CN102762549A - Phthalazinone derivative, and preparation method and pharmaceutical use thereof - Google Patents

Phthalazinone derivative, and preparation method and pharmaceutical use thereof Download PDF

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CN102762549A
CN102762549A CN2011800046122A CN201180004612A CN102762549A CN 102762549 A CN102762549 A CN 102762549A CN 2011800046122 A CN2011800046122 A CN 2011800046122A CN 201180004612 A CN201180004612 A CN 201180004612A CN 102762549 A CN102762549 A CN 102762549A
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protective embankment
heteroaryl
heterocyclic radical
embankment base
aryl
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CN102762549B (en
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邓炳初
张学军
李晓涛
朱耀平
杨斌斌
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/06—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Abstract

The present invention 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

Phthalazinone derivative, and preparation method and pharmaceutical use thereof
Phthalazines ketones derivant, its preparation method and its in applied technical field pharmaceutically
The present invention relates to phthalazines ketones derivant new shown in a kind of logical formula (I), its preparation method and contain the derivative pharmaceutical composition and its as purposes of the therapeutic agent as poly- (ADP- ribose) polymerase (PARP) inhibitor.Background technology
Chemotherapeutics and ionizing radiation treatment are two kinds of common methods for the treatment of cancer.Both treatment methods can induce DNA single-stranded and/or double-strand break and then produce cytotoxic effect, and target tumor is because chromosome damage is so as to dead.It is that cell cycle regulating site signal is activated as an important results of response DNA damage signal, its object is to protect cell in the case of DNA damage without mitosis to avoid cellular damage.In most cases, tumour cell while cell cycle regulating site signal defect is shown with very high proliferation rate.It can therefore be concluded that there is specific DNA repair mechanisms in tumour cell, with quick response and the chromosome damage related to propagation regulation can be repaired, so that its own survives the cytotoxic effect of some medicines and maintenance survival.
In clinical practice, the valid density or treatment radiation intensity of chemotherapeutics can resist these DNA repair mechanisms, it is ensured that to the fragmentation effect of target tumor.However, tumour cell can produce treatment tolerance effect by strengthening its DNA damage repair mechanism, it is allowed to survive from fatal DNA damage.In order to overcome the tolerance of generation, it is generally necessary to increase the dosage of medicine or improve radiation intensity, the adverse effect that this way will be produced to the normal structure near focus, so that with serious adverse reaction in therapeutic process, and then increase Operative risk.Meanwhile, ever-increasing tolerance will reduce therapeutic effect, it can therefore be concluded that by the regulation to DNA damage signal repair mechanism, the raising of the cytotoxicity to DNA damaging agents can be realized in the way of tumor cell specific.
The PARPs (Poly (ADP-ribose) polymerases) being characterized with poly- adenosine diphosphate-ribosylating activity, constitutes the superfamily of 18 kinds of cell ribozymes and cytoplasm enzyme.This poly- adenosine diphosphate-ribosylation can adjust the catalytic activity and protein-protein interaction of destination protein, and many basic bioprocess are regulated and controled, repaired including DNA, cell death, Genome stability is also associated (referring to D, Amours et al. Biochem. J, 1999,342,249).
PARP-1 activity accounts for 80 % of total cell PARP activity, it and turn into the member for possessing DNA plerosis lesion capability in PARP families jointly with its most close PARP-2.As the inductor and signal protein of DNA damage, PARP-1 with quick detection and can be bonded directly to DNA damage site, the multiple protein needed for induced aggregation DNA is repaired afterwards, and then DNA damage is 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, and expression of the PARPs albumen in solid tumor generally strengthens.In addition, The tumour (such as tumor of breast and oophoroma) of (such as BRCA-1 or BRCA-2) is lacked for DNA Related to repair gene, show the extreme sensitivity to PARP-1 inhibitor, this show PARP inhibitor as single dose treat it is this be referred to as triple negative breast cancer in terms of potential use（Referring to Plummer, E. R. Curr. Opin. Pharmacol. 2006,6,364; Ratnam, et al; Clin. Cancer Res. 2007,13, 1383).Simultaneously as DNA damage repair mechanism is tumour cell reply chemotherapeutics and ionizing radiation treatment produces resistance to main mechanism the affected, therefore PARP-1 is considered as an Effective target site for exploring new cancer treatment method.
The PARP inhibitor of early development design is all, to be catalyzed the NAD+ of substrate niacinamide as PARP as template, to develop its analog.These inhibitor compete PARP catalytic site with NAD+, and then prevent the synthesis of poly- (ADP- ribose) chain as NAD+ competitive inhibitor.PARP under not poly- (ADP- ribosylation) modification can not be disintegrated down from DNA damage site, the protein for causing other to participate in repairing be entered into injury site, and then can not perform repair process.Therefore, in the presence of cytotoxic drug or radiation, the presence of PARP inhibitor makes the impaired tumour cells of DNA finally dead.
In addition, the NAD+ for being catalyzed substrate as PARP and being consumed, is that cell synthesizes the factor essential in ATP building-up processes.Under high PARP activity levels, intracellular NAD+ levels can be remarkably decreased, and then influence the ATP levels of intracellular.Because the ATP contents of intracellular are not enough, cell can not realize the programmed cell death process that ATP is relied on, and can only turn to this downright bad special apoptotic process.During necrosis, substantial amounts of inflammatory factor can be released, so as to produce toxic action (Horvath EM et al Drug News Perspect, 2007,20,171-181) to other organs and tissue.Therefore, PARP inhibitor can also be used for treating a variety of diseases relevant with this mechanism, including nerve degenerative diseases (such as senile dementia, Huntington's chorea, Parkinson's), complication in diabetes, ischemic or Ischemia-Reperfusion Injury, such as myocardial infarction and acute renal failure, circulation system disease, such as infectious shock, and diseases associated with inflammation, such as chronic rheumatism is (referring to 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.).
A series of patent application of phthalazines ketone PARP inhibitor, including WO2002036576, WO2004080976 and WO2006021801 have been disclosed at present.
Although oneself discloses the PARP inhibitor of a series for the treatment of tumour at present, still need exploitation it is new there is the compound of more preferable drug effect, medicine for result, by being continually striving to, present invention design has formula（I the compound of the structure shown in), and find that the compound with this class formation shows excellent effect and effect.The content of the invention
It is an object of the invention to provide a kind of formula（I phthalazines ketones derivant shown in), and their dynamic isomer, enantiomer, diastereomer, raceme and pharmaceutically useful salt, and metabolite and metabolic precursor thereof or prodrug.
( I )
Wherein：
A and B form cycloalkyl, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein the ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10RU> -OC(O)NR10Rn, -NHC(O)NR10Rn> -C(O)(CH2)mNR10RnOr-S (0)mR9Substituent replaced；
E
Wherein nl, n2 and n3 are respectively selected from 0,1,2 and 3, and nl, n2 and n3 summation are that 1,2 or 3, Q are selected from 0, S, NH or C (O);
R1Selected from hydrogen atom, alkyl, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl or heteroaryl； R2、 R3And R4It is each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, protective embankment base, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR1QRU、 -OC(O)NR10Ru -NHC(O)NR10Ru > -C OXCH mNR1^11Or-S (0)mR9, wherein described protective embankment base, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each individually optional to be further selected from halogen, hydroxyl, protective embankment base, alkoxy ,-C (0) OR by one or more9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10RU> -OC(O)NR10Ru, -NHC(O)NR10Rn, -C(O)(CH2)mNR10RnOr-S (0)mR9Substituent replaced；
R5And R6It is each independently selected from hydrogen atom, hydroxyl, protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -C(0)R9Or-QOXCH^NR^R11, further replaced wherein described protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional by one or more substituents selected from halogen, hydroxyl, protective embankment base or protective embankment epoxide, or R5And R6- rise form oxo；
R7And R8It is each independently selected from hydrogen atom, hydroxyl, alkyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10Rn> -OC(O)NR10Rn -NHC(O)NR10Rn, - OXCH^NI^R11Or-S (0)mR9, further replaced wherein described protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional by one or more substituents selected from halogen, hydroxyl, protective embankment base or alkoxy, or R7And R8- rise form oxo；
R9Selected from hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from by one or more independently of one another Protective embankment base, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-NR^R11、 -OC(O)NR10RuOr (C NR^R11Substituent replaced；
R1QOr R11Hydrogen atom, alkyl, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, alkoxy, ring protective embankment base, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more independently of one another12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)mNR13R14Or-S (0)mR12Substituent replaced；
Or, R1()And R11Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, 0 or 8 (0) in described heterocyclic radical1Hetero atom, and the heterocyclic radical is optionally further selected from hydroxyl, protective embankment base, haloalkyl, halogen, cyano group, alkoxy, ring protective embankment base, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13RI4、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)mNR13R14Or-S (0)mR12Substituent replaced, wherein protective embankment base, cycloalkyl, benzyl, heteroaryl are optionally further replaced by one or more substituents selected from alkyl, halo protective embankment base, halogen, hydroxyl, alkoxy, heteroaryl or ring protective embankment base independently of one another；
R12、 R13Or R14Hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another15、 -OC(0)R15、 -C(0)R15、 -NHC(0)R15、 -NR16R17、 -OC(0)NR16R17、 -NHC(0)NR16R17、 -C(0)(CH2)mNR16R17Or-S (0)mR15Substituent replaced；
R15、 R16Or R17Hydrogen atom, alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl or heteroaryl by one or more independently of one another；And
M is 0,1 or 2.
The preferred scheme of the present invention, a kind of formula（I) compound or its pharmaceutically useful salt, including the compound shown in a kind of logical formula (II) or its pharmaceutically useful salt：
( II )
Wherein: A and B form ring protective embankment base, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein the cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl plug, cyano group, nitro, protective embankment base, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10RU -OC(O)NR10RU , -NHC(O)NR10RU、 -C(O)(CH2)MNR10RNOr-S (0)MR9Substituent replaced；
R1Selected from hydrogen atom, alkyl, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl or heteroaryl； R2、 R3And R4It is each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10RN -OC(O)NR10RL L -NHC(O)NR10RN , -C(O)(CH2)MNR10RNOr-S (0)MR9, wherein described protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional to be further selected from halogen, hydroxyl, protective embankment base, protective embankment epoxide ,-C (0) OR by one or more9、 -OC(0)R9、 -C(0)R9. -NHC(0)R9. -NR10RU , -OC(O)NR10RU、 -NHC(O)NR10RN > -C(O)(CH2)MNR10RNOr-S (0)MR9Substituent replaced；
R5And R6It is each independently selected from hydrogen atom, hydroxyl, protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -C(0)R9Or (OXCH^NRWR11, further replaced wherein described protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional by one or more substituents selected from halogen, hydroxyl, alkyl or protective embankment epoxide, or R5And R6- rise form oxo；
R7And R8It is each independently selected from hydrogen atom, hydroxyl, protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10RN , -OC(O)NR10RU , -NHC(O)NR10RU , -C(0)(CH2)MNR1 QRUOr-S (0)MR9, further replaced wherein described alkyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional by one or more substituents selected from halogen, hydroxyl, protective embankment base or alkoxy, or R7And R8- rise form oxo；
R9Selected from hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from alkyl, halogen, hydroxyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-NR''.-OC^NR^R by one or more independently of one another1 1Or-C NRWR11Substituent replaced；
R1 QOr R11Hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, alkyl, halogen, cyano group, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more independently of one another12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)MNR13R14Or-S (0)MR12Substituent replaced；
Or, R1 QAnd R1 1Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, 0 or 8 (0) in described heterocyclic radical1Hetero atom, and the heterocyclic radical is optionally further selected from hydroxyl, protective embankment base, haloalkyl, halogen, cyano group, alkoxy, ring protective embankment base, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)mNR13R14Or-S (0)mR12Substituent replaced, wherein protective embankment base, ring protective embankment base, benzyl, heteroaryl are optionally further replaced by one or more substituents selected from alkyl, haloalkyl, halogen, hydroxyl, protective embankment epoxide, heteroaryl or ring protective embankment base independently of one another；
R12、 R'3Or R14Hydrogen atom, alkyl, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, alkyl, halogen, cyano group, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another15、 -OC(0)R15、 -C(0)R15、 -NHC(0)R15、 -NR16R17、 -OC(0)NR16R17、 -NHC(0)NR16R17、 -C(0)(CH2)mNR16R17Or-S (0)mR15Substituent replaced；
R15、 R16Or R17Hydrogen atom, protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, alkoxy, ring protective embankment base, heterocyclic radical, aryl or heteroaryl by one or more independently of one another；And
M is 0,1 or 2.
The preferred scheme of the present invention, a kind of formula（I compound or its pharmaceutically useful salt shown in), wherein described compound or its pharmaceutically useful salt, wherein R2For halogen.
The preferred scheme of the present invention, a kind of formula（I) compound or its pharmaceutically useful salt, including the compound shown in a kind of logical formula (III) or its pharmaceutically useful salt：
(ΠΙ)
Wherein：
A and B form ring protective embankment base, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein the cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, alkyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10RU、 -OC(O)NR10Rn, -NHC(O)NR10Rn, -C(O)(CH2)mNR10R11Or-S (0)mR9Substituent replaced；
R1Selected from hydrogen atom, alkyl, hydroxyl or alkoxy, ring protective embankment base, heterocyclic radical, aryl or heteroaryl； R3And R4It is each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR1QRU、 -OC(O)NR10Rn> -NHC(O)NR10Rn -C(O)(CH2)mNR10RnOr-S (0)mR9, wherein described protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional further by one or many It is individual to be selected from halogen, hydroxyl, protective embankment base, alkoxy ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10RU、 -OC(O)NR10Ru、 -NHC(O)NR10Rn -C(O)(CH2)mNR10RnOr-S (0)mR9Substituent replaced；
R5And R6It is each independently selected from hydrogen atom, hydroxyl, protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -C(0)R9Or-OXCH^NR^R11, further replaced wherein described protective embankment base, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each individually optional by one or more substituents selected from halogen, hydroxyl, protective embankment base or alkoxy, or R5And R6- rise form oxo；
R7And R8It is each independently selected from hydrogen atom, hydroxyl, alkyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10Rn > -OC(O)NR10Rn ^ -NHC(O)NR10Rn, - OXCH^NR1^11Or-S (0)mR9, further replaced wherein described alkyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional by one or more substituents selected from halogen, hydroxyl, protective embankment base or protective embankment epoxide, or R7And R8- rise form oxo；
R9Selected from hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from protective embankment base, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-NR by one or more independently of one another1QR"、 -(X C NR^R11Or-^NR^R11Substituent replaced；
R1()Or R11Hydrogen atom, protective embankment base, cycloalkyl, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, alkyl, halogen, cyano group, alkoxy, cycloalkyl, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more independently of one another12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(C¾)mNR13R14Or-S (0)mR12Substituent replaced；
Or, R1QAnd R11Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, 0 or 8 (0) in described heterocyclic radical1Hetero atom, and the heterocyclic radical is optionally further selected from hydroxyl, protective embankment base, halo protective embankment base, halogen, cyano group, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14, -C(OXC¾)mNR13R14Or-S (0)mR12Substituent replaced, wherein alkyl, cycloalkyl, benzyl, heteroaryl are optionally further replaced by one or more substituents selected from protective embankment base, halo protective embankment base, halogen, hydroxyl, alkoxy, heteroaryl or cycloalkyl independently of one another；
R12、 R13Or R14Hydrogen atom, protective embankment base, cycloalkyl, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, alkyl, halogen, cyano group, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another15、 -OC(0)R15、 -C(0)R15、 -NHC(0)R15、 -NR16R17、 -OC(0)NR16R17、 -NHC(0)NR16R17、 -C(0)(CH2)mNR16R17Or-S (0)mR15Substituent replaced；
R15、 R10Or R17It is each independently selected from hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl Base, wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl by one or more independently of one another；And '
M is 0,1 or 2;
The preferred scheme of the present invention, a kind of formula（I) compound or its pharmaceutically useful salt, wherein R3And R4It is each independently selected from hydrogen atom or halogen, R5、 RK R7And R8It is each independently selected from hydrogen atom or halogen.
The preferred scheme of the present invention, a kind of formula（III compound or its different pharmaceutically useful salt shown in), including a kind of formula（IV compound or its pharmaceutically useful salt shown in)：
(IV)
Wherein：
A and B form ring protective embankment base, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected；
R1Selected from hydrogen atom；
R3And R4It is each independently selected from hydrogen atom or halogen；
R1GOr R11Hydrogen atom, alkyl, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, alkyl, halogen, cyano group, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more independently of one another12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)mNR13R14Or-S (0)mR12Substituent replaced；
Or, R1()And R11Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, O or 8 (0) in described heterocyclic radical1Hetero atom, and the heterocyclic radical is optionally further selected from hydroxyl, protective embankment base, halo protective embankment base, halogen, cyano group, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(C¾)mNR13R14Or-S (0)mR12Substituent replaced, wherein protective embankment base, cycloalkyl, benzyl, heteroaryl are optionally further replaced by one or more substituents selected from protective embankment base, halo protective embankment base, halogen, hydroxyl, protective embankment epoxide, heteroaryl or ring protective embankment base independently of one another；
R12、 R13Or R14Hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another15、 -OC(0)R15、 -C(0)R15、 -NHC(0)R15、 -NR16R17、 -OC(0)NR16R17、 -NHC(0)NR16R17、 -C(0)(CH2)mNR16R17Or-S (0)mR15Substituent institute Substitution；
R15、 R16Or R17Hydrogen atom, alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, alkyl, halogen, cyano group, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl by one or more independently of one another；And
M is 0,1 or 2;
The preferred scheme of the present invention, a kind of formula（I compound or its pharmaceutically useful salt shown in), wherein A and B form aryl, preferably phenyl together with the carbon atom being connected.
The preferred scheme of the present invention, a kind of formula（I compound or its pharmaceutically useful salt, wherein R shown in)1For hydrogen atom.
The preferred scheme of the present invention, a kind of logical formula (III) or compound or its pharmaceutically useful salt, wherein R shown in (IV)1()And R11Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein described heterocyclic radical is optionally further by one or more-C (0) R12Substituent replaced.
The preferred scheme of the present invention, a kind of logical formula (III) or compound or its pharmaceutically useful salt shown in (IV), wherein：
R1QAnd R11Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein described heterocyclic radical is optionally further by one or more-C (0) R12Substituent replaced；
R12Selected from protective embankment base, ring protective embankment base or heterocyclic radical, wherein described protective embankment base, ring protective embankment base or heterocyclic radical are optionally further selected from halogen, protective embankment base or-NR by one or more16R17Substituent replaced.
Formula（I) compound can contain asymmetric carbon atom, therefore can exist or exist as mesomer compound using in the form of optically pure diastereomer, non-enantiomer mixture, diastereomer racemic modification, the mixture of diastereomeric racemic modification.The present invention includes all these forms.The mixture of non-enantiomer mixture, diastereomeric racemic modification or diastereomeric racemic modification can be separated by conventional method such as by column chromatography, thin-layered chromatography and efficient liquid phase.
The equivalent considered --- those skilled in the art will appreciate that being, the form of dynamic isomer also may be present in compound (I).Compound（I tautomeric form) may include but be not limited to the structure represented by lower formula (V)：
(V)
The typical compound of the present invention includes, but are not limited to：
Embodiment numbering structure and name
Formula is prepared the present invention relates to one kind（III the method for compound or its pharmaceutically useful salt shown in), this method includes：
(IHA) (m)
Formula (Π Ι Α) compound is optionally further hydrolyzed and formula NHR^R11Reaction, obtains logical formula (III) compound；Wherein A, B, R1 , R3〜！8、 R10、 RuAs defined in logical formula (III), and R18As defined in formula (III A).
