CN102108078A - 1,4-substituted phthalazine compound and preparation method and applications thereof - Google Patents
1,4-substituted phthalazine compound and preparation method and applications thereof Download PDFInfo
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- CN102108078A CN102108078A CN2009102487251A CN200910248725A CN102108078A CN 102108078 A CN102108078 A CN 102108078A CN 2009102487251 A CN2009102487251 A CN 2009102487251A CN 200910248725 A CN200910248725 A CN 200910248725A CN 102108078 A CN102108078 A CN 102108078A
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Abstract
The invention belongs to the technical field of the medicine and relates to 1,4-substituted phthalazine compound shown in the general formula I and salt, solvate or predrug thereof which is acceptable in pharmacy, wherein substituents Ar1, Ar2, R3 and n are defined in the specification. The invention also relates to applications of the compound shown in the general formula I in the preparations of medicines used for curing and/or preventing tumour and other proliferative diseases.
Description
Technical field
The invention belongs to medical technical field, relate to 1,4-replaces Phthalazines and pharmacy acceptable salt, solvate or prodrug, their preparation method and the pharmaceutical composition that contains described compound.The invention still further relates to this derivative and be used for preparing the purposes of the medicine that treats and/or prevents tumour and other proliferative disease.
Background technology
Malignant tumour is the great refractory disease that threatens human life's health, and the mankind have experienced very long historical upheaval in the therapeutic process of malignant tumour.Turn to the searching of the targeted drug of highly selective from the screening of in the past nonselective cell toxicity medicament.It is the great potential of target treatment tumour that the appearance of targeted drug has fully proved with the molecule, indicates that the New Times of cancer therapy arrives.
Poly-adenosine diphosphate (ADP) ribose polymerase-1 (PARP-1) causes scientific research personnel's concern gradually as one of cancer therapy drug new target spot, becomes one of focus target spot of target therapeutic agent.PARP-1 is the main isomer of PARP, be a kind of high conservative, be rich in the cell ribozyme of nuclear chromatin, can cause some tumour cell DNA and repair obstacle, promote apoptosis of tumor cells, be the potential method of treatment tumour, particularly for BRCA1 or BRCA2 base sudden change patient.
Olaparib (BSI-201) is a kind of novel oral PARP inhibitor, and by the PTS of BIPAR company research and development, this medicine is in the II phase clinical study stage at present.This medicine plays a role by suppressing PARP-1.
The inventor is on the basis of reference, and design has been synthesized a series of 1, and 4-replaces Phthalazines, through external various tumor cell strains is carried out antitumor activity screening, and the result shows to have anti-tumor activity.
Summary of the invention
The present invention relates to compound and pharmacy acceptable salt, solvate or the prodrug of general formula I,
Wherein,
Ar
1Be phenyl, naphthyl or 5-10 unit heteroaryl, described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and Ar
1Optional 1-3 identical or different R
1Replace;
Ar
2Be phenyl, naphthyl or 5-10 unit heteroaryl, described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and Ar
2Optional 1-3 identical or different R
2Replace;
R
1Be hydrogen, halogen, halogenated methoxy, carboxyl, carboxylic acid ester groups, nitro, cyano group, (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, cycloalkyl, halogenated cycloalkyl, N, N-(C1-C4) alkylamino, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl, (C1-C4) alkyl acyl, N-(C1-C4) alkyl-carbamoyl, N, N-(C1-C4) alkyl-carbamoyl, N-(C1-C4) alkylamino sulfinyl, N, N-(C1-C4) alkyl amino sulfonyl, aryloxy, heteroaryloxy, substituted heteroaryloxy, substituted heterocyclic radical;
R
2Be hydrogen, halogen, halogenated methoxy, carboxyl, carboxylic acid ester groups, nitro, cyano group, (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, cycloalkyl, halogenated cycloalkyl, N, N-(C1-C4) alkylamino, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl, (C1-C4) alkyl acyl, N-(C1-C4) alkyl-carbamoyl, N, N-(C1-C4) alkyl-carbamoyl, N-(C1-C4) alkylamino sulfinyl, N, N-(C1-C4) alkyl amino sulfonyl, aryloxy, heteroaryloxy, substituted heteroaryloxy, substituted heterocyclic radical;
R
3Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano group, (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, aryloxy, heteroaryloxy, substituted heteroaryl, substituted heterocyclic radical; And described R
3Optional 1-3 identical or different above group;
N is the integer between the 1-4.
The present invention preferably relates to compound and pharmacy acceptable salt, solvate or the prodrug of general formula I,
Wherein,
Ar
1Be phenyl or 5-10 unit heteroaryl, described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and Ar
1Optional 1-3 identical or different R
1Replace;
Ar
2Be phenyl or 5-10 unit heteroaryl, described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and Ar
2Optional 1-3 identical or different R
2Replace;
R
1Be hydrogen, halogen, halogenated methoxy, carboxyl, carboxylic acid ester groups, nitro, cyano group, (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, cycloalkyl, halogenated cycloalkyl, N, N-(C1-C4) alkylamino, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl, (C1-C4) alkyl acyl, N-(C1-C4) alkyl-carbamoyl, N, N-(C1-C4) alkyl-carbamoyl, N-(C1-C4) alkylamino sulfinyl, N, N-(C1-C4) alkyl amino sulfonyl;
R
2Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano group, (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, (C1-C4) alkyl acyl, (C1-C4) alkyl aminoacyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl;
R
3Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano group, (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, and described R
3Optional 1-3 identical or different above group;
N is the integer between the 1-4.
The present invention also preferably relates to compound and pharmacy acceptable salt, solvate or the prodrug of general formula I,
Wherein,
Ar
1Be phenyl or 5-10 unit heteroaryl, described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and Ar
1Optional 1-3 identical or different R
1Replace;
Ar
2Be phenyl, and Ar
2Optional 1-3 identical or different R
2Replace;
R
1Be hydrogen, halogen, halogenated methoxy, carboxyl, carboxylic acid ester groups, nitro, cyano group, (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, cycloalkyl, halogenated cycloalkyl, N, N-(C1-C4) alkylamino, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl, (C1-C4) alkyl acyl, N-(C1-C4) alkyl-carbamoyl, N, N-(C1-C4) alkyl-carbamoyl, N-(C1-C4) alkylamino sulfinyl, N, N-(C1-C4) alkyl amino sulfonyl;
R
2Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano group, (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, (C1-C4) alkyl acyl, (C1-C4) alkyl aminoacyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl;
R
3Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, (C1-C4) alkyl, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group;
N is the integer between the 1-4.
The present invention also preferably relates to compound and pharmacy acceptable salt, solvate or the prodrug of general formula I,
Wherein,
Ar
1Be phenyl or 5-10 unit heteroaryl, described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and Ar
1Optional 1-3 identical or different R
1Replace;
R
1Be hydrogen, halogen, halogenated methoxy, carboxyl, carboxylic acid ester groups, nitro, cyano group, (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, cycloalkyl, halogenated cycloalkyl, N, N-(C1-C4) alkylamino, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl, (C1-C4) alkyl acyl, N-(C1-C4) alkyl-carbamoyl, N, N-(C1-C4) alkyl-carbamoyl, N-(C1-C4) alkylamino sulfinyl, N, N-(C1-C4) alkyl amino sulfonyl;
Ar
2Be 5-10 unit heteroaryl, described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and Ar
2Optional 1-3 identical or different R
2Replace;
R
2Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano group, (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, (C1-C4) alkyl acyl, (C1-C4) alkyl aminoacyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl;
R
3Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, (C1-C4) alkyl, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group;
N is the integer between the 1-4.
The present invention especially preferably relates to compound and pharmacy acceptable salt, solvate or the prodrug of the general formula I that is defined as follows,
Wherein,
Ar
1Be phenyl, and Ar
1Optional 1-3 identical or different R
1Replace;
R
1Be hydrogen, halogen, halogenated methoxy, carboxyl, carboxylic acid ester groups, nitro, cyano group, (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, cycloalkyl, halogenated cycloalkyl, N, N-(C1-C4) alkylamino, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl, (C1-C4) alkyl acyl, N-(C1-C4) alkyl-carbamoyl, N, N-(C1-C4) alkyl-carbamoyl, N-(C1-C4) alkylamino sulfinyl, N, N-(C1-C4) alkyl amino sulfonyl;
Ar
2Be 5-6 unit heteroaryl, described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and wherein 1 heteroatoms is a nitrogen-atoms, Ar
2Optional 1-3 identical or different R
2Replace;
R
2Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano group, (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, (C1-C4) alkyl acyl, (C1-C4) alkyl aminoacyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl;
R
3Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, (C1-C4) alkyl, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group;
N is the integer between the 1-4.
