2.15g, yield 93.2%.
Step 2
Figure BDA00001905040000433
Under argon shield by 2-(4-cyano group)-phenoxy ethylamine (2.85g, 17.6mmol) is dissolved in the dry DMF of 10ml, adds Anhydrous potassium carbonate (0.8g; 5.8mmol), ice-water bath is cooling, slowly drips compound 16-2(2.1g; dry DMF solution 20ml 5.88mmol), time for adding is 24h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 16-3 colorless oil 1.6g, yield 62%.1H?NMR(300MHz,CDCl3)δ7.57(d,J=8.7Hz,2H),7.22(s,1H),6.97(d,J=9.0Hz,2H),6.85(s,1H),5.20(s,2H),5.19(s,2H),4.18(t,J=5.1Hz,2H),3.78(s,2H),3.51(s,3H),3.48(s,3H),3.23-3.20(m,3H),2.96(s,2H),2.88(s,2H),1.19(s,3H),1.17(s,3H)。
Step 3
Figure BDA00001905040000441
Room temperature is by compound 16-3(580mg, 1.32mmol), be dissolved in 5ml acetone, add ethylene bromohyrin (1.01ml, 13.2mmol), Anhydrous potassium carbonate (236mg, 1.72mmol), room temperature tube sealing reaction 48h, reaction finishes, filter, solids washed with acetone, filtrate is concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=2:1, obtains compound 16-4, oily matter, 413mg, yield 65%.1H?NMR(300MHz,CDCl3)δ7.57(d,J=6.0Hz,2H),7.19(s,1H),6.97(d,J=6.0Hz,2H),6.85(s,1H),5.20(s,2H),5.19(s,2H),4.17(d,J=5.4Hz,2H),3.77(s,2H),3.69(t,J=5.1Hz,2H),3.50(s,3H),3.48(s,3H),3.25-3.21(m,1H),3.14(t,J=5.4Hz,2H),2.91(t,J=5.1Hz,2H),1.20(s,3H),1.10(s,3H)。
Step 4
Figure BDA00001905040000442
Room temperature is by compound 16-4(390mg, 0.81mmol) be dissolved in the dry CH2Cl2 of 4ml, stirring adds triphenylphosphine (297mg, 1.13mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (376mg in batches, 1.13mmol), after 60min, TLC detects raw material disappearance, add 4ml to be dried DMF, then add sodiumazide (79mg, 1.22mmol), reaction 24h, stopped reaction, in impouring water, CH2Cl2 extraction, dry concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=7:1, obtain compound 16-5, oily matter 230mg, yield 55.4%.1H?NMR(300MHz,CDCl3)δ7.56(d,J=6.0Hz,2H),7.19(s,1H),6.96(d,J=6.0Hz,2H),6.85(s,1H),5.20(s,2H),5.19(s,2H),4.18(t,J=5.7Hz,2H),3.78(s,2H),3.50(s,3H),3.48(s,3H),3.40(t,J=6.0Hz,2H),3.25-3.19(m,1H),3.12(t,J=5.7Hz,2H),2.97(t,J=6.0Hz,2H),1.20(s,3H),1.18(s,3H)。
Step 5
Figure BDA00001905040000443
By compound 16-5(200mg, 0.39mmol) be dissolved in 5ml toluene, reflux, after 5h, reaction finishes, and stopped reaction, removes solvent under reduced pressure, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 16-6,150mg, yield 75%.1H?NMR(300MHz,CDCl3)δ7.59-7.53(m,3H),6.95-6.91(m,3H),5.22(s,1H),5.07(s,1H),4.19(s,1H),4.19-4.07(m,2H),3.91(s,2H),3.52(s,3H),3.51(s,3H),3.37(s,3H),3.30(m,1H),3.18(s,2H),3.06(t,J=2.4Hz,2H)。
Step 6
Figure BDA00001905040000451
By compound 16-6(135mg, 0.27mmol) be dissolved in 2M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains target compound 70mg, yield 62%.1H?NMR(300MHz,DMSO)δ7.90(dd,J=6.3,37.8Hz,2H),7.26(s,2H),7.09(dd,J=6.3,23.1Hz,2H),6.54(s,1H),4.80(s,2H),4.70(s,2H),4.56(s,2H),3.82(s,2H),3.80(s,2H),3.14-3.11(m,1H),1.14(d,J=5.1Hz,6H).
HRMS?calcd?for?C23H26N5O3[M+H]+420.2036,found420.2024.
Embodiment 17:4-(5-(2-(4-(itrile group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-chlorinated benzene-1,3-diphenol
Figure BDA00001905040000452
Step 1
Figure BDA00001905040000453
Room temperature is by compound 17-1(1.9g, 6.46mmol) be dissolved in the dry CH2Cl2 of 15ml, stir and add triphenylphosphine (2.6g, 9.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (3.28g, 9.01mmol), reaction solution becomes brown in batches, there is solid to separate out, after 10min, react completely, silicagel column is separated fast, and eluent is sherwood oil: ethyl acetate=8:1, obtain compound 17-2 faint yellow solid 2.12g, yield 94%.