The present invention relates to the compound shown in a kind of formula (Π Ι Α) or its pharmaceutically useful salt：
(ΙΠΑ)
Wherein-
Α and Β form ring protective embankment base, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein the ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10Rl l、 -OC(O)NR10Rn, -NHC(O)NR10Ru、 -C(O)(CH2)mNR10RnOr-S (0)mR9Substituent replaced；
R1Selected from hydrogen atom, alkyl, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl or heteroaryl； R3And R4It is each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10Rn, -OC(O)NR10Rn> -NHC(O)NR10Ru、 -C(O)(CH2)mNR10RuOr-S (0)mR9, wherein described alkyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional to be further selected from halogen, hydroxyl, protective embankment base, protective embankment epoxide ,-C (0) OR by one or more9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10RU > -OC(O)NR10R' -NHC(O)NR10Ru, -C(O)(CH2)mNR10RnOr-S (0)MR9Substituent replaced；
R5And R6It is each independently selected from hydrogen atom, hydroxyl, alkyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -C(0)R9 ¾-C(O)(CH2)mNR10Rn, further replaced wherein described protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional by one or more substituents selected from halogen, hydroxyl, protective embankment base or alkoxy, or R5And R6- rise form oxo；
R7And R8It is each independently selected from hydrogen atom, hydroxyl, alkyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10Rn ^ -OC(O)NR10Rn ^ -NHC(O)NR10Rn, - OXCH^NRWR11Or-S (0)mR9, further replaced wherein described protective embankment base, alkoxy, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional by one or more substituents selected from halogen, hydroxyl, alkyl or protective embankment epoxide, or R7And R8- rise form oxo；
R9Selected from hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl, wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-NR by one or more independently of one another10Ru, -OC(O)NR10R11Or-CiC NR ^R11Substituent replaced；
R1()Or R11Be each independently selected from hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl independently of one another optionally further by It is one or more to be selected from hydroxyl, protective embankment base, halogen, cyano group, alkoxy, ring protective embankment base, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)mNR13R14Or-S (0)mR12Substituent replaced；
Or, R1QAnd R11Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, 0 or 8 (0) in described heterocyclic radical1Hetero atom, and the heterocyclic radical is optionally further selected from hydroxyl, protective embankment base, halo protective embankment base, halogen, cyano group, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)mNR13R14Or-S (0)mR12Substituent replaced, wherein protective embankment base, cycloalkyl, benzyl, heteroaryl are optionally further replaced by one or more substituents selected from protective embankment base, haloalkyl, halogen, hydroxyl, protective embankment epoxide, heteroaryl or cycloalkyl independently of one another；
R12、 R13Or R14Hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, alkyl, halogen, cyano group, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another15、 -OC(0)R15、 -C(0)R15、 -NHC(0)R15、 -NR16R17、 -OC(0)NR16R17、 -NHC(0)NR16R17、 -C(0)(CH2)mNR16R17Or-S (0)mR15Substituent replaced；
R15、 R16Or R17Hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, alkyl, halogen, cyano group, alkoxy, ring protective embankment base, heterocyclic radical, aryl or heteroaryl by one or more independently of one another；
R18Selected from hydrogen atom or alkyl；And
M is 0,1 or 2.
The compound shown in formula (Π Ι Α) is prepared the present invention relates to one kind, the method for pharmaceutically useful salt or solvate, this method includes：
By general formula compound a through oxygen
General formula compound b is changed into general formula compound c; By general formula compound
(IIIA)
General formula compound d is changed into general formula compound (IIIA);
Wherein A, B, R1. R3〜！8, R18Such as formula（III) defined, X is halogen.
Another aspect of the present invention is related to formula（I) compound or its pharmaceutically useful salt, the purposes in the medicine for suppressing PARP is prepared.
Another aspect of the present invention is related to a kind of suppression PARP method, and this method includes giving the formula for needing the patient treated to contain effective therapeutic dose（I) compound or its pharmaceutically useful salt.
Another aspect of the present invention is related to formula（I compound or its pharmaceutically useful salt shown in), the purposes in preparation is as assistant agent in cancer treatment procedure or for making tumour cell become sensitive medicine to ionising radiation or chemotherapy.
Another aspect of the present invention is related in cancer treatment procedure as assistant agent or for making tumour cell become the formula of sensitive medicine to ionising radiation or chemotherapy（I compound or its pharmaceutically useful salt shown in).
Another aspect of the present invention is related to the formula as the medicine for suppressing PARP（I) compound or its is pharmaceutically useful
± foretell
Another aspect of the present invention is related to formula（I compound or its pharmaceutically useful salt shown in), purposes in the medicine for preparing treating cancer, wherein described cancer is breast cancer, oophoroma, cancer of pancreas, prostate cancer, liver cancer or colon cancer, wherein described medicine further its be selected from following Drug combination with treatment effective dose：Temozolomide (Timozuoan), adriamycin, taxol (Taxol, Paclitaxel), cis-platinum (Cisplatin；), carboplatin（Carboplatin), Dacarbazine（Dacarbazine), TPT（Topotecan), Irinotecan (Irinotecan), gemcitabine (Gemcitabine) standing grain Jie bevacizumabs (Bevacizumab).
Another aspect of the present invention is related to a kind of method for the treatment of cancer, and this method gives the formula for the effective therapeutic dose of patient for needing to treat（I compound or its pharmaceutically useful salt shown in), wherein described cancer is breast cancer, oophoroma, cancer of pancreas, prostate cancer, liver cancer or colon cancer, wherein described formula（I compound or its pharmaceutically useful salt Jin mono- Walk shown in) its be selected from following Drug combination with treatment effective dose：Temozolomide, Ah Mycin, taxol, cis-platinum, carboplatin, Dacarbazine, TPT, Irinotecan, gemcitabine or shellfish cut down antibody.
Another aspect of the present invention is related to the formula of the medicine as treating cancer（I compound or its pharmaceutically useful salt shown in), wherein described cancer is breast cancer, oophoroma, cancer of pancreas, prostate cancer, liver cancer or colon cancer, wherein described medicine further its be selected from following Drug combination with treatment effective dose：Temozolomide, adriamycin, taxol, cis-platinum, carboplatin, Dacarbazine, TPT, Irinotecan, gemcitabine or shellfish cut down antibody.
Further, another aspect of the present invention is related to a kind of pharmaceutical composition, and it contains the formula of the present invention for the treatment of effective dose（I compound shown in) or its pharmaceutically acceptable salt, and its pharmaceutically useful carrier or excipient.The pharmaceutical composition, as assistant agent or for making tumour cell become the medicine of sensitivity to ionising radiation or chemotherapy, or can be used as the medicine for the treatment of cancer as the medicine for suppressing PARP, or as in cancer treatment procedure.Purposes of the pharmaceutical composition in the medicine for suppressing PARP is prepared.Purposes of the pharmaceutical composition in preparation is as assistant agent in cancer treatment procedure or for making tumour cell become sensitive medicine to ionising radiation or chemotherapy.Purposes of the pharmaceutical composition in the medicine for preparing treating cancer, wherein described cancer is breast cancer, oophoroma, cancer of pancreas, prostate cancer, liver cancer or colon cancer, wherein described composition further its be selected from following Drug combination with treatment effective dose：Temozolomide, adriamycin, taxol, cis-platinum, carboplatin, Dacarbazine, TPT, Irinotecan, gemcitabine and day 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 implications.
" protective embankment base " refers to the aliphatic hydrocarbon group of saturation, includes the straight chain and branched group of 1 to 20 carbon atom.Preferably comprise the alkyl of 1 to 12 carbon atom,Non-limiting example includes methyl,Ethyl,N-propyl,Isopropyl,Normal-butyl,Isobutyl group,The tert-butyl group,Sec-butyl,N-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propyls, 2,2- dimethyl propyls,1- ethyl propyls,2- methyl butyls,3- methyl butyls,N-hexyl,1- Ethyl-2-Methyl propyl group, 1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2- dimethylbutyls, 1,3- dimethylbutyls,2- ethyl-butyls,2- methyl amyls,3- methyl amyls,4- methyl amyls, 2,3- dimethylbutyls,N-heptyl,2- methylhexyls,3- methylhexyls,4- methylhexyls,5- methylhexyls, 2,3- dimethyl amyl groups, 2,4- dimethyl amyl groups, 2,2- dimethyl amyl groups, 3,3- dimethyl amyl groups,2- ethyl pentyl groups,3- ethyl pentyl groups,N-octyl, 2,3- dimethylhexanyls, 2,4- dimethylhexanyls, 2,5- dimethylhexanyls, 2,2- dimethylhexanyls, 3,3- dimethylhexanyls, 4,4- dimethylhexanyls,2- ethylhexyls,3- ethylhexyls,4- ethylhexyls,2- methyl -2- ethyl pentyl groups,2- methyl -3- ethyl pentyl groups,N-nonyl,2- methyl -2- ethylhexyls,2- methyl -3- ethylhexyls, 2,2- diethyl amyl groups,Positive decyl, 3,3- diethylhexyls, 2,2- diethylhexyls,And its various branched chain isomers etc..Rudimentary protective embankment base more preferably containing 1 to 6 carbon atom, non-limiting example includes methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1,1- dimethyl propyls, 1,2- dimethyl propyls, 2,2- dimethyl propyls, 1- ethyl propyls, 2- methyl butyls, 3- methyl butyls, n-hexyl, 1- Ethyl-2-Methyls propyl group, 1,1,2- thmethylpropyls, 1,1- dimethylbutyls, 1,2- dimethylbutyls, 2,2-- Methyl butyl, 1,3- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2,3- dimethylbutyls etc..Alkyl can be substituted or unsubstituted, when substituted, substituent can be substituted on any workable tie point, preferably one or more following groups, independently selected from protective embankment base, ' alkenyl, alkynyl, alkoxy, protective embankment sulfenyl, protective embankment base amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, Heterocyclylalkyl, aryl, heteroaryl, ring protective embankment epoxide, heterocycle protective embankment epoxide, ring protective embankment sulfenyl, heterocycle protective embankment sulfenyl, oxo ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10Rn -OC(O)NR10Ru, -NHC(O)NR10Rn -C(O)(CH2)mNR10RnOr-S (0)mR9。
" cycloalkyl " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably cycloalkyl ring includes 3 to 10 carbon atoms.The non-limiting example of monocyclic ring protective embankment base includes cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, cyclohexadienyl, suberyl, cycloheptatriene base, cyclooctyl etc..Polycyclic ring protective embankment base includes the ring protective embankment base of loop coil, condensed ring and bridged ring." loop coil protective embankment base " refers to 5 to 20 yuan, it is monocyclic between share the polycyclic moiety of a carbon atom (title spiro-atom), these can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Loop coil protective embankment base is divided into by single loop coil protective embankment base, double loop coil protective embankment base bases or many loop coil protective embankment bases according to the number of shared spiro-atom between ring and ring, is preferably single spiro cycloalkyl group and double loop coil protective embankment bases.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 groups.Loop coil protective embankment embodiment is included
" condensed ring protective embankment base " refers to 5 to 20 yuan, the full carbon polycyclic moiety of each ring and shared a pair of the carbon atoms adjoined of other rings in system in system, wherein one or more rings can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic fused ring protective embankment base, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 yuan pairs can be divided into according to the number of composition ring.The non-limiting example of cycloalkyl is included
" bridged ring protective embankment base " refers to 5 to 20 yuan, and any two ring shares the full carbon polycyclic moiety of two carbon atoms being not directly connected, and these can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge ring alkyl, preferably bicyclic, three rings or Fourth Ring can be divided into according to the number of composition ring, bicyclic or three rings are more elected as.The non-limiting example of bridged ring protective embankment base is included
The ring protective embankment basic ring can be condensed on aryl, heteroaryl or heterocycle protective embankment basic ring, wherein being ring protective embankment base with the ring that precursor structure links together, non-limiting example includes indanyl, tetralyl, benzocyclohepta protective embankment base etc..Ring protective embankment base can be optionally substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from protective embankment base, alkenyl, alkynyl, alkoxy, protective embankment sulfenyl, protective embankment base amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, heterocycle protective embankment base, aryl, heteroaryl, ring protective embankment epoxide, heterocycle protective embankment epoxide, cycloalkylthio, heterocycle alkylthio group, oxo ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9> -NR10Rn> -OC^NR^R11, -NHC(O)NR10Rn. - OXCH mNR10!^1Or-S (0)mR9。
" heterocyclic radical " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, and it includes 3 to 20 annular atoms, and wherein one or more annular atoms are selected from nitrogen, oxygen or S (0)mThe hetero atom of (wherein m is integer 0 to 2), but do not include -0-0-, -0-S- or-S-S- loop section, remaining annular atom is carbon.3 to 12 annular atoms are preferably included, wherein 14 are hetero atoms, more preferably cycloalkyl ring includes 3 to 10 annular atoms.The non-limiting example of monocyclic cycloalkyl includes pyrroles's protective embankment base, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc..Polycyclic ring protective embankment base includes the heterocyclic radical of loop coil, condensed ring and bridged ring." spiro heterocyclic radical " refers to 5 to 20 yuan, it is monocyclic between share the polycyclic heterocyclic group of an atom (title spiro-atom), wherein one or more annular atoms are selected from nitrogen, oxygen or S (0)pThe hetero atom of (wherein p is integer 0 to 2), remaining annular atom is carbon.These can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Spiro cycloalkyl group is divided into by single spiro heterocyclic radical, double spiro heterocyclic radicals or many spiro heterocyclic radicals according to the number of shared spiro-atom between ring and ring, is preferably single loop coil protective embankment base and double loop coil protective embankment bases.More preferably 4 yuan/4 yuan, 4 yuan/5 yuan, 4 yuan/6 yuan, 5 yuan/5 yuan or 5 yuan/6 yuan single loop coil protective embankment bases.The non-limiting example of loop coil protective embankment base is included
" condensed hetero ring base " refers to 5 to 20 yuan, the polycyclic heterocyclic group of each ring and shared a pair of the atoms adjoined of other rings in system in system, one or more rings can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, wherein one or more annular atoms are selected from nitrogen, oxygen or S (0)pThe hetero atom of (wherein ρ is integer 0 to 2), remaining annular atom is carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic fused heterocycloalkyl, preferably bicyclic or three rings, more preferably 5 yuan/5 yuan or 5 yuan/6 membered bicyclic condensed hetero ring bases can be divided into according to the number of composition ring.The non-limiting example of condensed hetero ring base is included
" bridge heterocyclic radical " refers to 5 to 14 yuan, any two ring shares the polycyclic heterocyclic group of two atoms being not directly connected, these can contain one or more double bonds, but neither one ring has the pi-electron system of total conjugated, wherein one or more annular atoms are selected from nitrogen, oxygen or S (0)mThe hetero atom of (wherein m is integer 0 to 2), remaining annular atom is carbon.Preferably 6 to 14 yuan, more preferably 7 to 10 yuan.7 to 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic bridge ring alkyl, preferably bicyclic, three rings or Fourth Ring can be divided into according to the number of composition ring, more there is choosing
The heterocyclic ring can be condensed on aryl, heteroaryl or ring protective embankment basic ring, wherein be heterocyclic radical with the ring that precursor structure links together,
Deng.Heterocyclic radical can be optionally substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, protective embankment epoxide, protective embankment sulfenyl, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, heterocycle protective embankment base, aryl, heteroaryl, ring protective embankment epoxide, heterocycle protective embankment epoxide, ring protective embankment sulfenyl, heterocycle alkylthio group, oxo ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10Rn -OC(O)NR10Ru、 -NHC(O)NR10Rn -C OXCH inNRWR11Or-S (0)mR9。
" aryl " refers to that 6 to 14 yuan of full carbon are monocyclic or fused polycycle (rings for namely sharing adjacent carbon atoms pair) group, polycyclic (i.e. its ring for the carrying phase adjacency pair carbon atom) group of pi-electron system with conjugation, preferably 6 to 10 yuan, such as phenyl and naphthyl.The aryl rings can be condensed on heteroaryl, heterocyclic radical or cycloalkyl ring, wherein the ring linked together with precursor structure is aryl rings, non-limiting example is included：
Aryl can be substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from protective embankment base, alkenyl, alkynyl, protective embankment epoxide, alkylthio group, protective embankment base amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, heterocycle protective embankment base, aryl, heteroaryl, ring protective embankment epoxide, heterocycle protective embankment epoxide, ring protective embankment sulfenyl, heterocycle protective embankment sulfenyl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10Rn, -OC(O)NR10Rn -NHC(O)NRI0Ru - OXCH mNR^R11Or-S (0)mR9。
" heteroaryl " refers to comprising 1 to 4 hetero atom, and the heteroaromatic system of 5 to 14 annular atoms, wherein hetero atom include oxygen, sulphur and nitrogen.Preferably 5 to 10 yuan.It is 5 yuan or 6 yuan that heteroaryl, which is preferably, such as furyl, thienyl, pyridine radicals, pyrrole radicals, N- protective embankment bases pyrrole radicals, pyrimidine radicals, pyrazinyl, imidazole radicals, tetrazole radical.The heteroaryl ring can be condensed on aryl, heterocyclic radical or ring protective embankment basic ring, wherein linked together with precursor structure
Heteroaryl can be optionally substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from alkyl, alkenyl, alkynyl, protective embankment epoxide, protective embankment sulfenyl, protective embankment base amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, heterocycle protective embankment base, aryl, heteroaryl, ring protective embankment epoxide, heterocycle protective embankment epoxide, ring protective embankment sulfenyl, heterocycle protective embankment sulfenyl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10Rn , -OC(O)NR10Rn . -NHC(O)NR10Rn> -C OXCPt NR^R11Or-S (0)mR9。
" protective embankment epoxide " refers to-o- (institute's base) and-o- (unsubstituted cycloalkyl), and wherein protective embankment base is as defined above.Non-limiting example includes methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, cyclopentyloxy, cyclohexyloxy etc..Protective embankment epoxide can be optionally substituted or unsubstituted, when substituted, substituent is preferably one or more following groups, independently selected from for protective embankment base, alkenyl, alkynyl, protective embankment epoxide, protective embankment sulfenyl, protective embankment base amino, halogen, mercaptan, hydroxyl, nitro, cyano group, ring protective embankment base, heterocycle protective embankment base, aryl, heteroaryl, ring protective embankment epoxide, heterocycle protective embankment epoxide, ring protective embankment sulfenyl, heterocycle protective embankment sulfenyl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10Rn、 -OC(O)NR10R -NHC(0)NR,uRH,
-C(O)(CH2)mNR10RnOr-S (0)mR9。
" halo protective embankment base " refers to alkyl and replaced by one or more halogens.
" hydroxyl " refers to-OH groups.
" halogen " refers to fluorine, chlorine, bromine or iodine.
" amino " refers to-NH2。
" cyano group " refers to-CN. " nitro " refers to-N02。
" benzyl " refers to-CH2- phenyl.
" oxo " refers to=0.
" carboxylic acid " refers to a C (0) OH.
" carboxylate " refers to a C (0) (protective embankment base) or (ring protective embankment base).
" optional " or " optionally " mean ground described later event or environment can with but need not occur, the explanation includes the event or environment occurs or not spot occasion.For example, " heterocyclic group optionally replaced by protective embankment base " mean protective embankment base can with but necessarily exist, the explanation includes the situation that the situation that is replaced by protective embankment base of heterocyclic group and heterocyclic group are not replaced by protective embankment base.
" substitution " refers to one or more of group hydrogen atom, and preferably at most 5, more preferably 13 hydrogen atoms are replaced by the substituent of respective number independently of one another.Self-evident, substituent is only in their possible chemical position, and those skilled in the art can determine (by experiment or theoretical) possible or impossible substitution in the case where not paying excessively effort.For example, amino or hydroxyl with free hydrogen are probably unstable when being combined with the carbon atom with unsaturated (such as olefinic) key.