The present invention very particularly preferably relates to compound and pharmacy acceptable salt, solvate or the prodrug of the general formula I that is defined as follows,
Wherein,
Ar
1Be phenyl, and Ar
1Optional 1-3 identical or different R
1Replace;
R
1Be hydrogen, halogen, halogenated methoxy, carboxyl, carboxylic acid ester groups, nitro, cyano group, (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, cycloalkyl, halogenated cycloalkyl, N, N-(C1-C4) alkylamino, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl, (C1-C4) alkyl acyl, N-(C1-C4) alkyl-carbamoyl, N, N-(C1-C4) alkyl-carbamoyl, N-(C1-C4) alkylamino sulfinyl, N, N-(C1-C4) alkyl amino sulfonyl;
Ar
2Be pyrroles-2-base, pyrroles-3-base, pyridine-2-base, pyridin-3-yl, pyridin-4-yl; Pyridine-4 base more preferably;
R
3Be hydrogen;
N is 1.
The compound of the preferred more especially following general formula I of the present invention and pharmacy acceptable salt, solvate or prodrug:
N-(2, the 5-3,5-dimethylphenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(3, the 5-bis trifluoromethyl phenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(3-chloro-4-fluorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(4-aminomethyl phenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(4-fluoro-3-trifluoromethyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(4-fluorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(5-fluoro-2-aminomethyl phenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(4-bromophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(3, the 4-3,5-dimethylphenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(4-Trifluoromethoxyphen-l)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(3-bromophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(3-fluorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(2-trifluoromethyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(3, the 4-difluorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(3, the 4-dichlorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(4-fluoro-3-trifluoromethyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide;
N-(3, the 4-difluorophenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide;
N-(4-aminomethyl phenyl)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide.
And, according to some usual methods in field under the present invention, 1 of general formula I of the present invention, 4-replaces Phthalazines can generate its pharmacy acceptable salt with acid.Acid comprises mineral acid or organic acid, and the salt that forms with following acid is particularly preferred: hydrochloric acid, sulfuric acid, phosphoric acid, Hydrogen bromide, oxalic acid, toxilic acid, fumaric acid, citric acid, Tartaric acid, oxysuccinic acid, isethionic acid, methylsulfonic acid, ethyl sulfonic acid, acetate, propionic acid, lactic acid, trifluoroacetic acid, phenylformic acid or tosic acid.
In addition, the present invention also comprises the prodrug of derivative of the present invention.According to the present invention, prodrug is the derivative of general formula I, they self may have more weak active or even do not have activity, but after administration, (for example by metabolism, solvolysis or other mode) is converted to corresponding biologically active form under physiological condition.
Unless otherwise noted, term used herein " halogen " is meant fluorine, chlorine, bromine or iodine atom; " alkyl " is meant the alkyl of straight or branched; " halogenated methoxy " is meant the methoxyl group that one or more halogens replace, and " halo C1-C4 alkyl " is meant the C1-C4 alkyl that one or more halogens replace; " alkylidene group " is meant the alkylidene group of straight or branched; " cycloalkyl " is meant and replaces or unsubstituted cycloalkyl; Heteroaryl comprises the heteroatoms that contains one or more O of being selected from, N and S, can be monocycle or polycyclic, the ring-type system is an aromaticity, can enumerate for example imidazolyl, pyridyl, pyrimidyl, (1,2,3)-and (1,2,4)-triazolyl, pyrazinyl, tetrazyl, furyl, thienyl, isoxazolyl, oxazolyl, pyrazolyl, pyrryl, thiazolyl, quinolyl, benzimidazolyl-, pyridine-imidazole base, benzothienyl, benzothiazolyl, indyl and Pyridopyrimidine base etc.
The present invention includes pharmaceutical composition, said composition contains 1 of general formula I, and 4-replaces Phthalazines, its geometrical isomer and pharmacy acceptable salt, solvate or prodrug as activeconstituents, and pharmaceutically acceptable excipient.Described pharmaceutically acceptable excipient is meant any thinner, auxiliary and/or carrier that can be used for pharmaceutical field.Derivative of the present invention can be used in combination with other activeconstituentss, as long as they do not produce other disadvantageous effect, for example anaphylaxis.
Pharmaceutical composition of the present invention can be mixed with some kinds of formulations, wherein contains some vehicle commonly used in the pharmaceutical field; For example, oral preparations (as tablet, capsule, solution or suspension); Injectable preparation (as injectable solution or suspension, or injectable dried powder, adding water for injection before injection can use immediately); Topical formulations (for example ointment or solution).
The carrier that is used for pharmaceutical composition of the present invention is the available common type of pharmaceutical field, comprising: the tackiness agent that oral preparations is used, lubricant, disintegrating agent, solubility promoter, thinner, stablizer, suspension agent, non-pigment, correctives etc.; The sanitas that injectable formulation is used, solubilizing agent, stablizer etc.; The matrix that topical formulations is used, thinner, lubricant, sanitas etc.Pharmaceutical preparation can oral administration or parenteral mode (for example intravenously, subcutaneous, intraperitoneal or part) administration, if some drugs is unsettled under the stomach condition, it can be mixed with enteric coated tablets.
Derivative of the present invention can be used as activeconstituents and is used for preparation and treats and/or prevents various tumours, and the present invention also provides treatment or prevents the method for above-mentioned disease, comprises the significant quantity of suffering from or easily suffering from this sick patient.1 of general formula I, 4-replace concrete approach that clinical dosage that Phthalazines is used for the patient must rely on the main body of being treated, administration, treated severity of disease and change, and optimal dose is definite by the doctor who treats concrete patient.
Active compound of the present invention can be used as unique cancer therapy drug and uses, and perhaps can unite use with one or more other antitumor drugs.Combination therapy realizes by each being treated component while, order or separating administration.
Following synthetic route A has described the preparation of compound of Formula I of the present invention, and all raw materials all are the method preparation known by the method for describing in these synoptic diagram, by the organic chemistry filed those of ordinary skill or commercially available.All final compound of the present invention all is to prepare by the method for describing in these synoptic diagram or by method similar with it, and these methods are that the organic chemistry filed those of ordinary skill is known.Whole variable factors of using in these synoptic diagram are as hereinafter definition or as the definition in the claim.
According to compound of Formula I of the present invention, in Scheme 1, Ar
1, Ar
2, R
3Define with n such as summary of the invention.Replace Tetra hydro Phthalic anhydride II with sodium borohydride reduction after, obtain replacing isobenzofuran-1 (3H)-ketone III, intermediate III and the aldehyde IV condensation that is connected with different substituents, obtain intermediate V, obtain intermediate VI after intermediate V and the hydrazine hydrate reaction, intermediate VI obtains intermediate VIII through chlorination, intermediate VIII obtains the compound shown in the general formula I with after intermediate compound I X docks.
The preparation route of Scheme 1 compound of Formula I
The compounds of this invention is external to have the inhibition tumor cell growth activity, can treat and/or prevent the medicine of cancer as preparation.Especially treat the cancer of mammary gland, ovary, prostate gland, liver, lung, colon, rectum, stomach, bladder and pancreas.The compounds of this invention also is supposed to be used for the treatment of other cell proliferative diseases such as psoriasis, benign prostatauxe, atherosclerosis and restenosis.
Embodiment
The compounds of this invention and preparation method thereof is further illustrated and illustrated to embodiment that hereinafter provides and preparation example.The scope that should be appreciated that following embodiment and preparation example also limits the scope of the invention never in any form.
Embodiment is intended to set forth rather than limit the scope of the invention.The proton nmr spectra of prepared compound is measured with Bruker ARX-300 among the present invention, and mass spectrum is measured with Agilent 1100LC/MSD; Agents useful for same is analytical pure or chemical pure.