Step 2
Figure BDA00001905040000461
Under argon shield by 2-(4-cyano group)-phenoxy ethylamine (2.9g, 17.9mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (1.08g; 7.8mmol), ice-water bath is cooling, slowly drips compound 17-2(2.1g; dry DMF solution 20ml 6.0mmol), time for adding is 24h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 17-3 colorless oil 1.39g, yield 57%.1H?NMR(300MHz,CDCl3)δ7.58(d,J=5.1Hz,2H),7.36(s,1H),6.98-6.94(m,3H),5.24(s,2H),5.20(s,2H),4.18(t,J=4.8Hz,2H),3.77(s,2H),3.52(s,3H),3.50(s,3H),3.21(t,J=5.1Hz,2H),3.23-3.20(m,3H),2.96(s,2H),2.88(s,2H),1.19(s,3H),1.17(s,3H)。
Step 3
Room temperature is by compound 17-3(600mg, 1.39mmol), be dissolved in 5ml acetone, add ethylene bromohyrin (1.2ml, 14mmol), Anhydrous potassium carbonate (250mg, 1.80mmol), room temperature tube sealing reaction 48h, reaction finishes, filter, solids washed with acetone, filtrate is concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=2:1, obtains compound 17-4, oily matter, 336mg, yield 51%.1HNMR(300MHz,CDCl3)δ7.60-7.56(m,4H),6.98-6.94(m,2H),5.24(s,2H),5.20(s,2H),4.18-4.08(m,4H),3.77(s,2H),3.67(t,J=5.1Hz,2H),3.52(s,3H),3.49(s,3H),3.12(t,J=4.8Hz,2H)。
Step 4
Room temperature is by compound 17-4(320mg, 0.67mmol) be dissolved in the dry CH2Cl2 of 3ml, stirring adds triphenylphosphine (240mg, 0.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (306mg in batches, 0.92mmol), after 60min, react completely, add 2ml to be dried DMF, then add sodiumazide (65mg, 1.0mmol), reaction is spent the night, stopped reaction, in impouring water, CH2Cl2 extraction, dry concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=7:1, obtain compound 17-5, oily matter 163mg, yield 49%.1H?NMR(300MHz,CDCl3)δ7.57(d,J=5.7Hz,2H),7.34(s,1H),6.98(s,1H),6.96(d,J=6.0Hz,2H),5.24(s,2H),5.20(s,2H),4.18(t,J=5.4Hz,2H),3.78(s,2H),3.52(s,3H),3.49(s,3H),3.40(t,J=5.7Hz,2H),3.11(t,J=5.7Hz,2H),2.95(t,J=5.17Hz,2H)。
Step 5
Figure BDA00001905040000471
By compound 17-5(150mg, 0.3mmol) be dissolved in 3ml toluene, reflux, after 5h, reaction finishes, and stopped reaction, removes solvent under reduced pressure, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 17-6,100mg, yield 67%.1H?NMR(300MHz,CDCl3)δ7.71(s,1H),7.58(d,J=8.7Hz,2H),7.06(s,1H),7.94(d,J=8.7Hz,2H),5.27(s,2H),5.11(s,2H),4.50(t,J=5.1Hz,2H),4.20(t,J=5.1Hz,2H),3.91(s,2H),3.55(s,3H),3.39(s,3H),3.19(t,J=5.4Hz,2H),4.20(t,J=5.4Hz,2H)。
Step 6
Figure BDA00001905040000472
By compound 17-6(90mg, 0.18mmol) be dissolved in 2M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 40mg, yield 54%.1H?NMR(300MHz,DMSO)δ10.37(br,2H),7.82(d,J=8.4Hz,2H),7.45(s,1H),7.17(d,J=8.4Hz,2H),6.75(s,1H),4.81(s,2H),4.73(s,2H),4.58(s,2H),3.99(s,2H),3.81(s,2H).HRMS?calcd?for?C20H18N5O3Cl[M+H]+412.1176,found?412.1153.
Embodiment 18:5-(2-(4-(itrile group) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-[1,2,3] triazolos [1,5-a] piperazine-6 (7H)-one
Figure BDA00001905040000481
Step 1:
Figure BDA00001905040000482
Ice-water bath, by compound 18-1(300mg, 0.68mmol) be dissolved in 3ml dry methylene chloride, stirring adds N, N-diisopropylethylamine (114mg, 0.89mmol), then slowly drip chloroacetyl chloride (81mg, 0.72mmol), drip and finish, 0 ℃ is stirred after 0.5h, add 2ml to be dried DMF, sodiumazide (50mg, 0.77mmol), naturally rise to room temperature reaction, stopped reaction after 48h, ethyl acetate extraction, anhydrous sodium sulfate drying, concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=4:1, obtain compound 18-2302mg, yield 85.2%.1H?NMR(300MHz,CDCl3)δ7.57(d,J=6.0Hz,2H),7.08(s,1H),6.97(d,J=8.4Hz,2H),6.86(s,1H),5.21(s,2H),5.17(s,2H),4.51(d,J=68.4Hz,2H),4.28(t,J=4.8Hz,2H),4.16-4.11(m,2H),3.97(t,J=4.8Hz,2H),3.49(s,6H),3.24-3.19(m,1H),1.18(s,3H),1.16(s,3H)。
Step 3
Figure BDA00001905040000483
By compound 18-2(290mg, 0.56mmol) be dissolved in 5ml toluene, reflux, after 4h, reaction finishes, and stopped reaction is concentrated, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 18-3,182mg, yield 63%.1H?NMR(300MHz,CDCl3)δ7.63(s,1H),7.55(d,J=8.4Hz,2H),6.96(s,1H),6.87(d,J=8.4Hz,2H),5.26(s,2H),5.16(s,2H),5.14(s,2H),4.29(t,J=4.8Hz,2H),3.95(t,J=4.8Hz,2H),3.54(s,3H),3.40(s,3H),3.34-3.30(m,1H),1.27(s,3H),1.25(s,3H).