" pharmaceutical composition " is represented containing one or more compounds described herein or its physiologically/pharmaceutically useful salt or pro-drug and the mixture of other chemical constituents, and other components such as physiology/pharmaceutically useful carrier and excipient.The purpose of pharmaceutical composition is to promote the administration to organism, the absorption beneficial to active component and then performance bioactivity.
M and R9R " definition such as formula（I) described in compound.The synthetic method of the compounds of this invention
In order to complete the purpose of the present invention, the present invention is adopted the following technical scheme that：
Formula is prepared the present invention relates to one kind（III the method for compound or its pharmaceutically useful salt shown in), this method includes：
(HIA) (III)
Benzofuran compounds a is dissolved in Ν, Ν-dimethylformamide, POCl3 is added at low temperature, Reaction obtains aldehyde compound b under heating condition;
Under argon gas or nitrogen, compound b obtains halogenated compound c in the presence of acetic acid and sodium acetate with halogen reaction;Compound c in methyl alcohol with isobenzofuran -1- ketone and first ' after sodium alkoxide reaction, compound mountain or compound c are obtained with hydration hydrazine reaction rearrangement in tetrahydrofuran with adding isobenzofuran -1- ketone-phosphate to occur after wittig reactions, then obtain compound d with hydration hydrazine reaction rearrangement again;Optionally by compound d, acid chloride and 1, double (diphenylphosphine) third protective embankments of 3- are passed through carbon monoxide after being put into reaction bulb, and in the presence of triethylamine and ethanol, be dissolved in heating response in dimethyl sulfoxide (DMSO) and obtain ester group compound (Π Ι Α);(Ι Π Α) compound optionally further carries out ester hydrolysis into after carboxylic acid in hydroxide solution, carboxylic acid compound and formula NHR9R1QIt is reacted to and obtains (III) compound；Or compound d optionally occurs after lithium-halogen exchange in tetrahydrofuran with butyl lithium, then the formic acid of (IIIA) is obtained with dry carbon dioxide gas precursor reactant, in the basic conditions with formula NHRWR11It is reacted to and obtains (III) compound.
In wherein above-mentioned reaction, carboxylic acid compound and NHR9R1QReacted under conditions of alkalescence condition and condensation reagent are present, condensation reagent used is selected from N, N- dicyclohexylcarbodiimides, Ν, Ν-DIC, 0- BTAs-Ν, Ν, Ν ', Ν '-tetramethylurea tetrafluoro boric acid ester (TBTU), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimine etc., preferably 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimine；Alkalescence condition is provided by organic base or inorganic base, and organic base is selected from such as diisopropylethylamine, pyridine, triethylamine, hexahydropyridine, N methyl piperazine, DMAP, I-hydroxybenzotriazole, preferably triethylamine；Solvent for use is selected from mixture of toluene, benzene, dichloromethane protective embankment, tetrahydrofuran, DMF, chloroform or above-mentioned solvent composition etc., preferably Ν, Ν-dimethylformamide；Reaction temperature control arrives 100'C, preferably 0 °C to 60 at -80 °C;Reaction time general control was at 1 minute to 72 hours, preferably 15 minutes to 24 hours.
Wherein A, B, R R3〜R8、 R10、 R11As defined in logical formula (III), and R18As defined in formula (IIIA), X is halogen.Embodiment
It is used to further describe the present invention with reference to embodiments, but these embodiments not limit the scope of the present invention.Embodiment
The structure of compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrum (MS).NMR displacements (δ) are with 106(ppm) unit is provided.NMR measure uses Bruker AVANCE-400 nuclear magnetic resonance spectrometers, and measure solvent is deuterated dimethyl sulfoxide (DMSO-), deuterochloroform (CDC13), deuterated methanol (CD3OD), inside it is designated as tetramethylsilane protective embankment (TMS).
MS measure uses FINNIGAN LCQAd (ESI) mass spectrograph (manufacturer：Thermo, model： Finnigan LCQ advantage MAX).
The measure of efficient liquid phase (HPLC) uses Agilent 1200DAD high pressure liquid chromatographs (Sunfire C18 150x4.6mm chromatographic columns) and Waters 2695-2996 high pressure liquid chromatographs (Gimini C18 150<4.6mm chromatographic columns). IC50The measure of value NovoStar ELIASAs (German BMG companies）.
Tlc silica gel plate uses Yantai Huanghai Sea HSGF254 or Qingdao GF254 silica gel plates, the specification that silica gel plate that thin-layered chromatography (TLC) is used is used is the mm of 0.15 mm 0.2, and the specification that thin-layer chromatography isolates and purifies product use is the mm of 0.4 mm ~ 0.5.
Column chromatography is carrier typically using the mesh silica gel of the Yantai Huanghai Sea 200 ~ 300.
The known initiation material of the present invention can be used or synthesized according to methods known in the art, or it is commercially available from ABCR GmbH ＆ Co. KG, Acros Organics, Aldrich Chemical Company, splendid remote chemistry science and technology and up to companies such as auspicious chemicals.
Without specified otherwise in embodiment, reaction is carried out under argon atmospher or blanket of nitrogen.
Argon atmospher or blanket of nitrogen refer to that reaction bulb connects the argon gas or nitrogen balloon of an about 1L volume.
Hydrogenation is generally vacuumized, and is filled with hydrogen, is operated 3 times repeatedly.
Microwave reaction uses the type microwave reactors of CEM Discover-S 908860.
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 reaction temperature, is 20 °C 30 °C.
The monitoring of reaction process in embodiment uses thin-layered chromatography (TLC), there is the system of solvent used in reaction： A:Dichloromethane protective embankment and methanol system, B:Just own protective embankment and ethyl acetate system, C:Petroleum ether and ethyl acetate system, D:Acetone, the volume ratio of solvent is adjusted according to the polarity difference of compound.
The system of eluant, eluent and the solvent system of thin-layered chromatography for the column chromatography that purifying compound is used include： A:Dichloromethane and methanol system, B:N-hexane and ethyl acetate system, the volume ratio of solvent are different and be adjusted according to the polarity of compound, can also add the alkalescence such as a small amount of triethylamine and acetic acid or acid reagent is adjusted.Embodiment 1
The first step
2,3- Dihydrobenzofuranes -5- formaldehyde
Will 2,3- Dihydrobenzofuranes la (2 g, 16 mmol) stir under be dissolved in Ν, Ν-dimethylformamide (2.60 g, 35.20 mmol) in, under ice bath, POCl3 (5.20 g, 52 mmol) is added dropwise, 90 °C are reacted 7 hours, are cooled to room temperature, are poured into 20 mL frozen water, are stirred 12 hours.Extracted with toluene (15 mLx3), merge organic phase, washed (20 mL), anhydrous sodium sulfate drying, filtered with ^ and sodium bicarbonate solution (20 mL), saturated nacl aqueous solution successively, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 2,3- Dihydrobenzofuranes -5- formaldehyde lb (1.70 g, colorless oil), yield： 70.8%.
MS m/z (ESI): 149.1 [M+l]
Second step
Bromo- 2, the 3- Dihydrobenzofuranes -5- formaldehyde of 7-
It is dissolved under 2,3- Dihydrobenzofuranes -5- formaldehyde lb (1.70 g, 11.50 mmol) is stirred in 15 mL acetic acid, add sodium acetate (1.10 g, 13.80 mmol) and bromine (3.60 g, 23 mmol), react 2 hours.Add 50 mL saturated sodium bicarbonate solutions, it is extracted with ethyl acetate (50 mLx2), merge organic phase, wash (30 mL), anhydrous sodium sulfate drying with saturated sodium bicarbonate solution (50 mL), saturated nacl aqueous solution successively, filtering, filtrate decompression is concentrated, and obtains bromo- 2,3- Dihydrobenzofuranes -5- formaldehyde lc (2.50 g of title product 7-, yellow solid), yield： 96.2%.
MS m/z (ESI): 227.9 [M+l]
3rd step
2- (the bromo- 2,3- Dihydrobenzofuranes -5- bases of 7-) indane -1,3- diketone
18 mL ethyl propionates and methanol (V/V=4 are dissolved under bromo- 2, the 3- Dihydrobenzofuranes -5- formaldehyde lc of 7- (0.22 g, 1 mmol) are stirred:5) in the mixed solvent, adds 3H- isobenzofuran -1- ketone (0.13 g, 1 mmol), and the methanol solution of the sodium methoxides of 1 mL 25% is slowly added dropwise, and stirs 15 minutes, back flow reaction 2 hours.It is cooled to room temperature, 20 mL water are added, are washed with ether (20 mLx3), glacial acetic acid is added dropwise to there is red precipitate precipitation, filtering, solid is washed with water (30 mL), vacuum drying, obtains title product 2- (7- bromo- 2,3- Dihydrobenzofuranes -5- bases) indane -1,3- diketone Id (0.25 g, red solid), yield： 73.5%.
MS m/z (ESI): 344.7 [M+l]
4th step
4- [(7- bromo- 2,3- Dihydrobenzofuranes -5- bases) methyl] -2H- phthalazines -1- ketone is by 2- (7- bromo- 2,3- Dihydrobenzofuranes -5- bases) indane -1,3- diketone Id (250 mg, 0.73 mmol) stirring under be dissolved in 15 mL hydrazine hydrates, back flow reaction 3 hours.Filtering, filter cake is washed with water (20 mL), is dried in vacuo, obtain title product 4- [(7- bromo- 2,3- Dihydrobenzofuranes -5- bases) methyl] -2H- phthalazines -1- ketone 1 (200 mg, white solid), yield： 76.9%.
MS m/z (ESI): 358.7 [M+l]
1H NMR (400 MHz, DMSO-^):δ 12.56 (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- ylmethyls) -2H- phthalazines -1- ketone
By 4- [(7- bromo- 2,3- Dihydrobenzofuranes -5- bases) methyl] small (177 mg of ketone 1 of -2H- phthalazines, 0.50 mmol) stirring under be dissolved in 5 mL tetrahydrofurans, add tetramethylethylenediamine (116 mg, 1 mmol), -78 °C are cooled to, the just own protective embankment solution of the M n-BuLis of 0.6 mL 1.6 is added dropwise, is kept for -78 °C react 3 hours.Add 5 mL water, it is extracted with ethyl acetate (15 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain title product 4- (2,3- Dihydrobenzofuranes -5- ylmethyls) -2H- phthalazines -1- ketone 2 (85 mg, white solid), yield： 61.6%.
MS m/z (ESI): 279.1 [M+l]
1H NMR (400 MHz, CDC13):δ 10.50 (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
The first step
5- [(- 1-yl of 4- oxo-3H- phthalazines) methyl]-2, 3- Dihydrobenzofuranes -7- methyl formates are by 4- [(7- bromo- 2, 3- Dihydrobenzofuranes -5- bases) methyl] 1 (480 mg of -2H- phthalazines -1- ketone, 1.34 mmol), palladium (30 mg, 0.13 mmol) and 1, double (diphenylphosphine) third protective embankment (55 mg of 3-, 0.13 mmol) it is placed in dry reaction bulb, carbon monoxide is passed through after closed, add 10 mL and contain triethylamine (0.41 g, 4 mmol) and (0.13 g of first 11, 4 mmol) dimethyl sulfoxide (DMSO), 75 °C are reacted 24 hours.Add 15 mL water, (20 mLx5) is extracted with dichloromethane protective embankment, merge organic phase, wash (30 mLx2), anhydrous sodium sulfate drying with water (30 mL), saturated nacl aqueous solution successively, filtering, filtrate decompression is concentrated, and obtains title product 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- methyl formates 3a (200 mg, white solid), yield： 44.4%
MS m/z (ESI): 337.1 [M+l] Second step
5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- formic acid is by 5- [(the small base of 4- oxo -3H- phthalazines) methyl] -2,60 mL tetrahydrofurans and water (V/V=1 are dissolved under 3- Dihydrobenzofuranes -7- methyl formates 3a (950 mg, 2.8 mmol) stirrings:1) in the mixed solvent, adds lithium hydroxide (600 mg, 14 mmol), reacts 12 hours.30 mL water are added, (30 mL are washed with ethyl acetate<2), be added dropwise 1 M hydrochloric acid to aqueous phase pH be 5, filtering, solid is collected, aqueous phase is extracted with ethyl acetate (30 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, gained solid 6 mL methanol and ether (V/V=1:5) mixed solvent washing, combining solid obtains title product 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- formic acid 3b (750 mg, pale solid), yield： 82.4%. MS m/z (ESI): 323.1 [M+l]
3rd step
4- [[7- (4- methyl piperazine -1- carbonyls) -2, 3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone is by 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (65 mg, 0.20 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sequentially add 4- methyl piperazines (24 mg, 0.24 mmol), I-hydroxybenzotriazole (30 mg, 0.22 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (57 mg, 0.30 mmol) and triethylamine (60 mg, 0.60 mmol), reaction 12 hours.Add 10 mL water, it is extracted with ethyl acetate (20 mLx2), merge organic phase, washed with saturated nacl aqueous solution (15 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- (4- methyl piperazine -1- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 3 (20 mg, white solid), yield： 24.7%.
MS m/z (ESI): 405.2 [M+l]
1H NMR (400 MHz, CDC13):δ 10.03 (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
The first step
4-[5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- formic acid tertiary fourth tenth of the twelve Earthly Branches I By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- formic acid 3b (250 mg, 0.78 mmol) stirring under be dissolved in 10 mL N, in dinethylformamide, sequentially add piperazine -1- t-butyl formates (170 mg, 0.93 mmol), 1 hydroxybenzotriazole (120 mg, 0.85 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (220 mg, 1.16 mmol) and triethylamine (240 mg, 2.33 mmol), react 12 hours.Add 20 mL water, it is extracted with ethyl acetate (20 mLx3), merge organic phase, (20 mLx2), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression Nong Shrink, obtain title product 4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- t-butyl formates 4a (300 mg, white solid), yield： 78.9%.
MS m/z (ESI): 982.4 [2M+1]
Second step
4- [[7- (piperazine -1- carbonyls) -2,3- Dihydrobenzofuranes -5- bases) methyl] -2H- phthalazines -1- ketone is by 4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- t-butyl formates 4a (300 mg, 0.60 mmol) stirring under be dissolved in 20 mL methanol, the methanol solution of the M hydrogen chloride of 5 mL 1 is added, is reacted 12 hours.It is concentrated under reduced pressure, 20 mL water are added, it is 10 that 2 M sodium hydroxide solutions, which are added dropwise, to reaction solution pH, is extracted with ethyl acetate (30 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain title product 4- [[7- (piperazine -1- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 4 (150 mg, white solid), yield： 63.0%.
MS m/z (ESI): 391.2 [M+l]
1H NMR (400 MHz, CDC13):δ 10.59 (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- furans -5- bases] methyl] -2H- phthalazines -1- ketone
The first step
Cyclopropyl (piperazine -1- bases) ketone
Under ice bath, piperazine 5a (5 g, 58 mmol) is stirred 70 mL acetic acid are dissolved under dissolving, stirred 30 minutes, Cyclopropyl carbonyl chloride (5.9 mL, 63.80 mmol) is added dropwise, reacted 8 hours.Filtering, filtrate decompression concentration, adds 55 mL toluene, is concentrated under reduced pressure, is repeated 3 times, obtain title product cyclopropyl (piperazine -1- bases) ketone 5b (8.20 G, colorless oil), yield： 75.0%.
Second step
4- [[7- [4- (cyclopropyl carbonyl) piperazine -1- carbonyls] -2, 3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone is by 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (100 mg, 0.30 mmol) stirring under be dissolved in 5 mL Ν, in Ν-dimethylformamide, sequentially add cyclopropyl (piperazine -1- bases) ketone 5b (72 mg, 0.46 mmol), I-hydroxybenzotriazole (46 mg, 0.34 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (89 mg, 0.46 mmol) and triethylamine (94 mg, 0.90 mmol), reaction 12 hours.Add 20 mL water, it is extracted with ethyl acetate (20 mLx2), merge organic phase, washed with saturated nacl aqueous solution (20 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- (cyclopropyl carbonyl) piperazine -1- Few yls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 5 (75 mg, white solid), yield： 52.8%.
MS m/z (ESI): 459.2 [M+l]
1H NMR (400 MHz, CDC13):δ 9.98 (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- (l- amino cyclopentyl alkyl carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines
The first step
The protective embankment base formic acid of 1- (tertbutyloxycarbonylamino) ring penta
By 1- amino cyclopentyl protective embankment base formic acid 6a (1.30 g, 10 mmol) it is dissolved in Isosorbide-5-Nitrae-dioxane solution of the M sodium hydroxides of 10 mL 1 under stirring, add di-tert-butyl dicarbonate (2.20 g, 10 mmol), react 5 hours.It is concentrated under reduced pressure, add 15 mL water, washed with ethyl acetate (25 mLx2), be added dropwise 1 M hydrochloric acid to aqueous phase pH be 2, it is extracted with ethyl acetate (30 mLx3), merge organic phase, washed with saturated nacl aqueous solution (30 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains protective embankment base formic acid 6b (2 g of title product 1- (tertbutyloxycarbonylamino) ring penta, white solid), yield： 87.0%.
MS m/z (ESI): 228.1 [M-l] Second step
N- [l- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] the small carbonyl of piperazine] pentamethylene base] t-butyl carbamate
By 4- [[7- (piperazine -1- carbonyls) -2, 3- Dihydrobenzofuranes -5- bases] methyl] small (80 mg of ketone 4 of -2H- phthalazines, 0.20 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sequentially add protective embankment base formic acid 6b (56 mg of 1- (tertbutyloxycarbonylamino) ring penta, 0.25 mmol), I-hydroxybenzotriazole (30 mg, 0.22 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (59 mg, 0.30 mmol) and triethylamine (62 mg, 0.60 mmol), reaction 12 hours.Add 15 mL water, it is extracted with ethyl acetate (30 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain title product N- [l- [4- [5- [(the small base of 4- oxo -3H- phthalazines) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] the small carbonyl of piperazine] pentamethylene base] t-butyl carbamate 6c (100 mg, colorless oil), yield： 83.3 %.
MS m/z (ESI): 502.3 [M-100+1]
3rd step
4- [[7- [4- (l- amino cyclopentyl protective embankment bases carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines
- 1- ketone
By N- [l- [4- [5- [(4- oxo -3H- phthalazines -1- bases）Methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] penta protective embankment base of ring] t-butyl carbamate 6c (100 mg, 0.17 mmol) stirring under be dissolved in 10 mL methanol, add the M hydrogen chloride of 5 mL 1 methanol solution, react 12 hours.It is concentrated under reduced pressure, obtain title product 4- [[7- [4- (1- amino cyclopentyl protective embankment bases carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 6 (70 mg, colorless oil), yield： 84.3 %.
MS m/z (ESI): 502.2 [M+l]
1H NMR (400 MHz, CDC13):δ 12.57 (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- (thio -4- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, it is dissolved under 3- Dihydrobenzofuranes -7- formic acid 3b (100 mg, 0.30 mmol) stirrings in 5 mL DMFs, sequentially add thiomorpholine (380 mg, 0.37 Mmol), I-hydroxybenzotriazole (63 mg, 0.47 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (89 mg, 0.47 mmol) and triethylamine (94 mg, 0.93 mmol), react 12 hours.Add 20 mL water, it is extracted with ethyl acetate (20 mLx2), merge organic phase, washed with saturated nacl aqueous solution (20 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- (thiomorpholine -4- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 7 (30 mg, white solid), yield： 23.1 %.
MS m/z (ESI): 408.1 [M+l]
1H NMR (400 MHz, OMSO-d6):δ 12.57 (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 acids, 4- Diazesuberane -1- carbonyls) -2,3- Dihydrobenzofuranes-yl] methyl] -2H- phthalazines is small
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (80 mg, 0.25 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sequentially add 4- methyl isophthalic acids, 4- Diazesuberanes (34 mg, 0.30 mmol), I-hydroxybenzotriazole (37 mg, 0.27 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (71 mg, 0.37 mmol) and triethylamine (75 mg, 0.75 mmol), reaction 12 hours.Add 20 mL water, it is extracted with ethyl acetate (20 mLx2), merge organic phase, washed with saturated nacl aqueous solution (20 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain (20 mg of title product 4- [[7- (4- methyl isophthalic acids, 4- diaza cycloheptyl protective embankment -1- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 8, white solid), yield： 19.2 %.