Embodiment 1:N-(2, the 5-3,5-dimethylphenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
Steps A: the preparation of isobenzofuran-1 (3H)-ketone
Tetra hydro Phthalic anhydride 123g (0.83mol) is dissolved in the 750mL tetrahydrofuran (THF), under the condition that cryosel is bathed, adds sodium borohydride 57.5g (3.32mol) gradually in batches, add 250mL methyl alcohol then.Finish room temperature reaction 3h.After reaction finished, concentration of reaction solution added the 1000mL aqueous hydrochloric acid that the 250mL concentrated hydrochloric acid is mixed with, stirred overnight at room temperature, suction filtration to doing, get white solid, then white solid is added aqueous sodium carbonate, stirring at room 1h, suction filtration, washing, drying gets white crystal 78g, yield 70%.m.p.：72-73℃.MS[MH+](m/z)：135.1.
1H?NMR(300MHz，DMSO)δ：7.85(d，J＝7.6Hz，1H)，7.78(t，J＝7.4Hz，1H)，7.68(d，J＝7.7Hz，1H)，7.59(t，J＝7.4Hz，1H)，5.42(s，2H)。
The preparation of step B:2-(pyridin-4-yl)-1H-indenes-1,3 (2H)-diketone
Isobenzofuran-1 (3H)-ketone 50g and 4-pyridylaldehyde 42g (1.05equl) are added in 200mL ethyl propionate and the 400mL methyl alcohol stirring and dissolving.Sodium methylate 82g (4qeu) is dissolved in the 400mL methyl alcohol, and above-mentioned prepared solution is dropwise added in the sodium methoxide solution, room temperature reaction 1h is warming up to reaction solution back flow reaction 1h then.After reaction finished, concentration of reaction solution was to doing, and in the impouring frozen water, the Glacial acetic acid adjust pH is to acid pH=2, and suction filtration gets safran solid 43.8g, and yield is 52.6%.m.p.：＞300℃.MS[MH+](m/z)：224.3(M+1).
1H-NMR(300MHz，DMSO-d6)δ：13.23(s，1H)，8.72(d，2H)，8.18(d，2H)，7.51(m，4H)。
The preparation of step C:4-(pyridin-4-yl methyl) phthalazines-1 (2H)-ketone
80% hydrazine hydrate 306.6mL (4.9mol) is added reaction flask, add 2-(pyridin-4-yl)-1H-indenes-1 gradually, 3 (2H)-diketone 43.8g (0.20mol), temperature raising to 100 ℃ reaction 5h, after reaction finishes, the cooling reaction solution, suction filtration, washing with alcohol gets ivory buff crystal 3 4.9g, and yield is 75%.m.p.：210-211℃.MS[MH+](m/z)：238.3.
1H-NMR(300MHz，DMSO-d6)δ：12.65(s，1H)，8.47(d，2H)，8.27(d，1H)，7.90(m，3H)，7.32(d，2H)，4.35(s，2H).
The preparation of step D:1-chloro-4-(pyridin-4-yl-methyl) phthalazines
General-(pyridin-4-yl methyl) phthalazines-1 (2H)-ketone 17.5g (0.07mol) is dissolved in the mixing solutions of phosphorus oxychloride 170mL and acetonitrile 80mL composition, adds 3 DMF, is warming up to 90 ℃ of reaction 3h, after reaction finishes, concentrated solvent adds trash ice to doing, and saturated sodium bicarbonate aqueous solution transfers pH to neutral, there is oyster white to separate out, suction filtration, washing, drying, get light yellow 13.5g, yield is 71.6%.m.p.：180-181℃.MS[MH+](m/z)：255.8(Cl＝35)，257.8(Cl＝37).
1H-NMR(300MHz，DMSO-d6)δ：8146(d，2H)，8.35(m，2H)，8.13(m，2H)，7.33(d，2H)，4.76(s，2H).
The preparation of step e: 1-(piperazine-1-yl)-4-(pyridin-4-yl methyl) phthalazines
Piperazine 30.4g (0.4mol) is dissolved among the dehydrated alcohol 260mL, under the stirring at room, to wherein adding chloro-product 13.5g (0.05mol), be warming up to 60 ℃ then, reaction 5h in batches, after reaction finishes, solvent evaporated is poured less water then into, after fully stirring, suction filtration obtains Off-white solid 11.45g, and yield is 71%.m.p.：209-210℃.MS[MH+](m/z)：306.4
Step F: the preparation of 2-chloro-N-(2, the 5-3,5-dimethylphenyl) ethanamide
With 2,5-xylidine 25g (0.2mol) is dissolved in the 250mL acetone, adds triethylamine 36.7mL (0.3mo), under the condition of ice bath, slowly drip chloroacetyl chloride 21.4mL (0.26mol), controlled temperature is lower than 20 ℃, room temperature reaction 4h, after reaction finished, concentrated solvent was to doing, add frozen water 200mL, stirring at room 1h, suction filtration, washing, an amount of methanol wash gets 35g, and yield is 86%.MS[MH+](m/z)：256.6
Step G:N-(2, the 5-3,5-dimethylphenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] preparation of ethanamide
With 1-(piperazine-1-yl)-4-(pyridin-4-yl methyl) phthalazines 0.2g (0.65mmol) and 2-chloro-N-(2, the 5-3,5-dimethylphenyl) ethanamide 0.14g (0.72mmol) is dissolved in the acetone, add salt of wormwood 0.23g (1.64mmol), back flow reaction 7h after reaction finishes, filters, concentrated filtrate is to doing, column chromatography for separation gets embodiment 1 compound 0.05g, and yield is 16.7%.
1H?NMR(300MHz，DMSO-d
6)δ9.41(s，1H)，8.45(s，2H)，8.15(s，2H)，7.93(s，2H)，7.66(s，1H)，7.31(s，2H)，7.10(s，1H)，6.87(s，1H)，4.62(s，2H)，3.48(s，4H)，3.27(s，2H)，2.88(s，4H)，2.25(s，3H)，2.21(s，3H).MS[MH
+](m/z)：467.4
According to the method for embodiment 1, select suitable raw material and reagent, make the compound of embodiment 2-86 respectively.When mentioning specific reaction raw materials, it should be understood that the technician who is proficient in this field can select proper raw material and reagent according to the needs of embodiment.