Step 4
Figure BDA00001905040000491
By compound 18-3(160mg, 0.31mmol) be dissolved in 2M hydrogen chloride methanol solution 4ml, 30 ℃ of tube sealing reactions, 7d reacts end, stopped reaction, filters, and solid methanol wash is dry, methyl alcohol-methylene dichloride recrystallization, obtains title compound 100mg, yield 75%.1H?NMR(300MHz,DMSO)δ9.48(s,2H),7.858(dd,J=9.0,40.5Hz,2H),7.23(s,1H),7.07(dd,J=8.1,19.8Hz,2H),6.63(s,1H),5.76(s,2H),4.49(s,2H),4.32(s,2H),3.74(s,2H),3.14-3.07(m,1H),1.15(d,J=5.1Hz,6H).
HRMS?calcd?for?C23H24N5O4[M+H]+434.1828,found434.1788
Embodiment 19:5-(2-(3-(itrile group) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-[1,2,3] triazolos [1,5-a] piperazine-6 (7H)-one
Figure BDA00001905040000492
Step 2
Figure BDA00001905040000493
Under argon shield by 2-(3-cyano group)-phenoxy ethylamine (2.9g, 17.6mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.8g; 5.8mmol), ice-water bath is cooling, slowly drips compound 19-2(1.9g; dry DMF solution 20ml 5.32mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 19-3 colorless oil 1.3g, yield 56%.1H?NMR(300MHz,CDCl3)δ7.39-7.33(m,1H),7.26(d,J=4.5Hz,1H),7.22(s,1H),7.17-7.14(m,2H),6.85(s,1H),5.21(s,1H),5.19(s,1H),4.14(t,J=5.1Hz,2H),4.22(s,2H),3.52(s,3H),3.48(s,3H),3.25-3.19(m,3H),1.25(d,J=6.9Hz,6H)。
Step 3
Figure BDA00001905040000501
Ice-water bath, by compound 19-3(300mg, 0.68mmol) be dissolved in 3ml dry methylene chloride, stirring adds N, N-diisopropylethylamine (115mg, 0.89mmol), then slowly drip chloroacetyl chloride (81mg, 0.72mmol), drip and finish, 0 ℃ is stirred after 0.5h, add 2ml to be dried DMF, sodiumazide (50mg, 0.77mmol), naturally rise to room temperature reaction, stopped reaction after 48h, ethyl acetate extraction, anhydrous sodium sulfate drying, concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=4:1, obtain compound 19-4294mg, yield 83%.1H?NMR(300MHz,CDCl3)δ7.36(t,J=7.8Hz,1H),7.24(t,J=9.0Hz,1H),7.15-7.10(m,3H),6.85(s,1H),5.20(s,2H),5.28(s,2H),4.51(d,J=67.5Hz,2H),4.24(t,J=5.4Hz,2H),4.22(s,2H),3.95(t,J=5.4Hz,2H),3.48(s,6H),3.21(m,1H),1.17(d,J=6.6Hz,6H)。
Step 4
Figure BDA00001905040000502
By compound 19-4(280mg, 0.53mmol) be dissolved in 5ml toluene, reflux, after 4h, reaction finishes, and stopped reaction is concentrated, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 19-5,150mg, yield 53%.1H?NMR(300MHz,CDCl3)δ7.63(s,1H),7.36(t,J=8.1Hz,1H),7.27(s,1H),7.10(s,1H),7.07-7.04(m,1H),6.96(s,1H),5.26(s,2H),5.15(s,2H),5.14(s,2H),4.92(s,2H),4.27(t,J=5.1Hz,2H),3.95(t,J=4.8Hz,2H),3.53(s,3H),3.41(s,3H),3.35-3.28(m,1H),1.27(s,3H),1.25(s,3H).
Step 5
Figure BDA00001905040000503
By compound 19-5(140mg, 0.27mmol) be dissolved in 2M hydrogen chloride methanol solution 4ml, 30 ℃ of tube sealing reactions, 7d reacts end, stopped reaction, filters, and solid methanol wash is dry, methyl alcohol-methylene dichloride recrystallization, obtains title compound 47mg, yield 40%.1H?NMR(300MHz,DMSO)δ9.76(s,1H),9.48(s,1H),7.54(s,1H),7.55-7.10(m,5H),6.52(s,1H),5.13(s,2H),4.89(s,2H),4.25(s,2H),3.86(s,2H),3.15-3.11(m,1H),1.15(d,J=6.9Hz,6H).