MS m/z (ESI): 419.2 [M+l]
1H NMR (400 MHz, DMSO-¾):δ 12.57 (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- methylpyrrole protective embankment -2- carbonyls) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines
The first step
2- methylpyrroles protective embankment -1, the 2-01- tert-butyl groups, 02- ethyls-dicarboxylic acid esters are by 2- methylpyrrole protective embankment -1,2-01- benzyls, 02- ethyls-dicarboxylic acid esters 9a (2.90 g, 10 tnmol) stirring under be dissolved in 30 mL ethanol, add palladium dydroxide (0.14 g, 1 mmol) and di-tert-butyl dicarbonate (3.30 g, 15 mmol), hydrogen is replaced three times, is reacted 12 hours.It is concentrated under reduced pressure, 40 mL dichloromethane are added, are filtered, filtrate is washed (40 mL) with water (40 mL), saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude title product 2- methylpyrrolidin- 1, the 2-01- tert-butyl groups, 02- ethyls-dicarboxylic acid esters 9b (2.50 g, yellow oil), product is not purified directly to carry 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 2-01- tert-butyl groups are dissolved in 25 mL second alcohol and waters (V/V=4 under 02- ethyls-dicarboxylic acid esters 9b (2.50 g, 10 mmol) stirring:1) in the mixed solvent, adds potassium hydroxide (2.80 g, 5 mmol), reacts 2 hours.It is concentrated under reduced pressure, add 20 mL water, it is 5 that 1 M hydrochloric acid, which is added dropwise, to reaction solution pH, is extracted with ethyl acetate (30 mLx2), merges organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude title product 1- tertbutyloxycarbonyl -2- methyl-B ratios and coughs up protective embankment -2- formic acid 9c (2.20 g, white solid), product is not purified directly to carry out next step reaction.
3rd step
2- methyl -2- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] pyrrolidines -1- t-butyl formates
By 4- [[7- (piperazine -1- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 4 (85 mg,
0.22 mmol) stirring under be dissolved in 5 mL DMFs, sequentially add crude product 1- tertbutyloxycarbonyls - 2- methyl-pyrrol protective embankment -2- formic acid 9c (60 mg, 0.26 mmol), I-hydroxybenzotriazole (44 mg, 0.33 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (63 mg, 0.33 mmol) and triethylamine (66 mg, 0.65 mmol), react 12 hours.20 mL water are added, (20 mL are extracted with ethyl acetate><2), merge organic phase, washed with saturated nacl aqueous solution (20 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain title product 2- methyl -2- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] pyrroles protective embankment -1- t-butyl formates 9d (100 mg, colorless oil), yield： 76.9%. MS m/z (ESI): 602.3 [M+l]
4th step
4- [[7- [4- (2- methylpyrrolidin- 2- carbonyls) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines
- 1- ketone
By 2- methyl -2- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] pyrroles protective embankment -1- t-butyl formates 9d (100 mg, 0.17 mmol) stirring under be dissolved in 7 mL methanol, the methanol solution of 3 mL l M hydrogen chloride is added, is reacted 12 hours.It is concentrated under reduced pressure, add 20 mL water, be added dropwise 2 M sodium hydroxide solutions to reaction solution ρ Η be 10, it is extracted with ethyl acetate (30 mLx5), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain (20 mg of title product 4- [[7- [4- (2- methylpyrrole protective embankment -2- carbonyls) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 9, white solid), yield： 24.1 %.
MS m/z (ESI): 502.2 [M+l]
1H NMR (400 MHz, OMSO-d6):δ 12.58 (s, IH), 8.24-8.26 (m, 1H), 7.82-7.98 (m, 3H), 7.24 (s, IH), 7.06 (s, IH), 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, IH), 2.66-2.68 (m, IH), 2.15-2.18 (m, 2H), 1.56-1.59 (m, 2H), 1.27 (s, 3H) embodiment 10
4- [[7- (- 1- ketone
The first step
4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] -1,4- diaza cycloheptyl protective embankment -1- t-butyl formates By 5- [(- 1-yl of 4- oxo-3H- phthalazines) methyl]-2, 3- Dihydrobenzofuranes -7- formic acid 3b (80 mg, 0.25 mmol) stirring under be dissolved in 5 mL Ν, in Ν-dimethylformamide, sequentially add 1, 4- diaza cycloheptyl protective embankment -1- t-butyl formates (60 mg, 0.30 mmol), 1- hydroxy benzenes man's cap used in ancient times triazoles (50 mg, 0.37 mmol), 1-ethyl-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (60 mg, 0.30 mmol) and triethylamine (75 mg, 0.75 mmol), reaction 12 hours.20 mL water are added, (20 mL are extracted with ethyl acetate><2), merge organic phase, washed (20 mL), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, obtain title product 4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] -1,4- diaza cycloheptyl protective embankment -1- t-butyl formates 10a (90 mg, white solid), yield： 72.0 %.
MS m/z (ESI): 527.2 [M+23]
Second step
4- [[7- (l, 4- diaza cycloheptyl protective embankment -1- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone is by 4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] -1,4- diaza cycloheptyl protective embankment -1- t-butyl formates 10a (90 mg, 0.18 mmol) stirring under be dissolved in 10 mL methanol, the methanol solution of the M hydrogen chloride of 3 mL 1 is added, is reacted 12 hours.It is concentrated under reduced pressure, add 20 mL water, be added dropwise 2 M sodium hydroxide solutions to reaction solution pH be 10, it is extracted with ethyl acetate (30 mLx5), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 4- [[7- (1,4- diaza cycloheptyl protective embankment -1- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 10 (20 mg, white solid), yield： 27.8 %.
MS m/z (ESI): 405.2 [M+l]
lH NMR (400 MHz, DMSO-i/6):δ 12.58 (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- (the protective embankment base carbonyl of l- methylaminos ring penta) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H-
By 4- [[7- [4- (1- amino cyclopentyl alkyl carbonyl) piperazine-1-carbonyl]-2,3- Dihydrobenzofuranes-5- bases] methyl] small (100 mg of ketone 6 of-2H- phthalazines, 0.20 mmol) stirring under be dissolved in 10 mL methanol, add 37% first Aldehyde solution (6 mg, 0.20 mmol), back flow reaction 20 minutes adds sodium borohydride (15 mg, 0.40 mmol), back flow reaction 2 hours.Add 20 mL water, it is extracted with ethyl acetate (20 mLx2), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- [[7- [4- (the protective embankment base carbonyl of 1- methylaminos ring penta) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] small ketone ll (30 mg of -2H- phthalazines, white solid), yield： 29.1 %.
MS m/z (ESI): 516.2 [M+l]
1H NMR (400 MHz, OMSO-d6):δ 12.57 (s, IH), 8.24-8.26 (m, IH), 7.80-7.98 (m, 3H), 7.24 (s, IH), 7.06 (s, IH), 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, IH), 1.56-1.59 (m, 5H), 1.42-1.44 (m, 3H) embodiment 12
4- [[7- (l, l- dioxo -1,-thiomorpholine -4- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1-
By 4- [[7- (thiomorpholine -4- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] 7 (40 mg of -2H- phthalazines -1- ketone, 0.10 mmol) stirring under be dissolved in 5 mL methanol, add 2 mL Oxone reagents (72 mg, 0.12 mmol) the aqueous solution, 40 °C react 48 hours.It is cooled to 0 °C, be added dropwise 2 M sodium hydroxide solutions to reaction solution pH be 12, filtering, filter cake is washed (20 mL) with methanol, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- (1,1- dioxos -1,4- thiomorpholine -4- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 12 (15 mg, white solid), yield： 35.0 %.
MS m/z (ESI): 440.1 [M+l]
1H NMR (400 MHz, DMSO-i 6):δ 12.58 (s, IH), 8.26-8.24 (d, IH), 7.97-7.95 (d, IH), 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- benzyls-l, 3,3a, 4,6,6a- hexahydropyrrolos simultaneously [3,4-c] pyrroles -2- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (50 mg, 0.16 mmol) stirring under be dissolved in 5 mL Ν, in Ν-dimethylformamide, sequentially add 5- benzyls -2, 3, 3a, 4, 6, 6a- hexahydro -1H- pyrrolo-es [3, 4-c] pyrroles (35 mg, 0.17 mmol), I-hydroxybenzotriazole (32 mg, 0.24 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (46 mg, 0.24 mmol) and triethylamine (32 mg, 0.32 mmol), reaction 12 hours.It is concentrated under reduced pressure, gained residue is purified with solvent system A with thin-layered chromatography, title product 4- [[7- (5- benzyls-l, 3 is obtained, 3a, 4,6,6a- hexahydropyrrolos simultaneously [3,4-c] pyrroles -2- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 13 (14 mg, white solid), yield： 17.0%.
MS m/z (ESI): 507.2 [M+l]
1H NMR (400 MHz, CD3OD):δ 8.35-8.33 (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- (morpholines-- phthalazines -1- ketone
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- formic acid 3b (60 mg, 0.19 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sequentially add morpholine (19 mg, 0.22 mmol), I-hydroxybenzotriazole (38 mg, 0.28 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (54 mg, 0.28 mmol) and triethylamine (56 mg, 0.56 mmol), react 12 hours.20 mL water are added, are extracted with ethyl acetate (20 mLx2), merge organic phase, washed (20 mL), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system A purify gained remnants Thing, obtains title product 4- [[7- (morpholine -4- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 14 (60 mg, white solid), yield： 82.2%.
MS m/z (ESI): 392.1 [M+1] '
1H NMR (400 MHz, DMSO- 6):δ 12.57 (s, IH), 8.24-8.26 (m, IH), 7.81-7.98 (m, 3H), 7.24 (s, IH), 7.05 (s, IH), 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- piperazine -1- ketone
The first step
4- isopropyl piperazine -1- t-butyl formates
It is dissolved under piperazine -1- t-butyl formates 15a (1 g, 5.40 mmol) is stirred in 15 mL dichloromethane protective embankments, sequentially adds acetone (0.5 mL, 6.60 mmol)>Acetic acid (0.3 mL, 5.20 mmol) and sodium triacetoxy borohydride (1.70 g, 8.10 mmol), react 12 hours.Be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 4- isopropyl piperazine -1- t-butyl formates 15b (0.60 g, light yellow liquid), yield： 48.8 %.
MS m/z (ESI): 229.2 [M+1]
Second step
1- isopropyl piperazines
It is dissolved under 4- isopropyl piperazine -1- t-butyl formates 15b (150 mg, 0.66 mmol) are stirred in 10 mL methanol, adds the methanol solution of 3 mL l M hydrogen chloride, is reacted 12 hours.It is concentrated under reduced pressure, add 20 mL water, it is 10 that 2 M sodium hydroxide solutions, which are added dropwise, to reaction solution ρ Η, is extracted with ethyl acetate (30 mLx5), merges organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains title product 1- isopropyl piperazine 15c (60 mg, colorless oil), yield： 71.4%.
MS m/z (ESI): 129.1 [M+1]
3rd step
4- [[7- (4- isopropyl piperazine -1- carbonyls) -2,3- Dihydrobenzofuranes -5- bases) methyl] -2H- phthalazines -1- ketone is by 5- [(the small base of 4- oxo -3H- phthalazines) methyl] -2,3- Dihydrobenzofuranes -7- formic acid 3b (125 mg, 0.39 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, 1- isopropyl piperazines 15c (60 is sequentially added Mg, 0.47 mmol), I-hydroxybenzotriazole (79 mg, 0.59 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (112 mg, 0.59 mmol) and triethylamine (118 mg, 1.17 mmol), react 12 hours.Add 20 mL water, it is extracted with ethyl acetate (20 mLx2), merge organic phase, washed with saturated nacl aqueous solution (20 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- [[7- (4- isopropyl piperazine -1- carbonyls) -2,3- Dihydrobenzofuranes -5- bases) methyl] -2H- phthalazines -1- ketone 15 (80 mg, white solid), yield： 47.3 %.
MS m/z (ESI): 433.2 [M+l]
1H NMR (400 MHz, OMSO-d6):δ 12.57 (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- dimethylaminos] -2H- phthalazines -1- ketone
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- formic acid 3b (80 mg, 0.25 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sequentially add Ν, Ν-lupetidine -4- amine (35 mg, 0.27 mmol), I-hydroxybenzotriazole (50 mg, 0.57 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (71 mg, 0.37 mmol) and triethylamine (76 mg, 0.75 mmol), react 12 hours.It is concentrated under reduced pressure, add 10 mL saturated sodium bicarbonate solutions, (10 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, washed with saturated nacl aqueous solution (20 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, gained residue is purified with solvent system A with thin-layered chromatography, (80 mg of title product 4- [[7- (4- dimethylaminopyridine -1- carbonyls) -2,3- Dihydrobenzofuranes -5- bases) methyl] -2H- phthalazines -1- ketone 16 are obtained, white solid), yield： 74.5 %.
MS m/z (ESI): 433.2 [M+l]
1H NMR (400 MHz, CDC13):δ 10.33 (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- methylsulfonyls] -2H- phthalazines -1- ketone
By 4- [[7- (piperazine -1- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] 4 (60 mg of -2H- phthalazines -1- ketone, 0.16 mmol) stirring under be dissolved in 10 mL dichloromethane protective embankments, add triethylamine (23 mg, 0.23 mmol), under 0 °C, mesyl chloride (21 mg are added dropwise, 0.19 mmol), 0 °C is reacted 1 hour.Add 20 mL dichloromethane protective embankments; washed (20 mL) with water (20 mL), saturated nacl aqueous solution successively; anhydrous sodium sulfate drying; filtering; filtrate decompression is concentrated; with silica gel column chromatography with eluant, eluent system A purify gained residue; obtain title product 4- [[7- (4- Nmethanesulphonylpiperazine -1- carbonyls) -2; 3- Dihydrobenzofuranes -5- bases] methyl] 17 (15 mg of -2H- phthalazines -1- ketone; white solid), yield： 20.8%.
MS m/z (ESI): 469.1 [M+l]
1H NMR (400 MHz, DMSO-^):δ 12.59 (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- [hexahydro-IH- cyclopentanos [c] pyrroles -2- carbonyls of 5- (benzyl (methyl) amino) -3,3a, 4,5,6,6a-] -2,3- dihydrobenzenes
The first step
5- (benzylamino) -3,3a, 4,5,6,6a- hexahydro -1H- cyclopentanos [c] pyrroles's -2- t-butyl formates
By 5- oxos-l, 3,3a, 4,6,6a- hexahydro cyclopentano [c] pyrroles -2- t-butyl formates 18a (0.20 g, 0.89 Mmol it is dissolved under) stirring in 15 mL acetonitriles, adds benzylamine (0.1 mL, 0.89 mmol), stirred 20 minutes, add sodium triacetoxy borohydride (0.24 g, 1.16 mmol), is reacted 12 hours.It is concentrated under reduced pressure, adds 20 mL dichloromethane protective embankments, washed with saturated sodium bicarbonate solution (20 mL), anhydrous sodium sulfate does Delicate, filtering, filtrate decompression concentration, obtain crude title product 5- (benzylamino) -3,3a, 4,5,6,6a- hexahydro -1H- cyclopentanos [c] pyrroles's -2- t-butyl formates 18b (0.28 g, khaki grease), product is not purified directly to carry out next step reaction.
Second step
5- (benzyl (methyl) amino) -3,3a, 4,5,6,6a- hexahydro -1H- cyclopentanos [c] pyrroles -2- t-butyl formates are by crude product 5- (benzylamino) -3,3a, 4,5,6,6a- hexahydro -1H- cyclopentanos [c] pyrroles -2- t-butyl formates 18b (280 mg, 0.89 mmol) stirring under be dissolved in 8 mL methanol, add 37% formalin (0.3 mL, 2.67 mmol), stirring 30 minutes, sodium triacetoxy borohydride (750 mg, 3.56 mmol) is added under ice bath, is reacted 12 hours.It is concentrated under reduced pressure, add 20 mL dichloromethane, washed with saturated sodium bicarbonate solution (20 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 5- (benzyl (methyl) amino) -3,3a, 4,5,6,6a- hexahydro -1H- cyclopentanos [c] pyrroles -2- t-butyl formates 18c (250 mg, khaki grease), yield： 85.0%.
MS m/z (ESI): 331.2 [M+1]
3rd step
N- Benzyl-N-methyls-l, 2,3,3a, 4,5,6,6a- octahydro cyclopentano [c] pyrroles -5- amine are by 5- (benzyl (methyl) amino) -3,3a, 4,5,6,6a- hexahydro -1H- cyclopentanos [c] pyrroles -2- t-butyl formates 18c (250 mg, 0.76 mmol) stirring under be dissolved in 10 mL methanol, add the M hydrogen chloride of 3 mL 1 methanol solution, react 12 hours.It is concentrated under reduced pressure, adds 20 mL water, 2 M sodium hydroxide solutions of dropwise addition to reaction solution pH is 10, it is extracted with ethyl acetate (30 mLx5), merges organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains title product N- Benzyl-N-methyls-l, 2,3,3a, 4,5,6,6a- octahydros cyclopentano [c] pyrroles's -5- amine 18d (130 mg, pale solid), yield： 74.7%.
MS m/z (ESI): 231.1 [M+1]
4th step
4- [[7- [hexahydro -1H- cyclopentanos [c] pyrroles -2- carbonyls of 5- (benzyl (methyl) amino) -3,3a, 4,5,6,6a-] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (152 mg, 0.47 mmol) stirring under be dissolved in 5 mL Ν, in Ν-dimethylformamide, sequentially add Ν-benzyl-Ν-methyl-l, 2, 3, 3a, 4, 5, 6, 6a- octahydros cyclopentano [c] pyrroles -5- amine 18d (130 mg, 0.57 mmol), I-hydroxybenzotriazole (95 mg, 0.71 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (135 mg, 0.71 mmol) and triethylamine (142 mg, 1.42 mmol), reaction 12 hours.Add 20 mL water, it is extracted with ethyl acetate (20 mLx2), merge organic phase, washed with saturated nacl aqueous solution (20 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- [[7- [5- (benzyl (methyl) amino) -3, 3a, 4, 5, 6, 6a- hexahydro -1H- cyclopentanos [c] pyrroles -2- carbonyls] -2, 3- Dihydrobenzofuranes -5- bases] methyl] small (150 mg of ketone 18 of -2H- phthalazines, white solid), yield： 59.5 %. Father-in-law: ϊΜ^ζ-[¾ώ[ -ς,¥ϋ^*¾:-ε'ε-[¾1Η-¾ι¾ι(¾7-¾ώ-ι-¾¾ΗΗ^ ]]^
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The first step
Piperidine-4-ethyl formate
It is dissolved under piperidines -4- formic acid 20a (10 g, 80 mmol) is stirred in 100 mL ethanol, thionyl chloride (11 g, 96 mmol), back flow reaction 3 hours is added dropwise under ice bath.It is concentrated under reduced pressure, obtains title product piperidine-4-ethyl formate 20b (13 g, white solid), yield： 83.0%.
Second step
Piperidines-Isosorbide-5-Nitrae -01- benzyls, 04- ethyls-dicarboxylic acid esters
By piperidine-4-ethyl formate 20b (13 g, 80 mmol) stirring under be dissolved in 100 mL chloroforms, triethylamine (24 g are added dropwise, 240 mmol), stirring 10 minutes, benzyl chloroformate (16 g, 96 mmol) is added dropwise under ice bath, reacts at room temperature 12 hours.Successively with 1 M hydrochloric acid (100 mL), saturated sodium bicarbonate solution (100 mL), water washing (100 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain crude title piperidines-Isosorbide-5-Nitrae -01- benzyls, 04- ethyls-dicarboxylic acid esters 20c (24 g, khaki liquid), product is not purified directly to carry out next step reaction.
