CN102762549B

CN102762549B - Phthalazinone derivative, and preparation method and pharmaceutical use thereof

Info

Publication number: CN102762549B
Application number: CN201180004612.2A
Authority: CN
Inventors: 邓炳初; 张学军; 李晓涛; 朱耀平; 杨斌斌
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2010-08-10
Filing date: 2011-08-02
Publication date: 2015-05-27
Anticipated expiration: 2031-08-02
Also published as: CN102762549A; WO2012019430A1; CN102372698A; WO2012019430A8

Abstract

The present invention relates to a phthalazinone derivative, and a preparation method and a pharmaceutical use thereof, and specifically the present invention relates to a new phthalazinone derivative represented by a general formula (I), a preparation method thereof, a pharmaceutical composition containing the derivative, and a use thereof as a therapeutic agent and especially as a poly (ADP-ribose) polymerase (PARP) inhibitor.

Description

Phthalazone analog derivative, its preparation method and in application pharmaceutically

Technical field

The present invention relates to phthalazone analog derivative new shown in a kind of general formula (I), its preparation method and the pharmaceutical composition containing this derivative and it is as the purposes of therapeutical agent as poly-(ADP-ribose) polysaccharase (PARP) inhibitor.

Background technology

Chemotherapeutics and ionizing radiation treatment are two kinds of common methods of Therapeutic cancer.These two kinds of methods for the treatment of all can induce dna strand and/or double-strand break and then produce cytotoxic effect, and target tumor is dead due to chromosome damage.Responsively an important results of DNA damage signal is that cell cycle regulating site signal is activated, and its object is to Cell protection and does not carry out mitotic division when DNA damage thus avoid cell injury.In most of the cases, tumour cell has very high proliferation rate while showing cell cycle regulating site signal defect.Therefore can infer in tumour cell, to there is specific DNA repair mechanism, can respond fast and repair and regulates relevant chromosome damage to propagation, thus make himself to survive the cytotoxic effect of some medicines and maintenance is survived.

In clinical application, effective concentration or the treatment yield of radiation of chemotherapeutics can resist these DNA repair mechanisms, ensure the fragmentation effect to target tumor.But tumour cell can produce tolerance effect to treatment by strengthening its DNA damage repair mechanism, makes it to survive from fatal DNA damage.In order to overcome the tolerance of generation, usually the dosage or the raising yield of radiation that increase medicine is needed, the disadvantageous effect that this way will produce the healthy tissues near focus, thus make with serious untoward reaction in therapeutic process, and then increase Operative risk.Meanwhile, ever-increasing tolerance will reduce result for the treatment of, therefore can infer, by the adjustment to DNA damage signal repair mechanism, and the Cytotoxic raising that can realize DNA damage medicament in the mode of tumor cell specific.

The PARPs being feature with poly-adenosine diphosphate (ADP)-ribosylating activity (Poly (ADP-ribose) polymerases), constitutes the superfamily of 18 kinds of cell ribozymes and tenuigenin enzyme.This poly-adenosine diphosphate (ADP)-ribosylation can regulate catalytic activity and the protein-protein interaction of target protein, and many basic bioprocesss are regulated and controled, comprise DNA to repair, necrocytosis, Genome stability is also associated (see D`Amours et al.Biochem.J, 1999,342,249).

PARP-1 activity accounts for 80% of total cell PARP activity, and it and the PARP-2 the most close with it become the member possessing DNA plerosis lesion capability in PARP family jointly.As inductor block and the signal protein of DNA damage, PARP-1 rapid detection also can directly be bonded to DNA damage site, the multiple protein needed for induced aggregation DNA reparation afterwards, and then makes DNA damage repaired.When the PARP-1 in cell lacks, PARP-2 can substitute the reparation that PARP-1 realizes DNA damage.

Research shows, compared with normal cell, the expression of PARPs albumen in solid tumor generally strengthens.In addition, for the tumour (as breast tumor and ovarian cancer) of DNA Related to repair gene disappearance (as BRCA-1 or BRCA-2), show the extreme sensitivity to PARP-1 inhibitor, this shows that PARP inhibitor is called as potential use in three negative breast cancer (see Plummer as single dose treatment is this, E.R.Curr.Opin.Pharmacol.2006,6,364; Ratnam, et al; Clin.Cancer Res.2007,13,1383).Meanwhile, because DNA damage repair mechanism is the main mechanism that tumour cell reply chemotherapeutics and ionizing radiation treatment produce tolerance effect, therefore PARP-1 is considered to the Effective target site exploring new cancer treatment method.

The PARP inhibitor of early development design is all using the NAD as PARP catalytic substrate ⁺niacinamide as template, develop its analogue.These inhibitor are as NAD ⁺competitive inhibitor, with NAD ⁺the catalytic site of competition PARP, and then the synthesis stoping poly-(ADP-ribose) chain.PARP under not having poly-(ADP-ribosylation) to modify cannot disintegrate down from DNA damage site, the protein causing other to participate in repairing is entered injury site, and then can not perform repair process.Therefore, under the effect of cytotoxic drug or radiation, the tumour cell that the existence of PARP inhibitor makes DNA impaired is finally dead.

In addition, the NAD be consumed as PARP catalytic substrate ⁺, be the requisite factor in cell synthesis ATP building-up process.Under high PARP activity level, intracellular NAD ⁺level can significantly decline, and then affects the ATP level in born of the same parents.Because the ATP in born of the same parents is containing quantity not sufficient, cell cannot realize the programmed cell death process that ATP relies on, and can only turn to this special apoptotic process downright bad.In the process of necrosis, a large amount of inflammatory factors can be released, thus produces toxic action (Horvath EM et al.DrugNews Perspect, 2007,20,171-181) to other Organ and tissues.Therefore, PARP inhibitor also can be used for treating the various diseases relevant with this mechanism, comprises nerve degenerative diseases (as senile dementia, Huntington Chorea, Parkinson's disease), diabetes, complication in ischemic or Ischemia-Reperfusion Injury, as myocardial infarction and acute renal failure, circulation system disease, as septic shock, and diseases associated with inflammation, if chronic rheumatism etc. is (see Tentori L, et al.Pharmacol Res, 2002,45,73-85; Horvath EM et al.Drug News Perspect, 2007,20,171.; Faro R, et al.Ann Thorac Surg, 2002,73,575.; Kumaran D, et al.Brain Res, 2008,192,178.).

Disclose the patent application of a series of phthalazines ketone PARP inhibitor at present, comprise WO2002036576, WO2004080976 and WO2006021801.

Although disclosed the PARP inhibitor of a series for the treatment of tumour at present, but still need to develop and new there is better drug effect, medicine for the compound of result, through continuous effort, the present invention's design has the compound of the structure shown in general formula (I), and finds that the compounds exhibit with this class formation goes out excellent effect and effect.

Summary of the invention

The object of the present invention is to provide phthalazone analog derivative shown in a kind of general formula (I), and their tautomer, enantiomorph, diastereomer, raceme and pharmaceutically useful salt, and meta-bolites and metabolic precursor thereof or prodrug.

Wherein:

A with B forms cycloalkyl, heterocyclic radical, aryl or heteroaryl together with the carbon atom be connected, and wherein said cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally selected from halogen, hydroxyl, cyano group, nitro, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more independently of one another further ⁹,-OC (O) R ⁹,-C (O) R ⁹,-NHC (O) R ⁹,-NR ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹,-NHC (O) NR ¹⁰r ¹¹,-C (O) (CH ₂) _mnR ¹⁰r ¹¹or-S (O) _mr ⁹substituting group replaced;

E is formula-(CH ₂) _n1-Q _n2-(CH ₂) _n3-;

Wherein n1, n2 and n3 be selected from respectively O, 1,2 and 3, n1, n2 and n3 summation be 1,2 or 3, Q be selected from O, S, NH or C (O);

R ¹be selected from hydrogen atom, alkyl, hydroxyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl;

R ², R ³and R ⁴be selected from hydrogen atom, halogen, hydroxyl, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR independently of one another ⁹,-OC (O) R ⁹,-C (O) R ⁹,-NHC (O) R ⁹,-NR ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹,-NHC (O) NR ¹⁰r ¹¹,-C (O) (CH ₂) mNR ¹⁰r ¹¹or-S (O) _mr ⁹, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl are independent separately is optionally selected from halogen, hydroxyl, alkyl, alkoxyl group ,-C (O) OR by one or more further ⁹,-OC (O) R ⁹,-C (O) R ⁹,-NHC (O) R ⁹,-NR ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹,-NHC (O) NR ¹⁰r ¹¹,-C (O) (CH ₂) _mnR ¹⁰r ¹¹or-S (O) _mr ⁹substituting group replaced;

R ⁵and R ⁶be selected from hydrogen atom, hydroxyl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR independently of one another ⁹,-C (O) R ⁹or-C (O) (CH ₂) _mnR ¹⁰r ¹¹, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately independent optional further by one or more be selected from the substituting group of halogen, hydroxyl, alkyl or alkoxyl group replace, or R ⁵and R ⁶form oxo together;

R ⁷and R ⁸be selected from hydrogen atom, hydroxyl, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR independently of one another ⁹,-OC (O) R ⁹,-C (O) R ⁹,-NHC (O) R ⁹,-NR ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹,-NHC (O) NR ¹⁰r ¹¹,-C (O) (CH ₂) _mnR ¹⁰r ¹¹or-S (O) _mr ⁹, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl separately independent optional further by one or more be selected from the substituting group of halogen, hydroxyl, alkyl or alkoxyl group replace, or R ⁷and R ⁸form oxo together;

R ⁹be selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl, benzyl or heteroaryl, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally selected from alkyl, halogen, hydroxyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-NR by one or more independently of one another further ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹or-C (O) NR ¹⁰r ¹¹substituting group replaced;

R ¹⁰or R ¹¹independently be selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl, benzyl or heteroaryl separately, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally selected from hydroxyl, alkyl, halogen, cyano group, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (O) OR by one or more independently of one another further ¹²,-OC (O) R ¹²,-C (O) R ¹²,-NHC (O) R ¹²,-NR ¹³r ¹⁴,-OC (O) NR ¹³r ¹⁴,-NHC (O) NR ¹³r ¹⁴,-C (O) (CH ₂) _mnR ¹³r ¹⁴or-S (O) _mr ¹²substituting group replaced;

Or, R ¹⁰and R ¹¹heterocyclic radical is formed, containing one or more N, O or S (O) in wherein said heterocyclic radical with the nitrogen-atoms be connected _mheteroatoms, and described heterocyclyl is selected from hydroxyl, alkyl, haloalkyl, halogen, cyano group, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (O) OR by one or more further ¹²,-OC (O) R ¹²,-C (O) R ¹²,-NHC (O) R ¹²,-NR ¹³r ¹⁴,-OC (O) NR ¹³r ¹⁴,-NHC (O) NR ¹³r ¹⁴,-C (O) (CH ₂) _mnR ¹³r ¹⁴or-S (O) _mr ¹²substituting group replaced, wherein alkyl, cycloalkyl, benzyl, heteroaryl independently of one another optional further by one or more be selected from the substituting group of alkyl, haloalkyl, halogen, hydroxyl, alkoxyl group, heteroaryl or cycloalkyl replace;

R ¹², R ¹³or R ¹⁴be selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl, benzyl or heteroaryl independently of one another, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally selected from hydroxyl, alkyl, halogen, cyano group, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR by one or more independently of one another further ¹⁵,-OC (O) R ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-NHC (O) NR ¹⁶r ¹⁷,-C (O) (CH ₂) _mnR ¹⁶r ¹⁷or-S (O) _mr ¹⁵substituting group replaced;

R ¹⁵, R ¹⁶or R ¹⁷be selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl independently of one another, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally selected from hydroxyl, alkyl, halogen, cyano group, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl by one or more independently of one another further; And

M is 0,1 or 2.

Preferred version of the present invention, a kind of general formula (I) compound or its pharmaceutically useful salt, comprising the compound shown in a kind of general formula (II) or its pharmaceutically useful salt:

Wherein:

R ², R ³and R ⁴be selected from hydrogen atom, halogen, hydroxyl, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR independently of one another ⁹,-OC (O) R ⁹,-C (O) R ⁹,-NHC (O) R ⁹,-NR ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹,-NHC (O) NR ¹⁰r ¹¹,-C (O) (CH ₂) _mnR ¹⁰r ¹¹or-S (O) _mr ⁹, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl are independent separately is optionally selected from halogen, hydroxyl, alkyl, alkoxyl group ,-C (O) OR by one or more further ⁹,-OC (O) R ⁹,-C (O) R ⁹,-NHC (O) R ⁹,-NR ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹,-NHC (O) NR ¹⁰r ¹¹,-C (O) (CH ₂) _mnR ¹⁰r ¹¹or-S (O) _mr ⁹substituting group replaced;

M is 0,1 or 2.

Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein said compound or its pharmaceutically useful salt, wherein R ²for halogen.

Preferred version of the present invention, a kind of general formula (I) compound or its pharmaceutically useful salt, comprising the compound shown in a kind of general formula (III) or its pharmaceutically useful salt:

Wherein:

R ¹be selected from hydrogen atom, alkyl, hydroxyl or alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl;

R ³and R ⁴be selected from hydrogen atom, halogen, hydroxyl, cyano group, alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (O) OR independently of one another ⁹,-OC (O) R ⁹,-C (O) R ⁹,-NHC (O) R ⁹,-NR ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹,-NHC (O) NR ¹⁰r ¹¹,-C (O) (CH ₂) _mnR ¹⁰r ¹¹or-S (O) _mr ⁹, wherein said alkyl, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl are independent separately is optionally selected from halogen, hydroxyl, alkyl, alkoxyl group ,-C (O) OR by one or more further ⁹,-OC (O) R ⁹,-C (O) R ⁹,-NHC (O) R ⁹,-NR ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹,-NHC (O) NR ¹⁰r ¹¹,-C (O) (CH ₂) _mnR ¹⁰r ¹¹or-S (O) _mr ⁹substituting group replaced;

M is 0,1 or 2;

Preferred version of the present invention, a kind of general formula (I) compound or its pharmaceutically useful salt, wherein R ³and R ⁴be selected from hydrogen atom or halogen independently of one another, R ⁵, R ⁶, R ⁷and R ⁸be selected from hydrogen atom or halogen independently of one another.

Preferred version of the present invention, the compound shown in a kind of general formula (III) or its different pharmaceutically useful salt, comprising the compound shown in a kind of general formula (IV) or its pharmaceutically useful salt:

Wherein:

A with B forms cycloalkyl, heterocyclic radical, aryl or heteroaryl together with the carbon atom be connected;

R ¹be selected from hydrogen atom;

R ³and R ⁴be selected from hydrogen atom or halogen independently of one another;

M is 0,1 or 2;

Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein A with B forms aryl together with the carbon atom be connected, and is preferably phenyl.

Preferred version of the present invention, the compound shown in a kind of general formula (I) or its pharmaceutically useful salt, wherein R ¹for hydrogen atom.

Preferred version of the present invention, a kind of general formula (III) or the compound shown in (IV) or its pharmaceutically useful salt, wherein R ¹⁰and R ¹¹form heterocyclic radical with the nitrogen-atoms be connected, wherein said heterocyclyl is further by one or more-C (O) R ¹²substituting group replaced.

Preferred version of the present invention, a kind of general formula (III) or the compound shown in (IV) or its pharmaceutically useful salt, wherein:

R ¹⁰and R ¹¹form heterocyclic radical with the nitrogen-atoms be connected, wherein said heterocyclyl is further by one or more-C (O) R ¹²substituting group replaced;

R ¹²be selected from alkyl, cycloalkyl or heterocyclic radical, wherein said alkyl, cycloalkyl or heterocyclyl are selected from halogen, alkyl or-NR by one or more further ¹⁶r ¹⁷substituting group replaced.

General formula (I) compound can contain unsymmetrical carbon, therefore can exist using the form of the mixture of optically pure diastereomer, non-enantiomer mixture, diastereomer racemic modification, diastereomeric racemic modification or exist as mesomeride compound.The present invention includes all these forms.The mixture of non-enantiomer mixture, diastereomeric racemic modification or diastereomeric racemic modification can pass through ordinary method, such as, be separated by column chromatography, tlc and high-efficient liquid are equal.

The Equivalent considered---those skilled in the art will appreciate that into, also can there is the form of tautomer in compound (I).The tautomeric form of compound (I) can include but not limited to the structure represented by lower formula V:

Typical compound of the present invention includes, but are not limited to:

Or its pharmaceutically useful salt.

The present invention relates to the method that one prepares the compound shown in general formula (III) or its pharmaceutically useful salt, the method comprises:

General formula (IIIA) compound is optionally hydrolyzed and formula NHR further ¹⁰r ¹¹reaction, obtains general formula (III) compound;

Wherein A, B, R ¹, R ³~ R ⁸, R ¹⁰, R ¹¹as in general formula (III) define, and R ¹⁸as in general formula (IIIA) define.

The present invention relates to the compound shown in a kind of general formula (IIIA) or its pharmaceutically useful salt:

Wherein:

R ¹⁵, R ¹⁶or R ¹⁷be selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl independently of one another, wherein said alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally selected from hydroxyl, alkyl, halogen, cyano group, alkoxyl group, cycloalkyl, heterocyclic radical, aryl or heteroaryl by one or more independently of one another further;

R ¹⁸be selected from hydrogen atom or alkyl; And

M is 0,1 or 2.

The present invention relates to one and prepare the compound shown in general formula (IIIA), the method for pharmaceutically useful salt or solvate, the method comprises:

General formula compound a is changed into general formula compound b after oxidation;

General formula compound b is changed into general formula compound c;

General formula compound c is changed into general formula compound d;

General formula compound d is changed into general formula compound (IIIA);

Wherein A, B, R ¹, R ³~ R ⁸, R ¹⁸as general formula (III) define, X is halogen.

Another aspect of the present invention relates to general formula (I) compound or its pharmaceutically useful salt, suppresses the purposes in the medicine of PARP in preparation.

Another aspect of the present invention relates to a kind of method suppressing PARP, and the method comprises general formula (I) compound or its pharmaceutically useful salt that the patient giving needs treatment contains effective therapeutic dose.

Another aspect of the present invention relates to the compound shown in general formula (I) or its pharmaceutically useful salt, be prepared in cancer treatment procedure as assistant agent or for make tumour cell become responsive to ionizing rays or chemotherapy medicine in purposes.

Another aspect of the present invention relates in cancer treatment procedure as assistant agent or for making tumour cell become the compound shown in the general formula (I) of responsive medicine or its pharmaceutically useful salt to ionizing rays or chemotherapy.

Another aspect of the present invention relates to general formula (I) compound of medicine or its pharmaceutically useful salt as suppressing PARP.

Another aspect of the present invention relates to the compound shown in general formula (I) or its pharmaceutically useful salt, purposes in the medicine preparing Therapeutic cancer, wherein said cancer is mammary cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, liver cancer or colorectal carcinoma, further it is selected from following Drug combination with treatment effective dose to wherein said medicine: Temozolomide (Timozuoan), Zorubicin, taxol (Taxol, Paclitaxel), cis-platinum (Cisplatin), carboplatin (Carboplatin), Dacarbazine (Dacarbazine), topotecan (Topotecan), irinotecan (Irinotecan), gemcitabine (Gemcitabine) and rhuMAb-VEGF (Bevacizumab).

Another aspect of the present invention relates to a kind of method of Therapeutic cancer, the method gives the compound shown in general formula (I) or its pharmaceutically useful salt of the effective therapeutic dose of patient needing treatment, wherein said cancer is mammary cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, liver cancer or colorectal carcinoma, it is selected from following Drug combination with treatment effective dose further for the wherein said compound shown in general formula (I) or its pharmaceutically useful salt: Temozolomide, Zorubicin, taxol, cis-platinum, carboplatin, Dacarbazine, topotecan, irinotecan, gemcitabine or shellfish cut down antibody.

Another aspect of the present invention relates to the compound shown in general formula (I) or its pharmaceutically useful salt of the medicine as Therapeutic cancer, wherein said cancer is mammary cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, liver cancer or colorectal carcinoma, and further it is selected from following Drug combination with treatment effective dose to wherein said medicine: Temozolomide, Zorubicin, taxol, cis-platinum, carboplatin, Dacarbazine, topotecan, irinotecan, gemcitabine or shellfish cut down antibody.

Further, another aspect of the present invention relates to a kind of pharmaceutical composition, compound or its pharmacy acceptable salt shown in its general formula of the present invention (I) containing treatment effective dose, and pharmaceutically useful carrier or vehicle.This pharmaceutical composition can be used as and suppresses the medicine of PARP, or as in cancer treatment procedure as assistant agent or for making tumour cell become the medicine of sensitivity to ionizing rays or chemotherapy, or as the medicine of Therapeutic cancer.This pharmaceutical composition suppresses the purposes in the medicine of PARP in preparation.This pharmaceutical composition be prepared in cancer treatment procedure as assistant agent or for make tumour cell become responsive to ionizing rays or chemotherapy medicine in purposes.The purposes of this pharmaceutical composition in the medicine preparing Therapeutic cancer, wherein said cancer is mammary cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, liver cancer or colorectal carcinoma, and further it is selected from following Drug combination with treatment effective dose to wherein said composition: Temozolomide, Zorubicin, taxol, cis-platinum, carboplatin, Dacarbazine, topotecan, irinotecan, gemcitabine and sky shellfish cut down antibody.

detailed description of the invention

Unless stated to the contrary, the term used in the specification and in the claims has following implication.

" alkyl " refers to saturated aliphatic hydrocarbon group, comprises straight chain and the branched group of 1 to 20 carbon atom.Alkyl preferably containing 1 to 12 carbon atom, non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1,1-dimethyl propyl, 1,2-dimethyl propyl, 2,2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1,1,2-thmethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethyl amyl group, 2,4-dimethyl amyl group, 2,2-dimethyl amyl group, 3,3-dimethyl amyl group, 2-ethyl pentyl group, 3-ethyl pentyl group, n-octyl, 2,3-dimethylhexanyl, 2,4-dimethylhexanyl, 2,5-dimethylhexanyl, 2,2-dimethylhexanyl, 3,3-dimethylhexanyl, 4,4-dimethylhexanyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethyl pentyl group, 2-methyl-3-ethyl pentyl group, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethyl amyl group, positive decyl, 3,3-diethylhexyl, 2,2-diethylhexyl, and various branched chain isomers etc.Low alkyl group more preferably containing 1 to 6 carbon atom, non-limiting example comprises methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, sec-butyl, n-pentyl, 1, 1-dimethyl propyl, 1, 2-dimethyl propyl, 2, 2-dimethyl propyl, 1-ethyl propyl, 2-methyl butyl, 3-methyl butyl, n-hexyl, 1-Ethyl-2-Methyl propyl group, 1, 1, 2-thmethylpropyl, 1, 1-dimethylbutyl, 1, 2-dimethylbutyl, 2, 2-dimethylbutyl, 1, 3-dimethylbutyl, 2-ethyl-butyl, 2-methyl amyl, 3-methyl amyl, 4-methyl amyl, 2, 3-dimethylbutyl etc.Alkyl can be replacement or unsubstituted, when substituted, substituting group can be substituted on any spendable tie point, be preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio, oxo ,-C (O) OR ⁹,-OC (O) R ⁹,-C (O) R ⁹,-NHC (O) R ⁹,-NR ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹,-NHC (O) NR ¹⁰r ¹¹,-C (O) (CH ₂) _mnR ¹⁰r ¹¹or-S (O) _mr ⁹.

" cycloalkyl " refers to the unsaturated monocycle of saturated or part or many rings cyclic hydrocarbon substituent, and it comprises 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably cycloalkyl ring comprises 3 to 10 carbon atoms.The non-limiting example of monocyclic cycloalkyl comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, suberyl, cycloheptatriene base, ring octyl group etc.Polycyclic naphthene base comprises the cycloalkyl of volution, condensed ring and bridged ring." spiro cycloalkyl group " refers to 5 to 20 yuan, and share the polycyclic moiety of a carbon atom (title spiro atom) between monocycle, these can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, be more preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro cycloalkyl group, two spiro cycloalkyl group base or many spiro cycloalkyl group by the number according to sharing spiro atom between ring and ring, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.Be more preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises

" cycloalkyl " refers to 5 to 20 yuan, each ring in system and other rings in system share the full carbon polycyclic moiety of a pair carbon atom adjoined, wherein one or more rings can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, be more preferably 7 to 10 yuan.Dicyclo, three rings, Fourth Ring or polycyclic fused ring alkyl can be divided into according to the number of makeup ring, be preferably dicyclo or three rings, be more preferably 5 yuan/5 yuan or 5 yuan/6 yuan bicyclic alkyls.The non-limiting example of cycloalkyl comprises

" bridge ring alkyl " refers to 5 to 20 yuan, and any two rings share the full carbon polycyclic moiety of two carbon atoms directly do not connected, and these can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, be more preferably 7 to 10 yuan.Dicyclo, three rings, Fourth Ring or many rings bridge ring alkyl can be divided into according to the number of makeup ring, be preferably dicyclo, three rings or Fourth Ring, more elect dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises

Described cycloalkyl ring can condense on aryl, heteroaryl or heterocycloalkyl ring, and the ring wherein linked together with precursor structure is cycloalkyl, and non-limiting example comprises indanyl, tetralyl, benzocyclohepta alkyl etc.Cycloalkyl can be optional replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio, oxo ,-C (O) OR ⁹,-OC (O) R ⁹,-C (O) R ⁹,-NHC (O) R ⁹,-NR ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹,-NHC (O) NR ¹⁰r ¹¹,-C (O) (CH ₂) _mnR ¹⁰r ¹¹or-S (O) _mr ⁹.