Embodiment 2:N-(3,5-two trifluoromethyls)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.55(s，1H)，8.45(d，4H)，8.15(dd，2H)，7.99～7.85(m，2H)，7.78(s，1H)，7.31(d，2H)，4.62(s，2H)，3.49(s，4H)，3.36(s，2H)，2.85(s，4H).MS[MH+](m/z)：575.5
Embodiment 3:N-(3-chloro-4-fluorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.11(s，1H)，8.45(d，2H)，8.14(dd，2H)，8.02(dd，1H)，7.96～7.88(m，2H)，7.70～7.59(m，1H)，7.42～7.29(m，3H)，4.62(s，2H)，3.47(s，4H)，3.29(s，2H)，2.83(s，4H).MS[MH
+](m/z)：491.1，493.1
Embodiment 4:N-(2, the 4-3,5-dimethylphenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.39(s，1H)，8.45(d，2H)，8.15(dd，2H)，8.01～7.84(m，2H)，7.65(d，1H)，7.32(d，2H)，7.11～6.96(m，2H)，4.63(s，2H)，3.48(s，4H)，3.27(s，2H)，2.88(s，4H)，2.24(s，3H)，2.23(s，3H).MS[MH
+](m/z)：467.1
Embodiment 5:N-(4-aminomethyl phenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.78(s，1H)，8.45(d，2H)，8.14(dd，2H)，7.99～7.80(m，2H)，7.55(d，2H)，7.31(d，2H)，7.11(d，2H)，4.62(s，2H)，3.46(s，4H)，3.26(s，2H)，2.83(s，4H)，2.25(s，3H).MS[MH
+](m/z)：453.2
Embodiment 6:N-(4-fluoro-3-trifluoromethyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.22(s，1H)，8.45(s，2H)，8.18(s，3H)，7.93(s，3H)，7.49(s，1H)，7.31(s，2H)，4.62(s，2H)，3.47(s，4H)，3.31～3.27(m，2H)，2.83(s，4H).MS[MH
+](m/z)：525.4
Embodiment 7:N-(4-fluorophenyl)-2-[4-[4-(pyridine 4-ylmethyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.93(s，1H)，8.45(d，2H)，8.22～8.03(m，2H)，7.92(d，2H)，7.70(dd，2H)，7.31(d，2H)，7.16(t，2H)，4.62(s，2H)，3.47(s，4H)，3.27(s，2H)，2.83(s，4H).MS[MH
+](m/z)：457.5
Embodiment 8:N-(quinoline-5-yl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.17(s，1H)，8.93(dd，J＝4.2，1.5Hz，1H)，8.50～8.43(m，2H)，8.39(d，J＝8.1Hz，1H)，8.22～8.09(m，2H)，7.94(m，2H)，7.88(dd，2H)，7.81～7.72(m，1H)，7.61(dd，1H)，7.32(d，2H)，4.63(s，2H)，3.54(s，4H)，3.44(s，2H)，2.94(s，4H).MS[MH
+](m/z)：490.2
Embodiment 9:N-(5-fluoro-2-aminomethyl phenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.61(s，1H)，8.45(d，2H)，8.22～8.07(m，2H)，7.93(d，2H)，7.82(dd，1H)，7.39～7.18(m，3H)，6.88(m，1H)，4.63(s，2H)，3.48(s，4H)，3.31(s，2H)，2.89(s，4H).MS[MH
+](m/z)：471.4
Embodiment 10:N-(4,6-SDM-2-yl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.61(s，1H)，8.45(d，2H)，8.22～8.07(m，2H)，7.93(d，2H)，7.82(dd，J＝11.3，2.6Hz，1H)，7.39～7.18(m，3H)，6.88(m，1H)，4.63(s，2H)，3.48(s，4H)，3.31(s，2H)，2.89(s，4H)，2.26(s，3H).MS[MH
+](m/z)：501.2
Embodiment 11:N-(4-bromophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.00(s，1H)，8.45(d，2H)，8.23～8.03(m，2H)，8.03～7.82(m，2H)，7.67(d，2H)，7.59～7.38(m，2H)，7.31(d，2H)，4.62(s，2H)，3.46(s，4H)，3.28(s，2H)，2.83(s，4H).MS[MH
+](m/z)：517.1，519.1
Embodiment 12:N-(3-chloro-phenyl-)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.00(s，1H)，8.45(d，2H)，8.14(dd，2H)，7.93(dd，2H)，7.72(d，2H)，7.37(d，2H)，7.31(d，2H)，4.62(s，2H)，3.47(s，4H)，3.29(s，2H)，2.83(s，4H).MS[MH
+](m/z)：473.1，475.1
Embodiment 13:N-(3, the 4-3,5-dimethylphenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.67(s，1H)，8.45(d，2H)，8.16(d，1H)，8.11(d，1H)，7.93(dd，2H)，7.47～7.35(m，2H)，7.31(d，2H)，7.05(d，1H)，4.62(s，2H)，3.46(s，4H)，3.24(s，2H)，2.82(s，4H)，2.19(s，3H)，2.16(s，3H).MS[MH
+](m/z)：467.4
Embodiment 14:N-(2-fluoro-5-aminomethyl phenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.66(s，1H)，8.45(d，2H)，8.22～8.08(m，2H)，7.92(d，2H)，7.85(d，1H)，7.32(d，2H)，7.15(dd，1H)，6.95(s，1H)，4.63(s，2H)，3.46(s，4H)，3.32(s，2H)，2.86(s，4H)，2.28(s，3H).MS[MH
+](m/z)：471.3
Embodiment 15:N-(2-aminomethyl phenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.48(s，1H)，8.45(d，2H)，8.15(dd，2H)，7.99～7.88(m，2H)，7.82(d，1H)，7.32(d，2H)，7.21(dd，2H)，7.05(t，1H)，4.63(s，2H)，3.49(s，4H)，3.29(s，2H)，2.89(s，4H)，2.27(s，3H).MS[MH
+](m/z)：453.3
Embodiment 16:N-(4-Trifluoromethoxyphen-l)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.10(s，1H)，8.45(d，2H)，8.14(dd，2H)，7.99～7.86(m，2H)，7.80(d，2H)，7.33(d，4H)，4.62(s，2H)，3.47(s，4H)，3.30(s，2H)，2.83(s，4H).MS[MH
+](m/z)：523.3
Embodiment 17:N-(2-fluorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.72(s，1H)，8.45(d，2H)，8.15(dd，2H)，8.02(d，1H)，7.98～7.88(m，2H)，7.34～7.25(m，3H)，7.24～7.13(m，2H)，4.63(s，2H)，3.47(s，4H)，3.33(s，2H)，2.87(s，4H).MS[MH
+](m/z)：457.3
Embodiment 18:N-(2, the 6-difluorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.60(s，1H)，8.45(d，2H)，8.20～8.10(m，2H)，7.92(d，2H)，7.38(dd，1H)，7.31(d，2H)，7.17(t，2H)，4.62(s，2H)，3.49(s，4H)，3.33(s，2H)，2.85(s，4H).MS[MH
+](m/z)：475.3
Embodiment 19:N-(3-chloro-phenyl-)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.10(s，1H)，8.45(d，2H)，8.14(dd，2H)，7.92(d，3H)，7.60(d，1H)，7.43～7.26(m，3H)，7.12(d，1H)，4.62(s，2H)，3.47(s，4H)，3.30(s，2H)，2.83(s，4H).MS[MH
+](m/z)：473.1，475.1
Embodiment 20:N-(3-bromophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.05(s，1H)，8.45(d，2H)，8.14(dd，2H)，8.04(s，1H)，7.99～7.86(m，2H)，7.64(d，1H)，7.36～7.22(m，4H)，4.62(s，2H)，3.47(s，4H)，3.29(s，2H)，2.83(s，4H).MS[MH
+](m/z)：517.9(Br＝79)，519.0(Br＝81)
Embodiment 21:N-(3-fluorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.09(s，1H)，8.45(d，2H)，8.14(dd，2H)，8.00～7.84(m，2H)，7.68(d，1H)，7.44(d，1H)，7.41～7.27(m，3H)，6.89(t，1H)，4.62(s，2H)，3.47(s，4H)，3.30(s，2H)，2.83(s，4H).MS[MH
+](m/z)：457.2
Embodiment 22:N-(2-chloro-5-trifluoromethyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.23(s，1H)，8.69(s，1H)，8.45(d，2H)，8.24～8.07(m，2H)，7.99～7.86(m，2H)，7.82(d，1H)，7.53(d，1H)，7.32(d，2H)，4.63(s，2H)，3.50(s，4H)，3.38(s，2H)，2.91(s，4H).MS[MH
+](m/z)：541.2，542.1
Embodiment 23:N-(2-trifluoromethyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.96(s，1H)，8.45(d，2H)，8.27(d，1H)，8.16(dd，2H)，7.94(dd，2H)，7.72(dd，2H)，7.34(dd，3H)，4.63(s，2H)，3.47(s，4H)，3.34(s，2H)，2.89(s，4H).MS[MH
+](m/z)：507.1
Embodiment 24:N-(2-chloro-6-aminomethyl phenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.54(s，1H)，8.45(d，2H)，8.15(t，2H)，7.92(d，2H)，7.40-7.28(m，3H)，7.22(q，2H)，4.62(s，2H)，3.50(s，4H)，3.30(s，2H)，2.89(s，4H)，2.21(s，3H).MS[MH
+](m/z)：487.1，489.2
Embodiment 25:N-(3, the 4-difluorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.12(s，1H)，8.45(d，2H)，8.24～8.07(m，2H)，8.01～7.82(m，3H)，7.51～7.36(m，2H)，7.32(t，2H)，4.62(s，2H)，3.47(s，4H)，3.29(s，2H)，2.83(s，4H).MS[MH+](m/z)：475.1
Embodiment 26:N-(3, the 4-Dimethoxyphenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO)δ9.67(s，1H)，8.45(d，2H)，8.14(dd，2H)，7.93(dd，2H)，7.47～7.35(m，2H)，7.31(d，2H)，7.05(d，1H)，4.62(s，2H)，3.46(s，4H)，3.24(s，2H)，2.82(s，4H)，2.19(s，3H)，2.16(s，3H).MS[MH