MS m/z (ESI): 292.2 [M+l]
3rd step
4-G- hydroxyl -1- methyl-ethyls) piperidines -1- benzyl formates
By crude product piperidines -1,4-01- benzyls, are dissolved in 10 mL tetrahydrofurans under 04- ethyls - dicarboxylic acid esters 20c (500 mg, 1.70 mmol) stirring, -78 diethyl ether solutions that the M methyl-magnesium-bromides of 1.3 mL 3 are added dropwise are kept, are reacted at room temperature 1 hour.Add 20 mL saturated ammonium chloride solutions, it is extracted with ethyl acetate (20 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system B purify gained residue, obtain title product 4- (1- hydroxyl -1- methyl-ethyls) piperidines -1- benzyl formates 20d (380 mg, colorless oil), yield： 81.0%.
4th step
2- (4- piperidyls)-isopropanol
It is dissolved under 4- (1- hydroxyl -1- methyl-ethyls) piperidines -1- benzyl formates 20d (180 mg, 0.65 mmol) are stirred in 15 mL methanol, adds 20 10% palladiums of mg/carbon, hydrogen is replaced three times, is reacted 12 hours.Filtering, filtrate decompression concentration, obtains title product 2- (4- piperidyls)-isopropanol 20e (80 mg, colorless oil), yield： 86.0%. 5th step
4- [[7- [4- (l- hydroxyl -1- methyl-ethyls) piperidines -1- carbonyls] -2, 3- Dihydrobenzofuranes -5- bases] methyl] the small ketone of -2H- phthalazines, by 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (80 mg, 0.25 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sequentially add 2- (4- piperidyls)-isopropanol 20e (43 mg, 0.30 mmol), I-hydroxybenzotriazole (50 mg, 0.38 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (72 mg, 0.38 mmol) and triethylamine (76 mg, 0.75 mmol), reaction 12 hours.Add 20 mL water, it is extracted with ethyl acetate (20 mLx2), merge organic phase, washed with saturated nacl aqueous solution (20 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- (the light base -1- methyl-ethyls of 1-) piperidines -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 20 (60 mg, white solid), yield： 58.0 %.
MS m/z (ESI): 448.2 [M+l]
1H gangsters R (400 MHz, DMSO-i):δ 12.59 (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- imidazos [l, 5-a] pyrazine -7- carbonyls] -2,3- Dihydrobenzofuranes -5- bases]
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- formic acid 3b (320 mg, 1 mmol) stirring under be dissolved in 10 mL Ν, in Ν-dimethylformamide, sequentially add 3- (trifluoromethyl) -5,6,7,8- imidazolidines simultaneously [1,5-a] pyrazine hydrochloride（190 mg, 1.20 mmol, it is prepared using known method " patent WO2009082881 "), I-hydroxybenzotriazole (200 mg, 1.50 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (290 mg, 1.50 mmol) and triethylamine (300 mg, 3 mmol), react 12 hours.Add 20 mL water, it is extracted with ethyl acetate (30 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- [[7- [3- (trifluoromethyl) -6,8- dihydro -5H- imidazos [l, 5-a] pyrazine -7- carbonyls Base] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 21 (180 mg, white solid), yield： 36.0
%。
MS m/z (ESI): 496.2 [M+l]
1H NMR (400 MHz, OMSO-d6):5 12.58 (s, IH), 8.24-8.26 (m, 1H), 7.82-7.98 (m, 3H), 7.29 (s, IH), 7.22 (s, IH), 7.01 (s, 1H), 4.82-4.84 (m, IH), 4.49-4.54 (m, 2H), 4.23 (s, 2H), 3.92-4.10 (m, 2H), 3.64-3.66 (m, IH), 3.14-3.17 (m, 2H), 2.91 (s, IH), 2.79 (s, IH) embodiment 22
4- [[7- [4- (l- amino cyclopropyl carbonyl) the small carbonyl of piperazine] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1-
The first step
1- (tertbutyloxycarbonylamino) ethylene-acetic acid
By 1- amino ethylene-acetic acid 22a (200 mg, 1.98 mmol) it is dissolved in the M sodium hydroxide solutions of 5 mL 0.5 under stirring, add 5 mL Isosorbide-5-Nitraes-dioxane and di-tert-butyl dicarbonate (648 mg, 2.97 mmol), react 15 hours.Extracted with ether (10 mLx2), be added dropwise 1 M hydrochloric acid to aqueous phase pH be 4, it is extracted with ethyl acetate (20 mLx3), merges organic phase, washed with saturated nacl aqueous solution (10 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains title product 1- (tertbutyloxycarbonylamino) ethylene-acetic acid 22b (318 mg, white solid), yield： 79.9%.
MS m/z (ESI): 146.1 [M-56+1]
Second step
N- [l- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] the small carbonyl of piperazine] cyclopropyl] t-butyl carbamate
By 4- [[7- (piperazine -1- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 4 (390 mg,
1 mmol) stirring under be dissolved in 10 mL Ν, in Ν-dimethylformamide, sequentially add 1- (tertbutyloxycarbonylamino) ethylene-acetic acid 22b (200 mg, 1 mmol), I-hydroxybenzotriazole (203 mg, 1.50 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (288 mg, 1.50 mmol) and triethylamine (303 mg, 3 mmol), react 15 hours.50 mL water are added, (50 mL are extracted with ethyl acetate><3), merge organic phase, washed (50 mLx2) with saturated sodium bicarbonate solution (20 mL), saturated nacl aqueous solution successively, anhydrous sodium sulfate is done It is dry, filtering, filtrate decompression is concentrated, obtain title product N- [l- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] cyclopropyl] t-butyl carbamate 22c (480 mg, light yellow solid), yield： 84.2%. 、
MS m/z (ESI): 474.2 [M-100+1]
3rd step
4- [[7- [4- (l- amino cyclopropyl carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By N- [l- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] cyclopropyl] t-butyl carbamate 22c (480 mg, 0.84 mmol) stirring under be dissolved in the methanol solution of the M hydrogen chloride of 20 mL 2, react 10 hours.It is concentrated under reduced pressure, add 20 mL water, be added dropwise ammoniacal liquor to reaction solution pH be 8, it is extracted with ethyl acetate (30 mLx5), merge organic phase, washed with saturated nacl aqueous solution (30 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- [[7- [4- (1- amino cyclopropyl carbonyl) piperazine -1- carbonyls] -2, 3- Dihydrobenzofuranes -5- bases] methyl] 22 (220 mg of -2H- phthalazines -1- ketone, white solid), yield： 51.2 %.
MS m/z (ESI): 474.2 [M+l]
1H NMR (400 MHz, CDC13):δ 10.09 (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- methoxyphenyls) methyl] the small carbonyl of piperazine] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines
The first step
4- [(4- methoxyphenyls) methyl] piperazine -1- t-butyl formates are by piperazine -1- t-butyl formates 15a (2 g, 10 mmol) stirring under be dissolved in 30 mL dichloromethane, add 4-methoxybenzaldehyde (1.5 mL, 12 mmol), stir 10 minutes.Under ice bath, sodium triacetoxy borohydride (3.17 g, 15 mmol) and 0.5 mL acetic acid are added, is reacted at room temperature 12 hours.Washed with saturated sodium bicarbonate solution (20 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 4- [(4- methoxyphenyls) methyl] piperazine -1- t-butyl formates 23a (0.40 g, yellow oil), yield： 13.1 %.
MS m/z (ESI): 307.2 [M+l]
Second step
L- [(4- methoxyphenyls) methyl] piperazine hydrochloride
It is dissolved in Isosorbide-5-Nitrae-dioxane solution of 15 mL 2M hydrogen chloride, reacts 48 hours under 4- [(4- methoxyphenyls) methyl] piperazine -1- t-butyl formates 23a (400 mg, 1.30 mmol) are stirred.It is concentrated under reduced pressure, is dried in vacuo, obtains title product 1- [(4- methoxyphenyls) methyl] piperazine hydrochloride 23b (120 mg, white solid), yield： 44.9%.
MS m/z (ESI): 207.2 [M+l]
3rd step
4- [[7- [4- [(4- methoxyphenyls) methyl] piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] small ketone of -2H- phthalazines
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (104 mg, 0.325 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sequentially add 1- [(4- methoxyphenyls) methyl] piperazine hydrochloride 23b (80 mg, 0.39 mmol), I-hydroxybenzotriazole (66.15 mg, 0.47 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (93.61 mg, 0.49 mmol) and triethylamine (0.1 mL, 0.98 mmol), reaction 12 hours.Add 20 mL water, it is extracted with ethyl acetate (20 mLx2), merge organic phase, washed with saturated nacl aqueous solution (20 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- [(4- methoxyphenyls) methyl] the small carbonyl of piperazine] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 23 (40 mg, white solid), yield： 24.0%.
MS m/z (ESI): 511.2 [M+l]
1H NMR (400 MHz, CDC13):δ 10.24 (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
'-[5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] -3- (trifluoromethyl) -6,8- dihydros
- 5H- imidazos [l, 5-a] piperazine -1- methyl formates
The first step
3- (trifluoromethyl) -5,6,7,8- imidazolidines simultaneously [1,5-a] pyrazine -1- methyl formate 07- tert-butyl group 01- methyl 3- (trifluoromethyl) -6,8- dihydro -5H- imidazos [l, 5-a] pyrazine -1,7- dicarboxylic acid esters 24a (600 mg, 1.72 mmol, it is prepared using known method " patent WO2009082881 ") it is dissolved in Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 20 mL 2, react 5 hours.It is concentrated under reduced pressure, adds 50 mL dichloromethane protective embankments, dropwise addition saturated sodium bicarbonate solution to reaction solution pH is 8, organic phase is separated, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain crude product 3- (trifluoromethyl) -5,6,7,8- imidazolidines simultaneously [1,5-a] pyrazine -1- methyl formates 24b (430 mg, white solid), product is not purified directly to carry out next step reaction.
Second step
7- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] -3- (trifluoromethyl) -6,8- dihydros
- 5H- imidazos [1,5-a] piperazine -1- methyl formates
By 5- [(4- oxo -3H- phthalazines -1- bases）Methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (155 mg, 0.5 mmol) stirring under be dissolved in 5 mL Ν, in Ν-dimethylformamide, sequentially add crude product 3- (trifluoromethyl) -5, 6, 7, 8- imidazolidines simultaneously [1, 5-a] pyrazine -1- methyl formates 24b (100 mg, 0.42 mmol), I-hydroxybenzotriazole (81 mg, 0.6 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (114.60 mg, 0.60 mmol) and triethylamine (101 mg, 0.80 mmol), reaction 12 hours.Add lO mL water, it is extracted with ethyl acetate (10 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product 7- [5- [(4- oxo -3H- phthalazines -1- bases）Methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] -3- (trifluoromethyl) -6,8- dihydro -5H- imidazoles [l, 5-a] piperazine -1- methyl formates 24 (170 mg, light yellow solid), yield： 76.6%.
MS m/z (ESI): 554.1 [M+l]
1H NMR (400 MHz, CDC13):δ 10.46 (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-[(2i) -2- methylpyrrolidin- 2- carbonyls] piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
The first step
(3S,7a ) [1,2-c] oxazole -1- ketone is by (2i for -3- (trichloromethyl) -5,6,7,7a- tetrahydrochysene -3H- pyrrolo-esIt is dissolved under)-pyrroles protective embankment -2- formic acid 25a (20 g, 174 mmol) stirrings in 200 mL chloroforms, adds 2,2,2- trichloroacetaldehyde 25b of hydration (44 g, 260 mmol), under point water condition, back flow reaction 5 hours.(100 mLx3) is washed with water, anhydrous sodium sulfate thousand is dry, filters, filtrate decompression is concentrated, with residue obtained by ethyl alcohol recrystallization, title product (3S, 7ai -3- (trichloromethyl) -5 is obtained, 6,7,7a- tetrahydrochysene -3H- pyrrolo-es [1,2-c] oxazole -1- ketone 25c (29 g, white solid), yield： 67.0 %.
MS m/z (ESI): 246.0 [M+l]
Second step
(3 & 7a ) -7a- methyl -3- (trichloromethyl) -3, simultaneously [1,2-c] oxazole -1- ketone is by (3S, 7a for 5,6,7- nafoxidines)-3-(trichloromethyl)-5,6,7,7a- tetrahydrochysene-3H- pyrrolo-es [-one 25c (25 g of 1,2-c] oxazoles-1,100 mmol) stirring under be dissolved in 500 mL tetrahydrofurans, tetrahydrofuran/just own protective embankment solution of the M lithium diisopropylamines of 80 mL 2 is added dropwise at-78 times, reacts 45 minutes, iodine first protective embankment (25 mL are added, 493 mmol), reacted 2 hours under-50 °C.150 mL water are added, (200 mL are extracted with chloroform><2), merge organic phase, washed with saturated nacl aqueous solution (200 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product (3S, 7a) -7a- methyl -3- (three chloromethanes
Base) -3,5,6,7- nafoxidines simultaneously [1,2-c] oxazole -1- ketone 25d (20 g, light yellow oil), yield： 75.0 %. MS m/z (ESI): 258.0 [M+l]
3rd step
(2R) -2- methylpyrrole protective embankment -2- methyl formate hydrochlorides
By (3S, 7ai) -7a- methyl -3- (trichloromethyl) -3,5,6,7- nafoxidines simultaneously [l, it is dissolved under 2-c] oxazole -1- ketone 25d (15 g, 58 mmol) stirrings in 300 mL methanol, adds thionyl chloride (14 mL, 174 mmol), back flow reaction 2.5 hours.It is concentrated under reduced pressure, with residue obtained by re-crystallizing in ethyl acetate, obtains title product (2i) -2- methylpyrrole protective embankment -2- methyl formate hydrochlorides 25e (8 g, white solid), yield： 70.0%.
MS m/z (ESI): 144.2 [M+l]
4th step
01-benzyl-02- methyl-(2i) -2- methylpyrrole protective embankment -1,2- dicarboxylic acid esters By (2i) -2- methylpyrrolidin- 2- methyl formate hydrochloride 25e (l g, 5.60 mmol) stirring under be dissolved in 10 mL 1, in 4- dioxane, add 5 mL saturated sodium bicarbonate solutions, benzyl chloroformate (1.05 g are added dropwise under ice bath, 6.22 mmol), react at room temperature 6 hours.Add 20 mL ethyl acetate, washed with saturated nacl aqueous solution (10 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, and obtains crude title product 01- benzyl -02- methyl-(2/0-2- methylpyrrole protective embankment -1,2- dicarboxylic acid esters 25f (2 g, colorless oil), product is not purified directly to carry out next step reaction.
MS m/z (ESI): 278.1 [M+l]
5th step
(2i)-l- benzyloxycarbonyl group -2- methyl-pyrrol protective embankment -2- formic acid
By crude product 01- benzyl -02- methyl-(2/) -2- methylpyrrole protective embankment -1,2- dicarboxylic acid esters 25f (2 g, 5.60 mmol) stirring under be dissolved in 10 mL tetrahydrofurans.Lithium hydroxide (0.50 g, 11.20 mmol) is dissolved in 10 mL water, is added in above-mentioned reaction solution.6 mL methanol are added, are reacted 8 hours.It is concentrated under reduced pressure, adds 15 mL water and lO mL dichloromethane, point liquid collects aqueous phase.It is 3 that l mL concentrated hydrochloric acids, which are added dropwise, to aqueous phase pH, is extracted with ethyl acetate (20 mLx3), merges organic phase, washed (20 mL), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, and obtains title product (2i)-l- benzyloxycarbonyl group -2- methyl-pyrrol protective embankment -2- formic acid 25g (1.50 g, light yellow solid).
MS m/z (ESI): 264.1 [M+l]
6th step
(2i) -2- methyl -2- [4- [5- [(4- oxo -3H- phthalazines 1- yls) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] pyrroles's protective embankment -1- benzyl formates
By 4- [[7- (piperazine -1- carbonyls) -2, 3- Dihydrobenzofuranes -5- bases] methyl] 4 (302 mg of -2H- phthalazines -1- ketone, 0.78 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sequentially add (2) -1- benzyloxycarbonyl group -2- methyl-pyrrol protective embankment -2- formic acid 25g (170 mg, 0.65 mmol), I-hydroxybenzotriazole (132 mg, 0.98 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (186 mg, 0.98 mmol) and triethylamine (197 mg, 1.95 mmol), reaction 12 hours.Add 20 mL water, it is extracted with ethyl acetate (20 mLx2), merge organic phase, washed with saturated nacl aqueous solution (20 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify gained residue, obtain title product (2i) -2- methyl
- 2- [4- [5- [(4- oxo -3H- phthalazines 1- yls) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] pyrroles protective embankment -1- benzyl formates 25h (270 mg, light yellow solid), yield： 66.0%.
MS m/z (ESI): 636.1 [M+l]
7th step
4-[[7-[4-[(2i) -2- methylpyrrole protective embankment -2- carbonyls] the small carbonyl of piperazine] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By (2i) -2- methyl -2- [4- [5- [(4- oxo -3H- phthalazines 1- yls) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] pyrroles protective embankment -1- benzyl formates 25h (270 mg, 0.43 mmol) stirring under be dissolved in 15 mL ethanol, add palladium dydroxide (6 mg, 0.043 mmol), hydrogen is replaced three times, is reacted 4 hours.Filtering, filtrate It is concentrated under reduced pressure, obtains title product 4- [[7- [4- [(2i) -2- methylpyrrole protective embankment -2- carbonyls] piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 25 (140 mg, white solid), yield： 66.0%.
MS lz (ESI): 502.2 [M+l]
1H NMR (400 MHz, DMSO- )：δ 12.45 (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- (the -one of phthalazines -1
The first step
4- (Cvclopropvlmethvl) piperazine -1- t-butyl formates
It is dissolved under the small t-butyl formate 15a of piperazine (300 mg, 1.60 mmol) is stirred in 10 mL methanol, adds the third protective embankment of ring formaldehyde (113 mg, 1.60 mmol), is stirred 30 minutes.Under ice bath, sodium borohydride (122 mg, 3.20 mmol) is added, is reacted at room temperature 12 hours.Add 20 mL saturated ammonium chloride solutions, it is extracted with ethyl acetate (20 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- (Cvclopropvlmethvl) piperazine -1- t-butyl formates 26a (310 mg, colorless oil), yield： 81.0%.
MS m/z (ESI): 241.2 [M+l]
Second step
1- (Cvclopropvlmethvl) piperazine hydrochloride
It is dissolved in Isosorbide-5-Nitrae-dioxane solution of 10 mL 2M hydrogen chloride, reacts 12 hours under 4- (Cvclopropvlmethvl) piperazine -1- t-butyl formates 26a (310 mg, 1.29 mmol) is stirred.It is concentrated under reduced pressure, obtains title product 1- (Cvclopropvlmethvl) piperazine hydrochlorides 26b (210 mg, white solid), yield： 93.0%.
MS m/z (ESI): 141.1 [M+l]
3rd step
4- [[7- [the small carbonyl of 4- (Cvclopropvlmethvl) piperazine] -2,3- Dihydrobenzofuranes -5- bases] methyl] the small ketone of -2H- phthalazines is by 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- formic acid 3b (182 mg, 0.57 Mmol 10 mL N are dissolved under) stirring, in dinethylformamide, sequentially add 1- (Cvclopropvlmethvl) piperazine hydrochloride 26b (100 mg, 0.57 mmol), I-hydroxybenzotriazole (116 mg, 0.86 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (165 mg, 0.86 mmol) and triethylamine (173 mg, 1.71 mmol), react 15 hours.50 mL water are added, (50 mL are extracted with ethyl acetate><3), merge organic phase, washed (30 mLx2) with saturated sodium bicarbonate solution (20 mLx2), saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- (Cvclopropvlmethvl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] 26 (152 mg of -2H- phthalazines -1- ketone, white solid), yield： 60.6%.