" heterocyclic radical " refers to the unsaturated monocycle of saturated or part or many rings cyclic hydrocarbon substituent, and it comprises 3 to 20 annular atomses, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) _mthe heteroatoms of (wherein m is integer 0 to 2), but do not comprise the loop section of-O-O-,-O-S-or-S-S-, all the other annular atomses are carbon.Preferably include 3 to 12 annular atomses, wherein 1 ~ 4 is heteroatoms, and more preferably cycloalkyl ring comprises 3 to 10 annular atomses.The non-limiting example of monocyclic cycloalkyl comprises pyrrolidyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc.Polycyclic naphthene base comprises the heterocyclic radical of volution, condensed ring and bridged ring." spiro heterocyclic radical " refers to 5 to 20 yuan, and share the polycyclic heterocyclic group of an atom (title spiro atom) between monocycle, wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) _pthe heteroatoms of (wherein p is integer 0 to 2), all the other annular atomses are carbon.These can contain one or more double bond, but neither one ring has the π-electron system of total conjugated.Be preferably 6 to 14 yuan, be more preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into single spiro heterocyclic radical, two spiro heterocyclic radical or many spiro heterocyclic radicals by the number according to sharing spiro atom between ring and ring, is preferably single spiro cycloalkyl group and two spiro cycloalkyl group.Be more preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single spiro cycloalkyl group.The non-limiting example of spiro cycloalkyl group comprises

" fused heterocycle base " refers to 5 to 20 yuan, each ring in system and other rings in system share the polycyclic heterocyclic group of a pair atom adjoined, one or more ring can contain one or more double bond, but neither one ring has the π-electron system of total conjugated, wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) _pthe heteroatoms of (wherein p is integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, be more preferably 7 to 10 yuan.Dicyclo, three rings, Fourth Ring or many rings fused heterocycloalkyl can be divided into according to the number of makeup ring, be preferably dicyclo or three rings, be more preferably 5 yuan/5 yuan or 5 yuan/6 yuan fused bicyclic heterocycle bases.The non-limiting example of fused heterocycle base comprises

" bridge heterocyclic radical " refers to 5 to 14 yuan, any two rings share the polycyclic heterocyclic group of the atom that two directly do not connect, these can contain one or more double bond, but neither one ring has the π-electron system of total conjugated, and wherein one or more annular atomses are selected from nitrogen, oxygen or S (O) _mthe heteroatoms of (wherein m is integer 0 to 2), all the other annular atomses are carbon.Be preferably 6 to 14 yuan, be more preferably 7 to 10 yuan.7 to 10 yuan.Dicyclo, three rings, Fourth Ring or many rings bridge ring alkyl can be divided into according to the number of makeup ring, be preferably dicyclo, three rings or Fourth Ring, more elect dicyclo or three rings as.The non-limiting example of bridge ring alkyl comprises:

Described heterocyclic ring can condense on aryl, heteroaryl or cycloalkyl ring, and the ring wherein linked together with precursor structure is heterocyclic radical, and non-limiting example comprises:

Deng.Heterocyclic radical can be optional replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio, oxo ,-C (O) OR ⁹,-OC (O) R ⁹,-C (O) R ⁹,-NHC (O) R ⁹,-NR ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹,-NHC (O) NR ¹⁰r ¹¹,-C (O) (CH ₂) mNR ¹⁰r ¹¹or-S (O) _mr ⁹.

" aryl " refers to 6 to 14 yuan of full carbon monocycles or fused polycycle (namely sharing the right ring of adjacent carbon atoms) group, there is many rings (namely it is with the ring of the phase adjacency pair carbon atom) group of the π-electron system of conjugation, be preferably 6 to 10 yuan, such as phenyl and naphthyl.Described aryl rings can condense on heteroaryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is aryl rings, and non-limiting example comprises:

Aryl can be replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio ,-C (O) OR ⁹,-OC (O) R ⁹,-C (O) R ⁹,-NHC (O) R ⁹,-NR ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹,-NHC (O) NR ¹⁰r ¹¹,-C (O) (CH ₂) _mnR ¹⁰r ¹¹or-S (O) _mr ⁹.

" heteroaryl " refers to comprise 1 to 4 heteroatoms, the heteroaromatic system of 5 to 14 annular atomses, and wherein heteroatoms comprises oxygen, sulphur and nitrogen.Be preferably 5 to 10 yuan.Heteroaryl is preferably 5 yuan or 6 yuan, such as furyl, thienyl, pyridyl, pyrryl, N-alkyl pyrryl, pyrimidyl, pyrazinyl, imidazolyl, tetrazyl etc.Described heteroaryl ring can condense on aryl, heterocyclic radical or cycloalkyl ring, and the ring wherein linked together with precursor structure is heteroaryl ring, and non-limiting example comprises:

Heteroaryl can be optional replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, independently selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio ,-C (O) OR ⁹,-OC (O) R ⁹,-C (O) R ⁹,-NHC (O) R ⁹,-NR ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹,-NHC (O) NR ¹⁰r ¹¹,-C (O) (CH ₂) _mnR ¹⁰r ¹¹or-S (O) _mr ⁹.

" alkoxyl group " refers to-O-(alkyl) and-O-(unsubstituted cycloalkyl), and wherein the definition of alkyl is described above.Non-limiting example comprises methoxyl group, oxyethyl group, propoxy-, butoxy, ring propoxy-, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc.Alkoxyl group can be optional replacement or unsubstituted, when substituted, substituting group is preferably one or more following group, independently selected from being alkyl, thiazolinyl, alkynyl, alkoxyl group, alkylthio, alkylamino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle alkylthio ,-C (O) OR ⁹,-OC (O) R ⁹,-C (O) R ⁹,-NHC (O) R ⁹,-NR ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹,-NHC (O) NR ¹⁰r ¹¹,-C (O) (CH ₂) _mnR ¹⁰r ¹¹or-S (O) _mr ⁹.

" haloalkyl " refers to that alkyl is by one or more halogen substiuted.

" hydroxyl " refers to-OH group.

" halogen " refers to fluorine, chlorine, bromine or iodine.

" amino " refers to-NH ₂.

" cyano group " refers to-CN.

" nitro " refers to-NO ₂.

" benzyl " refers to-CH ₂-phenyl.

" oxo " refers to=O.

" carboxylic acid " refers to-C (O) OH.

" carboxylicesters " refers to-C (O) O (alkyl) or (cycloalkyl).

" optionally " or " optionally " mean subsequently described ground event or environment can but need not occur, this explanation comprises this event or environment occurs or not spot occasion.Such as, " optionally by heterocyclic group that alkyl replaces " mean alkyl can but must not exist, this explanation comprises situation that heterocyclic group replaced by alkyl and heterocyclic group not by situation that alkyl replaces.

" replacement " refers to the one or more hydrogen atoms in group, is preferably maximum 5, is more preferably 1 ~ 3 hydrogen atom and is replaced by the substituting group of respective number independently of one another.Self-evident, substituting group is only in their possible chemical position, those skilled in the art can determine when not paying and too much making great efforts (by experiment or theoretical) may or impossible replacement.Such as, have the amino of free hydrogen or hydroxyl and the carbon atom with unsaturated (as olefinic) key in conjunction with time may be unstable.

" pharmaceutical composition " represent containing on one or more compounds described herein or its physiology/mixture of pharmaceutically useful salt or prodrug and other chemical compositions, and other components such as physiology/pharmaceutically useful carrier and vehicle.The object of pharmaceutical composition promotes the administration to organism, is beneficial to the absorption of activeconstituents and then plays biological activity.

M and R ⁹~ R ¹¹definition as described in general formula (I) compound.

the synthetic method of the compounds of this invention

In order to complete object of the present invention, the present invention adopts following technical scheme:

Benzofuran compounds a is dissolved in DMF, adds phosphorus oxychloride at low temperatures, under heating condition, be obtained by reacting aldehyde compound b;

Under argon gas or nitrogen, compound b, under acetic acid and sodium acetate exist, is obtained by reacting halogenated compound c with halogen; After compound c reacts with isobenzofuran-1-ketone and sodium methylate in methyl alcohol, then react rearrangement with hydrazine hydrate and obtain compound d; Or compound c in tetrahydrofuran (THF) with add isobenzofuran-1-ketone-phosphoric acid ester and occur after wittig reacts, then react rearrangement with hydrazine hydrate and obtain compound d; Optional by compound d, acid chloride and 1, carbon monoxide is passed into after two (diphenylphosphine) propane of 3-puts into reaction flask, and under the existence of triethylamine and ethanol, be dissolved in reacting by heating in dimethyl sulfoxide (DMSO) and obtain ester group compound (IIIA); (IIIA) compound optionally carries out after Ester hydrolysis becomes carboxylic acid at hydroxide solution further, carboxylic acid cpd and formula NHR ⁹r ¹⁰be reacted to and obtain (III) compound; Or compound d optionally in tetrahydrofuran (THF) with butyllithium generation lithium-halogen exchange after, then be obtained by reacting the formic acid of (IIIA) with the carbon dioxide of drying, in the basic conditions with formula NHR ¹⁰r ¹¹be reacted to and obtain (III) compound.

Wherein in above-mentioned reaction, carboxylic acid cpd and NHR ⁹r ¹⁰react under alkaline condition and condensation reagent existent condition, condensation reagent used is selected from N, N-dicyclohexylcarbodiimide, N, N-DIC, O-benzotriazole-N, N, N ', N '-tetramethyl-urea Tetrafluoroboric acid ester (TBTU), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimines etc., are preferably 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimine; Alkaline condition is provided by organic bases or mineral alkali, and organic bases is selected from as diisopropylethylamine, pyridine, triethylamine, hexahydropyridine, N methyl piperazine, DMAP, I-hydroxybenzotriazole etc., is preferably triethylamine; Solvent for use is selected from the mixture etc. of toluene, benzene, methylene dichloride, tetrahydrofuran (THF), DMF, chloroform or above-mentioned solvent composition, is preferably DMF; Temperature of reaction controls at-80 DEG C to 100 DEG C, is preferably 0 DEG C to 60 DEG C; Reaction times general control, at 1 minute to 72 hours, is preferably 15 minutes to 24 hours.

Wherein A, B, R ¹, R ³~ R ⁸, R ¹⁰, R ¹¹as in general formula (III) define, and R ¹⁸as in general formula (IIIA) define, X is halogen.

Embodiment

Be used for further describing the present invention below in conjunction with embodiment, but these embodiments not limit scope of the present invention.

embodiment

The structure of compound by nucleus magnetic resonance (NMR) or/and mass spectrum (MS) is determined.NMR displacement (δ) is with 10 ^-6(ppm) unit provides.The mensuration of NMR uses Bruker AVANCE-400 nuclear magnetic resonance spectrometer, and measuring solvent is deuterated dimethyl sulfoxide (DMSO-d ₆), deuterochloroform (CDCl ₃), deuterated methanol (CD ₃oD), tetramethylsilane (TMS) is inside designated as.

The mensuration of MS uses FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).

The mensuration of high performance liquid phase (HPLC) uses Agilent 1200DAD high pressure liquid chromatograph (Sunfire C18150 × 4.6mm chromatographic column) and Waters 2695-2996 high pressure liquid chromatograph (Gimini C 18 150 × 4.6mm chromatographic column).

IC ₅₀the mensuration NovoStar microplate reader (German BMG company) of value.

Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica-gel plate, and the specification that the silica-gel plate that tlc (TLC) uses adopts is 0.15mm ~ 0.2mm, and the specification that thin-layer chromatography separation and purification product adopts is 0.4mm ~ 0.5mm.

Column chromatography generally uses the Yantai Huanghai Sea 200 ~ 300 order silica gel to be carrier.

Known starting raw material of the present invention can adopt or synthesize according to methods known in the art, maybe can buy from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, splendid chemistry far away is scientific and technological and reach the companies such as auspicious chemical.

Without specified otherwise in embodiment, reaction is all carried out under argon atmospher or nitrogen atmosphere.

Argon atmospher or nitrogen atmosphere refer to that reaction flask connects argon gas or the nitrogen balloon of an about 1L volume.

Hydrogenation vacuumizes usually, is filled with hydrogen, repeatable operation 3 times.

Microwave reaction uses CEM Discover-S 908860 type microwave reactor.

Without specified otherwise in embodiment, solution refers to the aqueous solution.

Without specified otherwise in embodiment, the temperature of reaction is room temperature.

Room temperature is optimum temperature of reaction, is 20 DEG C ~ 30 DEG C.

The monitoring of the reaction process in embodiment adopts tlc (TLC), the system of reacting the developping agent used has: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, C: sherwood oil and ethyl acetate system, D: acetone, the volume ratio of solvent regulates according to the polarity difference of compound.

The system of eluent of the column chromatography that purifying compounds adopts and the developping agent system of tlc comprise: A: methylene dichloride and methanol system, B: normal hexane and ethyl acetate system, the volume ratio of solvent is different and regulate according to the polarity of compound, also can add the alkalescence such as a small amount of triethylamine and acetic acid or acid reagent regulates.

Embodiment 1

4-[(bromo-2, the 3-Dihydrobenzofuranes-5-bases of 7-) methyl]-2H-phthalazines-1-ketone

The first step

2,3-Dihydrobenzofuranes-5-formaldehyde

By 2,3-Dihydrobenzofuranes 1a (2g, 16mmol) is dissolved in DMF (2.60g under stirring, 35.20mmol) in, under ice bath, drip phosphorus oxychloride (5.20g, 52mmol), 90 DEG C are reacted 7 hours, be cooled to room temperature, pour in 20mL frozen water, stir 12 hours.With toluene extraction (15mL × 3), merge organic phase, use saturated sodium bicarbonate solution (20mL), saturated nacl aqueous solution to wash (20mL), anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 2,3-Dihydrobenzofuranes-5-formaldehyde 1b (1.70g, colorless oil), productive rate: 70.8%.

MS m/z(ESI)：149.1[M+1]

Second step

Bromo-2, the 3-Dihydrobenzofuranes-5-formaldehyde of 7-

Be dissolved in 15mL acetic acid under 2,3-Dihydrobenzofuranes-5-formaldehyde 1b (1.70g, 11.50mmol) is stirred, add sodium acetate (1.10g, 13.80mmol) and bromine (3.60g, 23mmol), react 2 hours.Add 50mL saturated sodium bicarbonate solution, be extracted with ethyl acetate (50mL × 2), merge organic phase, use saturated sodium bicarbonate solution (50mL), saturated nacl aqueous solution to wash (30mL), anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, obtains bromo-2, the 3-Dihydrobenzofuranes-5-formaldehyde 1c (2.50g of title product 7-, yellow solid), productive rate: 96.2%.

MS m/z(ESI)：227.9[M+1]

3rd step

2-(bromo-2, the 3-Dihydrobenzofuranes-5-bases of 7-) indane-1,3-diketone

By bromo-for 7-2,3-Dihydrobenzofuranes-5-formaldehyde 1c (0.22g, be dissolved in the mixed solvent of 18mL ethyl propionate and methyl alcohol (V/V=4: 5) under 1mmol) stirring, add 3H-isobenzofuran-1-ketone (0.13g, 1mmol), the methanol solution of slow dropping 1mL 25% sodium methylate, stirs 15 minutes, back flow reaction 2 hours.Be cooled to room temperature, add 20mL water, with washed with diethylether (20mL × 3), drip Glacial acetic acid and separate out to there being red precipitate, filter, solids washed with water (30mL), vacuum-drying, obtains title product 2-(7-bromo-2,3-Dihydrobenzofuranes-5-base) indane-1,3-diketone 1d (0.25g, red solid), productive rate: 73.5%.

MS m/z(ESI)：344.7[M+1]

4th step

Be dissolved in 15mL hydrazine hydrate under 2-(bromo-2, the 3-Dihydrobenzofuranes-5-bases of 7-) indane-1,3-diketone 1d (250mg, 0.73mmol) is stirred, back flow reaction 3 hours.Filter, filter cake washes with water (20mL), vacuum-drying, obtains title product 4-[(bromo-2, the 3-Dihydrobenzofuranes-5-bases of 7-) methyl]-2H-phthalazines-1-ketone 1 (200mg, white solid), productive rate: 76.9%.

MS m/z(ESI)：358.7[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.56(s，1H)，8.24-8.26(m，1H)，7.82-7.98(m，3H)，7.29(s，1H)，7.13(s，1H)，4.55(t，2H)，4.21(s，2H)，3.22(t，2H)

Embodiment 2

4-(2,3-Dihydrobenzofuranes-5-ylmethyl)-2H-phthalazines-1-ketone

By 4-[(7-bromo-2,3-Dihydrobenzofuranes-5-base) methyl]-2H-phthalazines-1-ketone 1 (177mg, be dissolved in 5mL tetrahydrofuran (THF) under 0.50mmol) stirring, add Tetramethyl Ethylene Diamine (116mg, 1mmol), be cooled to-78 DEG C, drip the hexane solution of 0.6mL 1.6M n-Butyl Lithium, keep-78 DEG C to react 3 hours.Add 5mL water, be extracted with ethyl acetate (15mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product 4-(2,3-Dihydrobenzofuranes-5-ylmethyl)-2H-phthalazines-1-ketone 2 (85mg, white solid), productive rate: 61.6%.

MS m/z(ESI)：279.1[M+1]

¹H NMR(400MHz，CDCl ₃)：δ10.50(s，1H)，8.46-8.48(m，1H)，7.74-7.80(m，3H)，7.04-7.10(m，2H)，6.71-6.73(m，1H)，4.54(t，2H)，4.23(s，2H)，3.16(t，2H)

Embodiment 3

4-[[7-(4-methylpiperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-methyl-formiates

By 4-[(7-bromo-2,3-Dihydrobenzofuranes-5-base) methyl]-2H-phthalazines-1-ketone 1 (480mg, 1.34mmol), palladium (30mg, 0.13mmol) He 1, two (diphenylphosphine) propane (55mg of 3-, 0.13mmol) be placed in dry reaction flask, carbon monoxide is passed into after airtight, add 10mL and contain triethylamine (0.41g, 4mmol) and the dimethyl sulfoxide (DMSO) of methyl alcohol (0.13g, 4mmol), 75 DEG C of reactions 24 hours.Add 15mL water, with dichloromethane extraction (20mL × 5), merge organic phase, use water (30mL), saturated nacl aqueous solution to wash (30mL × 2), anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, obtains title product 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-methyl-formiate 3a (200mg, white solid), productive rate: 44.4%

MS m/z(ESI)：337.1[M+1]

Second step

5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-methyl-formiate 3a (950mg, be dissolved in the mixed solvent of 60mL tetrahydrofuran (THF) and water (V/V=1: 1) under 2.8mmol) stirring, add lithium hydroxide (600mg, 14mmol), react 12 hours.Add 30mL water, by ethyl acetate washing (30mL × 2), dripping 1M hydrochloric acid is 5 to aqueous phase pH, filter, collect solid, aqueous phase is extracted with ethyl acetate (30mL × 3), merges organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, the gained solid mixed solvent of 6mL methyl alcohol and ether (V/V=1: 5) washs, combining solid, obtain title product 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (750mg, pale solid), productive rate: 82.4%.

MS m/z(ESI)：323.1[M+1]

3rd step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (65mg, 5mL N is dissolved under 0.20mmol) stirring, in dinethylformamide, add 4-methylpiperazine (24mg successively, 0.24mmol), I-hydroxybenzotriazole (30mg, 0.22mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (57mg, 0.30mmol) with triethylamine (60mg, 0.60mmol), react 12 hours.Add 10mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (15mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates by tlc with developping agent system A, obtain title product 4-[[7-(4-methylpiperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 3 (20mg, white solid), productive rate: 24.7%.

MS m/z(ESI)：405.2[M+1]

¹H NMR(400MHz，CDCl ₃)：δ10.03(s，1H)，8.44-8.47(m，1H)，7.77-7.78(m，3H)，7.12-7.14(m，2H)，4.58(t，2H)，4.22(s，2H)，3.80-3.82(m，2H)，3.36-3.39(m，2H)，3.17(t，2H)，2.49-2.51(m，2H)，2.36-2.37(m，2H)，2.34(s，3H)

Embodiment 4

4-[[7-(piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone

The first step

4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-t-butyl formate

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (250mg, 10mL N is dissolved under 0.78mmol) stirring, in dinethylformamide, add piperazine-1-t-butyl formate (170mg successively, 0.93mmol), 1`-hydroxybenzotriazole (120mg, 0.85mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (220mg, 1.16mmol) with triethylamine (240mg, 2.33mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 3), merge organic phase, with saturated nacl aqueous solution washing (20mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains title product 4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-t-butyl formate 4a (300mg, white solid), productive rate: 78.9%.

MS m/z(ESI)：982.4[2M+1]

Second step

4-[[7-(piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base) methyl]-2H-phthalazines-1-ketone

By 4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-t-butyl formate 4a (300mg, be dissolved in 20mL methyl alcohol under 0.60mmol) stirring, add the methanol solution of 5mL 1M hydrogenchloride, react 12 hours.Concentrating under reduced pressure, add 20mL water, dripping 2M sodium hydroxide solution is 10 to reaction solution pH, is extracted with ethyl acetate (30mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product 4-[[7-(piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (150mg, white solid), productive rate: 63.0%.

MS m/z(ESI)：391.2[M+1]

¹H NMR(400MHz，CDCl ₃)：δ10.59(s，1H)，8.45-8.46(m，1H)，7.76-7.79(m，3H)，7.12-7.14(m，2H)，4.58(t，2H)，4.23(s，2H)，3.81-3.83(m，2H)，3.39-3.41(m，2H)，3.17(t，2H)，3.01-3.03(m，2H)，2.90-2.92(m，2H)，1-80(s，1H)

Embodiment 5

4-[[7-[4-(cyclopropyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

Cyclopropyl (piperazine-1-base) ketone

Under ice bath, be dissolved in 70mL acetic acid under being stirred by piperazine 5a (5g, 58mmol), stir 30 minutes, drip Cyclopropyl carbonyl chloride (5.9mL, 63.80mmol), react 8 hours.Filter, filtrate reduced in volume, adds 55mL toluene, concentrating under reduced pressure, repeats 3 times, obtains title product cyclopropyl (piperazine-1-base) ketone 5b (8.20g, colorless oil), productive rate: 75.0%.

Second step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (100mg, 5mL N is dissolved under 0.30mmol) stirring, in dinethylformamide, add cyclopropyl (piperazine-1-base) ketone 5b (72mg successively, 0.46mmol), I-hydroxybenzotriazole (46mg, 0.34mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (89mg, 0.46mmol) with triethylamine (94mg, 0.90mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-[4-(cyclopropyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 5 (75mg, white solid), productive rate: 52.8%.

MS m/z(ESI)：459.2[M+1]

¹H NMR(400MHz，CDCl ₃)：δ9.98(s，1H)，8.45-8.47(m，1H)，7.76-7.78(m，3H)，7.15-7.18(m，2H)，4.60(t，2H)，4.23(s，2H)，3.63-3.82(m，6H)，3.32-3.34(m，2H)，3.20(t，2H)，1.01-1.03(m，1H)，0.90-0.93(m，2H)，0.78-0.82(m，2H)

Embodiment 6

4-[[7-[4-(1-amino cyclopentyl alkyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

1-(tertbutyloxycarbonylamino) pentamethylene base formic acid

Be dissolved in the Isosorbide-5-Nitrae-dioxane solution of 10mL 1M sodium hydroxide under 1-amino cyclopentyl alkyl formic acid 6a (1.30g, 10mmol) is stirred, add tert-Butyl dicarbonate (2.20g, 10mmol), react 5 hours.Concentrating under reduced pressure, adds 15mL water, by ethyl acetate washing (25mL × 2), dripping 1M hydrochloric acid is 2 to aqueous phase pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains title product 1-(tertbutyloxycarbonylamino) pentamethylene base formic acid 6b (2g, white solid), productive rate: 87.0%.

MS m/z(ESI)：228.1[M-1]

Second step

N-[1-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-carbonyl] pentamethylene base] t-butyl carbamate

By 4-[[7-(piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (80mg, 5mL N is dissolved under 0.20mmol) stirring, in dinethylformamide, add 1-(tertbutyloxycarbonylamino) pentamethylene base formic acid 6b (56mg successively, 0.25mmol), I-hydroxybenzotriazole (30mg, 0.22mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (59mg, 0.30mmol) with triethylamine (62mg, 0.60mmol), react 12 hours.Add 15mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product N-[1-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] pentamethylene base] t-butyl carbamate 6c (100mg, colorless oil), productive rate: 83.3%.

MS m/z(ESI)：502.3[M-100+1]

3rd step

By N-[1-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] pentamethylene base] t-butyl carbamate 6c (100mg, be dissolved in 10mL methyl alcohol under 0.17mmol) stirring, add the methanol solution of 5mL 1M hydrogenchloride, react 12 hours.Concentrating under reduced pressure, obtain title product 4-[[7-[4-(1-amino cyclopentyl alkyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 6 (70mg, colorless oil), productive rate: 84.3%.

MS m/z(ESI)：502.2[M+1]

¹H NMR(400MHz，CDCl ₃)：δ12.57(s，1H)，8.26-8.25(m，1H)，7.98-7.96(m，1H)，7.88-7.80(m，2H)，7.24(s，1H)，7.06(s，1H)，4.55-4.51(m，2H)，4.23(s，2H)，3.17-3.15(m，4H)，2.11-2.10(m，6H)，1.98(s，1H)，1.58(s，5H)，1.44-1.43(m，3H)

Embodiment 7

4-[[7-(thiomorpholine-4-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (100mg, 5mLN is dissolved under 0.30mmol) stirring, in dinethylformamide, add thiomorpholine (380mg successively, 0.37mmol), I-hydroxybenzotriazole (63mg, 0.47mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (89mg, 0.47mmol) with triethylamine (94mg, 0.93mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates by tlc with developping agent system A, obtain title product 4-[[7-(thiomorpholine-4-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 7 (30mg, white solid), productive rate: 23.1%.

MS m/z(ESI)：408.1[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，8.24-8.26(m，1H)，7.80-7.98(m，3H)，7.22(s，1H)，7.05(s，1H)，4.51(t，2H)，4.22(s，2H)，3.80-3.82(m，2H)，3.41-3.42(m，2H)，3.33-3.35(m，2H)，3.14(t，2H)，2.61-2.63(m，2H)

Embodiment 8

4-[[7-(4-methyl isophthalic acid, 4-Diazesuberane-1-carbonyl)-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (80mg, 5mL N is dissolved under 0.25mmol) stirring, in dinethylformamide, add 4-methyl isophthalic acid successively, 4-Diazesuberane (34mg, 0.30mmol), I-hydroxybenzotriazole (37mg, 0.27mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (71mg, 0.37mmol) and triethylamine (75mg, 0.75mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-(4-methyl isophthalic acid, 4-Diazesuberane-1-carbonyl)-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone 8 (20mg, white solid), productive rate: 19.2%.