HRMS?calcd?for?C23H24N5O4[M+H]+434.1828,found434.1083.
Embodiment 20:5-(2-(4-(nitro) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-[1,2,3] triazolos [1,5-a] piperazine-6 (7H)-one
Figure BDA00001905040000511
Step 2
Figure BDA00001905040000512
Under argon shield by 2-(4-nitro)-phenoxy ethylamine (2.9g, 15.9mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.8g; 5.8mmol), ice-water bath is cooling, slowly drips compound 20-2(1.9g; dry DMF solution 20ml 5.32mmol), time for adding is 24h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 20-3 colorless oil 1.2g, yield 50%.
Step 3
Figure BDA00001905040000513
Ice-water bath, is dissolved in compound 20-3 (300mg, 0.66mmol) in 3ml dry methylene chloride, stirring adds DIPEA (93mg, 0.72mmol), then slowly drip chloroacetyl chloride (81mg, 0.72mmol), drip and finish, 0 ℃ is stirred after 0.5h, add 2ml to be dried DMF, sodiumazide (50mg, 0.77mmol), rises to room temperature reaction naturally, stopped reaction after 48h, ethyl acetate extraction, anhydrous sodium sulfate drying, concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=4:1, obtains compound 20-4285mg, yield 80%.1H?NMR(300MHz,CDCl3)δ8.17(d,J=9.3Hz,2H),7.07(s,1H),6.97(d,J=9.3Hz,2H),6.85(s,1H),5.19(s,2H),5.17(s,2H),4.51(d,J=67.5Hz,2H),4.33(t,J=5.1Hz,2H),4.19(d,J=17.7Hz,2H),3.97(t,J=5.1Hz,2H),3.48(m,6H),3.20(m,1H),1.17(s,3H),1.14(s,3H)。
Step 3
Figure BDA00001905040000521
By compound 20-4(270mg, 0.5mmol) be dissolved in 5ml toluene, reflux, after 4h, reaction finishes, and stopped reaction is concentrated, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 20-5,160mg, yield 59%.1H?NMR(300MHz,CDCl3)δ8.16(d,J=9.3Hz,2H),7.64(s,1H),6.96(s,1H),6.89(d,J=9.3Hz,2H),5.27(s,2H),5.17(s,2H),5.15(s,2H),4.92(s,2H),4.34(t,J=4.8Hz,2H),3.97(t,J=4.5Hz,2H),3.54(s,3H),3.41(s,3H),3.33(m,1H),1.27(s,3H),1.25(s,3H).
Step 4
Figure BDA00001905040000522
By compound 20-5(150mg, 0.29mmol) be dissolved in 2M hydrogen chloride methanol solution 4ml, 30 ℃ of tube sealing reactions, 7d reacts end, stopped reaction, filters, and solid methanol wash is dry, methyl alcohol-methylene dichloride recrystallization, obtains title compound 45mg, yield 35%.1H?NMR(300MHz,DMSO)δ9.39(s,1H),8.23(d,J=9.0Hz,2H),7.24(s,1H),7.13(d,J=9.0Hz,2H),6.59(s,1H),5.74(s,2H),4.50(s,2H),4.38(s,2H),3.75(s,2H),3.17-3.09(m,1H),1.15(d,J=6.9Hz,6H).
HRMS?calcd?for?C22H24N5O6[M+H]+454.1727,found454.1704.
Embodiment 21:5-(2-(3-(methyl) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-isoxazoles are [4,3-c] piperidines-6 (7H)-one also
Figure BDA00001905040000531
Step 1
Figure BDA00001905040000532
Ice-water bath is by compound 21-1(300mg, 0.70mmol), 3-nitropropionic acid (117mg, 0.98mmol) is dissolved in 3ml dry methylene chloride, ice-water bath is cooling, and rapid stirring adds EDCI(188mg, 0.98mmol in batches), finish after 0.5h, reaction finishes, and adds 30ml methylene dichloride, washing, saturated common salt water washing, anhydrous sodium sulfate drying, concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=2:1, obtain compound 21-2, oily matter 298mg, yield 81.3%.1H?NMR(300MHz,CDCl3)δ7.18-7.13(m,2H),6.84(d,J=3.0Hz,1H),6.78(t,J=4.5Hz,1H),6.72(s,1H),6.89(s,1H),5.19(s,2H),5.16(s,2H),4.56(d,J=25.2Hz,2H),4.24(t,J=5.1Hz,1H),4.16(t,J=5.1Hz,1H),4.00(t,J=5.1Hz,1H),3.90(t,J=5.1Hz,1H),3.48(s,6H),3.29-3.16(m,3H),2.30(s,3H),1.19-1.16(m,6H).