MS m/z (ESI): 445.2 [M+l]
1H NMR (400 MHz, CDC13):(the s of δ 10.51, 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- piperazine -1- ketone
The first step
4- (1- hydroxycyclopropyls) piperidines -1- benzyl formates
By piperidines -1,4-01- benzyls, 04- ethyls-dicarboxylic acid esters 20c (500 mg, 1.70 mmol) stirring under be dissolved in 10 mL tetrahydrofurans, under 0 °C, the diethyl ether solution of the M ethylmagnesium bromides of 1.3 mL 3 is added dropwise, tetra isopropyl titanate (6 mL are added, 0.02 mmol), react at room temperature 12 hours.Add 20 mL saturated ammonium chloride solutions, it is extracted with ethyl acetate (20 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, with thin-layered chromatography with solvent system B purify obtained by residue, obtain title product 4- (1- hydroxycyclopropyls) piperidines -1- benzyl formates 27a (380 mg, colorless oil), yield： 81.0%.
MS m/z (ESI): 276.2 [M+l]
Second step
1- (4- piperidines) ring propyl alcohol
15 are dissolved under 4- (l- hydroxycyclopropyls) piperidines -1- benzyl formates 27a (100 mg, 0.36 mmol) is stirred In mL methanol, 10 mg l0% palladiums/carbon is added, hydrogen is replaced three times, is reacted 12 hours.Filtering, filtrate decompression concentration, obtains title product 1- (4- piperidines) ring propyl alcohol 27b (48 mg, colorless oil), yield： 94.0%. MS m/z (ESI): 142.1 [M+l]
3rd step '
4- [[7- [4- (the third protective embankment of l- hydroxyls ring) piperidines -1- carbonyls] -2, 3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone is by 5- [(the small base of 4- oxo -3H- phthalazines) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (97 mg, 0.30 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sequentially add 1- (4- piperidines) ring propyl alcohol 27b (70 mg, 0.36 mmol), I-hydroxybenzotriazole (60 mg, 0.45 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (86 mg, 0.45 mmol) and triethylamine (91 mg, 0.90 mmol), reaction 12 hours.Add 20 mL water, it is extracted with ethyl acetate (20 mLx2), merge organic phase, washed with saturated nacl aqueous solution (20 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- (the third protective embankment of 1- hydroxyls ring) piperidines -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 27 (80 mg, white solid), yield： 60.0%.
MS m/z (ESI): 446.2 [M+l]
1H NMR (400 MHz, DMSO-i¾):δ 12.57 (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- (the protective embankment base carbonyl of l- dimethylaminos basic ring penta) piperazine -1- carbonyls] -2,3-：Hydrogen benzofuran -5- bases] first
By 4- [[7- [4- (1- amino cyclopentyl protective embankment bases carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] 6 (70 mg of -2H- phthalazines -1- ketone, 0.14 mmol) stirring under be dissolved in 15 mL methanol, add 37% formalin (10 mg, 0.24 mmol), back flow reaction 20 minutes adds sodium triacetoxy borohydride (44 mg, 0.20 mmol), back flow reaction 2 hours.Add 15 mL water, it is extracted with ethyl acetate (20 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, with thin-layered chromatography with solvent system A purify obtained by residue, obtain title product 4- [[7- [4- (the protective embankment base carbonyl of 1- dimethylaminos basic ring penta) piperazine -1- carbonyls Base] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 28 (20 mg, white solid), yield： 27.0
%。
MS m/z (ESI): 530.3 [M+l]
1H NMR (400 MHz, CDC13):δ 10.10 (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- phthalazines -1- ketone
15a
The first step
4- Cyclopropylsulfonyl piperazine -1- t-butyl formates
By piperazine -1- t-butyl formates 15a (350 mg, 1.88 mmol) stirring under be dissolved in 10 mL dichloromethane, triethylamine (0.4 mL is added dropwise, 2.82 mmol), cyclopropyl sulfonyl chloride (320 mg are added dropwise under ice bath, 2.26 mmol), react 1 hour under ice bath.15 mL dichloromethane protective embankments are added, successively with saturated sodium bicarbonate solution (20 mL), saturated nacl aqueous solution（15 mL), water washing (20 mL); anhydrous sodium sulfate drying; filtering; filtrate decompression is concentrated; obtain crude title product 4- Cyclopropylsulfonyl piperazine -1- t-butyl formates 29a (480 mg; colorless oil), product is not purified directly to carry out next step reaction.
MS m/z (ESI): 191.1 [M-100+1]
Second step
1- Cyclopropylsulfonyl piperazine hydrochlorides
It is dissolved under crude product 4- Cyclopropylsulfonyl piperazine -1- t-butyl formates 29a (480 mg, 1.66 mmol) are stirred in 10 mL methanol, adds the methanol solution of the M hydrogen chloride of 3 mL 2, is reacted 12 hours.It is concentrated under reduced pressure, obtains title product 1- Cyclopropylsulfonyl piperazine hydrochlorides 29b (300 mg, white solid), yield： 96.8%. MS m/z (ESI): 191.2 [M+l]
3rd step
4- [[7- (4- Cyclopropylsulfonyls oh piperazine -1- carbonyls) -2; 3- Dihydrobenzofuranes -5- bases] methyl] the small ketone of -2H- phthalazines is by 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2; 3- Dihydrobenzofuranes -7- formic acid 3b (200 mg, 0.62 Mmol 10 mL N are dissolved under) stirring; in dinethylformamide; sequentially add 1- Cyclopropylsulfonyl piperazine hydrochloride 29b (142 mg; 0.75 mmol), I-hydroxybenzotriazole (126 mg, 0.93 mmol); 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (178 mg; 0.93 mmol) and three second meat chopped into small pieces (188 mg, 1.86 mmol), react 12 hours.Add 20 mL water, it is extracted with ethyl acetate (30 mLx2), merge organic phase, washed with saturated nacl aqueous solution (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- [[7- (4- Cyclopropylsulfonyl piperazine -1- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 29 (160 mg, white solid), yield： 52.3 %.
MS m/z (ESI): 495.2 [M+l]
1H NMR (400 MHz, DMSO-i/6):δ 12.57 (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-methyls-propiono) piperazine -1- carbonyls] -2,3 Dihydrobenzofuranes -5- bases] methyl] -2H- phthaleins
The first step
2- (tertbutyloxycarbonylamino) -2- rnethyl-propanoic acids
By 2- amino-2-methyl propionic acid 30a (2 g, 20 mmol) it is dissolved in 25 mL Isosorbide-5-Nitraes-dioxane under stirring, add the M sodium hydroxide solutions of 25 mL 2 and di-tert-butyl dicarbonate (5.20 g, 24 mmol), react 12 hours.It is concentrated under reduced pressure, adds 20 mL water, it is 2 that concentrated hydrochloric acid, which is added dropwise, to aqueous phase pH, and (30 mL are extracted with ethyl acetate><3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains title product 2- (tertbutyloxycarbonylamino) -2- rnethyl-propanoic acids 30b (3.90 g, white solid), yield： 99.0%.
MS m/z (ESI): 202.1 [M-l]
Second step
N- [l, l- dimethyl -2- oxos -2- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls Base] oh piperazine -1- bases] ethyl] t-butyl carbamate
By 4- [[7- (piperazine -1- carbonyls) -2, 3- Dihydrobenzofuranes -5- bases] methyl] 4 (190 mg of -2H- phthalazines -1- ketone, 0.44 mmol) stirring under be dissolved in 10 mL N, in dinethylformamide, sequentially add 2- (tertbutyloxycarbonylamino) -2- rnethyl-propanoic acids 30b (108 mg, 0.53 mmol), I-hydroxybenzotriazole (90 mg, 0.67 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (128 mg, 0.67 mmol) and triethylamine (135 mg, 1.33 mmol), reaction 12 hours.10 mL water are added, (20 mL are extracted with ethyl acetate<5), merge organic phase, washed with saturated nacl aqueous solution (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product N- [l, l- dimethyl -2- oxos -2- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- bases] ethyl] t-butyl carbamate 30c (120 mg, yellow oil), yield： 46.9%.
MS m/z (ESI): 576.2 [M+l]
3rd step
4- [[7- [4- (2- amino-2-methyls-propiono) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By Ν-[1,1- dimethyl -2- oxos -2- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- bases] ethyl] t-butyl carbamate 30c (100 mg, 0.17 mmol) stirring under be dissolved in 10 mL methanol, the methanol solution of the M hydrogen chloride of 3 mL 2 is added, is reacted 12 hours.It is concentrated under reduced pressure; add 10 mL methanol; be added dropwise saturated sodium bicarbonate solution to reaction solution ρ Η be 7; it is concentrated under reduced pressure; with thin-layered chromatography with solvent system Α purify gained residue, obtain (25 mg of title product 4- [[7- [4- (2- amino-2-methyls-propiono) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 30; white solid), yield： 30.1 %.
MS m/z (ESI): 476.2 [M+l]
Ή NMR (400 MHz, DMSO-^):δ 12.59 (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- (l- Aminocyclobutyls carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
The first step
1- (tertbutyloxycarbonylamino) cyclobutyl formate
By 1- Aminocyclobutyl formic acid 31a (500 mg, 4.34 mmol) it is dissolved in the M sodium hydroxide solutions of 10 mL 0.5 under stirring, add 10 mL Isosorbide-5-Nitraes-dioxane and di-tert-butyl dicarbonate (1.42 g, 6.51 mmol), react 15 hours.Extracted with ether (20 mLx2), be added dropwise 1 M hydrochloric acid to aqueous phase pH be 4, it is extracted with ethyl acetate (30 mLx3), merges organic phase, washed with saturated nacl aqueous solution (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains title product 1- (tertbutyloxycarbonylamino) cyclobutyl formate 31b (750 mg, white solid), yield： 80.6%.
Second step
N- [l- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] cyclobutyl] t-butyl carbamate
By 4- [[7- (piperazine -1- carbonyls) -2, 3- Dihydrobenzofuranes -5- bases] methyl] 4 (397 mg of -2H- phthalazines -1- ketone, 0.93 mmol) stirring under be dissolved in 10 mL N, in dinethylformamide, sequentially add 1- (tertbutyloxycarbonylamino) cyclobutyl formate 31b (200 mg, 0.93 mmol), I-hydroxybenzotriazole (189 mg, 1.40 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (268 mg, 1.40 mmol) and triethylamine (0.4 mL, 2.80 mmol), reaction 12 hours.Add 50 mL water, it is extracted with ethyl acetate (50 mLx3), merge organic phase, washed (50 mLx2) with saturated sodium bicarbonate solution (20 mL), saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain title product N- [l- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] the small carbonyl of piperazine] cyclobutyl] t-butyl carbamate 31c (430 mg, light yellow solid), yield： 79.6%.
MS m/z (ESI): 488.2 [M- 100+1]
3rd step
4- [[7- [4- (l- Aminocyclobutyls carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By N- [l- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] cyclobutyl] t-butyl carbamate 31c (430 mg, 0.73 mmol) stirring under be dissolved in the methanol solution of the M hydrogen chloride of 10 mL 2, react 10 hours.It is concentrated under reduced pressure, add 20 mL water, be added dropwise ammoniacal liquor to reaction solution ρ Η be 8, it is extracted with ethyl acetate (30 mLx5), merge organic phase, washed with saturated nacl aqueous solution (30 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- (1- Aminocyclobutyls carbonyl) piperazine -1- carbonyls] -2, 3- Dihydrobenzofuranes -5- bases] methyl] 31 (310 mg of -2H- phthalazines -1- ketone, white solid), yield： 86.8 %. ' the ζ of sui 7) ρ Bin-ι-father-in-law:|-//ζ-[ ώ[ -ς-» £ΐ#*¾:- ε ' ζ-(big-eared -]]
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89ZT00/ll0ZN3/X3d carves 0 Ζ OAV Cough up alkane -2- formic acid 32b (86 mg, 0.60 mmol), I-hydroxybenzotriazole (101 mg, 0.75 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (143 mg, 0.75 mmol) and triethylamine (151 mg, 1.50 mmol), react 12 hours.25 mL water are added, (20 mL are extracted with ethyl acetate<3), merge organic phase, washed (20 mLx2) with saturated sodium bicarbonate solution (20 mL), saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, with thin-layered chromatography with open up Jian agent systems A purify obtained by residue, obtain title product 4- [[7- [4- [(2i)-l, 2- dimethyl pyrrole protective embankment -2- carbonyls] piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 32 (210 mg, light yellow solid), yield： 81.6%.
MS m/z (ESI): 516.2 [M+l]
1H NMR (400 MHz, OMSO-d6): δ 12.45 (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- [3- fluoro- 5- (trifluoromethyl) -2- pyridines] piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H-
The first step
1- [3- fluoro- 5- (trifluoromethyl) -2- pyridines] piperazine
It is dissolved under piperazine (3.50 g, 41 mmol) is stirred in 30 mL tetrahydrofurans, fluoro- 5- (trifluoromethyl) the pyridines 33a (2.50 g, 13.7 mmol) of 2,3- bis- is added under ice bath, is reacted 3 hours.Add 100 mL water, it is extracted with ethyl acetate (100 mLx3), merge organic phase, washed (100 mLx2), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, obtain title product 1- [3- fluoro- 5- (trifluoromethyl) -2- pyridines] piperazine 33b (3.30 g, white solid), yield： 97.0%.
Second step
4- [[7- [4- [3- fluoro- 5- (trifluoromethyl) -2- pyridines] piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- formic acid 3b (150 mg, 0.47 Mmol 5 mL N are dissolved under) stirring, in dinethylformamide, sequentially add 1-[3- fluoro- 5- (trifluoromethyl)-2- pyridines] piperazine 33b (139 mg, 0.56 mmol), I-hydroxybenzotriazole (95 mg, 0.70 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimine hydrochloric acid i^ (134 mg, 0.70 mmol) and triethylamine (142 mg, 1.40 mmol), react 12 hours.20 mL water are added, (20 mL are extracted with ethyl acetate><2), merge organic phase, washed with saturated nacl aqueous solution (20 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- [3- fluoro- 5- (trifluoromethyl) -2- pyridines] piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] 33 (210 mg of -2H- phthalazines -1- ketone, white solid), yield： 80.8 %.
MS m/z (ESI): 554.2 [M+l]
1H NMR (400 MHz, DMSO-i/6):δ 12.57 (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-propanoyls) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] first
The first step
2- dimethylamino -2- rnethyl-propanoic acids
It is dissolved under 2- amino-2-methyl propionic acid 30a (1 g, 9.70 mmol) is stirred in the formalins of 25 mL 37%, adds lO mL methanol, add 100 mg 10% palladium/carbon, hydrogen is replaced three times, is reacted 12 hours.Filtering, filtrate decompression concentration, gained residue recrystallisation from isopropanol obtains title product 2- dimethylamino -2- rnethyl-propanoic acids 34a (480 mg, white solid), yield： 36.9%.
MS m/z (ESI): 130.1 [M-l]
Second step
4- [[7- [4- (2- dimethylamino -2- methyl-propanoyls) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl J-2H- phthalazines -1- ketone
By 4- [[7- (piperazine -1- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 4 (117 mg, 0.30 mmol) stirring under be dissolved in 10 mL Ν, in Ν-dimethylformamide, sequentially add 2- dimethylamino -2- rnethyl-propanoic acids 34a (39 mg, 0.30 mmol), I-hydroxybenzotriazole (61 mg, 0.45 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (86 mg, 0.45 mmol) and triethylamine (91 mg, 0.90 mmol), react 12 hours.Add 10 mL water; it is extracted with ethyl acetate (20 mLx5); merge organic phase; washed with saturated nacl aqueous solution (20 mLx2); anhydrous sodium sulfate drying; filtering; filtrate decompression is concentrated; with silica gel column chromatography with eluant, eluent system A purify gained residue; obtain title product 4- [[7- [4- (2- dimethylamino -2- methyl-propanoyls) piperazine -1- carbonyls] -2; 3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 34 (65 mg, white solid；), yield： 43.3 %.
MS m/z (ESI): 504.6 [M+l]
Ή NMR (400 MHz, CDC13):δ 9.98 (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-propanoyls] the small carbonyl of piperazine] -2,3- Dihydrobenzofuranes -5- bases]
By 4- [[7- [4- (2- amino-2-methyls-propiono) piperazine -1- carbonyls] -2; 3- Dihydrobenzofuranes -5- bases] methyl] 30 C70 mg of -2H- phthalazines -1- ketone; 0.15 mmol) stirring under be dissolved in 10 mL methanol; add cyclopropane-carboxylic acid (12 mg; 0.18 mmol), back flow reaction 20 minutes adds sodium triacetoxy borohydride (64 mg; 0.30 mmol), back flow reaction 4 hours.Add 15 mL saturated ammonium chloride solutions, (10 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- [[7- [4- [2- (Cyclopropyl-methyl-amino) -2- methyl-propanoyls] piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] 35 (40 mg of -2H- phthalazines -1- ketone, white solid), yield： 51.3 %.
MS m/z (ESI): 530.6 [M+l]
1H NMR (400 MHz, DMSO-i/6):(the s of δ 12.57, 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- pyridylmethyls) piperazine -1- mutter -5- bases] methyl] -2H- phthalazines -1- ketone
The first step
4- (2- pyridylmethyls) piperazine -1- formic acid tertiary fourth tenth of the twelve Earthly Branches I
By pyridine-2-formaldehyde 36a (2.87 g, 26.90 mmol) stirring under be dissolved in 100 mL 1, in the chloroethene protective embankments of 2- bis-, add piperazine -1- t-butyl formates (5 g, 26.90 mmol), sodium triacetoxy borohydride (11.40 g, 53.80 mmol) is added, is reacted 12 hours.Add 15 mL saturated sodium carbonate solutions, divide liquid, organic phase washed with water (20 mLx2), saturated nacl aqueous solution washing (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains title product 4- (2- pyridylmethyls) piperazine -1- t-butyl formates 36b (6.80 g, yellow oil), yield： 92.0%.
MS m/z (ESI): 278.2 [M+l]
Second step
L- (2- pyridylmethyls) piperazine hydrochloride
It is dissolved in the methanol solution of the M hydrogen chloride of 15 mL 2, reacts 12 hours under 4- (2- pyridylmethyls) piperazine -1- t-butyl formates 36b (2 g, 7.20 mmol) is stirred.It is concentrated under reduced pressure, obtains title product 1- (2- pyridylmethyls) piperazine hydrochloride 36c (1.19 g, white solid), yield： 93.0%.
MS m/z (ESI): 178.1 [M+l]
3rd step
4- [[7- [the small carbonyl of 4- (2- pyridylmethyls) piperazines] -2, 3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone is by 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (200 mg, 0.62 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sequentially add 1-(2- pyridylmethyls) piperazine hydrochloride 36c (159 mg, 0.74 mmol), I-hydroxybenzotriazole (126 mg, 0.93 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (178 mg, 0.93 mmol) and triethylamine (313 mg, 3.10 mmol), reaction 12 hours.Add 20 mL water, it is extracted with ethyl acetate (20 mLx2), merge organic phase, washed (20 mL) with water (20 mL), saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- (2- pyridylmethyls) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 36 (120 mg, white solid), yield： 40.0%. MS m/z (ESI): 482.2 [M+l]
1H NMR (400 MHz, DMSO-i¾:δ 12.58 (s, IH), 8.52 (d, IH), 8.26 (d, 1H), 7.97 (d, IH), 7.88-7.87 (t, IH), 7.82-7.79 (m, 2H), 7.47-7.45 (m, 1H), 7.30-7.23 (m, IH), 7.28 (s: IH), 7.03 (s, IH), 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- (l- methylaminos cyclobutyl carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthaleins
By 1- (tertbutyloxycarbonylamino) cyclobutyl formate 31b (500 mg, 2.32 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sodium hydride and mineral oil mixture (300 mg are added under ice bath, 60%, 6.97 mmol), react 30 minutes.Iodine first protective embankment (990 mg, 6.97 mmol) is added, is reacted at room temperature 12 hours.Add 10 mL water, be added dropwise 1 M hydrochloric acid to aqueous phase pH be 6, it is extracted with ethyl acetate (10 mLx3), merges organic phase, washed with saturated nacl aqueous solution (10 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains title product 1- (tert-butoxycarbonyl (methyl) amino) cyclobutyl formate methyl esters 37a (530 mg, light yellow liquid), yield： 92.9%.