MS m/z(ESI)：419.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，8.24-8.26(m，1H)，7.80-7.96(m，3H)，7.22(s，1H)，6.98(s，1H)，4.50(t，2H)，4.22(s，2H)，3.54-3.58(m，2H)，3.22(t，2H)，2.72-2.74(m，1H)，2.57-2.60(m，2H)，2.36-2.39(m，2H)，2.22-2.24(m，1H)，1.82-1.84(m，1H)，1.65-1.67(m，1H)，1.23(s，3H)

Embodiment 9

4-[[7-[4-(2-methylpyrrolidin-2-carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

2-methylpyrrolidin-1, the 2-O1-tertiary butyl, O2-ethyl-dicarboxylic acid esters

By 2-methylpyrrolidin-1,2-O1-benzyl, O2-ethyl-dicarboxylic acid esters 9a (2.90g, be dissolved in 30mL ethanol under 10mmol) stirring, add palladium hydroxide (0.14g, 1mmol) and tert-Butyl dicarbonate (3.30g, 15mmol), hydrogen exchange three times, reacts 12 hours.Concentrating under reduced pressure, add 40mL methylene dichloride, filter, filtrate uses water (40mL), saturated nacl aqueous solution to wash (40mL) successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains crude title product 2-methylpyrrolidin-1, the 2-O1-tertiary butyl, O2-ethyl-dicarboxylic acid esters 9b (2.50g, yellow oil), product is not purified directly carries out next step reaction.

MS m/z(ESI)：158.1[M-100+1]

Second step

1-tertbutyloxycarbonyl-2-methyi-pyrrofidinium-2-formic acid

By crude product 2-methylpyrrolidin-1, the 2-O1-tertiary butyl, O2-ethyl-dicarboxylic acid esters 9b (2.50g, be dissolved in the mixed solvent of 25mL second alcohol and water (V/V=4: 1) under 10mmol) stirring, add potassium hydroxide (2.80g, 5mmol), react 2 hours.Concentrating under reduced pressure, add 20mL water, dripping 1M hydrochloric acid is 5 to reaction solution pH, is extracted with ethyl acetate (30mL × 2), merges organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains crude title product 1-tertbutyloxycarbonyl-2-methyi-pyrrofidinium-2-formic acid 9c (2.20g, white solid), product is not purified directly carries out next step reaction.

3rd step

2-methyl-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-carbonyl] tetramethyleneimine-1-t-butyl formate

By 4-[[7-(piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (85mg, 5mL N is dissolved under 0.22mmol) stirring, in dinethylformamide, add crude product 1-tertbutyloxycarbonyl-2-methyi-pyrrofidinium-2-formic acid 9c (60mg successively, 0.26mmol), I-hydroxybenzotriazole (44mg, 0.33mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (63mg, 0.33mmol) with triethylamine (66mg, 0.65mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains title product 2-methyl-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-carbonyl] tetramethyleneimine-1-t-butyl formate 9d (100mg, colorless oil), productive rate: 76.9%.

MS m/z(ESI)：602.3[M+1]

4th step

By 2-methyl-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] tetramethyleneimine-1-t-butyl formate 9d (100mg, be dissolved in 7mL methyl alcohol under 0.17mmol) stirring, add the methanol solution of 3mL 1M hydrogenchloride, react 12 hours.Concentrating under reduced pressure, add 20mL water, dripping 2M sodium hydroxide solution is 10 to reaction solution pH, be extracted with ethyl acetate (30mL × 5), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates by tlc with developping agent system A, obtain title product 4-[[7-[4-(2-methylpyrrolidin-2-carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone 9 (20mg, white solid), productive rate: 24.1%.

MS m/z(ESI)：502.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.58(s，1H)，8.24-8.26(m，1H)，7.82-7.98(m，3H)，7.24(s，1H)，7.06(s，1H)，4.53(t，2H)，4.23(s，2H)，3.52-3.56(m，4H)，3.14-3.18(m，4H)，3.16(t，2H)，2.84-2.86(m，1H)，2.66-2.68(m，1H)，2.15-2.18(m，2H)，1.56-1.59(m，2H)，1.27(s，3H)

Embodiment 10

4-[[7-(Isosorbide-5-Nitrae-Diazesuberane-1-carbonyl)-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls]-Isosorbide-5-Nitrae-Diazesuberane-1-t-butyl formate

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (80mg, 5mL N is dissolved under 0.25mmol) stirring, in dinethylformamide, add 1 successively, 4-Diazesuberane-1-t-butyl formate (60mg, 0.30mmol), I-hydroxybenzotriazole (50mg, 0.37mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (60mg, 0.30mmol) and triethylamine (75mg, 0.75mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains title product 4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl]-1,4-Diazesuberane-1-t-butyl formate 10a (90mg, white solid), productive rate: 72.0%.

MS m/z(ESI)：527.2[M+23]

Second step

By 4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl]-1,4-Diazesuberane-1-t-butyl formate 10a (90mg, be dissolved in 10mL methyl alcohol under 0.18mmol) stirring, add the methanol solution of 3mL1M hydrogenchloride, react 12 hours.Concentrating under reduced pressure, add 20mL water, dripping 2M sodium hydroxide solution is 10 to reaction solution pH, be extracted with ethyl acetate (30mL × 5), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates by tlc with developping agent system A, obtains title product 4-[[7-(1,4-Diazesuberane-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 10 (20mg, white solid), productive rate: 27.8%.

MS m/z(ESI)：405.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.58(s，1H)，8.24-8.26(m，1H)，7.79-7.96(m，3H)，7.24(s，1H)，7.08(s，1H)，4.52(t，2H)，4.22(s，2H)，3.74-3.76(m，1H)，3.62-3.64(m，1H)，3.50-3.52(m，1H)，3.15(t，2H)，3.04-3.15(m，4H)，1.99-2.01(m，1H)，1.81-1.83(m，2H)

Embodiment 11

4-[[7-[4-(1-methylamino pentamethylene base carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

By 4-[[7-[4-(1-amino cyclopentyl alkyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 6 (100mg, be dissolved in 10mL methyl alcohol under 0.20mmol) stirring, add 37% formaldehyde solution (6mg, 0.20mmol), back flow reaction 20 minutes, adds sodium borohydride (15mg, 0.40mmol), back flow reaction 2 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A, obtain title product 4-[[7-[4-(1-methylamino pentamethylene base carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone 11 (30mg, white solid), productive rate: 29.1%.

MS m/z(ESI)：516.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，8.24-8.26(m，1H)，7.80-7.98(m，3H)，7.24(s，1H)，7.06(s，1H)，4.53(t，2H)，4.23(s，2H)，3.53-3.55(m，3H)，3.15-3.17(m，2H)，3.16(t，2H)，2.10-2.12(m，6H)，1.98(s，1H)，1.56-1.59(m，5H)，1.42-1.44(m，3H)

Embodiment 12

4-[[7-(1,1-dioxo-Isosorbide-5-Nitrae-thiomorpholine-4-carbonyl)-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

By 4-[[7-(thiomorpholine-4-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 7 (40mg, be dissolved in 5mL methyl alcohol under 0.10mmol) stirring, add 2mL Oxone reagent (72mg, aqueous solution 0.12mmol), 40 DEG C are reacted 48 hours.Be cooled to 0 DEG C, dripping 2M sodium hydroxide solution is 12 to reaction solution pH, filters, and filter cake is with methanol wash (20mL), filtrate reduced in volume, purify gained resistates by tlc with developping agent system A, obtain title product 4-[[7-(1,1-dioxo-1,4-thiomorpholine-4-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 12 (15mg, white solid), productive rate: 35.0%.

MS m/z(ESI)：440.1[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.58(s，1H)，8.26-8.24(d，1H)，7.97-7.95(d，1H)，7.90-7.81(m，2H)，7.26(s，1H)，7.16(s，1H)，4.56-4.52(t，2H)，4.23(s，2H)，3.97(s，2H)，3.59(s，2H)，3.20-3.11(m，6H)

Embodiment 13

4-[[7-(5-benzyl-1,3,3a, 4,6,6a-hexahydropyrrolo is [3,4-c] pyrroles-2-carbonyl also)-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2, 3-Dihydrobenzofuranes-7-formic acid 3b (50mg, 5mL N is dissolved under 0.16mmol) stirring, in dinethylformamide, add 5-benzyl-2 successively, 3, 3a, 4, 6, 6a-six hydrogen-1H-pyrrolo-[3, 4-c] pyrroles (35mg, 0.17mmol), I-hydroxybenzotriazole (32mg, 0.24mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (46mg, 0.24mmol) with triethylamine (32mg, 0.32mmol), react 12 hours.Concentrating under reduced pressure, purify gained resistates by tlc with developping agent system A, obtain title product 4-[[7-(5-benzyl-1,3,3a, 4,6,6a-hexahydropyrrolo also [3,4-c] pyrroles-2-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 13 (14mg, white solid), productive rate: 17.0%.

MS m/z(ESI)：507.2[M+1]

¹H NMR(400MHz，CD ₃OD)：δ8.35-8.33(m，1H)，7.93(d，1H)，7.81-7.78(m，2H)，7.34-7.27(m，6H)，7.09(s，1H)，4.60-4.55(t，3H)，4.29(s，2H)，3.69-3.62(m，4H)，3.50-3.48(m，1H)，3.24-3.17(m，2H)，2.90-2.75(m，4H)，2.51-2.50(m，1H)，2.36-2.34(m，1H)

Embodiment 14

4-[[7-(morpholine-4-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (60mg, 5mL N is dissolved under 0.19mmol) stirring, in dinethylformamide, add morpholine (19mg successively, 0.22mmol), I-hydroxybenzotriazole (38mg, 0.28mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (54mg, 0.28mmol) with triethylamine (56mg, 0.56mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A, obtain title product 4-[[7-(morpholine-4-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 14 (60mg, white solid), productive rate: 82.2%.

MS m/z(ESI)：392.1[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，8.24-8.26(m，1H)，7.81-7.98(m，3H)，7.24(s，1H)，7.05(s，1H)，4.52(t，2H)，4.22(s，2H)，3.56-3.58(m，4H)，3.47-3.49(m，2H)，3.15-3.17(m，2H)，3.14(t，2H)

Embodiment 15

4-[[7-(4-sec.-propyl piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-bases) methyl]-2H-phthalazines-1-ketone

The first step

4-sec.-propyl piperazine-1-t-butyl formate

By piperazine-1-t-butyl formate 15a (1g, be dissolved in 15mL methylene dichloride under 5.40mmol) stirring, add acetone (0.5mL successively, 6.60mmol), acetic acid (0.3mL, 5.20mmol) with sodium triacetoxy borohydride (1.70g, 8.10mmol), react 12 hours.Concentrating under reduced pressure, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product 4-sec.-propyl piperazine-1-t-butyl formate 15b (0.60g, light yellow liquid), productive rate: 48.8%.

MS m/z(ESI)：229.2[M+1]

Second step

1-sec.-propyl piperazine

Be dissolved in 10mL methyl alcohol under 4-sec.-propyl piperazine-1-t-butyl formate 15b (150mg, 0.66mmol) is stirred, add the methanol solution of 3mL 1M hydrogenchloride, react 12 hours.Concentrating under reduced pressure, add 20mL water, dripping 2M sodium hydroxide solution is 10 to reaction solution pH, is extracted with ethyl acetate (30mL × 5), merges organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains title product 1-sec.-propyl piperazine 15c (60mg, colorless oil), productive rate: 71.4%.

MS m/z(ESI)：129.1[M+1]

3rd step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (125mg, 5mL N is dissolved under 0.39mmol) stirring, in dinethylformamide, add 1-sec.-propyl piperazine 15c (60mg successively, 0.47mmol), I-hydroxybenzotriazole (79mg, 0.59mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (112mg, 0.59mmol) with triethylamine (118mg, 1.17mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product 4-[[7-(4-sec.-propyl piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base) methyl]-2H-phthalazines-1-ketone 15 (80mg, white solid), productive rate: 47.3%.

MS m/z(ESI)：433.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，8.24-8.26(m，1H)，7.81-7.96(m，3H)，7.23(s，1H)，6.98(s，1H)，4.51(t，2H)，4.22(s，2H)，3.51-3.53(m，2H)，3.14(t，2H)，3.12-3.14(m，2H)，2.62-2.67(m，1H)，2.41-2.43(m，2H)，2.25-2.27(m，2H)，0.95(d，6H)

Embodiment 16

4-[[7-(4-dimethylaminopyridine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-bases) methyl]-2H-phthalazines-1-ketone

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (80mg, 5mL N is dissolved under 0.25mmol) stirring, in dinethylformamide, add N successively, N-lupetidine-4-amine (35mg, 0.27mmol), I-hydroxybenzotriazole (50mg, 0.57mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (71mg, 0.37mmol) and triethylamine (76mg, 0.75mmol), react 12 hours.Concentrating under reduced pressure, add 10mL saturated sodium bicarbonate solution, with dichloromethane extraction (10mL × 3), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates by tlc with developping agent system A, obtain title product 4-[[7-(4-dimethylaminopyridine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-bases) methyl]-2H-phthalazines-1-ketone 16 (80mg, white solid), productive rate: 74.5%.

MS m/z(ESI)：433.2[M+1]

¹H NMR(400MHz，CDCl ₃)：δ10.33(s，1H)，8.46-8.44(t，1H)，7.78-7.73(m，3H)，7.13(d，2H)，4.85-4.82(m，1H)，4.60-4.55(t，2H)，4.22(s，2H)，3.72-3.67(m，1H)，3.20-3.15(t，2H)，3.01-2.72(m，3H)，2.55(s，6H)，2.05-2.01(m，2H)，1.65-1.61(m，2H)

Embodiment 17

4-[[7-(4-Nmethanesulphonylpiperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

By 4-[[7-(piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (60mg, be dissolved in 10mL methylene dichloride under 0.16mmol) stirring, add triethylamine (23mg, 0.23mmol), at 0 DEG C, drip methylsulfonyl chloride (21mg, 0.19mmol), 0 DEG C is reacted 1 hour.Add 20mL methylene dichloride; water (20mL), saturated nacl aqueous solution is used to wash (20mL) successively; anhydrous sodium sulfate drying; filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A; obtain title product 4-[[7-(4-Nmethanesulphonylpiperazine-1-carbonyl)-2; 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 17 (15mg, white solid), productive rate: 20.8%.

MS m/z(ESI)：469.1[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.59(s，1H)，8.24-8.26(m，1H)，7.82-7.97(m，3H)，7.27(s，1H)，7.05(s，1H)，4.54(t，2H)，4.23(s，2H)，3.65-3.67(m，2H)，3.27-3.29(m，2H)，3.16(t，2H)，3.13-3.15(m，2H)，3.00-3.02(m，2H)，2.89(s，3H)

Embodiment 18

4-[[7-[5-(benzyl (methyl) is amino)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carbonyls]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

5-(benzylamino)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-t-butyl formate

By 5-oxo-1,3,3a, 4,6,6a-six hydrogen cyclopentano [c] pyrroles-2-t-butyl formate 18a (0.20g, 0.89mmol) is dissolved in 15mL acetonitrile under stirring, add benzylamine (0.1mL, 0.89mmol), stir 20 minutes, add sodium triacetoxy borohydride (0.24g, 1.16mmol), react 12 hours.Concentrating under reduced pressure, adds 20mL methylene dichloride, with saturated sodium bicarbonate solution washing (20mL), anhydrous sodium sulfate drying, filters, filtrate reduced in volume, obtain crude title product 5-(benzylamino)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-t-butyl formate 18b (0.28g, khaki color oily matter), product is not purified directly carries out next step reaction.

Second step

5-(benzyl (methyl) is amino)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-t-butyl formates

By crude product 5-(benzylamino)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-t-butyl formate 18b (280mg, 0.89mmol) is dissolved in 8mL methyl alcohol under stirring, add 37% formaldehyde solution (0.3mL, 2.67mmol), stir 30 minutes, under ice bath, add sodium triacetoxy borohydride (750mg, 3.56mmol), react 12 hours.Concentrating under reduced pressure, adds 20mL methylene dichloride, with saturated sodium bicarbonate solution washing (20mL), anhydrous sodium sulfate drying, filters, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 5-(benzyl (methyl) is amino)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-t-butyl formate 18c (250mg, khaki color oily matter), productive rate: 85.0%.

MS m/z(ESI)：331.2[M+1]

3rd step

N-Benzyl-N-methyl-1,2,3,3a, 4,5,6,6a-octahydro cyclopentano [c] pyrroles-5-amine

By 5-(benzyl (methyl) is amino)-3,3a, 4,5,6,6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-t-butyl formate 18c (250mg, 0.76mmol) is dissolved in 10mL methyl alcohol under stirring, add the methanol solution of 3mL 1M hydrogenchloride, react 12 hours.Concentrating under reduced pressure, adds 20mL water, and dripping 2M sodium hydroxide solution is 10 to reaction solution pH, be extracted with ethyl acetate (30mL × 5), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains title product N-Benzyl-N-methyl-1,2,3,3a, 4,5,6,6a-octahydro cyclopentano [c] pyrroles-5-amine 18d (130mg, pale solid), productive rate: 74.7%.

MS m/z(ESI)：231.1[M+1]

4th step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2, 3-Dihydrobenzofuranes-7-formic acid 3b (152mg, 5mL N is dissolved under 0.47mmol) stirring, in dinethylformamide, add N-Benzyl-N-methyl-1 successively, 2, 3, 3a, 4, 5, 6, 6a-octahydro cyclopentano [c] pyrroles-5-amine 18d (130mg, 0.57mmol), I-hydroxybenzotriazole (95mg, 0.71mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (135mg, 0.71mmol) with triethylamine (142mg, 1.42mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product 4-[[7-[5-(benzyl (methyl) is amino)-3, 3a, 4, 5, 6, 6a-six hydrogen-1H-cyclopentano [c] pyrroles-2-carbonyl]-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 18 (150mg, white solid), productive rate: 59.5%.

MS m/z(ESI)：535.3[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，8.24-8.26(m，1H)，7.80-7.98(m，3H)，7.29-7.32(m，5H)，7.22(s，1H)，7.05(s，1H)，4.52(t，2H)，4.22(s，2H)，3.48-3.49(m，2H)，3.43-3.45(m，2H)，3.14(t，2H)，3.12-3.14(m，1H)，2.89(s，1H)，2.74-2.76(m，1H)，2.73(s，1H)，2.53-2.55(m，1H)，2.06-2.09(m，1H)，2.00(s，3H)，1.96-1.99(m，1H)，1.07-1.20(m，2H)

Embodiment 19

4-[[7-[3-(trifluoromethyl)-6,8-dihydro-SH-[1,2,4] triazolo [4,3-a] pyrazine-7-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2, 3-Dihydrobenzofuranes-7-formic acid 3b (184mg, 10mL N is dissolved under 0.57mmol) stirring, in dinethylformamide, add 3-trifluoromethyl-5 successively, 6, 7, 8-tetrahydrochysene-[1, 2, 4] triazolo [4, 3-a] pyrazine hydrochloride (100mg, 0.52mmol, known method " patent WO2004080958 " is adopted to prepare and obtain), I-hydroxybenzotriazole (105mg, 0.78mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (149mg, 0.78mmol) with triethylamine (158mg, 1.56mmol), react 15 hours.Add 30mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, use saturated sodium bicarbonate solution (20mL) successively, saturated nacl aqueous solution washing (30mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product 4-[[7-[3-(trifluoromethyl)-6, 8-dihydro-5H-[1, 2, 4] triazolo [4, 3-a] pyrazine-7-carbonyl]-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 19 (170mg, white solid), productive rate: 60.3%.

MS m/z(ESI)：497.1[M+1]

¹H NMR(400MHz，CDCl ₃)：δ10.33(s，1H)，8.45-8.47(m，1H)，7.76-7.79(m，3H)，7.22-7.24(m，2H)，4.88-4.90(m，1H)，4.60(t，2H)，4.23(s，2H)，4.22-4.24(m，3H)，3.46-3.50(m，1H)，3.20-3.24(m，1H)，3.22(m，2H)

Embodiment 20

4-[[7-[4-(1-hydroxyl-1-methyl-ethyl) piperidines-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

Piperidine-4-ethyl formate

Be dissolved in 100mL ethanol under piperidines-4-formic acid 20a (10g, 80mmol) is stirred, drip thionyl chloride (11g, 96mmol) under ice bath, back flow reaction 3 hours.Concentrating under reduced pressure, obtains title product piperidine-4-ethyl formate 20b (13g, white solid), productive rate: 83.0%.

Second step

Piperidines-Isosorbide-5-Nitrae-O1-benzyl, O4-ethyl-dicarboxylic acid esters

Be dissolved in 100mL chloroform under piperidine-4-ethyl formate 20b (13g, 80mmol) is stirred, drip triethylamine (24g, 240mmol), stir 10 minutes, under ice bath, drip chloroformic acid benzyl ester (16g, 96mmol), room temperature reaction 12 hours.Use 1M hydrochloric acid (100mL), saturated sodium bicarbonate solution (100mL), water washing (100mL) successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain crude title piperidines-Isosorbide-5-Nitrae-O1-benzyl, O4-ethyl-dicarboxylic acid esters 20c (24g, khaki color liquid), product is not purified directly carries out next step reaction.

MS m/z(ESI)：292.2[M+1]

3rd step

4-(1-hydroxyl-1-methyl-ethyl) piperidines-1-benzyl formate

By crude product piperidines-Isosorbide-5-Nitrae-O1-benzyl, O4-ethyl-dicarboxylic acid esters 20c (500mg, 1.70mmol) is dissolved in 10mL tetrahydrofuran (THF) under stirring, and keeps-78 DEG C of diethyl ether solutions dripping 1.3mL 3M methyl-magnesium-bromide, room temperature reaction 1 hour.Add 20mL saturated ammonium chloride solution, be extracted with ethyl acetate (20mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system B by tlc, obtain title product 4-(1-hydroxyl-1-methyl-ethyl) piperidines-1-benzyl formate 20d (380mg, colorless oil), productive rate: 81.0%.

4th step

2-(4-piperidyl)-Virahol

Be dissolved in 15mL methyl alcohol under 4-(1-hydroxyl-1-methyl-ethyl) piperidines-1-benzyl formate 20d (180mg, 0.65mmol) is stirred, add 20mg 10% palladium/carbon, hydrogen exchange three times, react 12 hours.Filter, filtrate reduced in volume, obtains title product 2-(4-piperidyl)-Virahol 20e (80mg, colorless oil), productive rate: 86.0%.

5th step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (80mg, 5mL N is dissolved under 0.25mmol) stirring, in dinethylformamide, add 2-(4-piperidyl)-Virahol 20e (43mg successively, 0.30mmol), I-hydroxybenzotriazole (50mg, 0.38mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (72mg, 0.38mmol) with triethylamine (76mg, 0.75mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-[4-(1-hydroxyl-1-methyl-ethyl) piperidines-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 20 (60mg, white solid), productive rate: 58.0%.

MS m/z(ESI)：448.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.59(s，1H)，8.25(d，1H)，7.96(d，1H)，7.89-7.79(m，2H)，7.21(s，1H)，6.97(s，1H)，4.52-4.48(t，3H)，4.22(s，1H)，4.14-4.12(t，3H)，3.48-3.38(m，1H)，3.17-3.14(m，4H)，2.87-2.81(m，1H)，1.75(d，1H)，1.53(d，1H)，1.41-1.35(t，1H)，1.10-1.01(m，6H)

Embodiment 21

4-[[7-[3-(trifluoromethyl)-6,8-dihydro-5H-imidazo [1,5-a] pyrazine-7-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2, 3-Dihydrobenzofuranes-7-formic acid 3b (320mg, 10mL N is dissolved under 1mmol) stirring, in dinethylformamide, add 3-(trifluoromethyl)-5 successively, 6, 7, 8-imidazolidine also [1, 5-a] pyrazine hydrochloride (190mg, 1.20mmol, known method " patent WO2009082881 " is adopted to prepare and obtain), I-hydroxybenzotriazole (200mg, 1.50mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (290mg, 1.50mmol) with triethylamine (300mg, 3mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product 4-[[7-[3-(trifluoromethyl)-6,8-dihydro-5H-imidazo [1,5-a] pyrazine-7-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone 21 (180mg, white solid), productive rate: 36.0%.

MS m/z(ESI)：496.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.58(s，1H)，8.24-8.26(m，1H)，7.82-7.98(m，3H)，7.29(s，1H)，7.22(s，1H)，7.01(s，1H)，4.82-4.84(m，1H)，4.49-4.54(m，2H)，4.23(s，2H)，3.92-4.10(m，2H)，3.64-3.66(m，1H)，3.14-3.17(m，2H)，2.91(s，1H)，2.79(s，1H)

Embodiment 22

4-[[7-[4-(the amino cyclopropyl carbonyl of 1-) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

1-(tertbutyloxycarbonylamino) ethylene-acetic acid

Be dissolved in 5mL 0.5M sodium hydroxide solution under amino for 1-ethylene-acetic acid 22a (200mg, 1.98mmol) is stirred, add 5mL Isosorbide-5-Nitrae-dioxane and tert-Butyl dicarbonate (648mg, 2.97mmol), react 15 hours.With extracted with diethyl ether (10mL × 2), dripping 1M hydrochloric acid is 4 to aqueous phase pH, be extracted with ethyl acetate (20mL × 3), merge organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains title product 1-(tertbutyloxycarbonylamino) ethylene-acetic acid 22b (318mg, white solid), productive rate: 79.9%.