Step 2
Figure BDA00001905040000533
Under argon shield, by compound 21-2(280mg, 0.53mmol), be dissolved in 3ml dry toluene; stirring adds DMAP (13mg, 0.11mmol), is heated to 90 ℃, drips the 3ml dry toluene solution of (Boc) 2O in 0.5h; finish, keep after 90 ℃ of reaction 4h, reaction finishes; remove solvent under reduced pressure, add dichloromethane extraction, anhydrous sodium sulfate drying; concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1; obtain compound 21-3,148mg, yield 56%.1H?NMR(300MHz,CDCl3)δ7.54(s,1H),7.13(t,J=7.5Hz,1H),6.99(s,1H),6.75(d,J=7.5Hz,1H),6.65(s,1H),6.62(s,1H),5.27(s,2H),5.10(s,2H),4.71(s,2H),4.22(t,J=4.5Hz,2H),3.86(t,J=4.5Hz,2H),3.77(s,2H),3.52(s,3H),3.44(s,3H),3.33-3.28(m,1H),2.28(s,3H),1.25(d,J=6.9Hz,6H).
Step 3
Figure BDA00001905040000541
By compound 21-3(140mg, 0.27mmol) be dissolved in 2M hydrogen chloride methanol solution 4ml, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 49mg, yield 43%.1H?NMR(300MHz,DMSO)δ10.57(s,1H),10.10(s,1H),7.18-7.15(m,2H),6.80-6.69(m,4H),4.20(s,2H),4.17(s,2H),3.67(s,2H),3.25(s,2H),3.13-3.09(m,1H),2.28(s,3H),1.14(d,J=5.1Hz,6H).HRMS?calcd?forC24H27N2O5[M+H]+423.1920,found?423.1931.
Embodiment 22:4-(5-(2-(3-(itrile group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
Figure BDA00001905040000542
Step 1:
Figure BDA00001905040000543
Room temperature is by compound 22-1(570mg, 1.3mmol), be dissolved in 5ml acetone, add ethylene bromohyrin (1.1ml, 15.5mmol), Anhydrous potassium carbonate (187mg, 1.36mmol), room temperature tube sealing reaction 48h, reaction finishes, filter, solids washed with acetone, filtrate is concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=2:1, obtains compound 22-2, oily matter, 371mg, yield 59%.1H?NMR(300MHz,CDCl3)δ7.39-7.34(m,1H),7.26-7.15(m,4H),6.85(s,1H),5.20(s,4H),4.12(t,J=4.8Hz,2H),3.78(s,2H),3.68(t,J=4.8Hz,2H),3.51(s,3H),3.48(s,3H),3.23(m,1H),3.13(t,J=5.4Hz,2H),2.91(t,J=5.4Hz,2H),1.10(d,J=4.2Hz,6H)。
Step 4
Figure BDA00001905040000551
Room temperature is by compound 22-2(350mg, 0.73mmol) be dissolved in the dry CH2Cl2 of 3ml, stirring adds triphenylphosphine (240mg, 0.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (306mg in batches, 0.92mmol), after 60min, react completely, add 2ml to be dried DMF, then add sodiumazide (65mg, 1.0mmol), reaction is spent the night, stopped reaction, in impouring water, CH2Cl2 extraction, dry concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=7:1, obtain compound 22-3, oily matter 188mg, yield 51.4%.1H?NMR(300MHz,CDCl3)δ7.39-7.33(m,1H),7.25-7.15(m,4H),6.85(s,1H),5.20(s,4H),4.15(t,J=5.7Hz,2H),3.79(s,2H),3.50(s,3H),3.48(s,3H),3.41(t,J=5.7Hz,2H),3.25-3.21(m,1H),3.11(t,J=5.7Hz,2H),2.97(t,J=6.0Hz,2H),1.20(s,3H),1.18(s,3H)。
Step 5
By compound 22-3(170mg, 0.34mmol) be dissolved in 3ml toluene, reflux, after 5h, reaction finishes, and stopped reaction, removes solvent under reduced pressure, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 22-4,113mg, yield 69%.1H?NMR(300MHz,CDCl3)δ7.54(s,1H),7.37(t,J=7.5Hz,1H),7.27(s,1H),7.14(s,1H),7.11(s,1H),6.94(s,1H),5.23(s,2H),5.08(s,2H),4.51(t,J=5.1Hz,2H),4.16(t,J=5.1Hz,2H),3.91(s,2H),3.52(s,3H),3.38(s,3H),3.35-3.26(m,1H),3.18(t,J=4.8Hz,2H),3.06(t,J=5.1Hz,2H),1.25(s,3H),1.23(s,3H)
Step 6
Figure BDA00001905040000561
By compound 22-4(100mg, 0.20mmol) be dissolved in 2M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 35mg, yield 39%.1H?NMR(300MHz,DMSO)δ9.82(s,1H),9.52(s,1H),7.58-7.20(m,5H),6.55(s,1H),4.78(s,2H),4.54(s,4H),3.86(s,2H),3.73(s,2H),3.14-3.10(m,1H),1.14(d,J=5.1Hz,6H).
HRMS?calcd?for?C23H26N5O3[M+H]+420.2036,found420.2018.