MS m/z (ESI): 144.1 [M-100+1]
Second step
1-(tert-butoxycarbonyl (methyl) amino) cyclobutyl formate
By 1- (tert-butoxycarbonyl (methyl) amino) cyclobutyl formate methyl esters 37a (530 mg, 2.18 mmol) stirring under be dissolved in 10 mL methanol and 5 mL water, add sodium hydroxide (131 mg, 3.27 mmol), react 10 hours.Add 10 mL water, it is extracted with ethyl acetate (5 mLx2), be added dropwise 1 M hydrochloric acid to aqueous phase pH be 4, it is extracted with ethyl acetate (10 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain title product 1- (tert-butoxycarbonyl (methyl) amino) cyclobutyl formate 37b (370 mg, white solid), yield： 74.0%. 3rd step
N- methyl-N- [l- [4- [5- [(the small base of 4- oxo -3H- phthalazines) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] cyclobutyl] t-butyl carbamate
By 4- [[7- (the small carbonyl of piperazine) -2, 3- Dihydrobenzofuranes -5- bases] methyl] 4 (200 mg of -2H- phthalazines -1- ketone, 0.47 mmol) stirring under be dissolved in 10 mL N, in dinethylformamide, sequentially add 1- (tert-butoxycarbonyl (methyl) amino) cyclobutyl formate 37b (118 mg, 0.52 mmol), I-hydroxybenzotriazole (96 mg, 0.71 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (136 mg, 0.71 mmol) and triethylamine (144 mg, 1.44 mmol), reaction 12 hours.50 mL water are added, (50 mL are extracted with ethyl acetate<3), merge organic phase, washed (50 mLx2) with saturated sodium bicarbonate solution (20 mL), saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain title product N- methyl-N- [l- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] cyclobutyl] t-butyl carbamate 37c (256 mg, light yellow solid), yield： 91.5 %.
MS m/z (ESI): 502.7 [M-100+1]
4th step
4- [[7- [4- (l- methylaminos cyclobutyl carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By N- methyl-N- [l- [4- [5- [(the small base of 4- oxo -3H- phthalazines) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] cyclobutyl] t-butyl carbamate 37c (256 mg, 0.43 mmol) stirring under be dissolved in the methanol solution of the M hydrogen chloride of 5 mL 2, react 10 hours.It is concentrated under reduced pressure, add 20 mL water, be added dropwise ammoniacal liquor to reaction solution ρ Η be 8, it is extracted with ethyl acetate (30 mLx5), merge organic phase, washed with saturated nacl aqueous solution (30 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- (1- methylaminos cyclobutyl carbonyl) piperazine -1- carbonyls] -2, 3- Dihydrobenzofuranes -5- bases] methyl] 37 (130 mg of -2H- phthalazines -1- ketone, white solid), yield： 61.0%.
MS m/z (ESI): 502.6 [M+l]
lH NMR (400 MHz, DMSO-i/6):δ 12.57 (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- (l- dimethylaminos cyclobutyl carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone By 4- [[7- [4- (l- methylaminos cyclobutyl carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] 37 (120 mg of -2H- phthalazines -1- ketone, 0.24 mmol) stirring under be dissolved in 3 mL dichloromethane protective embankments, add 37% formalin (11 mg, 0.36 mmol), sodium triacetoxy borohydride (76 mg, 0.36 mmol) is added under ice bath, is reacted at room temperature 3 hours.Add 5 mL saturated ammonium chloride solutions, extracted with dichloromethane (5 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- (1- dimethylaminos cyclobutyl carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] 38 (79 mg of -2H- phthalazines -1- ketone, white solid), yield： 63.7%.
MS m/z (ESI): 516.6 [M+l]
1H NMR (400 MHz, OMSO- 6):6 12.57 (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 simultaneously [3,4-b] pyridine -6- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1-
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, it is dissolved under 3- Dihydrobenzofuranes -7- formic acid 3b (151 mg, 0.47 mmol) stirrings in 4 mL DMFs, sequentially add 6,7- dihydro -5H- pyrrolo-es
[3,4-b] pyridine (60 mg, 0.39 mmol), I-hydroxybenzotriazole (80 mg, 0.59 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (111 mg, 0.59 mmol) and triethylamine (118 mg, 1.17 mmol), react 12 hours.LO mL water is added, (10 mL are extracted with ethyl acetate><3), merge organic phase, (10 mLx2), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression is concentrated, and obtains title product 4- [[7- (5,7- pyrrolin simultaneously [3,4-b] pyridine -6- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 39 (60 mg, white solid), yield： 44.0%. MS m/z (ESI): 425.4 [M+l]
1H NMR (400 MHz, DMSO-i¾):δ 12.58 (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- [(25 4,4- difluoro pyrroles protective embankment -2- carbonyls] piperazine -1- carbonyl -2,3- Dihydrobenzofuranes -5- bases] first
The first step
The 01- tert-butyl group -02- methyl-(2 ＆ 4i) -4- hydroxyl pyrrolidines -1,2- dicarboxylic acid esters are by (2 ＆ R) -4- hydroxypyrrole protective embankment -2- methyl formates 40a (0.90 g, 5 mmol) stirring under be dissolved in 30 mL dichloromethane protective embankments, add di-tert-butyl dicarbonate (1.20 g, 5.50 mmol) and triethylamine (1.50 g, 15 mmol), react 5 hours.It is concentrated under reduced pressure, add 15 mL water, it is extracted with ethyl acetate (20 mLx3), merge organic phase, (30 mLx2), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression is concentrated, and obtains the title product 01- tert-butyl group -02- methyl-(2S, 4i) -4- hydroxyl pyrrolidine -1,2- dicarboxylic acid esters 40b (1.30 g, white solid), yield： 96.0%
MS m/z (ESI): 146.1 [M-56+1]
Second step
01-tert-butyl group-02- methyl-(25)-4- oxo pyrroles's protective embankment-1,2- dicarboxylic acid esters
By the 01- tert-butyl group -02- methyl-(25) -4- hydroxypyrroles protective embankment -1,2- dicarboxylic acid esters 40b (0.20 g, 0.82 mmol) stirring under be dissolved in 20 mL dichloromethane, add pyridine chlorochromate drone salt (0.53 g, 2.50 mmol), reaction 18 hours.Add 100 mL ether, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the title product 01- tert-butyl group -02- methyl-(25) -4- oxo-pyrrolidines -1,2- dicarboxylic acid esters 40c (0.18 g, white solid), yield： 90.0%.
3rd step '
01-tert-butyl group-02- methyl-(2S)-4,4- difluoro pyrroles protective embankment-1,2- dicarboxylic acid esters are by the 01- tert-butyl group-02- methyl-(25)-4- oxo pyrroles protective embankment-1,2- dicarboxylic acid esters 40c (180 mg, 0.74 mmol) stirring under be dissolved in 5 mL dichloromethane, N- ethyls-N- (trifluoromethylthio) ethylamine (262 mg, 1.60 mmol) is added dropwise under-78, is reacted at room temperature 12 hours.Add 20 mL saturated sodium bicarbonate solutions, (20 mLx3) is extracted with dichloromethane protective embankment, merges organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain the title product 01- tert-butyl group -02- methyl-(25) -4,4- difluoropyrrolidins -1,2- dicarboxylic acid esters 40d (180 mg, colorless oil), yield： 91.8 %. MS m/z (ESI): 166.1 [M- 100+1]
4th step
(25) small tertbutyloxycarbonyl -4, the fluoro- pyrroles's protective embankment -2- formic acid of 4- bis- is by the 01- tert-butyl group -02- methyl-(25) -4,4- difluoro pyrroles protective embankment -1,15 mL first alcohol and waters (V/V=2 are dissolved under 2- dicarboxylic acid esters 40d (180 mg, 0.68 mmol) stirrings:1) in the mixed solvent, adds a hydronium(ion) lithia (142 mg, 3.40 mmol), reacts at room temperature 12 hours.It is concentrated under reduced pressure, add 20 mL water, (10 mLx3) is extracted with dichloromethane protective embankment, be added dropwise citric acid to aqueous phase pH be 4, (20 ml 3) is extracted with dichloromethane protective embankment, merge organic phase, washed with saturated nacl aqueous solution (10 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain title product (2S) -1- tertbutyloxycarbonyls -4,4- difluoro-pyrrolidin -2- formic acid 40e (170 mg, colorless oil), yield： 100%.
MS m/z (ESI): 249.8 [M-l]
5th step
The fluoro- 2- of (2S) -4,4- bis- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl -2,3- Dihydrobenzofuranes -7- carbonyls] the small carbonyl of piperazine] pyrrolidines -1- t-butyl formates
By 4- [[7- (piperazine -1- carbonyls) -2, 3- Dihydrobenzofuranes -5- bases] methyl] 4 (200 mg of -2H- phthalazines -1- ketone, 0.51 mmol) stirring under be dissolved in 10 mL N, in dinethylformamide, sequentially add (25) -1- tertbutyloxycarbonyls -4, the fluoro- Jie ratios of 4- bis- cough up protective embankment -2- formic acid 40e (128 mg, 0.51 mmol), I-hydroxybenzotriazole (103 mg, 0.76 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (147 mg, 0.76 mmol) and triethylamine (154 mg, 1.53 mmol), reaction 12 hours.Add 50 mL water, it is extracted with ethyl acetate (50 mLx3), merge organic phase, washed (50 mLx2) with saturated sodium bicarbonate solution (20 mL), saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain title product (25) -4, the fluoro- 2- of 4- bis- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] pyrroles protective embankment -1- t-butyl formates 40f (220 mg, white solid), yield： 68.0%.
MS m/z (ESI): 524.2 [M-l 00+1]
6th step 4- [[7- [4- [(2S) -4,4- difluoropyrrolidin -2- carbonyls] small carbonyl -2, the 3- Dihydrobenzofuranes -5- bases of piperazine] methyl] -2H- phthalazines -1- ketone
By (2S) -4, Μ-the 2- of 4- bis- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl -2,3- Dihydrobenzofuranes-' piperazine -1- carbonyls] pyrrolidines -1- t-butyl formates 40f (200 mg, 0.32 mmol) stirring under be dissolved in the methanol solution of the M hydrogen chloride of 5 mL 2, react 10 hours.It is concentrated under reduced pressure, add 20 mL water, be added dropwise ammoniacal liquor to reaction solution pH be 8, it is extracted with ethyl acetate (30 mLx5), merge organic phase, washed with saturated nacl aqueous solution (30 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- [(25 4, 4- difluoropyrrolidin -2- carbonyls] piperazine -1- carbonyls -2, 3- Dihydrobenzofuranes -5- bases] methyl] 40 (102 mg of -2H- phthalazines -1- ketone, white solid), yield： 61.0 %.
MS m/z (ESI): 524.2 [M+l]
1H NMR (400 MHz, OMSO-d6):δ 12.58 (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- [(2 ＆ S 4- fluoropyrrolidine -2- carbonyls] piperazine -1- carbonyls] -2,3-
The first step
The 01- tert-butyl group -02- methyl-(2＆45) -4- fluoropyrrolidines -1,2- formic acid esters is by the 01- tert-butyl group -02- methyl-(2S, 4i) -4- hydroxypyrrole protective embankment -1,2- dicarboxylic acid esters 40b (450 mg, 1.80 mmol) stirring under be dissolved in 10 mL dichloromethane, N- ethyl-N- (trifluoromethylthios are added dropwise under -78）Ethylamine (0.38 mL, 2.80 mmol), is reacted at room temperature 12 hours.40 mL saturated sodium bicarbonate solutions are added, (30 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is dense Contracting, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain the title product 01- tert-butyl group -02- methyl-(2S, 4S) -4- fluorine pyrroles protective embankment -1,2- dicarboxylic acid esters 41a (300 mg, colorless oil), yield： 67.1 %. '
' second step
(2S, 4S) the fluoro- P ratios of -1- tertbutyloxycarbonyls -4- cough up protective embankment -2- formic acid by the 01- tert-butyl group -02- methyl-(2＆45) -4- fluorine pyrroles protective embankment -1,2- dicarboxylic acid esters 41a (300 mg, 1.20 mmol) stirring under be dissolved in 2 mL methanol and 3 mL water, add hydronium(ion) lithia (151 mg, 3.60 mmol) and potassium hydroxide (201 mg, 3.60 mmol), react 12 hours.It is concentrated under reduced pressure, add 20 mL water, extracted with dichloromethane (10 mLx3), be added dropwise citric acid to aqueous phase pH be 4, (20 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, washed with saturated nacl aqueous solution (10 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain title product (2S, S) the fluoro- B ratios of -1- tertbutyloxycarbonyls -4- cough up alkane -2- formic acid 41b (250 mg, colorless oil), yield： 89.3%.
3rd step
(the fluoro- 2- of the 4- of 2 ＆ 45 [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] pyrroles's protective embankment -1- t-butyl formates
By 4- [[7- (piperazine -1- carbonyls) -2, 3- Dihydrobenzofuranes -5- bases] methyl] 4 (200 mg of -2H- phthalazines -1- ketone, 0.51 mmol) stirring under be dissolved in 10 mL N, in dinethylformamide, sequentially add the fluoro- Jie ratios of (2 ＆ 45) -1- tertbutyloxycarbonyls -4- and cough up protective embankment -2- formic acid 41b (119 mg, 0.51 mmol), I-hydroxybenzotriazole (103 mg, 0.76 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (147 mg, 0.76 mmol) and triethylamine (154 mg, 1.53 mmol), reaction 12 hours.Add 25 mL water, extracted with dichloromethane (20 mLx3), merge organic phase, saturated sodium bicarbonate solution (20 mL) is used successively, saturated nacl aqueous solution washs (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain the fluoro- 2- of title product (2 ＆ 45) -4- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl -2, 3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] pyrroles protective embankment -1- t-butyl formates 41c (200 mg, white solid), yield： 64.5 %.
MS m/z (ESI): 506.2 [M-100+1]
4th step
4- [[7- [4- [(2 ＆ S) -4- fluorine pyrroles protective embankment -2- carbonyls] piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl J-2H- phthalazines -1- ketone
By the fluoro- 2- of (2＆45) -4- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] pyrroles protective embankment -1- t-butyl formates 41c (200 mg, 0.33 mmol) stirring under be dissolved in the methanol solution of 5 mL dichloromethanes protective embankments and the M hydrogen chloride of 10 mL 2, react 10 hours.It is concentrated under reduced pressure, ammoniacal liquor is added dropwise into residue, it is 89 to adjust ρ Η, it is extracted with ethyl acetate (10 mLx2), the organic phase of merging uses anhydrous sodium sulfate drying successively, filtering, decompression is lower to be concentrated, vacuum drying, obtain (158 mg of title product 4- [[7- [4- [(2S, S 4- fluorine pyrroles protective embankment-2- carbonyls] piperazine-1- carbonyl-2,3- Dihydrobenzofuranes-5- bases] methyl]-1 -one of-2H- phthalazines 41, yellow solid), yield： 95.0%. MS m/z (ESI): 506.2 [M+l]
1H NMR (400 MHz, OMSO-d6):δ 12.58 (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-butyyls) the small carbonyl of piperazine] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthaleins
The first step
2- (t-butoxycarbonyl amino) -3- metliyl-butyric acids
12 mLl, 4- dioxane and water (V/V=1 are dissolved under 2- amino -3- metliyl-butyric acids 42a (1.02 g, 10 mmol) is stirred:1) in the mixed solvent, adds sodium hydroxide (1.20 g, 30 mmol) and di-tert-butyl dicarbonate (3.27 g, 15 mmol), reacts 5 hours.It is concentrated under reduced pressure, extracted with ether (20 mLx2), it is 4 that 1 M hydrochloric acid, which is added dropwise, to aqueous phase ρ Η, is extracted with ethyl acetate (30 mLx3), merge organic phase, washed (20 mLx2), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, obtain title product 2- (tertbutyloxycarbonylamino) -3- metliyl-butyric acids 42b (230 mg, light yellow solid), yield： 10.6%.
MS m/z (ESI): 215.9 [M-l]
Second step
N- [small [4- [5- [(4- oxo -3H- phthalazines -1- bases) the methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] propyl group of 2- methyl] t-butyl carbamate
By 4- [[7- (piperazine -1- carbonyls) -2, 3- Dihydrobenzofuranes -5- bases] methyl] 4 (100 mg of -2H- phthalazines -1- ketone, 0.26 mmol) stirring under be dissolved in 3 mL N, in dinethylformamide, sequentially add 2- (tertbutyloxycarbonylamino) -3- metliyl-butyric acids 42b (60 mg, 0.26 mmol), I-hydroxybenzotriazole (48.80 mg, 0.36 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (68.90 mg, 0.36 mmol) and triethylamine (0.1 mL, 0.76 mmol), reaction 12 hours.Add lO mL water, it is extracted with ethyl acetate (10 mLx3), merge organic phase, washed (10 mLx2) with saturated sodium bicarbonate solution (10 mL), saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product N- [small [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- of 2- methyl Carbonyl] piperazine -1- carbonyls] propyl group] t-butyl carbamate 42c (30 mg, white solid), yield： 20.0%.
3rd step
4- [[7- [4- (2- amino -3- methyl-butrylamino S) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By the N- [small [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2 of 2- methyl, 3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] propyl group] t-butyl carbamate 42c (30 mg, 0.05 mmol) stirring under be dissolved in the 1 of 4 mL saturation hydrogen chloride, in 4- dioxane solutions, react 10 hours.It is concentrated under reduced pressure, add 5 mL water, be added dropwise ammoniacal liquor to reaction solution pH be 8, it is extracted with ethyl acetate (8 mLx5), merge organic phase, washed with saturated nacl aqueous solution (10 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- (2- amino -3- Metliyl-butyyls) piperazine -1- carbonyls] -2, 3- Dihydrobenzofuranes -5- bases] methyl] 42 (17.60 mg of -2H- phthalazines -1- ketone, white solid), yield： 72.0%.
MS m/z (ESI): 490.2 [M +1]
1H NMR (400 MHz, DMSO-^):δ 12.58 (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- (l, 2,3,4,4a, 5,7,7a- octahydro pyrrolo- [3,4-b] pyridine -6- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] first
The first step
6- [5- [(4- oxo-3H- phthalazines-1- bases) methyl]-2,3- Dihydrobenzofuranes-7- carbonyls]-3,4,4a, 5,7,7a- hexahydro-2H- pyrrolo-es [3,4-b] pyridine-1-t-butyl formates
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (114 mg, 0.35 mmol) stirring under be dissolved in 4 mL N, in dinethylformamide, sequentially add 2, 3, 4, 4a, 5, 6, 7, 7a- octahydros pyrrolo- [3, 4-b] pyridine -1- t-butyl formates 43a (80 mg, 0.35 mmol), I-hydroxybenzotriazole (72 mg, 0.53 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (102 mg, 0.53 mmol) and Triethylamine (107 mg, 1.06 mmol), reacts 12 hours.Add lO mL water, it is extracted with ethyl acetate (10 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain title product 6- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- dihydrobenzo furans south -7- carbonyls] -3,4,4a, 5,7,7a- hexahydro -2H- pyrrolo-es [3,4-b] pyridine -1- t-butyl formates 43b (150 mg, light yellow solid), yield： 79.8 %.