MS m/z(ESI)：146.1[M-56+1]

Second step

N-[1-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-carbonyl] cyclopropyl] t-butyl carbamate

By 4-[[7-(piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (390mg, 10mL N is dissolved under 1mmol) stirring, in dinethylformamide, add 1-(tertbutyloxycarbonylamino) ethylene-acetic acid 22b (200mg successively, 1mmol), I-hydroxybenzotriazole (203mg, 1.50mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (288mg, 1.50mmol) with triethylamine (303mg, 3mmol), react 15 hours.Add 50mL water, be extracted with ethyl acetate (50mL × 3), merge organic phase, saturated sodium bicarbonate solution (20mL), saturated nacl aqueous solution is used to wash (50mL × 2) successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product N-[1-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] cyclopropyl] t-butyl carbamate 22c (480mg, light yellow solid), productive rate: 84.2%.

MS m/z(ESI)：474.2[M-100+1]

3rd step

By N-[1-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] cyclopropyl] t-butyl carbamate 22c (480mg, be dissolved in the methanol solution of 20mL 2M hydrogenchloride under 0.84mmol) stirring, react 10 hours.Concentrating under reduced pressure, add 20mL water, dripping ammoniacal liquor is 8 to reaction solution pH, be extracted with ethyl acetate (30mL × 5), merge organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A, obtain title product 4-[[7-[4-(the amino cyclopropyl carbonyl of 1-) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 22 (220mg, white solid), productive rate: 51.2%.

MS m/z(ESI)：474.2[M+1]

¹H NMR(400MHz，CDCl ₃)：δ10.09(s，1H)，8.44-8.47(m，1H)，7.76-7.79(m，3H)，7.16-7.17(m，2H)，4.59(t，2H)，4.23(s，2H)，3.79-3.81(m，4H)，3.66-3.68(m，2H)，3.36-3.38(m，2H)，3.19(m，2H)，1.04-1.07(m，2H)，0.82-0.85(m，2H)

Embodiment 23

4-[[7-[4-[(4-p-methoxy-phenyl) methyl] piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

4-[(4-p-methoxy-phenyl) methyl] piperazine-1-t-butyl formate

Be dissolved in 30mL methylene dichloride under piperazine-1-t-butyl formate 15a (2g, 10mmol) is stirred, add 4-methoxybenzaldehyde (1.5mL, 12mmol), stir 10 minutes.Under ice bath, add sodium triacetoxy borohydride (3.17g, 15mmol) and 0.5mL acetic acid, room temperature reaction 12 hours.With saturated sodium bicarbonate solution washing (20mL × 3), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 4-[(4-p-methoxy-phenyl) methyl] piperazine-1-t-butyl formate 23a (0.40g, yellow oil), productive rate: 13.1%.

MS m/z(ESI)：307.2[M+1]

Second step

1-[(4-p-methoxy-phenyl) methyl] piperazine hydrochloride

Be dissolved in the Isosorbide-5-Nitrae-dioxane solution of 15mL 2M hydrogenchloride under 4-[(4-p-methoxy-phenyl) methyl] piperazine-1-t-butyl formate 23a (400mg, 1.30mmol) is stirred, react 48 hours.Concentrating under reduced pressure, vacuum-drying, obtains title product 1-[(4-p-methoxy-phenyl) methyl] piperazine hydrochloride 23b (120mg, white solid), productive rate: 44.9%.

MS m/z(ESI)：207.2[M+1]

3rd step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (104mg, 5mL N is dissolved under 0.325mmol) stirring, in dinethylformamide, add 1-[(4-p-methoxy-phenyl) methyl] piperazine hydrochloride 23b (80mg successively, 0.39mmol), I-hydroxybenzotriazole (66.15mg, 0.47mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (93.61mg, 0.49mmol) with triethylamine (0.1mL, 0.98mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-[4-[(4-p-methoxy-phenyl) methyl] piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 23 (40mg, white solid), productive rate: 24.0%.

MS m/z(ESI)：511.2[M+1]

¹H NMR(400MHz，CDCl ₃)：δ10.24(s，1H)，8.50-8.48(d，1H)，7.80-7.77(m，3H)，7.30-7.26(d，2H)，7.15(d，2H)，6.91-6.89(d，2H)，4.62-4.58(t，2H)，4.25(s，2H)，3.84-3.82(m，2H)，3.53(s，3H)，3.39(s，2H)，3.19(s，2H)，3.17(s，2H)，2.93(s，2H)，2.56(s，2H)

Embodiment 24

7-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazo [1,5-a] piperazine-1-methyl-formiate

The first step

3-(trifluoromethyl)-5,6,7,8-imidazolidine is [1,5-a] pyrazine-1-methyl-formiate also

O7-tertiary butyl O1-methyl 3-(trifluoromethyl)-6,8-dihydro-5H-imidazo [1,5-a] pyrazine-1,7-dicarboxylic acid esters 24a (600mg, 1.72mmol, known method " patent WO2009082881 " is adopted to prepare and obtain) be dissolved in the Isosorbide-5-Nitrae-dioxane solution of 20mL 2M hydrogenchloride, react 5 hours.Concentrating under reduced pressure, adds 50mL methylene dichloride, and dripping saturated sodium bicarbonate solution is 8 to reaction solution pH, separate organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain crude product 3-(trifluoromethyl)-5,6,7,8-imidazolidine also [1,5-a] pyrazine-1-methyl-formiate 24b (430mg, white solid), product is not purified directly carries out next step reaction.

Second step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2, 3-Dihydrobenzofuranes-7-formic acid 3b (155mg, 5mL N is dissolved under 0.5mmol) stirring, in dinethylformamide, add crude product 3-(trifluoromethyl)-5 successively, 6, 7, 8-imidazolidine also [1, 5-a] pyrazine-1-methyl-formiate 24b (100mg, 0.42mmol), I-hydroxybenzotriazole (81mg, 0.6mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (114.60mg, 0.60mmol) with triethylamine (101mg, 0.80mmol), react 12 hours.Add 10mL water, be extracted with ethyl acetate (10mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product 7-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl]-3-(trifluoromethyl)-6,8-dihydro-5H-imidazoles [1,5-a] piperazine-1-methyl-formiate 24 (170mg, light yellow solid), productive rate: 76.6%.

MS m/z(ESI)：554.1[M+1]

¹H NMR(400MHz，CDCl ₃)：δ10.46(s，1H)，8.46(d，1H)，7.81(m，3H)，7.21(m，2H)，5.03(m，2H)，4.60(m，2H)，4.25(m，5H)，3.91(m，4H)，3.22(m，2H)

Embodiment 25

4-[[7-[4-[(2R)-2-methylpyrrolidin-2-carbonyl] piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

(3S, 7aR)-3-(trichloromethyl)-5,6,7,7a-tetrahydrochysene-3H-pyrrolo-[1,2-c] oxazole-1-ketone

Be dissolved in 200mL chloroform under (2R)-tetramethyleneimine-2-formic acid 25a (20g, 174mmol) is stirred, add hydration 2,2,2-trichoro-aldehyde 25b (44g, 260mmol), under point water condition, back flow reaction 5 hours.Wash with water (100mL × 3), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, with ethyl alcohol recrystallization gained resistates, obtain title product (3S, 7aR)-3-(trichloromethyl)-5,6,7,7a-tetrahydrochysene-3H-pyrrolo-[1,2-c] oxazole-1-ketone 25c (29g, white solid), productive rate: 67.0%.

MS m/z(ESI)：246.0[M+1]

Second step

(3S, 7aR)-7a-methyl-3-(trichloromethyl)-3,5,6,7-Pyrrolidine is [1,2-c] oxazole-1-ketone also

By (3S, 7aR)-3-(trichloromethyl)-5,6,7,7a-tetrahydrochysene-3H-pyrrolo-[1,2-c] oxazole-1-ketone 25c (25g, 100mmol) is dissolved in 500mL tetrahydrofuran (THF) under stirring, and drips the tetrahydrofuran (THF)/hexane solution of 80mL 2M lithium diisopropylamine at-78 DEG C, react 45 minutes, add methyl iodide (25mL, 493mmol), react 2 hours at-50 DEG C.Add 150mL water, with chloroform extraction (200mL × 2), merge organic phase, with saturated nacl aqueous solution washing (200mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product (3S, 7aR)-7a-methyl-3-(trichloromethyl)-3,5,6,7-Pyrrolidine also [1,2-c] oxazole-1-ketone 25d (20g, light yellow oil), productive rate: 75.0%.MS m/z(ESI)：258.0[M+1]

3rd step

(2R)-2-methylpyrrolidin-2-methyl-formiate hydrochloride

By (3S, 7aR)-7a-methyl-3-(trichloromethyl)-3,5,6,7-Pyrrolidine is [1,2-c] oxazole-1-ketone 25d (15g also, be dissolved in 300mL methyl alcohol under 58mmol) stirring, add thionyl chloride (14mL, 174mmol), back flow reaction 2.5 hours.Concentrating under reduced pressure, with re-crystallizing in ethyl acetate gained resistates, obtains title product (2R)-2-methylpyrrolidin-2-methyl-formiate hydrochloride 25e (8g, white solid), productive rate: 70.0%.

MS m/z(ESI)：144.2[M+1]

4th step

O1-benzyl-O2-methyl-(2R)-2-methylpyrrolidin-1,2-dicarboxylic acid esters

By (2R)-2-methylpyrrolidin-2-methyl-formiate hydrochloride 25e (1g, 10mL 1 is dissolved under 5.60mmol) stirring, in 4-dioxane, add 5mL saturated sodium bicarbonate solution, chloroformic acid benzyl ester (1.05g is dripped under ice bath, 6.22mmol), room temperature reaction 6 hours.Add 20mL ethyl acetate, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains crude title product O1-benzyl-O2-methyl-(2R)-2-methylpyrrolidin-1,2-dicarboxylic acid esters 25f (2g, colorless oil), product is not purified directly carries out next step reaction.

MS m/z(ESI)：278.1[M+1]

5th step

(2R)-1-carbobenzoxy-(Cbz)-2-methyi-pyrrofidinium-2-formic acid

Be dissolved in 10mL tetrahydrofuran (THF) under crude product O1-benzyl-O2-methyl-(2R)-2-methylpyrrolidin-1,2-dicarboxylic acid esters 25f (2g, 5.60mmol) is stirred.Lithium hydroxide (0.50g, 11.20mmol) is dissolved in 10mL water, joins in above-mentioned reaction solution.Add 6mL methyl alcohol, react 8 hours.Concentrating under reduced pressure, adds 15mL water and 10mL methylene dichloride, separatory, collects aqueous phase.Dripping 1mL concentrated hydrochloric acid is 3 to aqueous phase pH, be extracted with ethyl acetate (20mL × 3), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filters, filtrate reduced in volume, obtain title product (2R)-1-carbobenzoxy-(Cbz)-2-methyi-pyrrofidinium-2-formic acid 25g (1.50g, light yellow solid).

MS m/z(ESI)：264.1[M+1]

6th step

(2R)-2-methyl-2-[4-[5-[(4-oxo-3H-phthalazines 1-yl) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-carbonyl] tetramethyleneimine-1-benzyl formate

By 4-[[7-(piperazine-1-carbonyl)-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (302mg, 5mL N is dissolved under 0.78mmol) stirring, in dinethylformamide, add (2R)-1-carbobenzoxy-(Cbz)-2-methyi-pyrrofidinium-2-formic acid 25g (170mg successively, 0.65mmol), I-hydroxybenzotriazole (132mg, 0.98mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (186mg, 0.98mmol) with triethylamine (197mg, 1.95mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product (2R)-2-methyl-2-[4-[5-[(4-oxo-3H-phthalazines 1-yl) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] tetramethyleneimine-1-benzyl formate 25h (270mg, light yellow solid), productive rate: 66.0%.

MS m/z(ESI)：636.1[M+1]

7th step

By (2R)-2-methyl-2-[4-[5-[(4-oxo-3H-phthalazines 1-yl) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] tetramethyleneimine-1-benzyl formate 25h (270mg, be dissolved in 15mL ethanol under 0.43mmol) stirring, add palladium hydroxide (6mg, 0.043mmol), hydrogen exchange three times, reacts 4 hours.Filter, filtrate reduced in volume, obtain title product 4-[[7-[4-[(2R)-2-methylpyrrolidin-2-carbonyl] piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 25 (140mg, white solid), productive rate: 66.0%.

MS m/z(ESI)：502.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.45(s，1H)，8.48(d，1H)，7.92(d，1H)，7.85-7.83(t，1H)，7.82-7.80(t，1H)，7.25(s，1H)，7.01(s，1H)，4.52-4.50(t，2H)，4.25(s，2H)，3.65-3.45(m，7H)，3.21-3.18(m，4H)，2.78-2.68(m，4H)，1.64-1.54(m，2H)，1.51(s，3H)

Embodiment 26

4-[[7-[4-(Cvclopropvlmethvl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

4-(Cvclopropvlmethvl) piperazine-1-t-butyl formate

Be dissolved in 10mL methyl alcohol under piperazine-1-t-butyl formate 15a (300mg, 1.60mmol) is stirred, add cyclopanecarboxaldehyde (113mg, 1.60mmol), stir 30 minutes.Under ice bath, add sodium borohydride (122mg, 3.20mmol), room temperature reaction 12 hours.Add 20mL saturated ammonium chloride solution, be extracted with ethyl acetate (20mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product 4-(Cvclopropvlmethvl) piperazine-1-t-butyl formate 26a (310mg, colorless oil), productive rate: 81.0%.

MS m/z(ESI)：241.2[M+1]

Second step

1-(Cvclopropvlmethvl) piperazine hydrochloride

Be dissolved in the Isosorbide-5-Nitrae-dioxane solution of 10mL 2M hydrogenchloride under 4-(Cvclopropvlmethvl) piperazine-1-t-butyl formate 26a (310mg, 1.29mmol) is stirred, react 12 hours.Concentrating under reduced pressure, obtains title product 1-(Cvclopropvlmethvl) piperazine hydrochloride 26b (210mg, white solid), productive rate: 93.0%.

MS m/z(ESI)：141.1[M+1]

3rd step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (182mg, 10mLN is dissolved under 0.57mmol) stirring, in dinethylformamide, add 1-(Cvclopropvlmethvl) piperazine hydrochloride 26b (100mg successively, 0.57mmol), I-hydroxybenzotriazole (116mg, 0.86mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (165mg, 0.86mmol) with triethylamine (173mg, 1.71mmol), react 15 hours.Add 50mL water, be extracted with ethyl acetate (50mL × 3), merge organic phase, with saturated sodium bicarbonate solution (20mL × 2), saturated nacl aqueous solution washing (30mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-[4-(Cvclopropvlmethvl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 26 (152mg, white solid), productive rate: 60.6%.

MS m/z(ESI)：445.2[M+1]

¹H NMR(400MHz，CDCl ₃)：δ10.51(s，1H)，8.45-8.47(m，1H)，7.74-7.77(m，3H)，7.12-7.14(m，2H)，4.57(t，2H)，4.23(s，2H)，3.86-3.88(m，2H)，3.44-3.47(m，2H)，3.16(t，2H)，2.95-2.97(m，1H)，2.88-2.90(m，1H)，2.35-2.37(m，2H)，1.21(t，2H)，0.90-0.92(m，1H)，0.55-0.57(m，2H)，0.14-0.16(m，2H)

Embodiment 27

4-[[7-[4-(1-hydroxyl cyclopropane) piperidines-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

4-(1-hydroxycyclopropyl) piperidines-1-benzyl formate

By piperidines-1,4-O1-benzyl, O4-ethyl-dicarboxylic acid esters 20c (500mg, be dissolved in 10mL tetrahydrofuran (THF) under 1.70mmol) stirring, at 0 DEG C, drip the diethyl ether solution of 1.3mL 3M ethylmagnesium bromide, add tetra isopropyl titanate (6mL, 0.02mmol), room temperature reaction 12 hours.Add 20mL saturated ammonium chloride solution, be extracted with ethyl acetate (20mL × 3), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates by tlc with developping agent system B, obtains title product 4-(1-hydroxycyclopropyl) piperidines-1-benzyl formate 27a (380mg, colorless oil), productive rate: 81.0%.

MS m/z(ESI)：276.2[M+1]

Second step

1-(4-piperidines) ring propyl alcohol

Be dissolved in 15mL methyl alcohol under 4-(1-hydroxycyclopropyl) piperidines-1-benzyl formate 27a (100mg, 0.36mmol) is stirred, add 10mg 10% palladium/carbon, hydrogen exchange three times, react 12 hours.Filter, filtrate reduced in volume, obtains title product 1-(4-piperidines) ring propyl alcohol 27b (48mg, colorless oil), productive rate: 94.0%.MS m/z(ESI)：142.1[M+1]

3rd step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (97mg, 5mL N is dissolved under 0.30mmol) stirring, in dinethylformamide, add 1-(4-piperidines) ring propyl alcohol 27b (70mg successively, 0.36mmol), I-hydroxybenzotriazole (60mg, 0.45mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (86mg, 0.45mmol) with triethylamine (91mg, 0.90mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-[4-(1-hydroxyl cyclopropane) piperidines-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 27 (80mg, white solid), productive rate: 60.0%.

MS m/z(ESI)：446.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，8.25(d，1H)，7.98(d，1H)，7.89-7.81(m，2H)，7.20(s，1H)，7.01(s，1H)，4.95-4.48(m，3H)，4.22(s，2H)，3.43-3.41(m，1H)，3.17-3.12(m，3H)，2.91-2.86(m，1H)，2.57-2.54(m，1H)，1.64-0.85(m，5H)，0.50-0.48(m，2H)，0.34-0.33(m，2H)

Embodiment 28

4-[[7-[4-(1-dimethylamino cyclopentane base carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

By 4-[[7-[4-(1-amino cyclopentyl alkyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 6 (70mg, be dissolved in 15mL methyl alcohol under 0.14mmol) stirring, add 37% formaldehyde solution (10mg, 0.24mmol), back flow reaction 20 minutes, adds sodium triacetoxy borohydride (44mg, 0.20mmol), back flow reaction 2 hours.Add 15mL water, be extracted with ethyl acetate (20mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates by tlc with developping agent system A, obtain title product 4-[[7-[4-(1-dimethylamino cyclopentane base carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone 28 (20mg, white solid), productive rate: 27.0%.

MS m/z(ESI)：530.3[M+1]

¹H NMR(400MHz，CDCl ₃)：δ10.10(s，1H)，8.45-8.46(m，1H)，7.75-7.77(m，3H)，7.14-7.16(m，2H)，4.58(t，2H)，4.23(s，2H)，3.98-4.10(m，2H)，3.62-3.74(m，4H)，3.31-3.33(m，2H)，3.17(t，2H)，2.17(s，3H)，2.13(s，3H)，1.76-1.79(m，4H)，1.55-1.59(m，4H)

Embodiment 29

4-[[7-(4-Cyclopropylsulfonyl piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

4-Cyclopropylsulfonyl piperazine-1-t-butyl formate

Be dissolved in 10mL methylene dichloride under piperazine-1-t-butyl formate 15a (350mg, 1.88mmol) is stirred, drip triethylamine (0.4mL, 2.82mmol), drip cyclopropyl sulfonyl chloride (320mg, 2.26mmol) under ice bath, react 1 hour under ice bath.Add 15mL methylene dichloride; use saturated sodium bicarbonate solution (20mL), saturated nacl aqueous solution (15mL), water washing (20mL) successively; anhydrous sodium sulfate drying; filter; filtrate reduced in volume; obtain crude title product 4-Cyclopropylsulfonyl piperazine-1-t-butyl formate 29a (480mg, colorless oil), product is not purified directly carries out next step reaction.

MS m/z(ESI)：191.1[M-100+1]

Second step

1-Cyclopropylsulfonyl piperazine hydrochloride

Be dissolved in 10mL methyl alcohol under crude product 4-Cyclopropylsulfonyl piperazine-1-t-butyl formate 29a (480mg, 1.66mmol) is stirred, add the methanol solution of 3mL 2M hydrogenchloride, react 12 hours.Concentrating under reduced pressure, obtains title product 1-Cyclopropylsulfonyl piperazine hydrochloride 29b (300mg, white solid), productive rate: 96.8%.MS m/z(ESI)：191.2[M+1]

3rd step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2; 3-Dihydrobenzofuranes-7-formic acid 3b (200mg; 10mL N is dissolved under 0.62mmol) stirring; in dinethylformamide; add 1-Cyclopropylsulfonyl piperazine hydrochloride 29b (142mg successively; 0.75mmol); I-hydroxybenzotriazole (126mg; 0.93mmol); 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (178mg; 0.93mmol) with triethylamine (188mg, 1.86mmol), react 12 hours.Add 20mL water; be extracted with ethyl acetate (30mL × 2); merge organic phase; with saturated nacl aqueous solution washing (20mL × 2); anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product 4-[[7-(4-Cyclopropylsulfonyl piperazine-1-carbonyl)-2; 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 29 (160mg, white solid), productive rate: 52.3%.

MS m/z(ESI)：495.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，8.24-8.26(m，1H)，7.82-7.98(m，3H)，7.26(s，1H)，7.05(s，1H)，4.54(t，2H)，4.23(s，2H)，3.64-3.66(m，2H)，3.27-3.29(m，2H)，3.21-3.23(m，2H)，3.14(t，2H)，3.11-3.13(m，2H)，2.58-2.62(m，1H)，0.92-1.00(m，4H)

Embodiment 30

4-[[7-[4-(2-amino-2-methyl-propionyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

2-(tertbutyloxycarbonylamino)-2-rnethyl-propanoic acid

Be dissolved in 25mL Isosorbide-5-Nitrae-dioxane under 2-amino-2-methyl propionic acid 30a (2g, 20mmol) is stirred, add 25mL 2M sodium hydroxide solution and tert-Butyl dicarbonate (5.20g, 24mmol), react 12 hours.Concentrating under reduced pressure, add 20mL water, dripping concentrated hydrochloric acid is 2 to aqueous phase pH, is extracted with ethyl acetate (30mL × 3), merge organic phase, with saturated nacl aqueous solution washing (20mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product 2-(tertbutyloxycarbonylamino)-2-rnethyl-propanoic acid 30b (3.90g, white solid), productive rate: 99.0%.

MS m/z(ESI)：202.1[M-1]

Second step

N-[1,1-dimethyl-2-oxo-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-base] ethyl] t-butyl carbamate

By 4-[[7-(piperazine-1-carbonyl)-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (190mg, 10mL N is dissolved under 0.44mmol) stirring, in dinethylformamide, add 2-(tertbutyloxycarbonylamino)-2-rnethyl-propanoic acid 30b (108mg successively, 0.53mmol), I-hydroxybenzotriazole (90mg, 0.67mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (128mg, 0.67mmol) with triethylamine (135mg, 1.33mmol), react 12 hours.Add 10mL water, be extracted with ethyl acetate (20mL × 5), merge organic phase, with saturated nacl aqueous solution washing (20mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product N-[1, 1-dimethyl-2-oxo-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2, 3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-base] ethyl] t-butyl carbamate 30c (120mg, yellow oil), productive rate: 46.9%.

MS m/z(ESI)：576.2[M+1]

3rd step

By N-[1,1-dimethyl-2-oxo-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-base] ethyl] t-butyl carbamate 30c (100mg, be dissolved in 10mL methyl alcohol under 0.17mmol) stirring, add the methanol solution of 3mL 2M hydrogenchloride, react 12 hours.Concentrating under reduced pressure; add 10mL methyl alcohol; dripping saturated sodium bicarbonate solution is 7 to reaction solution pH; concentrating under reduced pressure; purify gained resistates by tlc with developping agent system A, obtain title product 4-[[7-[4-(2-amino-2-methyl-propionyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone 30 (25mg; white solid), productive rate: 30.1%.

MS m/z(ESI)：476.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.59(s，1H)，8.24-8.26(m，1H)，7.80-7.98(m，3H)，7.26(s，1H)，7.05(s，1H)，4.53(t，2H)，4.23(s，2H)，3.67-3.69(m，2H)，3.57-3.59(m，4H)，3.15-3.18(m，2H)，3.14(t，2H)，1.46(s，6H)

Embodiment 31

4-[[7-[4-(1-Aminocyclobutyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

1-(tertbutyloxycarbonylamino) cyclobutyl formate

Be dissolved in 10mL 0.5M sodium hydroxide solution under 1-Aminocyclobutyl formic acid 31a (500mg, 4.34mmol) is stirred, add 10mL Isosorbide-5-Nitrae-dioxane and tert-Butyl dicarbonate (1.42g, 6.51mmol), react 15 hours.With extracted with diethyl ether (20mL × 2), dripping 1M hydrochloric acid is 4 to aqueous phase pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, with saturated nacl aqueous solution washing (20mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains title product 1-(tertbutyloxycarbonylamino) cyclobutyl formate 31b (750mg, white solid), productive rate: 80.6%.

Second step

N-[1-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-carbonyl] cyclobutyl] t-butyl carbamate

By 4-[[7-(piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (397mg, 10mL N is dissolved under 0.93mmol) stirring, in dinethylformamide, add 1-(tertbutyloxycarbonylamino) cyclobutyl formate 31b (200mg successively, 0.93mmol), I-hydroxybenzotriazole (189mg, 1.40mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (268mg, 1.40mmol) with triethylamine (0.4mL, 2.80mmol), react 12 hours.Add 50mL water, be extracted with ethyl acetate (50mL × 3), merge organic phase, saturated sodium bicarbonate solution (20mL), saturated nacl aqueous solution is used to wash (50mL × 2) successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product N-[1-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] cyclobutyl] t-butyl carbamate 31c (430mg, light yellow solid), productive rate: 79.6%.

MS m/z(ESI)：488.2[M-100+1]

3rd step

By N-[1-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] cyclobutyl] t-butyl carbamate 31c (430mg, be dissolved in the methanol solution of 10mL 2M hydrogenchloride under 0.73mmol) stirring, react 10 hours.Concentrating under reduced pressure, add 20mL water, dripping ammoniacal liquor is 8 to reaction solution pH, be extracted with ethyl acetate (30mL × 5), merge organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates by tlc with developping agent system A, obtain title product 4-[[7-[4-(1-Aminocyclobutyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 31 (310mg, white solid), productive rate: 86.8%.