Embodiment 23:4-(5-(2-(4-(methyl) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-chlorinated benzene-1,3-diphenol
Figure BDA00001905040000562
Step 1
Figure BDA00001905040000563
Under argon shield by 2-(4-methyl)-phenoxy ethylamine (2.9g, 19.2mmol) is dissolved in the dry DMF of 5ml, adds Anhydrous potassium carbonate (0.8g; 5.8mmol), ice-water bath is cooling, slowly drips compound 23-1(1.9g; dry DMF solution 20ml 5.4mmol), time for adding is 26h, drips and finishes; stopped reaction, filters, and steaming desolventizes; silicagel column is separated; eluent is sherwood oil: ethyl acetate=1:1, obtains compound 23-2 colorless oil 1.2g, yield 52%.1H?NMR(300MHz,CDCl3)δ7.37(s,1H),7.07(d,J=8.1Hz,2H),6.97(s,1H),6.82(d,J=8.4Hz,2H),5.26(s,2H),5.20(s,2H),4.10(t,J=4.8Hz,2H),3.76(s,2H),3.54(s,3H),3.49(s,3H),3.15(t,J=5.1Hz,2H),2.32(s,3H)。
Step 3
Figure BDA00001905040000571
Room temperature is by compound 23-2(600mg, 1.4mmol), be dissolved in 5ml acetone, add ethylene bromohyrin (1.1ml, 15.5mmol), Anhydrous potassium carbonate (220mg, 1.6mmol), room temperature tube sealing reaction 48h, reaction finishes, filter, solids washed with acetone, filtrate is concentrated, silicagel column is separated, and eluent is sherwood oil: ethyl acetate=2:1, obtains compound 23-3, oily matter, 356mg, yield 55%.1H?NMR(300MHz,CDCl3)δ7.36(s,1H),7.07(d,J=8.1Hz,2H),6.97(s,1H),6.82(d,J=8.4Hz,2H),5.24(s,2H),5.20(s,2H),4.09(t,J=5.4Hz,2H),3.78(s,2H),3.67(t,J=5.1Hz,2H),3.52(s,3H),3.49(s,3H),3.09(t,J=5.4Hz,2H),2.90(t,J=5.1Hz,2H),2.28(s,3H)。
Step 4
Figure BDA00001905040000572
Room temperature is by compound 23-3(340mg, 0.73mmol) be dissolved in the dry CH2Cl2 of 3ml, stirring adds triphenylphosphine (240mg, 0.92mmol), after dissolving completely, ice-water bath is cooling, add carbon tetrabromide (306mg in batches, 0.92mmol), after 60min, react completely, add 2ml to be dried DMF, then add sodiumazide (65mg, 1.0mmol), reaction is spent the night, stopped reaction, in impouring water, CH2Cl2 extraction, dry concentrated, silicagel column is separated, eluent is sherwood oil: ethyl acetate=7:1, obtain compound 23-4, oily matter 181mg, yield 51%.1H?NMR(300MHz,CDCl3)δ7.35(s,1H),7.07(d,J=8.1Hz,2H),6.97(s,1H),6.81(d,J=8.4Hz,2H),5.23(s,2H),5.19(s,2H),4.11(t,J=6.0Hz,2H),3.78(s,2H),3.51(s,3H),3.49(s,3H),3.40(t,J=6.2Hz,2H),3.06(t,J=6.0Hz,2H),2.95(t,J=6.0Hz,2H),2.28(s,3H)。
Step 5
Figure BDA00001905040000573
By compound 23-4(170mg, 0.35mmol) be dissolved in 3ml toluene, reflux, after 5h, reaction finishes, and stopped reaction, removes solvent under reduced pressure, and silicagel column is separated, and eluent is sherwood oil: ethyl acetate=1:1, obtains compound 23-5,123mg, yield 72%.1H?NMR(300MHz,CDCl3)δ7.72(s,1H),7.09(s,1H),7.07(s,2H),6.80(s,1H),6.77(s,1H),5.27(s,2H),5.10(s,2H),5.45(t,J=5.7Hz,2H),4.14(t,J=4.8Hz,2H),3.91(s,2H),3.55(s,3H),3.38(s,3H),3.19(t,J=5.7Hz,2H),3.04(t,J=4.8Hz,2H),2.28(s,3H)。
Step 6
By compound 23-5(110mg, 0.23mmol) be dissolved in 2M hydrogen chloride methanol solution, 30 ℃ of tube sealing reactions, 7d reacts end, and stopped reaction filters, and solid methanol wash is dry, obtains title compound 46mg, yield 49%.1H?NMR(300MHz,DMSO)δ7.65(s,1H),7.15(s,1H),7.10(d,J=5.1Hz,2H),6.86(d,J=4.8Hz,2H),5.35(s,2H),5.24(s,2H),4.41(s,2H),3.44(s,4H),2.23(s,3H).HRMS?calcd?for?C20H22ClN4O3[M+H]+401.1380,found401.1362.
Pharmacological evaluation
The anti tumor activity in vitro of experimental example 1 the compounds of this invention
With internationally recognized method, by mtt assay, observe the impact (table 2) on human colon carcinoma HCT-8 cell, people's liver cancer Bel7402 cell, people's cancer of the stomach BGC823 cell and human lung adenocarcinoma A549 cell proliferation in vitro of different compounds.