+](m/z)：499.4，500.4
Embodiment 27:N-(3, the 4-dichlorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.21(s，1H)，8.45(d，2H)，8.20～8.14(m，1H)，8.11(t，2H)，7.99～7.86(m，2H)，7.67(dd，1H)，7.58(d，1H)，7.31(d，2H)，4.62(s，2H)，3.47(s，4H)，3.31(s，2H)，2.83(s，4H).MS[MH
+](m/z)：507.3，509.3
Embodiment 28:N-(3, the 4-fluorophenyl)-2-[4-[4-(pyridine-2-ylmethyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：475.4
Embodiment 29:N-(3-bromophenyl)-2-[4-[4-(pyridine-2-ylmethyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：517.9(Br＝79)，519.9(Br＝81)
Embodiment 30:N-(3, the 5-dichlorophenyl)-2-[4-[4-(pyridin-3-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：507.3(Cl＝35)，509.3
Embodiment 31:N-(3, the 4-difluorophenyl)-2-[4-[4-(pyridin-3-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：475.5
Embodiment 32:N-(3-chloro-4-fluorophenyl)-2-[4-[4-(pyridazine-2-ylmethyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：492.5(Cl＝35)，494.5(Cl＝35)
Embodiment 33:N-(3, the 4-difluorophenyl)-2-[4-[4-(pyridazine-2-ylmethyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：476.4
Embodiment 34:N-(3, the 5-dichlorophenyl)-2-[4-[4-(pyrimidine-2-base methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：508.1(Cl＝35)，510.1(Cl＝37)
Embodiment 35:N-(3-chloro-phenyl-)-2-[4-[4-(pyrimidine-2-base methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：474.5(Cl＝35)，476.5(Cl＝37)
Embodiment 36:N-(3-chloro-phenyl-)-2-[4-[4-(pyrroles-2-ylmethyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：461.4(Cl＝35)，463.4(Cl＝37)
Embodiment 37:N-(3, the 4-dichlorophenyl)-2-[4-[4-(pyrroles-2-ylmethyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：495.2(Cl＝35)，497.2(Cl＝37)
Embodiment 38:N-(3, the 4-difluorophenyl)-2-[4-[4-(pyridin-4-yl ethyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：489.4
Embodiment 39:N-(3-chloro-4-fluorophenyl)-2-[4-[4-(pyridin-4-yl ethyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：504.6(Cl＝35)506.6(Cl＝37)
Embodiment 40:N-(3-bromophenyl)-2-[4-[4-(pyridin-4-yl ethyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：530.4(Br＝79)，532.4(Br＝81)
Embodiment 41:N-(3, the 4-difluorophenyl)-2-[4-[4-(pyridin-4-yl propyl group) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：503.5
Embodiment 42:N-(3-chloro-4-fluorophenyl)-2-[4-[4-(pyridin-4-yl propyl group) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：518.6(Cl＝35)520.6(Cl＝37)
Embodiment 43:N-(3-bromophenyl)-2-[4-[4-(pyridin-4-yl propyl group) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：544.5(Br＝79)，546.5(Br＝81)
Embodiment 44:N-(3, the 4-difluorophenyl)-2-[4-[4-(pyridin-4-yl butyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：517.5
Embodiment 45:N-(3-chlorine 4-fluorophenyl)-2-[4-[4-(pyridin-4-yl butyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：532.6(Cl＝35)534.6(Cl＝37)
Embodiment 46:N-(3-bromophenyl)-2-[4-[4-(pyridin-4-yl butyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：558.5(Br＝79)，560.5(Br＝81)
Embodiment 47:N-(3, the 4-3,5-dimethylphenyl)-2-[4-[4-(pyridin-4-yl butyl) phthalazines-1-yl] piperazine-1-yl] ethanamide
MS[MH
+](m/z)：509.6
Embodiment 48:N-(quinoline-5-yl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.18(s，1H)，8.93(dd，1H)，8.40(d，1H)，8.20(dd，1H)，8.16～8.10(m，1H)，7.90(m，4H)，7.83～7.72(m，1H)，7.61(dd，1H)，7.37～7.23(m，4H)，7.17(t，1H)，4.59(s，2H)，3.53(s，4H)，3.44(s，2H)，2.94(s，4H).MS[MH
+](m/z)：489.3
Embodiment 49:N-(4,6-dimethoxypyridin-2-yl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.14(s，1H)，8.13(d，2H)，7.97～7.81(m，2H)，7.40～7.21(m，4H)，7.18(d，1H)，5.94(s，1H)，4.58(s，2H)，3.88(s，6H)，3.47(s，2H)，3.42(s，4H)，2.86(s，4H).MS[MH
+](m/z)：500.4
Embodiment 50:N-(5-fluoro-2-aminomethyl phenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.61(s，1H)，8.14(d，2H)，8.00～7.77(m，3H)，7.44～7.22(m，5H)，7.18(d，1H)，6.89(t，1H)，4.59(s，2H)，3.47(s，4H)，3.31(s，2H)，2.89(s，4H)，2.27(s，3H).MS[MH+](m/z)：470.1
Embodiment 51:N-(4-bromophenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.03(s，1H)，8.23～8.14(m，1H)，8.14～8.04(m，1H)，7.90(dd，2H)，7.68(d，2H)，7.50(d，2H)，7.29(m，4H)，7.17(t，1H)，4.58(s，2H)，3.45(s，4H)，3.29(s，2H)，2.83(s，4H).MS[MH
+](m/z)：516.1，518.1
Embodiment 52:N-(3, the 5-dichlorophenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.24(s，1H)，8.18(s，1H)，8.09(s，1H)，7.91(s，2H)，7.83(s，2H)，7.34～7.24(m，5H)，7.18(d，J＝6.8Hz，1H)，4.58(s，2H)，3.48(s，4H)，3.34(s，2H)，2.86(s，4H).MS[MH
+](m/z)：507.3，508.1
Embodiment 53:N-(4-fluorophenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.93(s，1H)，8.18(d，1H)，8.08(s，1H)，7.95～7.84(m，2H)，7.70(dd，2H)，7.36～7.22(m，4H)，7.16(t，3H)，4.58(s，2H)，3.46(s，4H)，3.27(s，2H)，2.83(s，4H).MS[MH
+](m/z)：456.3
Embodiment 54:N-(4-fluoro-3-trifluoromethyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.25(s，1H)，8.19(t，2H)，8.09(d，1H)，7.99(s，1H)，7.95～7.83(m，2H)，7.49(t，1H)，7.39～7.21(m，4H)，7.18(d，1H)，4.58(s，2H)，3.46(s，4H)，3.31(s，2H)，2.83(s，4H).MS[MH
+](m/z)：524.1
Embodiment 55:N-(3,5-two trifluoromethyls)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.58(s，1H)，8.47(s，2H)，8.18(d，1H)，8.10(d，1H)，7.96～7.84(m，2H)，7.78(s，1H)，7.37～7.21(m，4H)，7.16(t，1H)，4.58(s，2H)，3.48(s，4H)，3.36(s，2H)，2.85(s，4H).MS[MH
+](m/z)：574.3
Embodiment 56:N-(2-aminomethyl phenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.49(s，1H)，8.19(d，1H)，8.10(s，1H)，7.98～7.86(m，2H)，7.83(d，1H)，7.28(m，5H)，7.18(d，2H)，7.05(t，1H)，4.59(s，2H)，3.48(s，4H)，3.29(s，2H)，2.89(s，4H)，2.28(s，3H).MS[MH
+](m/z)：452.3
Embodiment 57:N-(3-chloro-4-fluorophenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.12(s，1H)，8.18(dd，1H)，8.10(dd，1H)，8.03(dd，1H)，7.90(m，2H)，7.64(m，1H)，7.40(d，1H)，7.30(m，4H)，7.17(t，1H)，4.58(s，2H)，3.46(s，4H)，3.29(s，2H)，2.83(s，4H).MS[MH
+](m/z)：490.3，492.3
Embodiment 58:N-(2, the 4-3,5-dimethylphenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.40(s，1H)，8.19(d，1H)，8.10(s，1H)，7.97～7.85(m，2H)，7.65(d，1H)，7.37～7.23(m，4H)，7.18(d，1H)，7.12～6.93(m，2H)，4.58(s，2H)，3.47(s，4H)，3.26(s，2H)，2.87(s，4H)，2.23(d，6H).MS[MH
+](m/z)：466.2
Embodiment 59:N-(4-aminomethyl phenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.78(s，1H)，8.22～8.16(m，1H)，8.10(d，1H)，7.89(d，2H)，7.55(d，2H)，7.34～7.23(m，4H)，7.18(d，1H)，7.12(d，2H)，4.58(s，2H)，3.46(s，4H)，3.26(s，2H)，2.83(s，4H)，2.25(s，3H).MS[MH
+](m/z)：452.2