MS m/z(ESI)：488.2[M+1]

¹H NMR(400MHz，CDCl ₃)：δ10.09(s，1H)，8.44-8.46(m，1H)，7.74-7.78(m，3H)，7.14-7.15(m，2H)，4.58(t，2H)，4.22(s，2H)，3.75-3.77(m，2H)，3.68-3.70(m，2H)，3.58-3.60(m，2H)，3.34-3.36(m，2H)，3.18(t，2H)，2.71-2.75(m，2H)，1.95-1.99(m，4H)

Embodiment 32

4-[[7-[4-[(2R)-1,2-dimethyl pyrrolidine-2-carbonyl] piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

(2R)-2-methylpyrrolidin-2-formic acid

Be dissolved in 10mL ethanol under (2R)-1-carbobenzoxy-(Cbz)-2-methyi-pyrrofidinium-2-formic acid 25g (263mg, 1mmol) is stirred, add palladium hydroxide (20mg, 0.14mmol), hydrogen exchange three times, react 12 hours.Filter, filtrate reduced in volume, obtains title product (2R)-2-methylpyrrolidin-2-formic acid 32a (120mg, colorless oil), productive rate: 93.0%.

Second step

(2R)-1,2-dimethyl pyrrolidine-2-formic acid

Be dissolved in 3mL 37% formaldehyde solution under (2R)-2-methylpyrrolidin-2-formic acid 32a (120mg, 0.93mmol) is stirred, add the palladium/carbon of 24mg 10%, hydrogen exchange three times, react 16 hours.Filter, filtrate reduced in volume, obtains title product (2R)-1,2-dimethyl pyrrolidine-2-formic acid 32b (110mg, white solid), productive rate: 83.0%.

MS m/z(ESI)：142.1[M-1]

3rd step

By 4-[[7-(piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (214mg, 5mL N is dissolved under 0.50mmol) stirring, in dinethylformamide, add (2R)-1 successively, 2-dimethyl pyrrolidine-2-formic acid 32b (86mg, 0.60mmol), I-hydroxybenzotriazole (101mg, 0.75mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (143mg, 0.75mmol) and triethylamine (151mg, 1.50mmol), react 12 hours.Add 25mL water, be extracted with ethyl acetate (20mL × 3), merge organic phase, use saturated sodium bicarbonate solution (20mL) successively, saturated nacl aqueous solution washing (20mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-[4-[(2R)-1, 2-dimethyl pyrrolidine-2-carbonyl] piperazine-1-carbonyl]-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 32 (210mg, light yellow solid), productive rate: 81.6%.

MS m/z(ESI)：516.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.45(s，1H)，8.52(d，1H)，7.92(d，1H)，7.83-7.81(t，1H)，7.80-7.78(t，1H)，7.45(s，1H)，7.23(s，1H)，4.65-4.63(t，2H)，3.78-3.75(m，8H)，3.42-3.18(m，4H)，2.78-2.60(m，4H)，2.26(s，3H)，1.64-1.54(m，2H)，1.51(s，3H)

Embodiment 33

4-[[7-[4-[the fluoro-5-of 3-(trifluoromethyl)-2-pyridine] piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

1-[the fluoro-5-of 3-(trifluoromethyl)-2-pyridine] piperazine

Be dissolved in 30mL tetrahydrofuran (THF) under piperazine (3.50g, 41mmol) is stirred, add the fluoro-5-of 2,3-bis-(trifluoromethyl) pyridine 33a (2.50g, 13.7mmol) under ice bath, react 3 hours.Add 100mL water, be extracted with ethyl acetate (100mL × 3), merge organic phase, with saturated nacl aqueous solution washing (100mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product 1-[the fluoro-5-of 3-(trifluoromethyl)-2-pyridine] piperazine 33b (3.30g, white solid), productive rate: 97.0%.

Second step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (150mg, 5mL N is dissolved under 0.47mmol) stirring, in dinethylformamide, add 1-[the fluoro-5-of 3-(trifluoromethyl)-2-pyridine] piperazine 33b (139mg successively, 0.56mmol), I-hydroxybenzotriazole (95mg, 0.70mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (134mg, 0.70mmol) with triethylamine (142mg, 1.40mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, with saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-[4-[the fluoro-5-of 3-(trifluoromethyl)-2-pyridine] piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 33 (210mg, white solid), productive rate: 80.8%.

MS m/z(ESI)：554.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，8.36(s，1H)，8.26-8.24(d，1H)，7.98-7.95(m，2H)，7.88-7.79(m，2H)，7.26(s，1H)，7.09(s，1H)，4.56-4.52(t，2H)，4.23(s，2H)，3.70-3.55(m，6H)，3.18-3.14(m，2H)，2.89(s，1H)，2.73(s，1H)

Embodiment 34

4-[[7-[4-(2-dimethylamino-2-methyl-propanoyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

2-dimethylamino-2-rnethyl-propanoic acid

Be dissolved in 25mL 37% formaldehyde solution under 2-amino-2-methyl propionic acid 30a (1g, 9.70mmol) is stirred, add 10mL methyl alcohol, add the palladium/carbon of 100mg 10%, hydrogen exchange three times, react 12 hours.Filter, filtrate reduced in volume, gained residue recrystallisation from isopropanol, obtains title product 2-dimethylamino-2-rnethyl-propanoic acid 34a (480mg, white solid), productive rate: 36.9%.

MS m/z(ESI)：130.1[M-1]

Second step

By 4-[[7-(piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (117mg, 10mL N is dissolved under 0.30mmol) stirring, in dinethylformamide, add 2-dimethylamino-2-rnethyl-propanoic acid 34a (39mg successively, 0.30mmol), I-hydroxybenzotriazole (61mg, 0.45mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (86mg, 0.45mmol) with triethylamine (91mg, 0.90mmol), react 12 hours.Add 10mL water; be extracted with ethyl acetate (20mL × 5); merge organic phase; with saturated nacl aqueous solution washing (20mL × 2); anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product 4-[[7-[4-(2-dimethylamino-2-methyl-propanoyl) piperazine-1-carbonyl]-2; 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 34 (65mg, white solid), productive rate: 43.3%.

MS m/z(ESI)：504.6[M+1]

¹H NMR(400MHz，CDCl ₃)：δ9.98(s，1H)，8.46-8.44(m，1H)，7.77-7.75(m，3H)，7.16-7.14(m，2H)，4.61-4.57(t，2H)，4.34(s，1H)，4.22(s，3H)，3.74(s，2H)，3.58(s，1H)，3.50(s，1H)，3.33(s，2H)，3.20-3.16(t，2H)，2.22(s，6H)，1.26(s，6H)

Embodiment 35

4-[[7-[4-[2-(Cyclopropyl-methyl-amino)-2-methyl-propanoyl] piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

By 4-[[7-[4-(2-amino-2-methyl-propionyl) piperazine-1-carbonyl]-2; 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 30 (70mg; be dissolved in 10mL methyl alcohol under 0.15mmol) stirring; add cyclopanecarboxaldehyde (12mg; 0.18mmol), back flow reaction 20 minutes, adds sodium triacetoxy borohydride (64mg; 0.30mmol), back flow reaction 4 hours.Add 15mL saturated ammonium chloride solution; with dichloromethane extraction (10mL × 3); merge organic phase; with anhydrous sodium sulfate drying; filter; filtrate reduced in volume; gained resistates is purified with eluent system A with silica gel column chromatography; obtain title product 4-[[7-[4-[2-(Cyclopropyl-methyl-amino)-2-methyl-propanoyl] piperazine-1-carbonyl]-2; 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 35 (40mg; white solid), productive rate: 51.3%.

MS m/z(ESI)：530.6[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，8.24-8.26(m，1H)，7.80-7.98(m，3H)，7.25(s，1H)，7.06(s，1H)，4.53(t，2H)，4.23(s，2H)，3.54-3.56(m，2H)，3.28-3.30(m，2H)，3.15-3.17(m，2H)，3.13(t，2H)，2.21-2.25(m，2H)，1.79-1.83(m，1H)，1.22(s，6H)，0.79-0.82(m，2H)，0.36-0.38(m，2H)，0.07-0.08(m，2H)

Embodiment 36

4-[[7-[4-(2-pyridylmethyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

4-(2-pyridylmethyl) piperazine-1-t-butyl formate

By pyridine-2-formaldehyde 36a (2.87g, 100mL 1 is dissolved under 26.90mmol) stirring, in 2-ethylene dichloride, add piperazine-1-t-butyl formate (5g, 26.90mmol), add sodium triacetoxy borohydride (11.40g, 53.80mmol), react 12 hours.Add 15mL saturated sodium carbonate solution, separatory, organic phase washed with water (20mL × 2), saturated nacl aqueous solution washing (20mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains title product 4-(2-pyridylmethyl) piperazine-1-t-butyl formate 36b (6.80g, yellow oil), productive rate: 92.0%.

MS m/z(ESI)：278.2[M+1]

Second step

1-(2-pyridylmethyl) piperazine hydrochloride

Be dissolved in the methanol solution of 15mL 2M hydrogenchloride under 4-(2-pyridylmethyl) piperazine-1-t-butyl formate 36b (2g, 7.20mmol) is stirred, react 12 hours.Concentrating under reduced pressure, obtains title product 1-(2-pyridylmethyl) piperazine hydrochloride 36c (1.19g, white solid), productive rate: 93.0%.

MS m/z(ESI)：178.1[M+1]

3rd step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (200mg, 5mL N is dissolved under 0.62mmol) stirring, in dinethylformamide, add 1-(2-pyridylmethyl) piperazine hydrochloride 36c (159mg successively, 0.74mmol), I-hydroxybenzotriazole (126mg, 0.93mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (178mg, 0.93mmol) with triethylamine (313mg, 3.10mmol), react 12 hours.Add 20mL water, be extracted with ethyl acetate (20mL × 2), merge organic phase, water (20mL), saturated nacl aqueous solution is used to wash (20mL) successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-[4-(2-pyridylmethyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 36 (120mg, white solid), productive rate: 40.0%.

MS m/z(ESI)：482.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.58(s，1H)，8.52(d，1H)，8.26(d，1H)，7.97(d，1H)，7.88-7.87(t，1H)，7.82-7.79(m，2H)，7.47-7.45(m，1H)，7.30-7.23(m，1H)，7.28(s，1H)，7.03(s，1H)，4.54-4.49(m，2H)，4.23(s，2H)，3.64-3.60(m，4H)，3.21-3.12(m，4H)，2.46-2.36(m，4H)

Embodiment 37

4-[[7-[4-(1-methylamino cyclobutyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

1-(tert-butoxycarbonyl (methyl) is amino) cyclobutyl formate methyl esters

Be dissolved in 5mL DMF under 1-(tertbutyloxycarbonylamino) cyclobutyl formate 31b (500mg, 2.32mmol) is stirred, sodium hydride and mineral oil mixture (300mg is added under ice bath, 60%, 6.97mmol), react 30 minutes.Add methyl iodide (990mg, 6.97mmol), room temperature reaction 12 hours.Add 10mL water, dripping 1M hydrochloric acid is 6 to aqueous phase pH, be extracted with ethyl acetate (10mL × 3), merge organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product 1-(tert-butoxycarbonyl (methyl) is amino) cyclobutyl formate methyl esters 37a (530mg, light yellow liquid), productive rate: 92.9%.

MS m/z(ESI)：144.1[M-100+1]

Second step

1-(tert-butoxycarbonyl (methyl) is amino) cyclobutyl formate

By 1-(tert-butoxycarbonyl (methyl) is amino) cyclobutyl formate methyl esters 37a (530mg, be dissolved in 10mL methyl alcohol and 5mL water under 2.18mmol) stirring, add sodium hydroxide (131mg, 3.27mmol), react 10 hours.Add 10mL water, be extracted with ethyl acetate (5mL × 2), dripping 1M hydrochloric acid is 4 to aqueous phase pH, is extracted with ethyl acetate (10mL × 3), merge organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product 1-(tert-butoxycarbonyl (methyl) is amino) cyclobutyl formate 37b (370mg, white solid), productive rate: 74.0%.

3rd step

N-methyl-N-[1-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-carbonyl] cyclobutyl] t-butyl carbamate

By 4-[[7-(piperazine-1-carbonyl)-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (200mg, 10mL N is dissolved under 0.47mmol) stirring, in dinethylformamide, add 1-(tert-butoxycarbonyl (methyl) is amino) cyclobutyl formate 37b (118mg successively, 0.52mmol), I-hydroxybenzotriazole (96mg, 0.71mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (136mg, 0.71mmol) with triethylamine (144mg, 1.44mmol), react 12 hours.Add 50mL water, be extracted with ethyl acetate (50mL × 3), merge organic phase, saturated sodium bicarbonate solution (20mL), saturated nacl aqueous solution is used to wash (50mL × 2) successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product N-methyl-N-[1-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] cyclobutyl] t-butyl carbamate 37c (256mg, light yellow solid), productive rate: 91.5%.

MS m/z(ESI)：502.7[M-100+1]

4th step

By N-methyl-N-[1-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] cyclobutyl] t-butyl carbamate 37c (256mg, be dissolved in the methanol solution of 5mL 2M hydrogenchloride under 0.43mmol) stirring, react 10 hours.Concentrating under reduced pressure, add 20mL water, dripping ammoniacal liquor is 8 to reaction solution pH, be extracted with ethyl acetate (30mL × 5), merge organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates by tlc with developping agent system A, obtain title product 4-[[7-[4-(1-methylamino cyclobutyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 37 (130mg, white solid), productive rate: 61.0%.

MS m/z(ESI)：502.6[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，8.24-8.26(m，1H)，7.80-7.98(m，3H)，7.24(s，1H)，7.05(s，1H)，4.53(t，2H)，4.22(s，2H)，3.38-3.40(m，4H)，3.36-3.38(m，2H)，3.12-3.17(m，2H)，3.18(t，2H)，2.45-2.50(m，2H)，2.01-2.08(m，5H)，1.87-1.88(m，1H)，1.53-1.55(m，1H)

Embodiment 38

4-[[7-[4-(1-dimethylamino cyclobutyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

By 4-[[7-[4-(1-methylamino cyclobutyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 37 (120mg, be dissolved in 3mL methylene dichloride under 0.24mmol) stirring, add 37% formaldehyde solution (11mg, 0.36mmol), sodium triacetoxy borohydride (76mg, 0.36mmol) is added, room temperature reaction 3 hours under ice bath.Add 5mL saturated ammonium chloride solution, with dichloromethane extraction (5mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-[4-(1-dimethylamino cyclobutyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 38 (79mg, white solid), productive rate: 63.7%.

MS m/z(ESI)：516.6[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，8.24-8.26(m，1H)，7.79-7.87(m，3H)，7.25(s，1H)，7.04(s，1H)，4.52(t，2H)，4.22(s，2H)，3.51-3.53(m，2H)，3.43-3.45(m，2H)，3.28-3.30(m，2H)，3.18(t，2H)，3.13-3.17(m，2H)，2.23-2.25(m，3H)，2.11-2.15(m，6H)，1.41-1.43(m，3H)

Embodiment 39

4-[[7-(5,7-pyrrolin is [3,4-b] pyridine-6-carbonyl also)-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (151mg, 4mL N is dissolved under 0.47mmol) stirring, in dinethylformamide, add 6 successively, 7-dihydro-5H-pyrrolo-[3,4-b] pyridine (60mg, 0.39mmol), I-hydroxybenzotriazole (80mg, 0.59mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (111mg, 0.59mmol) with triethylamine (118mg, 1.17mmol), react 12 hours.Add 10mL water, be extracted with ethyl acetate (10mL × 3), merge organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filters, filtrate reduced in volume, obtain title product 4-[[7-(5,7-pyrrolin is [3,4-b] pyridine-6-carbonyl also)-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone 39 (60mg, white solid), productive rate: 44.0%.

MS m/z(ESI)：425.4[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.58(s，1H)，8.52(d，1H)，8.26(d，1H)，7.97(d，1H)，7.88-7.87(t，1H)，7.82-7.79(m，1H)，7.47-7.45(m，1H)，7.30-7.23(m，1H)，7.28(s，1H)，7.03(s，1H)，5.43(s，2H)，4.93(s，2H)，4.46(s，2H)，4.23-4.21(t，2H)，3.64-3.60(t，2H)

Embodiment 40

4-[[7-[4-[(2S)-4,4-difluoropyrrolidin-2-carbonyl] piperazine-1-carbonyl-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone

The first step

The O1-tertiary butyl-O2-methyl-(2S, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxylic acid esters

By (2S, 4R)-4-hydroxyl pyrrolidine-2-methyl-formiate 40a (0.90g, be dissolved in 30mL methylene dichloride under 5mmol) stirring, add tert-Butyl dicarbonate (1.20g, 5.50mmol) with triethylamine (1.50g, 15mmol), react 5 hours.Concentrating under reduced pressure, adds 15mL water, is extracted with ethyl acetate (20mL × 3), merge organic phase, with saturated nacl aqueous solution washing (30mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain the title product O1-tertiary butyl-O2-methyl-(2S, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxylic acid esters 40b (1.30g, white solid), productive rate: 96.0%.

MS m/z(ESI)：146.1[M-56+1]

Second step

The O1-tertiary butyl-O2-methyl-(2S)-4-oxo-pyrrolidine-1,2-dicarboxylic acid esters

By the O1-tertiary butyl-O2-methyl-(2S)-4-hydroxyl pyrrolidine-1,2-dicarboxylic acid esters 40b (0.20g, 0.82mmol) is dissolved in 20mL methylene dichloride under stirring, and adds pyridinium chlorochromate drone salt (0.53g, 2.50mmol), react 18 hours.Add 100mL ether, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain the title product O1-tertiary butyl-O2-methyl-(2S)-4-oxo-pyrrolidine-1,2-dicarboxylic acid esters 40c (0.18g, white solid), productive rate: 90.0%.

3rd step

The O1-tertiary butyl-O2-methyl-(2S)-4,4-difluoropyrrolidin-1,2-dicarboxylic acid esters

By the O1-tertiary butyl-O2-methyl-(2S)-4-oxo-pyrrolidine-1,2-dicarboxylic acid esters 40c (180mg, be dissolved in 5mL methylene dichloride under 0.74mmol) stirring, N-ethyl-N-(trifluoromethylthio) ethylamine (262mg is added dropwise at-78 DEG C, 1.60mmol), room temperature reaction 12 hours.Add 20mL saturated sodium bicarbonate solution, with dichloromethane extraction (20mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains the title product O1-tertiary butyl-O2-methyl-(2S)-4,4-difluoropyrrolidin-1,2-dicarboxylic acid esters 40d (180mg, colorless oil), productive rate: 91.8%.MS m/z(ESI)：166.1[M-100+1]

4th step

(2S)-1-tertbutyloxycarbonyl-4,4-difluoro-pyrrolidin-2-formic acid

By the O1-tertiary butyl-O2-methyl-(2S)-4,4-difluoropyrrolidin-1,2-dicarboxylic acid esters 40d (180mg, be dissolved in 15mL first alcohol and water (V/V=2: 1) mixed solvent under 0.68mmol) stirring, add a hydronium(ion) Lithium Oxide 98min (142mg, 3.40mmol), room temperature reaction 12 hours.Concentrating under reduced pressure, adds 20mL water, with dichloromethane extraction (10mL × 3), dripping citric acid is 4 to aqueous phase pH, with dichloromethane extraction (20mL × 3), merges organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filters, filtrate reduced in volume, obtain title product (2S)-1-tertbutyloxycarbonyl-4,4-difluoro-pyrrolidin-2-formic acid 40e (170mg, colorless oil), productive rate: 100%.

MS m/z(ESI)：249.8[M-1]

5th step

(2S) the fluoro-2-of-4,4-bis-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] tetramethyleneimine-1-t-butyl formate

By 4-[[7-(piperazine-1-carbonyl)-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (200mg, 10mL N is dissolved under 0.51mmol) stirring, in dinethylformamide, add (2S)-1-tertbutyloxycarbonyl-4 successively, 4-difluoro-pyrrolidin-2-formic acid 40e (128mg, 0.51mmol), I-hydroxybenzotriazole (103mg, 0.76mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (147mg, 0.76mmol) with triethylamine (154mg, 1.53mmol), react 12 hours.Add 50mL water, be extracted with ethyl acetate (50mL × 3), merge organic phase, saturated sodium bicarbonate solution (20mL), saturated nacl aqueous solution is used to wash (50mL × 2) successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product (2S)-4, the fluoro-2-of 4-bis-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] tetramethyleneimine-1-t-butyl formate 40f (220mg, white solid), productive rate: 68.0%.

MS m/z(ESI)：524.2[M-100+1]

6th step

By (2S)-4, the fluoro-2-of 4-bis-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] tetramethyleneimine-1-t-butyl formate 40f (200mg, be dissolved in the methanol solution of 5mL 2M hydrogenchloride under 0.32mmol) stirring, react 10 hours.Concentrating under reduced pressure, add 20mL water, dripping ammoniacal liquor is 8 to reaction solution pH, be extracted with ethyl acetate (30mL × 5), merge organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-[4-[(2S)-4, 4-difluoropyrrolidin-2-carbonyl] piperazine-1-carbonyl-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 40 (102mg, white solid), productive rate: 61.0%.

MS m/z(ESI)：524.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.58(s，1H)，9.39(br.s，1H)，8.25(d，1H)，7.97(d，1H)，7.89-7.80(m，2H)，7.27(s，1H)，7.06(d，1H)，5.00(d，1H)，4.56-4.51(t，2H)，4.23(s，2H)，3.78-3.37(m，8H)，3.26(s，2H)，3.19-3.14(t，2H)，3.18-3.01(m，1H)，2.59-2.51(m，1H)

Embodiment 41

4-[[7-[4-[(2S, 4S)-4-fluoropyrrolidine-2-carbonyl] piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

The O1-tertiary butyl-O2-methyl-(2S, 4S)-4-fluoropyrrolidine-1,2-dicarboxylic acid esters

By the O1-tertiary butyl-O2-methyl-(2S, 4R)-4-hydroxyl pyrrolidine-1,2-dicarboxylic acid esters 40b (450mg, be dissolved in 10mL methylene dichloride under 1.80mmol) stirring, N-ethyl-N-(trifluoromethylthio) ethylamine (0.38mL is added dropwise at-78 DEG C, 2.80mmol), room temperature reaction 12 hours.Add 40mL saturated sodium bicarbonate solution, with dichloromethane extraction (30mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains the title product O1-tertiary butyl-O2-methyl-(2S, 4S)-4-fluoropyrrolidine-1,2-dicarboxylic acid esters 41a (300mg, colorless oil), productive rate: 67.1%.

Second step

The fluoro-tetramethyleneimine of (2S, 4S)-1-tertbutyloxycarbonyl-4--2-formic acid

By the O1-tertiary butyl-O2-methyl-(2S, 4S)-4-fluoropyrrolidine-1,2-dicarboxylic acid esters 41a (300mg, be dissolved in 2mL methyl alcohol and 3mL water under 1.20mmol) stirring, add a hydronium(ion) Lithium Oxide 98min (151mg, 3.60mmol) with potassium hydroxide (201mg, 3.60mmol), react 12 hours.Concentrating under reduced pressure, adds 20mL water, with dichloromethane extraction (10mL × 3), dripping citric acid is 4 to aqueous phase pH, with dichloromethane extraction (20mL × 3), merges organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filters, filtrate reduced in volume, obtain title product (2S, 4S) the fluoro-tetramethyleneimine of-1-tertbutyloxycarbonyl-4--2-formic acid 41b (250mg, colorless oil), productive rate: 89.3%.

3rd step

The fluoro-2-of (2S, 4S)-4-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] tetramethyleneimine-1-t-butyl formate

By 4-[[7-(piperazine-1-carbonyl)-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (200mg, 10mL N is dissolved under 0.51mmol) stirring, in dinethylformamide, add (2S successively, 4S) the fluoro-tetramethyleneimine of-1-tertbutyloxycarbonyl-4--2-formic acid 41b (119mg, 0.51mmol), I-hydroxybenzotriazole (103mg, 0.76mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (147mg, 0.76mmol) with triethylamine (154mg, 1.53mmol), react 12 hours.Add 25mL water, with dichloromethane extraction (20mL × 3), merge organic phase, use saturated sodium bicarbonate solution (20mL) successively, saturated nacl aqueous solution washing (20mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product (2S, 4S) the fluoro-2-of-4-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl-2, 3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] tetramethyleneimine-1-t-butyl formate 41c (200mg, white solid), productive rate: 64.5%.

MS m/z(ESI)：506.2[M-100+1]

4th step

By (2S, 4S) the fluoro-2-of-4-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] tetramethyleneimine-1-t-butyl formate 41c (200mg, be dissolved in the methanol solution of 5mL methylene dichloride and 10mL2M hydrogenchloride under 0.33mmol) stirring, react 10 hours.Concentrating under reduced pressure, drips ammoniacal liquor in residue, regulates pH to be 8 ~ 9, be extracted with ethyl acetate (10mL × 2), the organic phase merged uses anhydrous sodium sulfate drying successively, filters, concetrated under reduced pressure, vacuum-drying, obtain title product 4-[[7-[4-[(2S, 4S)-4-fluoropyrrolidine-2-carbonyl] piperazine-1-carbonyl-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 41 (158mg, yellow solid), productive rate: 95.0%.

MS m/z(ESI)：506.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.58(s，1H)，10.47(br.s，1H)，8.85(s，1H)，8.26(d，1H)，7.98(d，1H)，7.91-7.81(m，2H)，7.28(s，1H)，7.07(d，1H)，5.42(d，1H)，4.76-4.70(m，1H)，4.57-4.52(t，2H)，4.24(s，2H)，3.78-3.27(m，10H)，3.19-3.15(t，2H)，2.82-2.67(m，1H)，2.26-2.20(m，1H)

Embodiment 42

4-[[7-[4-(2-amino-3-Metliyl-butyyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

2-(t-butoxycarbonyl amino)-3-metliyl-butyric acid

By 2-amino-3-metliyl-butyric acid 42a (1.02g, 12mL1 is dissolved under 10mmol) stirring, in 4-dioxane and water (V/V=1: 1) mixed solvent, add sodium hydroxide (1.20g, 30mmol) with tert-Butyl dicarbonate (3.27g, 15mmol), react 5 hours.Concentrating under reduced pressure, with extracted with diethyl ether (20mL × 2), dripping 1M hydrochloric acid is 4 to aqueous phase pH, is extracted with ethyl acetate (30mL × 3), merge organic phase, with saturated nacl aqueous solution washing (20mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product 2-(tertbutyloxycarbonylamino)-3-metliyl-butyric acid 42b (230mg, light yellow solid), productive rate: 10.6%.