The different compounds of table 2. are the impact on human tumor cells propagation in vitro
Figure BDA00001905040000582
Figure BDA00001905040000591
Experimental example 2LD053(embodiment 23 compounds) impact on people's cancer of the stomach BGC823 cell heat shock protein(HSP) and the expression of downstream signal pathway associated protein
The activity of Hsp90 is relevant to many signal paths in cell, comprises PI3K/Akt and MAPK signal path.By the expression of heat shock protein(HSP) Hsp90, Hsp70 and downstream signal path albumen after Western blot method detection different concns LD053 effect BGC823 cell 48h.Result shows, LD053 can induce the expression of Hsp90 and Hsp70, reduces PI3K(p85), the expression (Fig. 1) of P-AKT (S473), AKT, c-Raf.
Further adopted Western blot methods analyst 10 -5the expression of heat shock protein(HSP) Hsp90, Hsp70 and downstream signal path albumen after M concentration LD053 effect BGC823 cell different time.Result shows, 10 -5the expression that can induce Hsp90 and Hsp70 after M concentration LD053 effect BGC823 cell different time, reduces the expression (Fig. 2) of P-AKT, AKT, P-GSK3 β, c-Raf, but on the impact of PTEN, PDK1, MEK1/2 and Erk2 not significantly (scheming not shown).
These results suggest that, LD053 induction Hsp90 expresses and the expression that affects its downstream signal pathway associated protein all has good time and dose-dependently.
The restraining effect of embodiment 3LD053 to the growth of xenografts in nude mice cancer of the stomach BGC823 cell heteroplastic transplantation knurl
In order to illustrate that LD053 also can suppress tumor growth in vivo, carried out xenografts in nude mice cancer of the stomach BGC823 cell heteroplastic transplantation knurl growth-inhibiting experimental study for this reason.BGC823 knurl liquid aseptic inoculation is become to knurl to nude mice armpit is subcutaneous to observe it.After inoculating one week, start administration, establish blank group, positive drug endoxan (CTX) control group (100mg/kg), LD05360mg/kg, 90mg/kg, 120mg/kg dosage group, all adopts the mode administration of abdominal injection.With vernier caliper measurement knurl volume and weigh, within every 2 days, measure once.Within the 18th day, put to death animal, weigh and knurl weight, according to gross tumor volume, draw tumor proliferation curve, respectively organize the growing state of tumour.Result shows, the gross tumor volume that 120mg/kg dosage group forms obviously reduces.From the multiplication rate of relative tumour volume, compare (as shown in Figure 3A), the T/C% of 120mg/kg dosage group is 47.51%; From tumor weight inhibiting rate, compare (as shown in Figure 3 B), the tumour inhibiting rate of 120mg/kg dosage group is 51.53%; From gross tumor volume multiplication rate curve aspect (as shown in Figure 3 C), the tumor proliferation speed of 120mg/kg dosage group obviously slows down.
Reference
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2.V.C.H.da?Silva,C.H.I.Ramos;The?network?interaction?of?the?human?cytosolic90?kDa?heat?shock?protein?Hsp90:A?target?for?cancer?therapeutics;J.Prot.2012,inpress.DOI:10.1016/j.jprot.2011.12.028.
3.H.Zhang,F.Burrows;Targeting?multiple?signal?transduction?pathways?through?inhibition?of?Hsp90;J.Mol.Med.82,488,2004.
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Claims (10)

1. the compound as shown in I, II, III and pharmacy acceptable salt thereof:
Figure FDA00001905039900011
Wherein, R 1be connected with any applicable position on phenyl ring, and represent one or more substituting groups, be selected from H, substituted or non-substituted C1-6 straight or branched alkyl, hydroxyl, substituted or non-substituted C1-6 straight or branched alkoxyl group, sulfydryl, substituted or non-substituted C1-6 straight or branched alkylthio, C1-6 alcoxyl C1-6 alkyl, amino, substituted or non-substituted C1-6 straight or branched alkylamino, comprising single alkylamino and two alkylamino, aldehyde radical, substituted or non-substituted C1-6 straight or branched alkyloyl, substituted or non-substituted C1-6 straight or branched alkoxyl group acyl group, carboxyl, substituted or non-substituted C1-6 straight or branched alkanoyloxy, formamyl, substituted or non-substituted C1-6 straight or branched alkanamine acyl group, substituted or non-substituted C1-6 straight or branched alkyl amide, the alkene of C2-6, halogen, nitro, cyano group,
Substituting group on substituted or non-substituted C1-6 straight or branched alkyl is selected from: hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group;
X is a Sauerstoffatom or a sulphur atom;
N is selected from 1,2,3,4 natural number;
R group is selected from halogen atom, the alkyl of C1-C6, C3-C6 cycloalkyl, C2-C6 thiazolinyl, C3-C6 cycloalkenyl group, C2-C6 alkynyl.