Embodiment 60:N-(3-chloro-phenyl-)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.10(s，1H)，8.18(dd，1H)，8.10(dd，1H)，7.97～7.83(m，3H)，7.61(d，1H)，7.39～7.23(m，5H)，7.22～7.06(m，2H)，4.58(s，2H)，3.46(s，4H)，3.30(s，2H)，2.83(s，4H).MS[MH
+](m/z)：472.1，473.1
Embodiment 61:N-(4-Trifluoromethoxyphen-l)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.11(s，1H)，8.18(dd，1H)，8.10(dd，1H)，7.94～7.84(m，2H)，7.84～7.77(m，2H)，7.36～7.23(m，6H)，7.17(t，1H)，4.58(s，2H)，3.46(s，4H)，3.31(s，2H)，2.84(s，4H).MS[MH
+](m/z)：522.4
Embodiment 62:N-(2, the 6-difluorophenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO)δ9.61(s，1H)，8.17(dd，1H)，8.09(dd，1H)，7.94～7.83(m，2H)，7.41～7.22(m，5H)，7.16(dd，3H)，4.57(s，2H)，3.46(s，4H)，3.31(s，2H)，2.83(s，4H).MS[MH
+](m/z)：474.3
Embodiment 63:N-(3-bromophenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO)δ10.11(s，1H)，8.25～8.14(m，1H)，8.14～8.02(m，2H)，7.96～7.82(m，2H)，7.65(d，1H)，7.28(m，6H)，7.16(t，1H)，4.58(s，2H)，3.45(s，4H)，3.30(s，2H)，2.83(s，4H).MS[MH
+](m/z)：516.3，518.3
Embodiment 64:N-(3-fluorophenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.20(s，1H)，8.18(d，1H)，8.09(d，1H)，7.89(d，2H)，7.70(d，1H)，7.46(d，1H)，7.39～7.23(m，5H)，7.17(d，1H)，6.88(t，1H)，4.58(s，2H)，3.46(s，4H)，3.33(s，2H)，2.85(s，4H).MS[MH
+](m/z)：456.4
Embodiment 65:N-(2-chloro-5-trifluoromethyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.23(s，1H)，8.69(s，1H)，8.20(d，1H)，8.11(d，1H)，8.00～7.87(m，2H)，7.82(d，1H)，7.52(d，1H)，7.37～7.22(m，4H)，7.18(d，1H)，4.59(s，2H)，3.49(s，4H)，3.38(s，2H)，2.91(s，4H).MS[MH
+](m/z)：540.3，542.3
Embodiment 66:N-(2-trifluoromethyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.97(s，1H)，8.27(d，1H)，8.18(s，1H)，8.11(s，1H)，8.00～7.85(m，2H)，7.73(dd，2H)，7.43-7.23(m，5H)，7.18(d，1H)，4.59(s，2H)，3.46(s，4H)，3.34(s，2H)，2.89(s，4H).MS[MH
+](m/z)：506.1
Embodiment 67:N-(2-chloro-6-aminomethyl phenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.55(s，1H)，8.18(d，1H)，8.11(d，1H)，7.97～7.82(m，2H)，7.39～7.13(m，8H)，4.58(s，2H)，3.49(s，4H)，3.30(s，2H)，2.89(s，4H)，2.22(s，3H).MS[MH
+](m/z)：486.4，488.4
Embodiment 68:N-(3, the 4-difluorophenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.24(s，1H)，8.18(d，1H)，8.09(d，1H)，7.88(dd，3H)，7.51～7.36(m，2H)，7.36～7.21(m，4H)，7.16(t，1H)，4.58(s，2H)，3.47(s，4H)，3.37(s，2H)，2.88(s，4H).MS[MH
+](m/z)：474.4
Embodiment 69:N-(3, the 4-Dimethoxyphenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.73(s，1H)，8.18(d，1H)，8.09(d，1H)，7.88(dd，2H)，7.26(m，7H)，6.89(d，1H)，4.58(s，2H)，3.73(s，3H)，3.71(s，3H)，3.46(s，4H)，3.26(s，2H)，2.84(s，4H).MS[MH
+](m/z)：498.4
Embodiment 70:N-(3, the 5-difluorophenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.37(s，1H)，8.18(d，1H)，8.09(d，1H)，7.96～7.84(m，2H)，7.50(d，2H)，7.37～7.21(m，4H)，7.16(t，1H)，6.92(t，1H)，4.58(s，2H)，3.45(s，4H)，3.32(s，2H)，2.89～2.70(m，4H).MS[MH
+](m/z)：474.4
Embodiment 71:N-(3, the 5-difluorophenyl)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.23(s，1H)，7.53～7.40(m，3H)，7.35(d，2H)，7.30～7.23(m，3H)，7.17(t，1H)，6.92(t，1H)，4.55(s，2H)，3.94(s，3H)，3.87(s，3H)，3.41(s，4H)，3.30(s，2H)，2.81(s，4H).MS[MH
+](m/z)：534.1
Embodiment 72:N-(3, the 4-difluorophenyl)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.23(s，1H)，7.88(dd，1H)，7.43(t，3H)，7.35(d，2H)，7.30～7.22(m，3H)，7.16(t，1H)，4.55(s，2H)，3.94(s，3H)，3.87(s，3H)，3.41(s，4H)，3.32(s，2H)，2.83(s，4H).MS[MH
+](m/z)：534.4
Embodiment 73:N-(2-trifluoromethyl)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ：9.97(s，1H)，8.27(d，1H)，7.85(t，1H)，7.81-7.62(m，3H)，7.43(s，1H)，7.36(d，2H)，7.31～7.22(m，3H)，4.56(s，2H)，3.95(s，3H)，3.88(s，3H)，3.38(s，4H)，3.33(s，2H)，2.88(s，4H).MS[MH
+](m/z)：566.3
Embodiment 74:N-(2-fluorophenyl)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.72(s，1H)，8.02(t，1H)，7.42(s，1H)，7.36(d，2H)，7.31～7.23(m，4H)，7.22～7.13(m，3H)，4.55(s，2H)，3.95(s，3H)，3.87(s，3H)，3.40(s，4H)，3.32(s，2H)，2.86(s，4H).MS[MH
+](m/z)：516.3
Embodiment 75:N-(4-Trifluoromethoxyphen-l)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.07(s，1H)，7.80(d，2H)，7.42(s，1H)，7.33(dd，5H)，7.26(d，2H)，7.18(d，1H)，4.55(s，2H)，3.94(s，3H)，3.87(s，3H)，3.41(s，4H)，3.29(s，2H)，2.82(s，4H).MS[MH
+](m/z)：582.4
Embodiment 76:N-(3-chloro-phenyl-)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.06(s，1H)，7.90(s，1H)，7.59(d，1H)，7.42(s，1H)，7.34(t，3H)，7.30～7.24(m，3H)，7.15(dd，2H)，4.55(s，2H)，3.94(s，3H)，3.87(s，3H)，3.41(s，4H)，3.29(s，2H)，2.82(s，4H).MS[MH
+](m/z)：532.4，534.4
Embodiment 77:N-(4-aminomethyl phenyl)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.76(s，1H)，7.55(d，2H)，7.42(s，1H)，7.35(d，2H)，7.30～7.23(m，3H)，7.18(d，1H)，7.11(d，2H)，4.55(s，2H)，3.94(s，3H)，3.87(s，3H)，3.40(s，4H)，3.25(s，2H)，2.82(s，4H)，2.25(s，3H).MS[MH
+](m/z)：512.3
Embodiment 78:N-(2, the 5-3,5-dimethylphenyl)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.43(s，1H)，7.66(s，1H)，7.43(s，1H)，7.36(d，2H)，7.30～7.25(m，3H)，7.21～7.09(m，2H)，6.87(d，1H)，4.55(s，2H)，3.95(s，3H)，3.88(s，3H)，3.42(s，4H)，3.27(s，2H)，2.87(s，4H)，2.26(s，3H)，2.22(s，3H).MS[MH
+](m/z)：526.4
Embodiment 79:N-(2, the 4-3,5-dimethylphenyl)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.41(s，1H)，7.64(d，1H)，7.43(s，1H)，7.36(d，2H)，7.30～7.24(m，3H)，7.17(t，1H)，7.04(s，1H)，6.99(d，1H)，4.55(s，2H)，3.95(s，3H)，3.88(s，3H)，3.42(s，4H)，3.27(s，2H)，2.87(s，4H)，2.24(s，3H)，2.23(s，3H).MS[MH
+](m/z)：526.2
Embodiment 80:N-(4-fluorophenyl)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.30(s，1H)，7.70(dd，2H)，7.44(s，1H)，7.36(d，2H)，7.32～7.23(m，3H)，7.17(t，3H)，4.57(s，2H)，3.96(s，3H)，3.88(s，3H)，3.49(s，4H)，3.37(s，2H)，3.03(s，4H).MS[MH
+](m/z)：516.3
Embodiment 81:N-(3, the 5-dichlorophenyl)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.28(s，1H)，7.83(d，2H)，7.43(s，1H)，7.35(d，2H)，7.31～7.22(m，4H)，7.17(t，1H)，4.55(s，2H)，3.95(s，3H)，3.88(s，3H)，3.43(s，4H)，3.34(s，2H)，2.86(s，4H).MS[MH
+](m/z)：566.3，568.4
Embodiment 82:N-(4-chloro-phenyl-)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ10.06(s，1H)，7.72(d，2H)，7.42(s，1H)，7.35(s，4H)，7.25(d，3H)，7.16(s，1H)，4.54(s，2H)，3.94(s，3H)，3.87(s，3H)，3.39(s，4H)，3.28(s，2H)，2.81(s，4H).MS[MH
+](m/z)：532.1，534.1
Embodiment 83:N-(2-fluorine 5-aminomethyl phenyl)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.66(s，1H)，7.84(d，1H)，7.42(s，1H)，7.36(d，2H)，7.31～7.22(m，3H)，7.21～7.11(m，2H)，6.94(s，1H)，4.55(s，2H)，3.95(s，3H)，3.87(s，3H)，3.40(s，4H)，3.31(s，2H)，2.85(s，4H)，2.28(s，3H).MS[MH
+](m/z)：530.4.