MS m/z(ESI)：215.9[M-1]

Second step

N-[2-methyl isophthalic acid-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-carbonyl] propyl group] t-butyl carbamate

By 4-[[7-(piperazine-1-carbonyl)-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (100mg, 3mL N is dissolved under 0.26mmol) stirring, in dinethylformamide, add 2-(tertbutyloxycarbonylamino)-3-metliyl-butyric acid 42b (60mg successively, 0.26mmol), I-hydroxybenzotriazole (48.80mg, 0.36mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (68.90mg, 0.36mmol) with triethylamine (0.1mL, 0.76mmol), react 12 hours.Add 10mL water, be extracted with ethyl acetate (10mL × 3), merge organic phase, use saturated sodium bicarbonate solution (10mL) successively, saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product N-[2-methyl isophthalic acid-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2, 3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] propyl group] t-butyl carbamate 42c (30mg, white solid), productive rate: 20.0%.

3rd step

By N-[2-methyl isophthalic acid-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] propyl group] t-butyl carbamate 42c (30mg, 1 of the saturated hydrogenchloride of 4mL is dissolved under 0.05mmol) stirring, in 4-dioxane solution, react 10 hours.Concentrating under reduced pressure; add 5mL water; dripping ammoniacal liquor is 8 to reaction solution pH; be extracted with ethyl acetate (8mL × 5); merge organic phase; with saturated nacl aqueous solution washing (10mL); anhydrous sodium sulfate drying; filter, filtrate reduced in volume, purify gained resistates by tlc with developping agent system A; obtain title product 4-[[7-[4-(2-amino-3-Metliyl-butyyl) piperazine-1-carbonyl]-2; 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 42 (17.60mg, white solid), productive rate: 72.0%.

MS m/z(ESI)：490.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.58(br.s，1H)，8.82(s，1H)，8.35-8.33(m，2H)，8.15-8.11(m，2H)，7.95(s，1H)，4.95(s，2H)，3.64(s，4H)，3.42-3.38(m，2H)，3.18-3.14(m，4H)，2.96-2.85(m，1H)，2.78(s，4H)，2.06(m，1H)，0.97-0.95(m，6H)

Embodiment 43

4-[[7-(1,2,3,4,4a, 5,7,7a-octahydro pyrrolo-[3,4-b] pyridine-6-carbonyl)-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

6-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls]-3,4,4a, 5,7,7a-six hydrogen-2H-pyrrolo-[3,4-b] pyridine-1-t-butyl formates

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2, 3-Dihydrobenzofuranes-7-formic acid 3b (114mg, 4mL N is dissolved under 0.35mmol) stirring, in dinethylformamide, add 2 successively, 3, 4, 4a, 5, 6, 7, 7a-octahydro pyrrolo-[3, 4-b] pyridine-1-t-butyl formate 43a (80mg, 0.35mmol), I-hydroxybenzotriazole (72mg, 0.53mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (102mg, 0.53mmol) with triethylamine (107mg, 1.06mmol), react 12 hours.Add 10mL water, be extracted with ethyl acetate (10mL × 3), merge organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filters, filtrate reduced in volume, obtain title product 6-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl]-3,4,4a, 5,7,7a-six hydrogen-2H-pyrrolo-[3,4-b] pyridine-1-t-butyl formate 43b (150mg, light yellow solid), productive rate: 79.8%.

MS m/z(ESI)：531.4[M+1]

Second step

By 6-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl]-3,4,4a, 5,7,7a-six hydrogen-2H-pyrrolo-[3,4-b] pyridine-1-t-butyl formate 43b (150mg, 0.28mmol) stir under be dissolved in the methanol solution of 3mL 2M hydrogenchloride, react 10 hours.Concentrating under reduced pressure, add 20mL water, dripping ammoniacal liquor is 8 to reaction solution pH, be extracted with ethyl acetate (30mL × 5), merge organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-(1, 2, 3, 4, 4a, 5, 7, 7a-octahydro pyrrolo-[3, 4-b] pyridine-6-carbonyl)-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 43 (83mg, white solid), productive rate: 67.9%.

MS m/z(ESI)：431.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.59(s，1H)，8.24-8.26(m，1H)，7.81-7.98(m，3H)，7.25(d，1H)，7.16(s，0.5H)，7.09(s，0.5H)，4.51-4.56(m，2H)，4.23(s，2H)，3.42-3.58(m，3H)，3.16-3.24(m，5H)，2.95-3.00(m，1H)，2.66-2.69(m，1H)，2.34(s，1H)，1.50-1.68(m，4H)

Embodiment 44

4-[[7-[4-(1-methylamino cyclopropyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

1-(tert-butoxycarbonyl (methyl) is amino) ethylene-acetic acid methyl esters

By 1-(tertbutyloxycarbonylamino) ethylene-acetic acid 22b (600mg, 5mL N is dissolved under 2.98mmol) stirring, in dinethylformamide, sodium hydride and mineral oil mixture (214.70mg is added under ice bath, 60%, 8.95mmol), react 30 minutes.Add methyl iodide (1.27g, 8.95mmol), room temperature reaction 12 hours.Add 10mL water, dripping 1M hydrochloric acid is 6 to aqueous phase pH, be extracted with ethyl acetate (10mL × 3), merge organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 1-(tert-butoxycarbonyl (methyl) is amino) ethylene-acetic acid methyl esters 44a (270mg, colourless liquid), productive rate: 40.0%.

MS m/z(ESI)：130.1[M-100+1]

Second step

1-(tert-butoxycarbonyl (methyl) is amino) ethylene-acetic acid

By 1-(tert-butoxycarbonyl (methyl) is amino) ethylene-acetic acid methyl esters 44a (270mg, be dissolved in 10mL first alcohol and water (V/V=7: 3) mixed solvent under 1.18mmol) stirring, add sodium hydroxide (70.80mg, 1.77mmol), react 10 hours.Add 10mL water, be extracted with ethyl acetate (5mL × 2), dripping 1M hydrochloric acid is 4 to aqueous phase pH, is extracted with ethyl acetate (10mL × 3), merge organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product 1-(tert-butoxycarbonyl (methyl) is amino) ethylene-acetic acid 44b (223mg, white solid), productive rate: 87.9%.

MS m/z(ESI)：214.2[M+1]

3rd step

N-methyl-N-[1-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-carbonyl] cyclopropyl] t-butyl carbamate

By 4-[[7-(piperazine-1-carbonyl)-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (445mg, 10mL N is dissolved under 1.14mmol) stirring, in dinethylformamide, add 1-(tert-butoxycarbonyl (methyl) is amino) ethylene-acetic acid 44b (223mg successively, 1.04mmol), I-hydroxybenzotriazole (210mg, 1.56mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (298mg, 1.56mmol) with triethylamine (315mg, 3.12mmol), react 12 hours.Add 50mL water, be extracted with ethyl acetate (50mL × 3), merge organic phase, saturated sodium bicarbonate solution (20mL), saturated nacl aqueous solution is used to wash (50mL × 2) successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product N-methyl-N-[1-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] cyclopropyl] t-butyl carbamate 44c (446mg, white solid), productive rate: 73.0%.

MS m/z(ESI)：488.2[M-100+1]

4th step

By N-methyl-N-[1-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] cyclopropyl] t-butyl carbamate 44c (446mg, be dissolved in the methanol solution of 5mL 2M hydrogenchloride under 0.75mmol) stirring, react 10 hours.Concentrating under reduced pressure, add 20mL water, dripping ammoniacal liquor is 8 to reaction solution pH, be extracted with ethyl acetate (30mL × 5), merge organic phase, with saturated nacl aqueous solution washing (30mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-[4-(1-methylamino cyclopropyl carbonyl) piperazine-1-carbonyl]-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 44 (240.50mg, white solid), productive rate: 65.0%.

MS m/z(ESI)：488.5[M+1]

¹H NMR(400MHz，D ₂O)：δ8.22(s，1H)，7.84(m，3H)，7.30(s，1H)，6.99(s，1H)4.57(m，2H)，4.24(s，2H)，3.76(m，4H)，3.55(m，2H)，3.36(m，2H)，3.15(m，2H)，2.77(s，3H)，1.43(m，4H)

Embodiment 45

4-[[7-[4-(1-dimethylamino cyclopropyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

By 4-[[7-[4-(the amino cyclopropyl carbonyl of 1-) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 22 (142mg, be dissolved in 3mL methylene dichloride under 0.30mmol) stirring, add 37% formaldehyde solution (27mg, 0.90mmol), sodium triacetoxy borohydride (190.70mg, 0.90mmol) is added, room temperature reaction 12 hours under ice bath.Add 5mL saturated ammonium chloride solution, with dichloromethane extraction (5mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-[4-(1-dimethylamino cyclopropyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 45 (67mg, white solid), productive rate: 45.0%.

MS m/z(ESI)：502.2[M+1]

¹H NMR(400MHz，CDCl ₃)：δ10.18(s，1H)，8.45(m，1H)，7.77(m，3H)，7.15(m，1H)，4.59(m，2H)，4.23(s，2H)，3.77(m，2H)，3.65(m，2H)，3.35(m，2H)，3.34(m，2H)，3.19(m，2H)，2.27(m，6H)，0.88(m，4H)

Embodiment 46

4-[[7-(3,4,4a, 5,7,7a-six hydrogen-2H-pyrrolo-[3,4-b] [Isosorbide-5-Nitrae] oxazine-6-carbonyl)-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

The bromo-4-of 3-(2-hydroxyl-oxethyl) tetramethyleneimine-1-t-butyl formate

By 2,5-pyrrolin-1-t-butyl formate 46a (9.50g, 56.14mmol, adopt known method " Organic Process Research & Development, 2009,13 (3); 638-640 " prepare and obtain) stirring under be dissolved in 50mL ethylene glycol, divide ten batches and add N-bromosuccinimide (10.99g, 61.75mmol), react 12 hours.Add 100mL water, be extracted with ethyl acetate (100mL × 3), merge organic phase, with saturated nacl aqueous solution washing (25mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain the bromo-4-of 3-(2-hydroxyl-oxethyl) tetramethyleneimine-1-t-butyl formate 46b (12g, reddish-brown oily matter), productive rate: 72.3%.MS m/z(ESI)：254.2[M-56+1]

Second step

The bromo-4-of 3-[2-(toluene-4-sulfonyloxy) oxyethyl group] tetramethyleneimine-1-t-butyl formate

By bromo-for 3-4-(2-hydroxyl-oxethyl) tetramethyleneimine-1-t-butyl formate 46b (12g, be dissolved in 100mL toluene under 38.69mmol) stirring, add triethylamine (8.1mL, 58.03mmol) with DMAP (0.50g, 4mmol), under ice bath, add Tosyl chloride (10.06g, 58.03mmol), react 12 hours.Add 100mL water, separatory, aqueous phase is extracted with ethyl acetate (100mL × 3), merges organic phase, with saturated nacl aqueous solution washing (25mL × 2), anhydrous sodium sulfate drying, filters, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain the bromo-4-of 3-[2-(toluene-4-sulfonyloxy) oxyethyl group] tetramethyleneimine-1-t-butyl formate 46c (14.30g, colorless oil), productive rate: 79.6%.

3rd step

4-benzyl-2,3,4a, 5,7,7a-hexahydropyrrolo is [3,4-b] [Isosorbide-5-Nitrae] oxazine-6-t-butyl formate also

By bromo-for 3-4-[2-(toluene-4-sulfonyloxy) oxyethyl group] tetramethyleneimine-1-t-butyl formate 46c (14.30g, be dissolved in 80mL p-Xylol under 30.78mmol) stirring, add benzylamine (3.30g, 30.78mmol), 140 DEG C are reacted 5 hours.Concentrating under reduced pressure, adds 100mL water, is extracted with ethyl acetate (150mL × 3), merge organic phase, with saturated nacl aqueous solution washing (75mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains 4-benzyl-2,3,4a, 5,7,7a-hexahydropyrrolo is [3,4-b] [1 also, 4] oxazine-6-t-butyl formate 46d (7.50g, light brown oily matter), productive rate: 76.0%.

MS m/z(ESI)：319.2[M+1]

4th step

4-benzyl-3,4a, 5,6,7,7a-six hydrogen-2H-pyrrolo-[3,4-b] [Isosorbide-5-Nitrae] oxazine hydrochloride

By 4-benzyl-2,3,4a, 5,7,7a-hexahydropyrrolo also [3,4-b] [Isosorbide-5-Nitrae] oxazine-6-t-butyl formate 46d (150mg, 0.47mmol) stir under be dissolved in the Isosorbide-5-Nitrae-dioxane solution of 10mL hydrogenchloride, react 12 hours.Concentrating under reduced pressure, obtains crude product 4-benzyl-3,4a, 5,6,7,7a-six hydrogen-2H-pyrrolo-[3,4-b] [Isosorbide-5-Nitrae] oxazine hydrochloride 46e (180mg, white solid), and product is not purified directly carries out next step reaction.

MS m/z(ESI)：391.2[M+1]

5th step

4-[[7-(4-benzyl-2,3,4a, 5,7,7a-hexahydropyrrolo also [3,4-b] [Isosorbide-5-Nitrae] oxazine-6-carbonyl)-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2, 3-Dihydrobenzofuranes-7-formic acid 3b (127mg, 4mL N is dissolved under 0.39mmol) stirring, in dinethylformamide, add crude product 4-benzyl-3 successively, 4a, 5, 6, 7, 7a-six hydrogen-2H-pyrrolo-[3, 4-b] [1, 4] oxazine hydrochloride 46e (180mg, 0.47mmol), I-hydroxybenzotriazole (79mg, 0.59mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (113mg, 0.59mmol) with triethylamine (118mg, 1.17mmol), react 12 hours.Add 10mL water, be extracted with ethyl acetate (10mL × 3), merge organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates by tlc with developping agent system A, obtains title product 4-[[7-(4-benzyl-2,3,4a, 5,7,7a-hexahydropyrrolo also [3,4-b] [Isosorbide-5-Nitrae] oxazine-6-carbonyl)-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone 46f (120mg, white solid), productive rate: 59.0%.

MS m/z(ESI)：523.2[M+1]

6th step

By 4-[[7-(4-benzyl-2,3,4a, 5,7,7a-hexahydropyrrolo is [3,4-b] [1 also, 4] oxazine-6-carbonyls)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 46f (90mg, 0.17mmol) stir under be dissolved in 5mL ethanol, add 10mg palladium hydroxide, hydrogen exchange three times, reacts 12 hours.Filter, filtrate reduced in volume, obtains title product 4-[[7-(3,4,4a, 5,7,7a-six hydrogen-2H-pyrrolo-[3,4-b] [Isosorbide-5-Nitrae] oxazine-6-carbonyl)-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone 46 (15mg, white solid), productive rate: 20.0%.

MS m/z(ESI)：433.1[M+1]

¹H NMR(400MHz，CDCl ₃)：δ10.55(d，1H)，8.54(d，1H)，7.79-7.72(m，3H)，7.21-7.11(m，2H)，4.63-4.55(m，2H)，4.22(s，2H)，4.20-3.98(m，1H)，3.85-3.73(m，3H)，3.61-3.59(m，2H)，3.52-3.38(m，2H)，3.17-3.14(m，3H)，2.73-2.71(m，1H)

Embodiment 47

4-[[7-[2-(trifluoromethyl)-6,8-dihydro-5H-imidazo [1,2-a] pyrazine-7-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

2-(trifluoromethyl) imidazo [1,2-a] pyrazine

Be dissolved in 12mL ethanol under pyrazine-2-amine 47a (5.25g, 55.20mmol) is stirred, add bromo-1,1,1-tri-fluoro-propane-2-ketone 47b (5.7mL, 55.20mmol) of 3-, back flow reaction 24 hours.Concentrating under reduced pressure, adds 100mL ethyl acetate and 100mL saturated sodium bicarbonate solution, separatory.Aqueous phase is extracted with ethyl acetate (50mL × 3), merge organic phase, with saturated nacl aqueous solution washing (50mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain title product 2-(trifluoromethyl) imidazo [1,2-a] pyrazine 47c (2.40g, yellow solid), productive rate: 22.8%.

Second step

2-(trifluoromethyl)-5,6,7,8-imidazolidine also [1,2-a] pyrazine

Be dissolved in 100mL methyl alcohol under 2-(trifluoromethyl) imidazo [1,2-a] pyrazine 47c (2.40g, 12.55mmol) is stirred, add 480mg 10% palladium/carbon, hydrogen exchange three times, react 12 hours.Filter, filtrate reduced in volume, obtains title product 2-(trifluoromethyl)-5,6,7,8-imidazolidine also [1,2-a] pyrazine 47d (2.30g, light yellow oil), productive rate: 95.8%.

3rd step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2, 3-Dihydrobenzofuranes-7-formic acid 3b (168mg, 5mL N is dissolved under 0.52mmol) stirring, in dinethylformamide, add 2-(trifluoromethyl)-5 successively, 6, 7, 8-imidazolidine also [1, 2-a] pyrazine 47d (180mg, 0.52mmol), I-hydroxybenzotriazole (108mg, 0.80mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (153mg, 0.80mmol) with triethylamine (161mg, 1.60mmol), react 12 hours.Add 10mL water, be extracted with ethyl acetate (10mL × 3), merge organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates by tlc with developping agent system A, obtain title product 4-[[7-[2-(trifluoromethyl)-6,8-dihydro-5H-imidazo [1,2-a] pyrazine-7-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 47 (160mg, white solid), productive rate: 62.0%.

MS m/z(ESI)：496.1[M+1]

¹H NMR(400MHz，CDCl ₃)：δ10.38(s，1H)，8.45(d，1H)，7.78-7.75(m，3H)，7.22-7.19(m，3H)，4.97(s，1H)，4.79(s，1H)，4.60-4.56(t，2H)，4.22-4.13(m，5H)，3.58(m，1H)，3.21-3.17(m，2H)

Embodiment 48

5-[(4-oxo-3H-phthalazines-1-base) methyl]-N-(3-picolyl)-2,3-Dihydrobenzofuranes-7-methane amide

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (160mg, 5mL N is dissolved under 0.50mmol) stirring, in dinethylformamide, add 3-picolyl amine (64mg successively, 0.50mmol), I-hydroxybenzotriazole (101mg, 0.75mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (143mg, 0.75mmol) with triethylamine (150mg, 1.50mmol), react 12 hours.Add 10mL water, be extracted with ethyl acetate (10mL × 3), merge organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained solid washed with ether (20mL), obtain title product 5-[(4-oxo-3H-phthalazines-1-base) methyl]-N-(3-picolyl)-2,3-Dihydrobenzofuranes-7-methane amide 48 (100mg, white solid), productive rate: 48.8%.

MS m/z(ESI)：413.1[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，8.24-8.53(m，4H)，7.68-7.93(m，4H)，7.57(s，1H)，7.31-7.34(m，2H)，4.66(t，2H)，4.50(d，2H)，4.25(s，2H)，3.17(t，2H)

Embodiment 49

N-[2-(1H-imidazol-4 yl) ethyl-5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-methane amides

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (160mg, 5mL N is dissolved under 0.50mmol) stirring, in dinethylformamide, add 2-(1H-imidazol-4 yl) ethylamine hydrochloride (110mg successively, 0.60mmol), I-hydroxybenzotriazole (101mg, 0.75mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (143mg, 0.75mmol) with triethylamine (150mg, 1.50mmol), react 12 hours.Add 10mL water, be extracted with ethyl acetate (10mL × 3), merge organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product N-[2-(1H-imidazol-4 yl) ethyl-5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-methane amide 49 (100mg, white solid), productive rate: 48.5%.

MS m/z(ESI)：416.1[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，11.82(br.s，1H)，8.23-8.25(m，1H)，7.80-7.94(m，4H)，7.56(s，1H)，7.52(s，1H)，7.32(s，1H)，6.80(br.s，1H)，4.61(t，2H)，4.24(s，2H)，3.46-3.51(m，2H)，3.15(t，2H)，2.69(t，2H)

Embodiment 50

5-[(4-oxo-3H-phthalazines-1-base) methyl]-N-(3-piperidine methyl)-2,3-Dihydrobenzofuranes-7-carboxamide hydrochloride

The first step

3-[[[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] are amino] methyl] piperidines-1-t-butyl formate

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (100mg, 4mL N is dissolved under 0.31mmol) stirring, in dinethylformamide, add 3-(amino methyl) piperidines-1-t-butyl formate 50a (66mg successively, 0.31mmol), I-hydroxybenzotriazole (63mg, 0.47mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (89mg, 0.47mmol) with triethylamine (94mg, 0.93mmol), react 12 hours.Add 10mL water, be extracted with ethyl acetate (10mL × 3), merge organic phase, with saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product 3-[[[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] amino] methyl] piperidines-1-t-butyl formate 50b (120mg, white solid), productive rate: 75.0%.

MS m/z(ESI)：419.2[M-100+1]

Second step

By 3-[[[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] amino] methyl] piperidines-1-t-butyl formate 50b (120mg, 0.23mmol) stir under be dissolved in 5mL 2M hydrogenchloride methanol solution and 10mL methylene dichloride in, react 5 hours.Filter, solid washed with ether (20mL), obtain title product 5-[(4-oxo-3H-phthalazines-1-base) methyl]-N-(3-piperidine methyl)-2,3-Dihydrobenzofuranes-7-carboxamide hydrochloride 50 (100mg, white solid), productive rate: 95.0%.

MS m/z(ESI)：419.1[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.58(s，1H)，8.87(s，1H)，8.61(s，1H)，8.25(d，1H)，7.95-7.81(m，3H)，7.53(s，1H)，7.35(s，1H)，4.68-4.64(t，2H)，4.41(s，2H)，3.23-3.16(m，6H)，2.74-2.70(m，2H)，2.61-2.52(m，1H)，1.96(s，1H)，1.78-1.70(m，1H)，1.60-1.57(m，1H)，1.23-1.17(m，1H)

Embodiment 51

4-[[7-[4-(4-pyridylmethyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

4-(4-pyridylmethyl) piperazine-1-t-butyl formate

Be dissolved in 10mL 1,2-ethylene dichloride under Pyridine-4-Carboxaldehyde 51a (1.07g, 0.01mol) is stirred, add piperazine-1-t-butyl formate (1.86g, 0.01mmol), add sodium triacetoxy borohydride (4.20g, 0.02mol), react 12 hours.Under ice bath, add 20mL saturated sodium bicarbonate solution, with dichloromethane extraction (20mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product 4-(4-pyridylmethyl) piperazine-1-t-butyl formate 51b (2.70g, white solid), productive rate: 97.0%.

MS m/z(ESI)：278.2[M+1]

Second step

1-(4-pyridylmethyl) piperazine hydrochloride

Be dissolved in 15mL methylene dichloride under 4-(4-pyridylmethyl) piperazine-1-t-butyl formate 51b (2g, 7.20mmol) is stirred, under ice bath, add the methanol solution of 15mL2M hydrogenchloride, react 3 hours.Filter, collect solid, obtain title product 1-(4-pyridylmethyl) piperazine hydrochloride 51c (1.50g, white solid), productive rate: 97.0%.

3rd step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (100mg, 5mL N is dissolved under 0.31mmol) stirring, in dinethylformamide, add 1-(4-pyridylmethyl) piperazine hydrochloride 51c (66mg successively, 0.31mmol), I-hydroxybenzotriazole (62mg, 0.46mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (89mg, 0.46mmol) with triethylamine (93mg, 0.93mmol), react 12 hours.Add 30mL water, filter, filter cake uses water (10mL), saturated ammonium chloride solution to wash (10mL) successively, gained filter cake is purified with developping agent system A by tlc, obtain title product 4-[[7-[4-(4-pyridylmethyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 51 (100mg, white solid), productive rate: 67.0%.

MS m/z(ESI)：482.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.58(s，1H)，8.51(d，2H)，8.25(d，1H)，7.96(d，1H)，7.89-7.83(m，2H)，7.33(d，2H)，7.23(s，1H)，7.00(s，1H)，4.53-4.49(t，2H)，4.22(s，2H)，3.58(s，2H)，3.52(s，2H)，3.19-3.12(m，4H)，2.39(s，2H)，2.27(s，2H)

Embodiment 52

N-[(1-methyl-3-piperidyl) methyl]-5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-methane amides

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-N-(3-piperidine methyl)-2,3-Dihydrobenzofuranes-7-carboxamide hydrochloride 50 (60mg, be dissolved in 20mL methylene dichloride under 0.13mmol) stirring, add triethylamine (0.2mL successively, 1mmol), 37% formaldehyde solution (21mg, 0.26mmol) and sodium triacetoxy borohydride (54mg, 0.26mmol), react 12 hours.Add 20mL water, separatory, collect organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, 10mL water and salt of wormwood (500mg is added in residue, 3.62mmol), stir 12 hours, with dichloromethane extraction (10mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained residue is purified with developping agent system A by tlc, obtain title product N-[(1-methyl-3-piperidyl) methyl]-5-[(4-oxo-3H-phthalazines-1-base) methyl]-2, 3-Dihydrobenzofuranes-7-methane amide 52 (30mg, white solid), productive rate: 52.6%.

MS m/z(ESI)：433.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.58(s，1H)，9.58(br.s，1H)，8.25(d，1H)，7.95-7.81(m，3H)，7.54(s，1H)，7.36(s，1H)，4.69-4.64(t，2H)，4.25(s，2H)，3.21-3.17(m，5H)，2.62(s，3H)，1.98(s，1H)，1.77-1.62(m，3H)，1.25-1.23(m，2H)，1.20-1.08(m，2H)

Embodiment 53

4-[[the fluoro-7-of 6-[3-(trifluoromethyl)-6,8-dihydro-5H-[1,2,4] triazolo [4,3-a] piperazine-7-carbonyl-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone

The first step

2-(the fluoro-phenoxy group of the bromo-5-of 2-) ethanol

Be dissolved in 100mL ethylene glycol under bromo-for 1-2,4-bis-fluoro-benzene 53a (10g, 51.80mmol) being stirred, add 10mL 1-methylpyrrolidin-2-ketone, add potassium tert.-butoxide (20.34g, 181.30mmol) in batches, 100 DEG C are reacted 7 hours.Add 100mL water, be extracted with ethyl acetate (120mL × 3), merge organic phase, with saturated nacl aqueous solution washing (50mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system B, obtains title product 2-(the fluoro-phenoxy group of the bromo-5-of 2-) ethanol 53b (7.91g, light yellow oil), productive rate: 64.9%.