According to claim 1 compound and pharmacy acceptable salt thereof, it is characterized in that,
R 1be selected from H, substituted or non-substituted C1-4 straight or branched alkyl, hydroxyl, substituted or non-substituted C1-4 straight or branched alkoxyl group, sulfydryl, substituted or non-substituted C1-4 straight or branched alkylthio, C1-4 alcoxyl C1-4 alkyl, amino, substituted or non-substituted C1-4 straight or branched alkylamino, comprising single alkylamino and two alkylamino, aldehyde radical, substituted or non-substituted C1-4 straight or branched alkyloyl, substituted or non-substituted C1-4 straight or branched alkoxyl group acyl group, carboxyl, substituted or non-substituted C1-4 straight or branched alkanoyloxy, formamyl, substituted or non-substituted C1-4 straight or branched alkanamine acyl group, substituted or non-substituted C1-4 straight or branched alkyl amide, the alkene of C2-6, halogen, nitro, cyano group,
Substituting group on substituted or non-substituted C1-4 straight or branched alkyl is selected from: hydroxyl, sulfydryl, amino, aldehyde radical, carboxyl, formamyl, halogen, nitro, cyano group.
According to claim 1 compound and pharmacy acceptable salt thereof, it is characterized in that, X is selected from Sauerstoffatom.
According to claim 1 compound and pharmacy acceptable salt thereof, it is characterized in that, n is selected from 1.
According to claim 1 compound and pharmacy acceptable salt thereof, it is characterized in that, R group is selected from Cl, ethyl, sec.-propyl.
According to claim 1 compound and pharmacy acceptable salt thereof, it is characterized in that, described compound is selected from
1) 5-(2-(2-(methylthio group) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-[1,2,3] triazolos [1,5-a] piperazine-6 (7H)-one
2) 5-(2-(4-(nitro) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-[1,2,3] triazolos [1,5-a] piperazine-6 (7H)-one
3) 5-(2-(4-(itrile group) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-[1,2,3] triazolos [1,5-a] piperazine-6 (7H)-one
4) 5-(2-(3-(itrile group) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-[1,2,3] triazolos [1,5-a] piperazine-6 (7H)-one
5) 4-(5-(2-(4-(methyl) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-chlorinated benzene-1,3-diphenol
6) 4-(5-(2-(3-(chlorine) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
7) 4-(5-(2-(3-(methoxyl group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
8) 4-(5-(2-(4-(itrile group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
9) 4-(5-(2-(4-(itrile group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-chloro-benzene-1,3-diphenol
10) 4-(5-(2-(4-(methylthio group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
11) 4-(5-(2-(3-(chlorine) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-chloro-benzene-1,3-diphenol
12) 4-(5-(2-(3-(itrile group) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
13) 4-(5-(2-(4-(formamyl) phenoxy group) ethyl)-4,5,6,7-tetrahydrochysene-[1,2,3] triazolos [1,5-a] piperazine-3-yl)-6-isopropyl benzene-1,3-diphenol
14) 5-(2-(3-chlorophenoxy) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-isoxazoles are [4,3-c] piperidines-6 (7H)-one also
15) 5-(2-(3-chlorophenoxy) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-chloro-phenyl-)-isoxazoles are [4,3-c] piperidines-6 (7H)-one also
16) 5-(2-(4-chlorophenoxy) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-ethylphenyl)-isoxazoles are [4,3-c] piperidines-6 (7H)-one also
17) 5-(2-(4-(methylthio group) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-isoxazoles are [4,3-c] piperidines-6 (7H)-one also
18) 5-(2-(4-(methoxyl group) phenoxy group) ethyl)-4,5-dihydro-3-(2,4-dihydroxyl-5-isopropyl phenyl)-isoxazoles are [4,3-c] piperidines-6 (7H)-one also.
7. a pharmaceutical composition, is characterized in that, comprises acceptable carrier in the compound of any one in the claim 1-6 of effective dose and salt and pharmacodynamics.
8. the compound of any one and the application of salt in preparing antitumor drug thereof in claim 1-6.
9. application according to Claim 8, is characterized in that, described tumour is selected from melanoma, cancer of the stomach, lung cancer, mammary cancer, kidney, liver cancer, oral cavity epidermal carcinoma, cervical cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, colorectal carcinoma.
In claim 1-6 the compound of any one and salt thereof in preparation prevention and application in the treatment disease relevant to heat shock protein 90.
CN201210250715.3A 2012-07-19 2012-07-19 Triazolopyrazine(one) and isoxazolopiperidone compounds Pending CN103570721A (en)

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Cited By (1)

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Publication number Priority date Publication date Assignee Title
CN110128325A (en) * 2019-04-11 2019-08-16 广州医科大学 Substituted phenylpiperidines ketone compounds and its synthetic method and application

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YANAN ZHANG ET AL.: ""Identifying structural features on 1,1-diphenyl-hexahydro-oxazolo[3,4-a]pyrazin-3-ones critical for Neuropeptide S antagonist activity"", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110128325A (en) * 2019-04-11 2019-08-16 广州医科大学 Substituted phenylpiperidines ketone compounds and its synthetic method and application

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