Embodiment 84:N-(2,4 dichloro benzene base)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，DMSO-d
6)δ9.69(s，1H)，7.42(s，2H)，7.40～7.31(m，3H)，7.31～7.23(m，3H)，7.17(t，1H)，7.05(d，1H)，4.55(s，2H)，3.94(s，3H)，3.87(s，3H)，3.40(s，4H)，3.24(s，2H)，2.82(s，4H)，2.18(s，3H)，2.16(s，3H).MS[MH
+](m/z)：526.5
Embodiment 85:N-(2, the 6-difluorophenyl)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，CDCl
3)δ8.78(s，1H)，7.35(d，J＝7.1Hz，2H)，7.29(d，J＝7.9Hz，4H)，7.21(dd，J＝10.4，3.3Hz，3H)，6.99(t，J＝8.0Hz，2H)，4.60(s，2H)，4.03(s，3H)，3.88(s，3H)，3.62～3.55(m，4H)，3.38(s，2H)，3.02～2.96(m，4H).MS[MH
+](m/z)：526.5
Embodiment 86:N-(3,5-two trifluoromethyls)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide
1H?NMR(300MHz，CDCl
3)δ9.64(s，1H)，8.14(s，2H)，7.63(s，1H)，7.35(d，2H)，7.29(d，3H)，7.22(s，2H)，4.64(s，2H)，4.03(s，3H)，3.89(s，3H)，3.61(s，4H)，3.37(s，2H)，2.98(s，4H).MS[MH
+](m/z)：634.5
The pharmacological research of product of the present invention
To according to 1 of following formula I of the present invention, 4-replaces Phthalazines and has carried out the anti tumor activity in vitro screening.
The anti tumor activity in vitro test
(1) A549 (non-small cell lung cancer cell), HT-29 (human colon cancer cell), three kinds of cell strains of MB-MDA-231 (human breast cancer cell) are recovered respectively and go down to posterity 2-3 time stable after, with trypsin solution (0.25%) it is digested bottom culturing bottle.Cell dissociation buffer poured into then add nutrient solution in the centrifuge tube to stop digestion.With centrifuge tube centrifugal 3min under 1300r/min, add the 5mL nutrient solution gently after the abandoning supernatant, piping and druming mixing cell is drawn in the 10 μ L cell suspensions adding cell counting count board and is counted, and adjusting cell concn is 10
4Individual/hole.Removing the A1 hole in 96 orifice plates is that blank well does not add the extracellular, and all the other all add the 100uL cell suspension.96 orifice plates are put into incubator cultivate 24h.
(2) with 50 μ L dmso solution given the test agent, add an amount of nutrient solution then, make sample dissolution become the 2mg/mL soup.In 24 orifice plates, be 100,20,4,0.8 then with diluted sample, 0.16 μ g/mL.Each concentration adds 3 holes, and wherein two row, two row cell growing ways are affected by environment bigger on every side, only uses as blank cell hole.96 orifice plates are put into incubator cultivate 72H.
(3) will be in 96 orifice plates band medicine nutrient solution discard, with cell flushing twice, in every hole, add MTT (tetrazole) (0.5mg/mL) after 100 μ L put into incubator 4h with phosphate buffer solution (PBS), discard MTT solution, add dimethyl sulfoxide (DMSO) 100 μ L.Vibration is fully dissolved survivaling cell and MTT reaction product Jia Za on the magnetic force vibrator, puts into the microplate reader measurement result, can obtain medicine IC by the Bliss method
50Value.
The extracorporeal anti-tumor cytoactive of compound the results are shown in Table 1.
Table 1 embodiment compound anti tumor activity in vitro
Can clearly be seen that from above-mentioned test-results; the compound of the claimed general formula I of the present invention; has good anti tumor activity in vitro; overwhelming majority compounds quite or the antitumor drug Gefitinib (Iressa) that is better than having gone on the market, and all compounds all are far superior to the antitumor drug Gefitinib (Iressa) of having gone on the market for the inhibition activity of MB-MDA-231.
The compound of formula of I of the present invention can be used separately, but normally give with the pharmaceutical carrier mixture, the selection of described pharmaceutical carrier will be according to required route of administration and standard drug practice, use the various pharmaceutical dosage forms of this compounds below respectively, for example the preparation method of tablet, capsule, injection, aerosol, suppository, film, pill, externally-applied liniment and ointment illustrates its new application in pharmacy field.
Embodiment 87: tablet
With the compound that contains compound in the claim 1 (is example with embodiment 1 compound) 10g, add auxiliary material 20g mixing according to the general pressed disc method of pharmaceutics after, be pressed into 100, every heavy 300mg.
Embodiment 88: capsule
With the compound that contains compound in the claim 1 (is example with embodiment 1 compound) 10g, according to the requirement of pharmaceutics capsule with auxiliary material 20g mixing after, the Capsules of packing into, the heavy 300mg of each capsule.
Embodiment 89: injection
With the compound that contains compound in the claim 1 (is example with embodiment 1 compound) 10g,, carry out charcoal absorption according to the pharmaceutics ordinary method, behind 0.65 μ m filtering with microporous membrane, insert nitrogen pot and make hydro-acupuncture preparation, every dress 2mL, can is 100 bottles altogether.
Embodiment 90: aerosol
With the compound that contains compound in the claim 1 (is example with embodiment 1 compound) 10g, after the dissolving of an amount of propylene glycol, add distilled water and other spoke material after, the settled solution of making 500mL is promptly.
Embodiment 91: suppository
With the compound that contains compound in the claim 1 (is example with embodiment 1 compound) 10g, it porphyrize adding glycerine is an amount of, grind well the back and add the glycogelatin that has melted, to grind evenly, impouring has been coated with in the model of lubricant, makes 50 of suppositorys
Embodiment 92: film
With the compound that contains compound in the claim 1 (is example with embodiment 1 compound) 10g, polyvinyl alcohol, medicinal glycerin, water etc. are stirred the dissolving of expansion post-heating, 80 eye mesh screens filter, and again embodiment 18 compounds are joined stirring and dissolving in the filtrate, 100 of the machine-processed films of filming.