Second step

The fluoro-benzene of the bromo-2-of 1-(2-bromine oxethyl)-4-

Under ice bath, by 2-(the fluoro-phenoxy group of the bromo-5-of 2-) ethanol 53b (7.91g, be dissolved in 80mL methylene dichloride under 33.65mmol) stirring, add carbon tetrabromide (13.95g successively, 42.06mmol) with triphenyl phosphorus (13.24g, 50.48mmol), room temperature reaction 2 hours.Concentrating under reduced pressure, purifies gained resistates with silica gel column chromatography with eluent system B, obtains the fluoro-benzene 53c of the bromo-2-of title product 1-(2-bromine oxethyl)-4-(10.09g, colorless oil), productive rate: 100%.

3rd step

Fluoro-2, the 3-Dihydrobenzofuranes of 6-

In dry ice acetone bath, be dissolved in 110mL tetrahydrofuran (THF) under fluoro-for bromo-for 1-2-(2-bromine oxethyl)-4-benzene 53c (10.06g, 33.76mmol) is stirred, dropwise add the hexane solution of 14.2mL2.5M n-Butyl Lithium,-78 DEG C are reacted 2 hours, rise to room temperature gradually.Under ice bath, drip 50mL water, be extracted with ethyl acetate (100mL × 3), merge organic phase, with saturated nacl aqueous solution washing (50mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain fluoro-2, the 3-Dihydrobenzofuranes 53d (3.86g of title product 6-, colorless oil), productive rate: 82.8%.

4th step

Fluoro-2, the 3-Dihydrobenzofuranes-5-formaldehyde of 6-

Under ice bath, by fluoro-for 6-2,3-Dihydrobenzofuranes 53d (3.86g, be dissolved in DMF (4.8mL, 61.50mmol) under 28mmol) stirring, drip phosphorus oxychloride (5.1mL, 56mmol), 85 DEG C are reacted 7 hours.Add in 30mL frozen water, stir 10 hours.Be extracted with ethyl acetate (40mL × 3), merge organic phase, with saturated nacl aqueous solution washing (30mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system B, obtain fluoro-2, the 3-Dihydrobenzofuranes-5-formaldehyde 53e (2.38g of title product 6-, white solid), productive rate: 51.2%.

5th step

Fluoro-2, the 3-Dihydrobenzofuranes-5-formaldehyde of the bromo-6-of 7-

Be dissolved in 20mL acetic acid under fluoro-for 6-2,3-Dihydrobenzofuranes-5-formaldehyde 53e (1.50g, 9mmol) are stirred, add sodium acetate (0.88g, 10.80mmol) and bromine (2.88g, 18mmol), react 15 hours.Add 20mL saturated sodium bisulfite solution and 20mL saturated sodium bicarbonate solution successively, be extracted with ethyl acetate (50mL × 3), merge organic phase, with saturated nacl aqueous solution washing (40mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains fluoro-2, the 3-Dihydrobenzofuranes-5-formaldehyde 53f (1.61g of the bromo-6-of crude title product 7-, light yellow solid), product is not purified directly carries out next step reaction.

MS m/z(ESI)：256.9[M+1]

6th step

(3Z)-3-[(fluoro-2, the 3-Dihydrobenzofuranes-5-bases of the bromo-6-of 7-) methylene radical] isobenzofuran-1-ketone

By bromo-for crude product 7-6-fluoro-2,3-Dihydrobenzofuranes-5-formaldehyde 53f (1.35g, be dissolved in 30mL tetrahydrofuran (THF) under 5.51mmol) stirring, add 3-dimethoxy phosphorus base-3H-isobenzofuran-1-ketone 53g (1.34g, 5.51mmol, known method " Journal of Medicinal Chemistry; 2008; 51 (20); 6581-6591 " is adopted to prepare and obtain), control temperature of reaction at 15 DEG C, drip triethylamine (0.8mL, 5.51mmol), room temperature reaction 5 hours, reacts 12 hours at 50 DEG C.Concentrating under reduced pressure, add 20mL water, stir after 30 minutes, filter, filter cake uses water (10mL), ether (10mL), petroleum ether (20mL) successively, vacuum-drying, obtain crude title product (3Z)-3-[(the bromo-6-of 7-fluoro-2,3-Dihydrobenzofuranes-5-base) methylene radical] isobenzofuran-1-ketone 53h (1.28g, gray solid), product is not purified directly carries out next step reaction.

MS m/z(ESI)：361.9[M+1]

7th step

4-[(fluoro-2, the 3-Dihydrobenzofuranes-5-bases of the bromo-6-of 7-) methyl]-2H-phthalazines-1-ketone

By crude product (3Z)-3-[(the bromo-6-of 7-fluoro-2,3-Dihydrobenzofuranes-5-base) methylene radical] isobenzofuran-1-ketone 53h (100mg, be dissolved in 15mL hydrazine hydrate under 0.28mmol) stirring, 100 DEG C are reacted 7 hours.Ice bath cools, filter, filter cake uses water (10mL), washed with diethylether (10mL) successively, vacuum-drying, obtain title product 4-[(the bromo-6-of 7-fluoro-2,3-Dihydrobenzofuranes-5-base) methyl]-2H-phthalazines-1-ketone 53i (60mg, white solid), productive rate: 57.1%.

MS m/z(ESI)：376.0[M+1]

8th step

The fluoro-5-of 6-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid

At-78 DEG C, by 4-[(the bromo-6-of 7-fluoro-2,3-Dihydrobenzofuranes-5-base) methyl]-2H-phthalazines-1-ketone 53i (100g, be dissolved in 5mL tetrahydrofuran (THF) under 0.27mmol) stirring, dropwise add the hexane solution of 0.3mL 2.5M n-Butyl Lithium, react 40 minutes, carbon dioxide replacement three times, room temperature reaction 1 hour under carbon dioxide atmosphere.Add 5mL water, concentrating under reduced pressure, add 10mL ethyl acetate and 10mL water, separatory, collect aqueous phase, dripping 1M hydrochloric acid is 2 to aqueous phase pH, is extracted with ethyl acetate (15mL × 3), merges organic phase, with saturated nacl aqueous solution washing (10mL), anhydrous sodium sulfate drying, filters, filtrate reduced in volume, obtain the fluoro-5-of title product 6-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 53j (40mg, white solid), productive rate: 44.0%.

MS m/z(ESI)：295.1[M-46+1]

9th step

By fluoro-for 6-5-[(4-oxo-3H-phthalazines-1-base) methyl]-2, 3-Dihydrobenzofuranes-7-formic acid 53j (30mg, 5mL N is dissolved under 0.09mmol) stirring, in dinethylformamide, add 3-trifluoromethyl-5 successively, 6, 7, 8-tetrahydrochysene-[1, 2, 4] triazolo [4, 3-a] pyrazine hydrochloride (17mg, 0.10mmol, known method " patent WO2004080958 " is adopted to prepare and obtain), I-hydroxybenzotriazole (18mg, 0.13mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (26mg, 0.13mmol) with triethylamine (36mg, 0.35mmol), react 15 hours.Add 20mL water, be extracted with ethyl acetate (50mL × 2), merge organic phase, use 1M hydrochloric acid (20mL) successively, saturated sodium bicarbonate solution (20mL), saturated nacl aqueous solution washing (20mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product 4-[[the fluoro-7-of 6-[3-(trifluoromethyl)-6, 8-dihydro-5H-[1, 2, 4] triazolo [4, 3-a] piperazine-7-carbonyl-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 53 (28mg, white solid), productive rate: 62.2%.

MS m/z(ESI)：515.1[M+1]

¹H NMR(400MHz，CDCl ₃)：δ10.34(s，1H)，8.50-8.52(m，1H)，7.81-7.93(m，3H)，7.12-7.14(m，1H)，4.94-4.96(m，2H)，4.62-4.71(m，2H)，4.32(s，2H)，4.25-4.29(m，3H)，3.91-3.93(m，1H)，3.17-3.21(m，2H)

Embodiment 54

4-[[7-[4-(3-pyridylmethyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

4-(3-pyridylmethyl) piperazine-1-t-butyl formate

By pyridine-3-formaldehyde 54a (1.07g, 50mL 1 is dissolved under 10mmol) stirring, in 2-ethylene dichloride, add piperazine-1-t-butyl formate (1.95g, 10.50mmol), react 30 minutes, under ice bath, add sodium triacetoxy borohydride (4.23g, 20mmol), room temperature reaction 12 hours.Add 15mL water, separatory, collect organic phase, use saturated sodium carbonate solution (5mL × 3), water (5mL × 3), saturated nacl aqueous solution to wash (5mL × 3), anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, obtain title product 4-(3-pyridylmethyl) piperazine-1-t-butyl formate 54b (2.30g, brown oil), productive rate: 83.0%.

MS m/z(ESI)：278.2[M+1]

Second step

1-(3-pyridylmethyl) piperazine hydrochloride

Be dissolved in the methanol solution of 10mL 2M hydrogenchloride under 4-(3-pyridylmethyl) piperazine-1-t-butyl formate 54b (2.10g, 7.58mmol) is stirred, react 12 hours.Concentrating under reduced pressure, obtain brown solid, wash with the mixed solvent of methyl alcohol and sherwood oil (V/V=1: 5), obtain title product 1-(3-pyridylmethyl) piperazine hydrochloride 54c (1.30g, white solid), productive rate: 81.0%.

3rd step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 3b (200mg, 5mLN is dissolved under 0.62mmol) stirring, in dinethylformamide, add 1-(3-pyridylmethyl) piperazine hydrochloride 54c (159mg successively, 0.74mmol), I-hydroxybenzotriazole (126mg, 0.93mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (178mg, 0.93mmol) with triethylamine (313mg, 3.10mmol), react 12 hours.Add 50mL water, with dichloromethane extraction (20mL × 3), merge organic phase, water (5mL × 3), saturated nacl aqueous solution is used to wash (5mL × 3) successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-[4-(3-pyridylmethyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 54 (120mg, white solid), productive rate: 40.2%.

MS m/z(ESI)：482.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.58(s，1H)，8.52(d，1H)，8.26(d，1H)，7.97(d，1H)，7.88-7.87(t，1H)，7.82(s，1H)，7.47-7.30(m，3H)，7.28(s，1H)，7.03(s，1H)，4.57-4.52(m，2H)，4.37(s，2H)，3.82-3.75(m，4H)，3.21-3.12(m，4H)，2.32-2.25(m，4H)

Embodiment 55

4-[[7-[4-(2-glycyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

2-(t-butoxycarbonyl amino) acetic acid

Be dissolved in 32mL Isosorbide-5-Nitrae-dioxane solution under 2-Padil 55a (1g, 13.30mmol) is stirred, add tert-Butyl dicarbonate (4.36g successively, 19.98mmol) with sodium hydroxide (0.60g, 15.99mmol), react 12 hours.Concentrating under reduced pressure, add 20mL water, by ethyl acetate washing (40mL × 2), dripping 1M hydrochloric acid is 4 to aqueous phase pH, be extracted with ethyl acetate (40mL × 2), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product 2-(t-butoxycarbonyl amino) acetic acid 55b (2.20g, white solid), productive rate: 98.0%.

MS m/z(ESI)：351.0[2M+1]

Second step

N-[2-oxo-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-base] ethyl] t-butyl carbamate

By 4-[[7-(piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (223mg, 20mL N is dissolved under 0.57mmol) stirring, in dinethylformamide, add 2-(t-butoxycarbonyl amino) acetic acid 55b (100mg successively, 0.57mmol), I-hydroxybenzotriazole (115mg, 0.86mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (163mg, 0.86mmol) with triethylamine (173mg, 1.71mmol), react 12 hours.Add 50mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product N-[2-oxo-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-base] ethyl] t-butyl carbamate 55c (221mg, light yellow solid), productive rate: 70.6%.

MS m/z(ESI)：448.2[M-100+1]

3rd step

By N-[2-oxo-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-base] ethyl] t-butyl carbamate 55c (221mg, be dissolved in the methanol solution of 10mL 1M hydrogenchloride under 0.40mmol) stirring, react 12 hours.Concentrating under reduced pressure; dripping ammoniacal liquor is 8 to reaction solution pH; be extracted with ethyl acetate (20mL × 3); merge organic phase, concentrating under reduced pressure, purify gained resistates by tlc with developping agent system A; obtain title product 4-[[7-[4-(2-glycyl) piperazine-1-carbonyl]-2; 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 55 (100mg, colorless oil), productive rate: 55.0%.

MS m/z(ESI)：448.2[M+1]

¹H NMR(400MHz，CD ₃OD)：δ8.35(m，1H)，7.96(m，1H)，7.87(m，2H)，7.32(s，1H)，7.11(s，1H)，4.59(m，2H)4.30(s，2H)，3.79(m，4H)，3.55(m，2H)，3.42(m，4H)，3.21(m，2H)

Embodiment 56

4-[[7-[4-(2-methylamino ethanoyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-keto hydrochloride

The first step

2-(tertbutyloxycarbonyl (methyl) is amino) methyl acetate

By 2-(t-butoxycarbonyl amino) acetic acid 55b (0.80g, 5mL N is dissolved under 4.57mmol) stirring, in dinethylformamide, add sodium hydride and mineral oil mixture (548mg, 60%, 22.80mmol), under ice bath, react 1 hour, add methyl iodide (1.94g, 13.70mmol), room temperature reaction 12 hours.Add 10mL water, with dichloromethane extraction (10mL × 2), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system B with silica gel column chromatography, obtain title product 2-(tertbutyloxycarbonyl (methyl) is amino) methyl acetate 56a (780mg, colorless oil), productive rate: 84.0%.

MS m/z(ESI)：104.1[M-100+1]

Second step

2-(tertbutyloxycarbonyl (methyl) is amino) acetic acid

2-(tertbutyloxycarbonyl (methyl) is amino) methyl acetate 56a (780mg, 3.80mmol) is dissolved in 3.8mL methyl alcohol under stirring, adds 3.8mL 1M sodium hydroxide solution, react 12 hours.Concentrating under reduced pressure, dripping 1M hydrochloric acid is 4 to aqueous phase pH, be extracted with ethyl acetate (10mL × 2), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product 2-(tertbutyloxycarbonyl (methyl) is amino) acetic acid 56b (670mg, colorless oil), productive rate: 92.0%.

MS m/z(ESI)：188.1[M-1]

3rd step

N-methyl-N-[2-oxo-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-base] ethyl] t-butyl carbamate

By 4-[[7-(piperazine-1-carbonyl)-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 4 (412mg, 10mL N is dissolved under 1.06mmol) stirring, in dinethylformamide, add 2-(tertbutyloxycarbonyl (methyl) is amino) acetic acid 56b (200mg successively, 1.06mmol), I-hydroxybenzotriazole (215mg, 1.59mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (304mg, 1.59mmol) with triethylamine (321mg, 3.18mmol), react 12 hours.Add 50mL water, be extracted with ethyl acetate (50mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product N-methyl-N-[2-oxo-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-base] ethyl] t-butyl carbamate 56c (540mg, white solid), productive rate: 90.0%.

MS m/z(ESI)：462.2[M-100+1]

4th step

By N-methyl-N-[2-oxo-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-base] ethyl] t-butyl carbamate 56c (540mg, be dissolved in the methanol solution of 10mL 1M hydrogenchloride under 0.96mmol) stirring, react 12 hours.Concentrating under reduced pressure; obtain title product 4-[[7-[4-(2-methylamino ethanoyl) piperazine-1-carbonyl]-2; 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-keto hydrochloride 56 (370mg, light yellow solid), productive rate: 83.5%.

MS m/z(ESI)：462.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，8.25(m，1H)，7.88(m，3H)，7.26(s，1H)，7.06(s，1H)，4.53(m，2H)，4.23(s，2H)，3.14-3.52(m，12H)，2.33(s，3H)

Embodiment 57

4-[[7-[4-[[6-(trifluoromethyl)-3-pyridyl] methyl] piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone

The first step

4-[[6-(trifluoromethyl)-3-pyridyl] methyl] piperazine-1-t-butyl formate

By 6-(trifluoromethyl) pyridine-3-formaldehyde 57a (350mg, 5mL 1 is dissolved under 2mmol) stirring, in 2-ethylene dichloride, add piperazine-1-t-butyl formate (409mg, 2.20mmol), react 30 minutes, under ice bath, add sodium triacetoxy borohydride (848mg, 4mmol), room temperature reaction 12 hours.Add 15mL water, separatory, collect organic phase, use saturated sodium carbonate solution (5mL × 3), water (5mL × 3), saturated nacl aqueous solution to wash (5mL × 3), anhydrous sodium sulfate drying successively, filter, filtrate reduced in volume, obtain title product 4-[[6-(trifluoromethyl)-3-pyridyl] methyl] piperazine-1-t-butyl formate 57b (650mg, yellow solid), productive rate: 94.0%.

Second step

1-[[6-(trifluoromethyl)-3-pyridyl] methyl] piperazine hydrochloride

Be dissolved in the methanol solution of 3mL 2M hydrogenchloride under 4-[[6-(trifluoromethyl)-3-pyridyl] methyl] piperazine-1-t-butyl formate 57b (0.60g, 1.74mmol) is stirred, react 12 hours.Concentrating under reduced pressure, obtains title product 1-[[6-(trifluoromethyl)-3-pyridyl] methyl] piperazine hydrochloride 57c (0.40g, white solid), productive rate: 81.6%.

3rd step

By 5-[(4-oxo-3H-phthalazines-1-base) methyl]-2, 3-Dihydrobenzofuranes-7-formic acid 3b (200mg, 5mL N is dissolved under 0.62mmol) stirring, in dinethylformamide, add 1-[[6-(trifluoromethyl)-3-pyridyl] methyl] piperazine hydrochloride 57c (174mg successively, 0.62mmol), I-hydroxybenzotriazole (126mg, 0.93mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (177mg, 0.93mmol) with triethylamine (188mg, 1.86mmol), react 12 hours.Add 30mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, use water (10mL × 2) successively, saturated nacl aqueous solution washing (10mL × 2), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with developping agent system A by tlc, obtain title product 4-[[7-[4-[[6-(trifluoromethyl)-3-pyridyl] methyl] piperazine-1-carbonyl]-2, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 57 (130mg, white solid), productive rate: 38.0%.

MS m/z(ESI)：550.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.58(br.s，1H)，8.71(s，1H)，8.28(d，1H)，7.96-7.89(m，1H)，7.83-7.81(m，2H)，7.76-7.73(t，1H)，7.24(s，1H)，7.02(s，1H)，5.76(s，1H)，4.53-4.49(t，2H)，4.23(s，2H)，3.64(s，4H)，3.18-3.14(m，4H)，2.78(s，4H)

Embodiment 58

4-[6-fluoro-[7-[4-(1-methylamino cyclobutyl carbonyl) piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-keto hydrochloride

The first step

4-[the fluoro-5-of 6-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-t-butyl formate

By fluoro-for 6-5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-formic acid 53j (135mg, 15mL N is dissolved under 0.40mmol) stirring, in dinethylformamide, add piperazine-1-t-butyl formate (89mg successively, 0.48mmol), I-hydroxybenzotriazole (80mg, 0.60mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (114mg, 0.60mmol) with triethylamine (120mg, 1.20mmol), react 12 hours.Add 15mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product 4-[the fluoro-5-of 6-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-t-butyl formate 58a (160mg, yellow oil), productive rate: 79.2%.

MS m/z(ESI)：509.2[M+1]

Second step

4-[6-fluoro-[7-(piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base) methyl]-2H-phthalazines-1-ketone

By 4-[the fluoro-5-of 6-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-t-butyl formate 58a (160mg, be dissolved in 10mL methyl alcohol under 0.31mmol) stirring, add the methanol solution of 3mL 2M hydrogenchloride, react 12 hours.Concentrating under reduced pressure, add 10mL methylene dichloride, dripping 10% sodium hydroxide solution to reaction solution pH is 9, with dichloromethane extraction (30mL × 3), merge organic phase, with saturated nacl aqueous solution washing (15mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains title product 4-[6-fluoro-[7-(piperazine-1-carbonyl)-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 58b (100mg, white solid), productive rate: 78.1%.

MS m/z(ESI)：409.1[M+1]

3rd step

N-[1-[4-[the fluoro-5-of 6-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-carbonyl] the cyclobutyl]-N-Methyl-carbamic acid tert-butyl ester

By the 4-[fluoro-[7-(piperazine-1-carbonyl)-2 of 6-, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 58b (100mg, 10mL N is dissolved under 0.25mmol) stirring, in dinethylformamide, add 1-(tert-butoxycarbonyl (methyl) is amino) cyclobutyl formate 37b (68mg successively, 0.29mmol), I-hydroxybenzotriazole (50mg, 0.37mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (70mg, 0.37mmol) with triethylamine (74mg, 0.74mmol), react 12 hours.Add 50mL water, be extracted with ethyl acetate (50mL × 3), merge organic phase, saturated sodium bicarbonate solution (20mL), saturated nacl aqueous solution is used to wash (50mL × 2) successively, anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product N-[1-[4-[the fluoro-5-of 6-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] cyclobutyl]-N-Methyl-carbamic acid tert-butyl ester 58c (130mg, yellow oil), productive rate: 83.3%.

MS m/z(ESI)：520.2[M-100+1]

4th step

By N-[1-[4-[the fluoro-5-of 6-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] cyclobutyl]-N-Methyl-carbamic acid tert-butyl ester 58c (130mg, be dissolved in 10mL methyl alcohol under 0.21mmol) stirring, add the methanol solution of 3mL 2M hydrogenchloride, react 12 hours.Concentrating under reduced pressure, add 10mL methylene dichloride, dripping 10% sodium hydroxide solution to reaction solution pH is 9, with dichloromethane extraction (30mL × 3), merge organic phase, with saturated nacl aqueous solution washing (15mL), anhydrous sodium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A.Products obtained therefrom is dissolved in 10mL methyl alcohol, add 0.5mL concentrated hydrochloric acid, react 12 hours, concentrating under reduced pressure, obtain the title product 4-[fluoro-[7-[4-(1-methylamino cyclobutyl carbonyl) piperazine-1-carbonyl]-2 of 6-, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-keto hydrochloride 58 (75mg, white solid), productive rate: 66.4%.

MS m/z(ESI)：520.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.53(s，1H)，8.26-8.28(m，1H)，7.84-7.98(m，3H)，7.14-7.16(m，1H)，4.59(t，2H)，4.23(s，2H)，3.47-3.59(m，6H)，3.27-3.29(m，2H)，3.12(t，2H)，2.33(s，1H)，2.05(s，3H)，1.88-1.92(m，2H)，1.75-1.79(m，1H)，1.22-1.24(m，2H)，0.83-0.87(m，1H)

Embodiment 59

4-[[the fluoro-7-of 6-[4-[(2R)-2-methylpyrrolidin-2-carbonyl] piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-keto hydrochloride

The first step

The O1-tertiary butyl-O2-methyl-(2R)-2-methylpyrrolidin-1,2-dicarboxylic acid esters

By (2R)-2-methylpyrrolidin-2-methyl-formiate hydrochloride 25e (1.38g, be dissolved in 30mL Isosorbide-5-Nitrae-dioxane under 7.70mmol) stirring, add 15mL 1M sodium hydroxide solution and tert-Butyl dicarbonate (2g, 9.20mmol), react 12 hours.Concentrating under reduced pressure, add 20mL water, be extracted with ethyl acetate (30mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains the title product O1-tertiary butyl-O2-methyl-(2R)-2-methylpyrrolidin-1,2-dicarboxylic acid esters 59a (1.50g, white solid), productive rate: 83.3%.

MS m/z(ESI)：144.1[M-100+1]

Second step

(2R)-1-tertbutyloxycarbonyl-2-methylpyrrolidin-2-formic acid

Be dissolved in 20mL methyl alcohol under the O1-tertiary butyl-O2-methyl-(2R)-2-methylpyrrolidin-1,2-dicarboxylic acid esters 59a (1.50g, 6.20mmol) is stirred, add 30mL 1M sodium hydroxide solution, react 12 hours.Add 15mL water, with washed with dichloromethane (20mL × 2).Collect aqueous phase, dripping concentrated hydrochloric acid is 3 to aqueous phase pH, be extracted with ethyl acetate (30mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product (2R)-1-tertbutyloxycarbonyl-2-methylpyrrolidin-2-formic acid 59b (0.85g, light yellow solid), productive rate: 60.7%.

MS m/z(ESI)：228.1[M+1]

3rd step

(2R)-2-[4-[the fluoro-5-of 6-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-carbonyl]-2-methyi-pyrrofidinium-1-t-butyl formate

By the 4-[fluoro-[7-(piperazine-1-carbonyl)-2 of 6-, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 58b (100mg, 10mL N is dissolved under 0.25mmol) stirring, in dinethylformamide, add (2R)-1-tertbutyloxycarbonyl-2-methylpyrrolidin-2-formic acid 59b (67mg successively, 0.29mmol), I-hydroxybenzotriazole (50mg, 0.37mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (70mg, 0.37mmol) with triethylamine (74mg, 0.74mmol), react 12 hours.Add 50mL water, be extracted with ethyl acetate (50mL × 5), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain title product (2R)-2-[4-[the fluoro-5-of 6-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl]-2-methyi-pyrrofidinium-1-t-butyl formate 59c (140mg, yellow oil), productive rate: 92.1%.

MS m/z(ESI)：520.2[M-100+1]

4th step

By (2R)-2-[4-[fluoro-5-of 6-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl]-2-methyi-pyrrofidinium-1-t-butyl formate 59c (100mg, be dissolved in 10mL methyl alcohol under 0.16mmol) stirring, add the methanol solution of 3mL 2M hydrogenchloride, react 12 hours.Dripping 1M sodium hydroxide solution is 9 to reaction solution pH, with dichloromethane extraction (30mL × 3), merges organic phase, with anhydrous sodium sulfate drying, filters, filtrate reduced in volume, purifies gained resistates with silica gel column chromatography with eluent system A.Products obtained therefrom is dissolved in the methanol solution of 3mL 2M hydrogenchloride, react 12 hours, concentrating under reduced pressure, obtain title product 4-[[the fluoro-7-of 6-[4-[(2R)-2-methylpyrrolidin-2-carbonyl] piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-keto hydrochloride 59 (25mg, white solid), productive rate: 21.4%.

MS m/z(ESI)：520.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.55(s，1H)，8.26-8.28(m，1H)，7.84-8.00(m，3H)，7.17-7.19(m，1H)，4.59(t，2H)，4.24(s，2H)，3.53-3.68(m，6H)，3.13(t，2H)，1.86-2.32(m，5H)，1.58-1.60(m，2H)，1.45-1.47(m，1H)，1.23(s，3H)

Embodiment 60

4-[[7-[4-(the amino cyclobutanecarbonyl of 1-) piperazine-1-carbonyl] fluoro-2, the 3-Dihydrobenzofuranes-5-bases of-6-] methyl]-2H-phthalazines-1-ketone

The first step

N-[1-[4-[the fluoro-5-of 6-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls]-piperazine-1-carbonyl] tetramethylene] t-butyl carbamate

By the 4-[fluoro-[7-(piperazine-1-carbonyl)-2 of 6-, 3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 58b (25mg, 0.61mmol), 1-(t-butoxycarbonyl amino) cyclobutane formate 60a (16mg, 0.73mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (21mg, 0.11mmol), I-hydroxybenzotriazole (15mg, 0.11mmol) with triethylamine (19mg, 0.18mmol) be dissolved in 5mLN, in dinethylformamide, react 15 hours.Add 30mL water, be extracted with ethyl acetate (40mL × 3), merge organic phase, use 1M hydrochloric acid (30mL) successively, saturated sodium bicarbonate solution (30mL), saturated nacl aqueous solution washing (30mL), with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, gained resistates is purified with eluent system A with silica gel column chromatography, obtain title product N-[1-[4-[the fluoro-5-of 6-[(4-oxo-3H-phthalazines-1-base) methyl]-2, 3-Dihydrobenzofuranes-7-carbonyl]-piperazine-1-carbonyl] tetramethylene] t-butyl carbamate 60b (29mg, white solid), productive rate: 78.4%.

MS m/z(ESI)：506.2[M-100+1]

Second step

5mL methanol hydrochloride solution is joined N-[1-[4-[the fluoro-5-of 6-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl]-piperazine-1-carbonyl] tetramethylene] t-butyl carbamate 60b (29mg, 0.48mmol), react 12 hours.Concentrating under reduced pressure, in residue, drip ammoniacal liquor, regulate pH to be 8 ~ 9, be extracted with ethyl acetate (10mL × 2), the organic phase merged uses anhydrous sodium sulfate drying successively, filter, concetrated under reduced pressure, vacuum-drying, obtain title product 4-[[7-[4-(the amino cyclobutanecarbonyl of 1-) piperazine-1-carbonyl]-6-fluoro-2,3-Dihydrobenzofuranes-5-base] methyl]-2H-phthalazines-1-ketone 60 (20.6mg, white solid), productive rate: 84.6%.

MS m/z(ESI)：543.2[M+1]

¹H NMR(400MHz，D ₂O)：δ8.16-8.14(m，2H)，7.82-7.80(m，3H)，7.13-7.11(m，2H)，4.63-4.58(m，2H)，4.17-4.14(m，2H)，3.83-3.82(m，2H)，3.68(s，2H)，3.57-3.55(m，2H)，3.49-3.47(m，2H)，3.07-3.05(m，2H)，2.81-2.79(m，2H)，2.47-2.45(m，2H)，2.19-2.16(m，1H)，2.00-1.98(m，1H)

Embodiment 61

The first step

By (3S, 7aR)-3-(trichloromethyl)-5,6,7,7a-tetrahydrochysene-3H-pyrrolo-[1,2-c] oxazole-1-ketone 61a (24.40g, 100mmol) be dissolved in 500mL tetrahydrofuran (THF), at-78 DEG C, drip the tetrahydrofuran solution of the diisopropylamino lithium of 80mL 2M, react 1 hour at-78 DEG C, drip 30mL methyl iodide, react 1 hour.Add 150mL water, with chloroform extraction (300mL × 2), merge organic layer, with anhydrous magnesium sulfate drying, filter, filtrate reduced in volume, purify gained resistates with silica gel column chromatography with eluent system A, obtain title product (3S, 7aR)-7a-methyl-3-(trichloromethyl)-3,5,6,7-Pyrrolidine is [1,2-c] oxazole-1-ketone 61b (21.50g also, weak yellow liquid), productive rate: 82.6%.

MS m/z(ESI)：260.0[M+1]

Second step

(2R)-2-methylpyrrolidin-2-methyl-formiate

By (3S, 7aR)-7a-methyl-3-(trichloromethyl)-3,5,6, also [1,2-c] oxazole-1-ketone 61b (18g, 70mmol) is dissolved in 360mL methyl alcohol 7-Pyrrolidine, stir 30 minutes, drip 17mL thionyl chloride, back flow reaction 3 hours.Concentrating under reduced pressure, adds 50mL ethyl acetate, stirs, and filter, filter cake vacuum-drying, obtains title product (2R)-2-methylpyrrolidin-2-methyl-formiate 61c (10g, white solid), productive rate: 80.2%.

MS m/z(ESI)：144.2[M+1]

3rd step

(2R)-2-methylpyrrolidin-1,2-dioctyl phthalate-O1-tertiary butyl ester-O2-methyl esters

By (2R)-2-methylpyrrolidin-2-methyl-formiate 61c (9g, 50mmol) be dissolved in 180mL1, in 4-dioxane, add sodium hydroxide solution and the tert-Butyl dicarbonate (13g of 75mL1M, 60mmol), react 17 hours.Concentrating under reduced pressure, add 100mL water, be extracted with ethyl acetate (100mL × 4), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains furnish crude title compound (2R)-2-methylpyrrolidin-1,2-dioctyl phthalate-O1-tertiary butyl ester-O2-methyl esters 61d (9.50g, yellow oil), product is not purified is directly used in the next step.

MS m/z(ESI)：144.1[M-100+1]

4th step

(2R)-1-tertbutyloxycarbonyl-2-methyl-pyrolidinyl-2-formic acid

Crude product (2R)-2-methylpyrrolidin-1,2-dioctyl phthalate-O1-tertiary butyl ester-O2-methyl esters 61d (7.30g, 30mmol) is dissolved in 70mL methyl alcohol, adds 140mL1M sodium hydroxide solution, react 16 hours.Add 70mL water, with washed with dichloromethane (100mL × 2), merge aqueous phase, dripping concentrated hydrochloric acid is 2 ~ 3 to aqueous phase pH, be extracted with ethyl acetate (150mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain furnish crude title compound (2R)-1-tertbutyloxycarbonyl-2-methyl-pyrolidinyl-2-formic acid 61e (5.70g, off-white color solid), product is not purified is directly used in the next step.

MS m/z(ESI)：228.1[M-1]

5th step

(2R)-2-methyl-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyls] piperazine-1-carbonyl] tetramethyleneimine-1-t-butyl formate

By (2R)-2-methyl-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2, 3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] tetramethyleneimine-1-t-butyl formate 4 (1.28g, 3mmol) be dissolved in 50mL N, in dinethylformamide, add crude product (2R)-1-tertbutyloxycarbonyl-2-methyl-pyrolidinyl-2-formic acid 61e (824mg successively, 3.60mmol), I-hydroxybenzotriazole (608mg, 4.50mmol), 1-ethyl-(3-dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate (860mg, 4.50mmol) with triethylamine (879mg, 8.70mmol), react 48 hours.Concentrating under reduced pressure, add 10mL methylene dichloride, wash with water (20mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtain furnish crude title compound (2R)-2-methyl-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] tetramethyleneimine-1-t-butyl formate 61f (1.70g, yellow solid), product is not purified is directly used in the next step.

MS m/z(ESI)：502.2[M+1]

6th step

By crude product (2R)-2-methyl-2-[4-[5-[(4-oxo-3H-phthalazines-1-base) methyl]-2,3-Dihydrobenzofuranes-7-carbonyl] piperazine-1-carbonyl] tetramethyleneimine-1-t-butyl formate 61f (1.50g, 2.50mmol) be dissolved in 15mL methylene dichloride, add trifluoroacetic acid (1.5mL, 20mmol), react 16 hours.Add 1M sodium hydroxide solution (800mg, 20mmol), with dichloromethane extraction (50mL × 3), merge organic phase, with anhydrous sodium sulfate drying, filter, filtrate reduced in volume, obtains title product 4-[[7-[4-[(2R)-2-methylpyrrolidin-2-carbonyl] piperazine-1-carbonyl]-2,3-Dihydrobenzofuranes-5-bases] methyl]-2H-phthalazines-1-ketone 61 (1.10g, yellow solid), productive rate 88.0%.

MS m/z(ESI)：502.2[M+1]

¹H NMR(400MHz，DMSO-d ₆)：δ12.57(s，1H)，8.26(d，1H)，7.97(d，1H)，7.89-7.87(t，1H)，7.85-7.83(t，1H)，7.25(s，1H)，7.05(s，1H)，4.55-4.53(t，2H)，4.22(s，2H)，3.63-3.32(m，8H)，3.17-3.12(m，2H)，2.78-2.68(m，2H)，2.24-2.18(m，1H)，1.69-1.64(m，3H)，1.32(s，3H)

Test case:

biological assessment

Example 1 PARP-1 enzyme assay is tested

Body outer screening test is below used to measure the restraining effect of the compounds of this invention for PARP-enzymic activity.

The experiment of the following stated suppresses test kit (TREVIGEN HT F homogeneous PARP Inhibition Assay Kit, article No. .No4690-096-K) to measure the restraining effect of invention compound to PARP enzymic activity by using poly-(adenosine diphosphate (ADP)-ribose) polymerase of TREVIGEN HT F homology.Test the DNA repair process participated in based on PARP to need to consume NAD ⁺, NAD ⁺in another reaction, being used to the molecule substrate of unstressed configuration activity being catalyzed into high fluorescence activity simultaneously, therefore by measuring the enhancing degree of fluorescent signal, NAD in reaction system can being learnt ⁺level, thus calculate test compounds to the suppression degree of PARP enzymic activity.

The detailed operation of experiment and the preparation of reagent used, as reaction mixture (reaction mix), circulating reaction mixed solution (cycling mix) and damping fluid (buffer) etc., can refer to poly-(adenosine diphosphate (ADP)-ribose) polymerase of TREVIGEN HT F homology and suppress test kit specification sheets.

Experimental procedure is summarized as follows: test compounds is dissolved in dimethyl sulfoxide (DMSO), is diluted to experiment desired concn subsequently with 1x damping fluid.First in round bottom 96 orifice plate, 25 μ L are added, 200nM, NAD ⁺solution, adds 1 μ L test compounds solution subsequently and arranges the contrast of multiple hole.Backward each hole in add 25 μ L and contain DNA, the reaction mixture of PARP enzyme and reaction buffer.At room temperature incubation is after 30 minutes, adds 50 μ L circulating reaction mixed solutions, lucifuge, incubation at room temperature 15 ~ 40 minutes in each hole.Add 50 μ L stop buffers subsequently, microplate reader reads the fluorescent value (Ex544nm, Em590nm) in each hole.Pass through NAD ⁺typical curve equation can calculate the inhibiting rate of compound to PARP enzymic activity.

The IC of compound ₅₀value calculates by the inhibiting rate under different concns

Conclusion: preferred compound of the present invention has obvious inhibit activities to the kinase whose Inhibit proliferaton of PARP-1.

Example 2 cell growth inhibition assay

Experiment is below used for measuring the proliferation inhibition activity of compound of the present invention to the breast carcinoma cell strain MDA-MB-436 cell of three negative phenotype under in vitro conditions.

The In vitro cell experiment of the following stated can measure the proliferation inhibition activity of test-compound to the breast cancer cell of three negative phenotype, and the inhibit activities of compound can use IC ₅₀value represents.

Experimental program is summarized as follows: first add 10%FBS (being all purchased from Gibco) as perfect medium using DMEM F12, MDA-MB-436 cell is inoculated on 96 well culture plates with suitable cell density (e.g.3000/mL medium), at 37 DEG C, under 5% carbon dioxide conditions, overnight incubation in constant incubator.First test compounds uses dmso solution, is diluted to the concentration needed for experiment subsequently with the substratum not containing FBS.After cell attachment, original substratum is replaced by the fresh culture adding a series of gradient concentration test-compound (being generally 7 or 9 concentration point) solution.After this, by Tissue Culture Plate at 37 DEG C, 5%CO ₂cultivation 72 hours is continued under condition.After 72 hours, CCK8 (Cell Counting Kit-8, article No.: CK04, is purchased from Dojindo) method is adopted to measure the inhibit activities of compound for cell proliferation.

The IC of compound ₅₀value draws by the suppression numerical evaluation of test-compound under different concns for cell proliferation.

Conclusion: preferred compound of the present invention has obvious inhibit activities to MDA-MB-436 Carbazole alkaloid propagation.

pharmacokinetic Evaluation

The pharmacokinetics test of test case 1 embodiment of the present invention 22,25 and 33 compound

1, make a summary

With SD rat for animal subject, application LC/MS/MS method determines the drug level that rat intravenous injection to give after embodiment 22,25 and 33 compound not in blood plasma in the same time.The pharmacokinetics behavior of research the compounds of this invention in rat body, evaluates its characteristics of pharmacokinetics.

2, testing program

2.1 test drug

Embodiment 22,25 and 33 compound

2.2 experimental animal

Healthy adult SD rat 12, male and female half and half, purchased from Shanghai western pul-Bi Kai laboratory animal company limited, animal productiong credit number: SCXK (Shanghai) 2003-0002.

2.3 Pharmaceutical formulations

Take appropriate amount of drug, after add 0.5% Xylo-Mucine and be mixed with 1.5mg/mL suspension.

2.4 administration

Healthy adult SD rat 12, male and female half and half, intravenous injection respectively after overnight fasting, dosage is 15.0mg/kg, administration volume 10mL/kg.

2.5 sample collecting

Before administration and after administration 2 minutes, 15 minutes, 0.5,1.0,2.0,3.0,4.0,6.0,8.0,12.0, within 24.0 hours, to be taken a blood sample 0.2mL by eye socket, be placed in heparinised tubes, 3500 revs/min, centrifugal 20 minutes separated plasmas, in-20 DEG C of preservations.

3, operate

After drawing medicine, each 20 μ L of the rat blank plasma in each moment, add inner mark solution 50 μ L, methyl alcohol 140 μ L, and vortex mixed 3 minutes after mixing, centrifugal 10 minutes (13500 revs/min), get supernatant liquor 20 μ L and carry out LC-MS/MS analysis.Main pharmacokinetic parameter adopts DAS 2.0 computed in software.

4, pharmacokinetic parameter result

The pharmacokinetic parameter of the compounds of this invention is as follows:

Conclusion: embodiment of the present invention compound medicine codes or data is better, and pharmacokinetic property obviously improves.

tumor-inhibiting action is evaluated

Test case 2 tests the tumor-inhibiting action of the compounds of this invention to mouse

1. experiment purpose

With BALB/cA-nude nude mice for animal subject, evaluate the curative effect to human colon carcinoma SW620 or people three negative breast cancer cells MDA-MB-436 transplanted tumor transplanted tumor nude mouse after the compounds of this invention and Temozolomide (TMZ) Combined Preparation.

2. test medicine

Embodiment 25 compound

3. laboratory animal

BALB/cA-nude nude mouse, SPF, 16-20g, ♀, purchased from Shanghai western pul Bi Kai laboratory animal limited liability company.Conformity certification number: SCXK (Shanghai) 2008-0016.

4. experimental procedure

4.1 nude mouse laboratory environments adapt to three days.

4.2 nude mouse right flank subcutaneous vaccination colorectal carcinoma SW620 cell, treats that tumour grows to 339 ± 132mm ³after by animal random packet (d0).

Nude mouse right flank subcutaneous vaccination MDA-MB-436 cell, tumor growth 53 days, grows to 360 ± 49mm ³after by animal random packet (D0).

4.3 dosages and dosage regimen see the following form.Survey weekly 2 ~ 3 knurl volumes, claim mouse heavy, record data.

Gross tumor volume (V) calculation formula is:

V＝1/2×a×b ²

Wherein: a, b represent length and width respectively.

Tumour inhibiting rate (%)=(C-T)/C (%)

Wherein: the experimental group (testing compound) at the end of T, C are respectively experiment and the gross tumor volume of blank group.

5. dosage, dosage regimen and experimental result

Conclusion: tumour inhibiting rate % data area represents: "+": 40% ~ 60%; " ++ ": 60% ~ 80%; " +++ ": 80% ~ 100%.The compound that the present invention is to be measured and TMZ coupling to colorectal carcinoma SW620 cell and or people three negative breast cancer MDA-MB-436 cell there is good tumour inhibiting rate, major part is higher than 60%.

Claims

1. the compound shown in a general formula (II) or its pharmaceutically useful salt:

Wherein:

A with B forms phenyl together with the carbon atom be connected;

R ¹be selected from hydrogen atom;

R ²be selected from hydrogen atom, halogen ,-C (O) R ⁹or-C (O) (CH ₂) _mnR ¹⁰r ¹¹;

R ³and R ⁴be selected from hydrogen atom or halogen separately;

R ⁵and R ⁶be selected from hydrogen atom independently of one another;

R ⁷and R ⁸be selected from hydrogen atom independently of one another;

R ⁹be selected from hydrogen atom, C _1-12alkyl, C _3-10cycloalkyl or heterocyclic radical, wherein said C _1-12alkyl, C _3-10cycloalkyl or heterocyclic radical are optionally selected from C by one or more independently of one another further _1-12alkyl, halogen, hydroxyl, C _1-12alkoxyl group, C _3-10cycloalkyl, heterocyclic radical, C _6-10aryl, heteroaryl ,-NR ¹⁰r ¹¹,-OC (O) NR ¹⁰r ¹¹or-C (O) NR ¹⁰r ¹¹substituting group replaced;

R ¹⁰or R ¹¹independently be selected from hydrogen atom, C separately _1-12alkyl, C _3-10cycloalkyl, heterocyclic radical, C _6-10aryl, benzyl or heteroaryl, wherein said C _1-12alkyl, C _3-10cycloalkyl, heterocyclic radical, C _6-10aryl or heteroaryl are optionally selected from hydroxyl, C by one or more independently of one another further _1-12alkyl, halogen, cyano group, C _1-12alkoxyl group, C _3-10cycloalkyl, heterocyclic radical, C _6-10aryl, benzyl, heteroaryl ,-C (O) OR ¹²,-OC (O) R ¹²,-C (O) R ¹²,-NHC (O) R ¹²,-NR ¹³r ¹⁴,-OC (O) NR ¹³r ¹⁴,-NHC (O) NR ¹³r ¹⁴,-C (O) (CH ₂) _mnR ¹³r ¹⁴or-S (O) _mr ¹²substituting group replaced;

Or, R ¹⁰and R ¹¹heterocyclic radical is formed, containing one or more N, O or S (O) in wherein said heterocyclic radical with the nitrogen-atoms be connected _mheteroatoms, and described heterocyclyl is selected from hydroxyl, C by one or more further _1-12alkyl, C _1-12haloalkyl, halogen, cyano group, C _1-12alkoxyl group, C _3-10cycloalkyl, heterocyclic radical, C _6-10aryl, benzyl, heteroaryl ,-C (O) OR ¹²,-OC (O) R ¹²,-C (O) R ¹²,-NHC (O) R ¹²,-NR ¹³r ¹⁴,-OC (O) NR ¹³r ¹⁴,-NHC (O) NR ¹³r ¹⁴,-C (O) (CH ₂) _mnR ¹³r ¹⁴or-S (O) _mr ¹²substituting group replaced, wherein C _1-12alkyl, C _3-10cycloalkyl, benzyl, heteroaryl are optionally selected from C by one or more independently of one another further _1-12alkyl, C _1-12haloalkyl, halogen, hydroxyl, C _1-12alkoxyl group, heteroaryl or C _3-10the substituting group of cycloalkyl replaced;

R ¹², R ¹³or R ¹⁴be selected from hydrogen atom, C independently of one another _1-12alkyl, C _3-10cycloalkyl, heterocyclic radical, C _6-10aryl, benzyl or heteroaryl, wherein said C _1-12alkyl, C _3-10cycloalkyl, heterocyclic radical, C _6-10aryl or heteroaryl are optionally selected from hydroxyl, C by one or more independently of one another further _1-12alkyl, halogen, cyano group, C _1-12alkoxyl group, C _3-10cycloalkyl, heterocyclic radical, C _6-10aryl, heteroaryl ,-C (O) OR ¹⁵,-OC (O) R ¹⁵,-C (O) R ¹⁵,-NHC (O) R ¹⁵,-NR ¹⁶r ¹⁷,-OC (O) NR ¹⁶r ¹⁷,-NHC (O) NR ¹⁶r ¹⁷,-C (O) (CH ₂) _mnR ¹⁶r ¹⁷or-S (O) _mr ¹⁵substituting group replaced;

R ¹⁵, R ¹⁶or R ¹⁷be selected from hydrogen atom, C independently of one another _1-12alkyl, C _3-10cycloalkyl, heterocyclic radical, C _6-10aryl or heteroaryl, wherein said C _1-12alkyl, C _3-10cycloalkyl, heterocyclic radical, C _6-10aryl or heteroaryl are optionally selected from hydroxyl, C by one or more independently of one another further _1-12alkyl, halogen, cyano group, C _1-12alkoxyl group, C _3-10cycloalkyl, heterocyclic radical, C _6-10aryl or heteroaryl; And

M is 0,1 or 2;

Described heterocyclic radical is 3 to 10 annular atomses, and wherein 1-4 is be selected from N, O or S (O) _mheteroatoms;

Described heteroaryl is 5 to 10 yuan, wherein comprises 1-4 atom N.

2. the compound shown in general formula according to claim 1 (II) or its pharmaceutically useful salt, wherein R ²for halogen.

3. the compound shown in general formula according to claim 1 (II) or its pharmaceutically useful salt, it is the compound shown in a kind of general formula (III) or its pharmaceutically useful salt:

Wherein: R ¹, R ³~ R ⁸, R ¹⁰, R ¹¹, A and B definition as described in the appended claim 1.

4. the compound shown in general formula according to claim 1 (II) or its pharmaceutically useful salt, wherein R ³and R ⁴be selected from hydrogen atom independently of one another.

5. the compound shown in general formula according to claim 3 (III) or its pharmaceutically useful salt, wherein R ¹⁰and R ¹¹form heterocyclic radical with the nitrogen-atoms be connected, wherein said heterocyclyl is further by one or more-C (O) R ¹²substituting group replaced.

6. compound according to claim 5 or its pharmaceutically useful salt, wherein R ¹²be selected from C _1-12alkyl, C _3-10cycloalkyl or heterocyclic radical, wherein said C _1-12alkyl, C _3-10cycloalkyl or heterocyclyl are selected from halogen, C by one or more further _1-12alkyl or-NR ¹⁶r ¹⁷substituting group replaced;

Described heterocyclic radical is 3 to 10 annular atomses, and wherein 1-4 is be selected from N, O or S (O) _mheteroatoms.

7. the compound shown in general formula according to claim 1 (II) or its pharmaceutically useful salt, wherein this compound is:

8. prepare a method for the compound shown in general formula according to claim 3 (III) or its pharmaceutically useful salt, the method comprises:

Wherein: A, B, R ¹, R ³~ R ⁸, R ¹⁰, R ¹¹definition as claimed in claim 3;

R ¹⁸be selected from hydrogen atom or C _1-12alkyl.

9. the compound shown in a general formula (IIIA) or its pharmaceutically useful salt:

Wherein:

R ¹, R ³~ R ⁸, A and B definition as described in the appended claim 1;

R ¹⁸be selected from hydrogen atom or C _1-12alkyl.

10. prepare a method for the compound shown in general formula according to claim 9 (IIIA) or its pharmaceutically useful salt, the method comprises:

General formula compound a is become general formula compound b through oxidation conversion;

General formula compound b is changed into general formula compound c;

General formula compound c is changed into general formula compound d;

General formula compound d is changed into general formula compound (IIIA);

Wherein A, B, R ¹, R ³~ R ⁸, R ¹⁸definition as claimed in claim 9, X is halogen.

11. 1 kinds of pharmaceutical compositions, it contains the compound according to any one of claim 1 ~ 7 or its pharmaceutically useful salt and pharmaceutically useful carrier or vehicle for the treatment of effective dose.

12. the compound according to any one of claim 1 ~ 7 or its pharmaceutically useful salt, the purposes of pharmaceutical composition according to claim 11 in the medicine of preparation suppression PARP.

13. compounds according to any one of claim 1 ~ 7 or its pharmaceutically useful salt, pharmaceutical composition according to claim 11 be prepared in cancer treatment procedure as assistant agent or for make tumour cell become responsive to ionizing rays or chemotherapy medicine in purposes.

14. the compound according to any one of claim 1 ~ 7 or its pharmaceutically useful salt, the purposes of pharmaceutical composition according to claim 11 in the medicine preparing Therapeutic cancer.

15. purposes according to claim 14, wherein said cancer is mammary cancer, ovarian cancer, carcinoma of the pancreas, prostate cancer, the rectum cancer, liver cancer or colorectal carcinoma.

16. purposes according to any one of claim 12 ~ 15, wherein said medicine further with treatment effective dose be selected from following Drug combination: Temozolomide, Zorubicin, taxol, cis-platinum, carboplatin, Dacarbazine, topotecan, irinotecan, gemcitabine and rhuMAb-VEGF.