Embodiment 93: pill
With the compound that contains compound in the claim 1 (is example with embodiment 1 compound) 10g, behind matrix 50g heat fused mixings such as gelatin, splash in the cryogenic liquid paraffin, make dripping pill 1000 balls altogether.
Embodiment 94: externally-applied liniment
With the compound that contains compound in the claim 1 (is example with embodiment 1 compound) 10g, according to auxiliary material 2.5g mixed grindings such as conventional dose method and emulsifying agents, adding distil water makes to 200mL again.
Embodiment 95: ointment
With the compound that contains compound in the claim 1 (is example with embodiment 1 compound) 10g, grind well with oleaginous base 500g such as Vaseline behind the porphyrize and make.
Although described the present invention by particular, modification and equivalent variations are obvious for the technician who is proficient in this field, and they are included within the scope of the invention.
Claims (11)
1. the compound of general formula I and pharmacy acceptable salt thereof, solvate or prodrug,
Wherein
Ar
1Be phenyl, naphthyl or 5-10 unit heteroaryl, described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and Ar
1Optional 1-3 identical or different R
1Replace;
Ar
2Be phenyl, naphthyl or 5-10 unit heteroaryl, described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and Ar
2Optional 1-3 identical or different R
2Replace;
R
1Be hydrogen, halogen, halogenated methoxy, carboxyl, carboxylic acid ester groups, nitro, cyano group, (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, cycloalkyl, halogenated cycloalkyl, N, N-(C1-C4) alkylamino, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl, (C1-C4) alkyl acyl, N-(C1-C4) alkyl-carbamoyl, N, N-(C1-C4) alkyl-carbamoyl, N-(C1-C4) alkylamino sulfinyl, N, N-(C1-C4) alkyl amino sulfonyl, aryloxy, heteroaryloxy, substituted heteroaryloxy, substituted heterocyclic radical;
R
2Be hydrogen, halogen, halogenated methoxy, carboxyl, carboxylic acid ester groups, nitro, cyano group, (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, cycloalkyl, halogenated cycloalkyl, N, N-(C1-C4) alkylamino, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl, (C1-C4) alkyl acyl, N-(C1-C4) alkyl-carbamoyl, N, N-(C1-C4) alkyl-carbamoyl, N-(C1-C4) alkylamino sulfinyl, N, N-(C1-C4) alkyl amino sulfonyl, aryloxy, heteroaryloxy, substituted heteroaryloxy, substituted heterocyclic radical;
R
3Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano group, (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, aryloxy, heteroaryloxy, substituted heteroaryl, substituted heterocyclic radical; And described R
3Optional 1-3 identical or different above group;
N is the integer between the 1-4.
2. the compound of the general formula I of claim 1 and pharmacy acceptable salt thereof, solvate or prodrug,
Wherein,
Ar
1Be phenyl or 5-10 unit heteroaryl, described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and Ar
1Optional 1-3 identical or different R
1Replace;
Ar
2Be phenyl or 5-10 unit heteroaryl, described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and Ar
2Optional 1-3 identical or different R
2Replace;
R
1Be hydrogen, halogen, halogenated methoxy, carboxyl, carboxylic acid ester groups, nitro, cyano group, (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, cycloalkyl, halogenated cycloalkyl, N, N-(C1-C4) alkylamino, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl, (C1-C4) alkyl acyl, N-(C1-C4) alkyl-carbamoyl, N, N-(C1-C4) alkyl-carbamoyl, N-(C 1-C4) alkylamino sulfinyl, N, N-(C1-C4) alkyl amino sulfonyl;
R
2Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano group, (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, (C1-C4) alkyl acyl, (C1-C4) alkyl aminoacyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl;
R
3Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano group, (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, and described R
3Optional 1-3 identical or different above group;
N is the integer between the 1-4.
3. the compound of the general formula I of claim 2 and pharmacy acceptable salt thereof, solvate or prodrug,
Wherein,
Ar
2Be phenyl, and Ar
2Optional 1-3 identical or different R
2Replace;
R
2Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano group, (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, (C1-C4) alkyl acyl, (C1-C4) alkyl aminoacyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl;
R
3Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, (C1-C4) alkyl, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group.
4. the compound of the general formula I of claim 2 and pharmacy acceptable salt thereof, solvate or prodrug,
Wherein,
Ar
2Be 5-10 unit heteroaryl, described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and Ar
2Optional 1-3 identical or different R
2Replace;
R
2Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano group, (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, (C1-C4) alkyl acyl, (C1-C4) alkyl aminoacyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl;
R
3Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, (C1-C4) alkyl, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group.
5. the compound of the general formula I of claim 4 and pharmacy acceptable salt thereof, solvate or prodrug,
Wherein,
Ar
1Be phenyl, and Ar
1Optional 1-3 identical or different R
1Replace;
R
1Be hydrogen, halogen, halogenated methoxy, carboxyl, carboxylic acid ester groups, nitro, cyano group, (C1-C4) alkyl, halo (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, cycloalkyl, halogenated cycloalkyl, N, N-(C1-C4) alkylamino, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl, (C1-C4) alkyl acyl, N-(C1-C4) alkyl-carbamoyl, N, N-(C1-C4) alkyl-carbamoyl, N-(C1-C4) alkylamino sulfinyl, N, N-(C1-C4) alkyl amino sulfonyl;
Ar
2Be 5-6 unit heteroaryl, described heteroaryl contains 1-3 heteroatoms that is selected from O, N and S, and wherein 1 heteroatoms is a nitrogen-atoms, Ar
2Optional 1-3 identical or different R
2Replace;
R
2Be hydrogen, halogen, trifluoromethyl, trifluoromethoxy, nitro, cyano group, (C1-C4) alkyl, (C1-C4) alkoxyl group, (C1-C4) alkoxy methyl, (C1-C3) alkylenedioxy group, (C1-C4) alkyl acyl, (C1-C4) alkyl aminoacyl, (C1-C4) alkyl sulphinyl, (C1-C4) alkyl sulphonyl;
6. the compound of the general formula I of claim 5 and pharmacy acceptable salt thereof, solvate or prodrug,
Wherein,
Ar
2Be pyrroles-2-base, pyrroles-3-base, pyridine-2-base, pyridin-3-yl, pyridin-4-yl;
R
3Be hydrogen;
N is 1.
7. the compound of the general formula I of claim 6 and pharmacy acceptable salt thereof, solvate or prodrug,
Wherein,
Ar
2Be pyridin-4-yl
R
3Be hydrogen;
N is 1.
8. the compound of following general formula I and pharmacy acceptable salt thereof, solvate or prodrug,
N-(2, the 5-3,5-dimethylphenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(3, the 5-bis trifluoromethyl phenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(3-chloro-4-fluorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(4-aminomethyl phenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(4-fluoro-3-trifluoromethyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(4-fluorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(5-fluoro-2-aminomethyl phenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(4-bromophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(3, the 4-3,5-dimethylphenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(4-Trifluoromethoxyphen-l)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(3-bromophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(3-fluorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(2-trifluoromethyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(3, the 4-difluorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(3, the 4-dichlorophenyl)-2-[4-[4-(pyridin-4-yl methyl) phthalazines-1-yl] piperazine-1-yl] ethanamide;
N-(4-fluoro-3-trifluoromethyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide;
N-(3, the 4-difluorophenyl)-2-[4-(4-benzyl phthalazines-1-yl) piperazine-1-yl] ethanamide;
N-(4-aminomethyl phenyl)-2-[4-(4-benzyl-6,7-dimethoxy phthalazines-1-yl) piperazine-1-yl] ethanamide.
9. medicinal compositions, comprise among the claim 1-8 any one compound and pharmacy acceptable salt, solvate or prodrug as activeconstituents and pharmaceutically acceptable excipient.
10. the compound of any one and pharmacy acceptable salt, solvate or prodrug treat and/or prevent application in the medicine of various proliferative diseases in preparation among the claim 1-8.
11. compound of any one and pharmacy acceptable salt thereof, solvate or prodrug treat and/or prevent application in the medicine of various cancers in preparation among the claim 1-8.
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