MS m/z (ESI): 531.4 [M +1]
Second step
4- [[7- (l, 2,3,4,4a, 5,7,7a- octahydro pyrrolo- [3,4-b] pyridine -6- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By 6- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] -3,4,4a, 5,7,7a- hexahydro -2H- pyrrolo-es [3,4-b] pyridine -1- t-butyl formates 43b (150 mg, 0.28 mmol) stirring under be dissolved in the methanol solution of the M hydrogen chloride of 3 mL 2, react 10 hours.It is concentrated under reduced pressure, add 20 mL water, be added dropwise ammoniacal liquor to reaction solution ρ Η be 8, it is extracted with ethyl acetate (30 mLx5), merge organic phase, washed with saturated nacl aqueous solution (30 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- (l, 2, 3, 4, 4a, 5, 7, 7a- octahydros pyrrolo- [3, 4-b] pyridine -6- carbonyls) -2, 3- Dihydrobenzofuranes -5- bases] methyl] 43 (83 mg of -2H- phthalazines -1- ketone, white solid), yield： 67.9%.
MS m/z (ESI): 431.2 [M +1]
1H NMR (400 MHz, OMSO-d6):δ 12.59 (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- (l- methylaminos cyclopropyl carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
The first step
1-(tert-butoxycarbonyl (methyl) amino) ethylene-acetic acid methyl esters is by 1- (tertbutyloxycarbonylamino) ethylene-acetic acid 22b (600 mg, 2.98 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sodium hydride and mineral oil mixture (214.70 mg are added under ice bath, 60%, 8.95 mmol), react 30 minutes.Iodine first protective embankment (1.27 g, 8.95 mmol) is added, is reacted at room temperature 12 hours.Add 10 mL water, be added dropwise 1 M hydrochloric acid to aqueous phase pH be 6, it is extracted with ethyl acetate (10 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 1- (tert-butoxycarbonyl (methyl) amino) ethylene-acetic acid methyl esters 44a (270 mg, colourless liquid), yield： 40.0%.
MS m/z (ESI): 130.1 [M-100+1]
Second step
1-(tert-butoxycarbonyl (methyl) amino) ethylene-acetic acid
10 mL first alcohol and water (V V=7 are dissolved under 1- (tert-butoxycarbonyl (methyl) amino) ethylene-acetic acid methyl esters 44a (270 mg, 1.18 mmol) are stirred:3) in the mixed solvent, adds sodium hydroxide (70.80 mg, 1.77 mmol), reacts 10 hours.10 mL water are added, (5 mL are extracted with ethyl acetate><2), be added dropwise 1 M hydrochloric acid to aqueous phase pH be 4, it is extracted with ethyl acetate (10 mLx3), merges organic phase, washed with saturated nacl aqueous solution (10 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains title product 1- (tert-butoxycarbonyl (methyl) amino) ethylene-acetic acid 44b (223 mg, white solid), yield： 87.9%.
MS m/z (ESI): 214.2 [M+l]
3rd step
N- methyl-N- [l- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] cyclopropyl] t-butyl carbamate
By 4- [[7- (piperazine -1- carbonyls) -2, 3- Dihydrobenzofuranes -5- bases] methyl] 4 (445 mg of -2H- phthalazines -1- ketone, 1.14 mmol) stirring under be dissolved in 10 mL N, in dinethylformamide, sequentially add 1- (tert-butoxycarbonyl (methyl) amino) ethylene-acetic acid 44b (223 mg, 1.04 mmol), I-hydroxybenzotriazole (210 mg, 1.56 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (298 mg, 1.56 mmol) and triethylamine (315 mg, 3.12 mmol), reaction 12 hours.50 mL water are added, (50 ml 3) is extracted with ethyl acetate, Merge organic phase, washed (50 mLx2) with saturated sodium bicarbonate solution (20 mL), saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain title product N- methyl-N- [l- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, the carbonyl of 3- Dihydrobenzofuranes -7] piperazine -1- carbonyls] cyclopropyl] t-butyl carbamate 44c (446 mg, white solid), yield： 73.0%.
MS m/z (ESI): 488.2 [M- 100+1]
4th step
4- [[7- [4- (l- methylaminos cyclopropyl carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By N- methyl-N- [l- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] cyclopropyl] t-butyl carbamate 44c (446 mg, 0.75 mmol) stirring under be dissolved in the methanol solution of the M hydrogen chloride of 5 mL 2, react 10 hours.It is concentrated under reduced pressure, add 20 mL water, be added dropwise ammoniacal liquor to reaction solution pH be 8, it is extracted with ethyl acetate (30 mLx5), merge organic phase, washed with saturated nacl aqueous solution (30 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- (1- methylaminos cyclopropyl carbonyl) piperazine -1- carbonyls] -2, 3- Dihydrobenzofuranes -5- bases] methyl] 44 (240.50 mg of -2H- phthalazines -1- ketone, white solid), yield： 65.0%. MS m/z (ESI): 488.5 [M+l]
Ή NMR (400 MHz, D20):δ 8.22 (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- (l- dimethylaminos cyclopropyl carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H-
By 4- [[7- [4- (1- amino cyclopropyl carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] 22 (142 mg of -2H- phthalazines -1- ketone, 0.30 mmol) stirring under be dissolved in 3 mL dichloromethane protective embankments, add 37% formalin (27 mg, 0.90 mmol), sodium triacetoxy borohydride (190.70 mg, 0.90 mmol) is added under ice bath, is reacted at room temperature 12 hours.5 mL saturations chlorinations hinge solution is added, (5 mLx3) is extracted with dichloromethane protective embankment, merges organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration is pure with solvent system A with thin-layered chromatography Change gained residue, obtain title product 4- [[7- [4- (1- dimethylaminos cyclopropyl carbonyl) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 45 (67 mg, white solid), yield： 45.0%. MS m/z (ESI): 502.2 [M+l]
Ή NMR (400 MHz, CDC13):δ 10.18 (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- hexahydro -2H- pyrrolo-es [3,4-b] [l, 4] oxazine -6- carbonyls) -2,3- Dihydrobenzofuranes -5- bases]
The first step
The bromo- 4- of 3- (2- hydroxyl-oxethyls) P ratios cough up protective embankment -1- t-butyl formates
By 2,5- pyrrolin -1- t-butyl formates 46a (9.50 g, 56.14 mmol, using known method
" Organic Process Research ＆ Development; 2009; 13 (3); 638-640 " be prepared) stirring under be dissolved in 50 mL ethylene glycol, ten batches are divided to add N-bromosuccinimide (10.99 g, 61.75 mmol), react 12 hours.Add 100 mL water, it is extracted with ethyl acetate (100 mLx3), merge organic phase, washed (25 ml 2), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, obtain the bromo- 4- of 3- (2- hydroxyl-oxethyls) pyrroles's protective embankment -1- t-butyl formates 46b (12 g, rufous grease), yield： 72.3%. MS m/z (ESI): 254.2 [M-56+1]
Second step
The bromo- 4- of 3- [2- (toluene -4- sulfonyloxies) ethyoxyl] pyrroles's protective embankment -1- t-butyl formates
The bromo- 4- of 3- (2- hydroxyl-oxethyls) P ratios are coughed up into alkane -1- t-butyl formates 46b (12 g, 38.69 mmol) stirring under be dissolved in 100 mL toluene, add triethylamine (8.1 mL, 58.03 mmol) and DMAP (0.50 g, 4 mmol), under ice bath, add paratoluensulfonyl chloride (10.06 g, 58.03 mmol), react 12 hours.Add 100 mL water, divide liquid, aqueous phase is extracted with ethyl acetate (100 mLx3), merge organic phase, washed with saturated nacl aqueous solution (25 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with wash meat chopped into small pieces agent system B purify gained residue, obtain the bromo- 4- of 3- [2- (toluene -4- sulfonyloxies) ethyoxyl] pyrroles protective embankment -1- t-butyl formates 46c (14.30 g, colorless oil), yield： 79.6%.
3rd step
4- benzyls -2,3,4a, 5,7,7a- hexahydropyrrolos simultaneously [3,4-b] [l, 4] oxazine -6- t-butyl formates are by the bromo- 4- of 3- [2- (toluene -4- sulfonyloxies) ethyoxyl] small t-butyl formate 46c (14.30 g of pyrrolidines, 30.78 mmol) stirring under be dissolved in 80 mL paraxylene, benzylamine (3.30 g, 30.78 mmol) is added, 140 °C are reacted 5 hours.It is concentrated under reduced pressure, adds lOO mL water, be extracted with ethyl acetate (150 mLx3), merge organic phase, (75 mLx2), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression concentration, obtains 4- benzyls -2,3,4a, 5,7,7a- hexahydropyrrolos simultaneously [3,4-b] [l, 4] oxazine -6- t-butyl formates 46d (7.50 g, light brown grease), yield： 76.0%.
MS m/z (ESI): 319.2 [M+l]
4th step
4- benzyls -3,4a, 5,6,7,7a- hexahydro -2H- pyrrolo-es [3,4-b] [l, 4] oxazines hydrochlorides are by 4- benzyls -2,3,4a, 5,7,7a- hexahydropyrrolos simultaneously [3,4-b] [l, 4] oxazine -6- t-butyl formates 46d (150 mg, 0.47 mmol) stirring under be dissolved in Isosorbide-5-Nitrae-dioxane solution of 10 mL hydrogen chloride, react 12 hours.It is concentrated under reduced pressure, obtains crude product 4- benzyls -3,4a, 5,6,7,7a- hexahydro -2H- pyrrolo-es [3,4-b] [l, 4] oxazine hydrochloride 46e (180 mg, white solid), the not purified directly progress next step reaction of product.
MS m/z (ESI): 391.2 [M+l]
5th step
4- [[7- (and 4- benzyls -2,3,4a, 5,7,7a- hexahydropyrrolos simultaneously [3,4-b] [l, 4] oxazine -6- carbonyls) -2,3- Dihydrobenzofuranes
- 5- bases] methyl] -2H- phthalazines -1- ketone
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (127 mg, 0.39 mmol) stirring under be dissolved in 4 mL N, in dinethylformamide, sequentially add crude product 4- benzyls -3, 4a, 5, 6, 7, 7a- hexahydro -2H- pyrrolo-es [3, 4-b] [l, 4] oxazine hydrochloride 46e (180 mg, 0.47 mmol), 1- hydroxybenzotriazoles (79 mg, 0.59 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (113 mg, 0.59 mmol) and triethylamine (118 mg, 1.17 mmol), reaction 12 hours.Add 10 mL water, it is extracted with ethyl acetate (10 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- (4- benzyls -2, 3, 4a, 5, 7, 7a- hexahydropyrrolos simultaneously [3, 4-b] [l, 4] oxazine -6- carbonyls) -2, 3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 46f (120 mg, white solid), yield： 59.0 %.
MS m/z (ESI): 523.2 [M+l]
6th step
4- [[7- (3,4,4a, 5,7,7a- hexahydro -2H- pyrrolo-es [3,4-b] [l, 4] oxazine -6- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] Methyl]-1 -one of-2H- phthalazines
By 4- [[7- (4- benzyls -2,3,4a, 5,7,7a- hexahydropyrrolos simultaneously [3,4-b] [l, 4] oxazine -6- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 46f (90 mg, 0.17 mmol) stirring under be dissolved in 5 mL ethanol, add 10 mg palladium dydroxides, hydrogen is replaced three times, is reacted 12 hours.Filtering, filtrate decompression concentration, obtains title product 4- [[7- (3,4,4a, 5,7,7a- hexahydro -2H- pyrrolo-es [3,4-b] [l, 4] oxazine -6- carbonyls) -2,3- Dihydrobenzofuranes -5- bases] methyl] 46 (15 mg of -2H- phthalazines -1- ketone, white solid), yield： 20.0%.
MS m/z (ESI): 433.1 [M+l]
1H NMR (400 MHz, CDC13):δ 10.55 (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- imidazos [1,2-a] pyrazine -7- carbonyls] -2,3- Dihydrobenzofuranes -5- bases]
The first step
2- (trifluoromethyl) imidazo [1,2-a] pyrazine
It is dissolved under pyrazine -2- amine 47a (5.25 g, 55.20 mmol) is stirred in 12 mL ethanol, adds 3- bromo- 1,1,1- tri- fluoro- third protective embankment -2- ketone 47b (5.7 mL, 55.20 mmol), back flow reaction 24 hours.It is concentrated under reduced pressure, adds 100 mL ethyl acetate and 100 mL saturated sodium bicarbonate solutions, point liquid.Aqueous phase is extracted with ethyl acetate (50 mLx3), merge organic phase, washed (50 mLx2), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 2- (trifluoromethyl) imidazo [l, 2-a] pyrazine 47c (2.40 g, yellow solid), yield： 22.8%.
Second step
2- (trifluoromethyl) -5,6,7,8- imidazolidines simultaneously [l, 2-a] pyrazine
100 are dissolved under 2- (trifluoromethyl) imidazo [1,2-a] pyrazine 47c (2.40 g, 12.55 mmol) is stirred In mL methanol, 480 10% palladiums of mg/carbon is added, hydrogen is replaced three times, is reacted 12 hours.Filtering, filtrate decompression concentration, obtains title product 2- (trifluoromethyl) -5,6,7,8- imidazolidines simultaneously [1,2-a] pyrazine 47d (2.30 g, light yellow oil), yield： 95.8%.
3rd step '
4- [[7- [2- (trifluoromethyl) -6,8- dihydro -5H- imidazos [1,2-a] pyrazine -7- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (168 mg, 0.52 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sequentially add 2- (trifluoromethyl) -5, 6, 7, 8- imidazolidines simultaneously [1, 2-a] pyrazine 47d (180 mg, 0.52 mmol), I-hydroxybenzotriazole (108 mg, 0.80 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (153 mg, 0.80 mmol) and triethylamine (161 mg, 1.60 mmol), reaction 12 hours.Add 10 mL water, it is extracted with ethyl acetate (10 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [2- (trifluoromethyl) -6, 8- dihydro -5H- imidazos [l, 2-a] pyrazine -7- carbonyls] -2, 3- Dihydrobenzofuranes -5- bases] methyl] 47 (160 mg of -2H- phthalazines -1- ketone, white solid), yield： 62.0%.
MS m/z (ESI): 496.1 [M+l]
1H NMR (400 MHz, CDC13):δ 10.38 (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- phthalein -1- bases) methyl]-N- (3- picolyls) -2,3- Dihydrobenzofuranes -7- formamides
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- formic acid 3b (160 mg, 0.50 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sequentially add 3- picolyls amine (64 mg, 0.50 mmol), I-hydroxybenzotriazole (101 mg, 0.75 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (143 mg, 0.75 mmol) and triethylamine (150 mg, 1.50 mmol), react 12 hours.Add 10 mL water, it is extracted with ethyl acetate (10 mLx3), merge organic phase, washed (10 mLx2), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, gained solid washs (20 mL) with ether, obtains title product 5- [(4- oxo-3H- phthalazines-1- bases) methyl]-N- (3-picolyl)-2,3- Dihydrobenzofuranes-7- Formamide 48 (100 mg, white solid), yield： 48.8 %.
MS m/z (ESI): 413.1 [M+l]
1H NMR (400 MHz, DMSO-i¾:δ 12.57 (s, 1H), 8.24-8.53 (m, 4H), 7.68-7.93 (m, 4H), 7.57 (s, IH), 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- (lH- imidazol-4 yls) ethyl -5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- formyls
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (160 mg, 0.50 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sequentially add 2- (lH- imidazol-4 yls) ethylamine hydrochloride (l lO mg, 0.60 mmol), I-hydroxybenzotriazole (101 mg, 0.75 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (143 mg, 0.75 mmol) and triethylamine (150 mg, 1.50 mmol), reaction 12 hours.Add 10 mL water, it is extracted with ethyl acetate (10 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product N- [2- (lH- imidazol-4 yls）Ethyl -5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- formamides 49 (100 mg, white solid), yield： 48.5 %.
MS m/z (ESI): 416.1 [M+l]
Ή NMR (400 MHz, DMSO-^):δ 12.57 (s, 1H), 11.82 { br. s, IH), 8.23-8.25 (m, 1H), 7.80-7.94 (m, 4H), 7.56 (s, IH), 7.52 (s, 1H), 7.32 (s, IH), 6.80 (br. s, IH), 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- [(the small base of 4- oxo -3H- phthalazines) methyl]-N- (3- piperidine methyls) -2,3- Dihydrobenzofuranes -7- carboxamide hydrochlorides
The first step
3- [[[5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] amino] methyl] small t-butyl formate of piperidines
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (100 mg, 0.31 mmol) stirring under be dissolved in 4 mL N, in dinethylformamide, sequentially add 3- (amino methyl) piperidines -1- t-butyl formates 50a (66 mg, 0.31 mmol), I-hydroxybenzotriazole (63 mg, 0.47 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (89 mg, 0.47 mmol) and triethylamine (94 mg, 0.93 mmol), reaction 12 hours.Add 10 mL water, it is extracted with ethyl acetate (10 mLx3), merge organic phase, washed with saturated nacl aqueous solution (10 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 3- [[[5- [(the small base of 4- oxo -3H- phthalazines) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] amino] methyl] piperidines -1- t-butyl formates 50b (120 mg, white solid), yield： 75.0%.
MS m/z (ESI): 419.2 [M-100+1]
Second step
5- [(the small base of 4- oxo -3H- phthalazines) methyl]-N- (3- piperidine methyls) -2,3- Dihydrobenzofuranes -7- carboxamide hydrochlorides are by 3- [[[5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] amino] methyl] piperidines -1- t-butyl formates 50b (120 mg, 0.23 mmol) stirring under be dissolved in the methanol solution and 10 mL dichloromethane of the M hydrogen chloride of 5 mL 2, react 5 hours.Filtering, solid is washed (20 mL) with ether, obtain title product 5- [(the small base of 4- oxo -3H- phthalazines) methyl]-N- (3- piperidine methyls) -2, (100 mg of 3- Dihydrobenzofuranes -7- carboxamide hydrochlorides 50, white solid), yield： 95.0%.
MS m/z (ESI): 419.1 [M+l]
Ή NMR (400 MHz, DMSO-i¾):δ 12.58 (s, IH), 8.87 (s, IH), 8.61 (s, IH), 8.25 (d, IH), 7.95-7.81 (m, 3H), 7.53 (s, IH), 7.35 (s, IH), 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, IH), 1.96 (s, IH), 1.78-1.70 (m, IH), 1.60-1.57 (m, IH), 1.23-1.17 (m, IH) embodiment 51
4- [[7- [4- (4- pyridylmethyls) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
The first step
4- (4- pyridylmethyls) piperazine -1- t-butyl formates
By Pyridine-4-Carboxaldehyde 51a (1.07 g, 0.01 mol) stirring under be dissolved in 10 mL 1, in the chloroethene protective embankments of 2- bis-, add piperazine -1- t-butyl formates (1.86 g, 0.01 mmol), sodium triacetoxy borohydride (4.20 g, 0.02 mol) is added, is reacted 12 hours.Under ice bath, add 20 mL saturated sodium bicarbonate solutions, (20 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain title product 4- (4- pyridylmethyls) piperazine -1- t-butyl formates 51b (2.70 g, white solid), yield： 97.0%.
MS m/z (ESI): 278.2 [M+l]
Second step
L- (4- pyridylmethyls) piperazine hydrochloride
It is dissolved under the small t-butyl formate 51b of 4- (4- pyridylmethyls) piperazine (2 g, 7.20 mmol) is stirred in 15 mL dichloromethane protective embankments, under ice bath, adds the methanol solution of the M hydrogen chloride of 15 mL 2, react 3 hours.Filtering, collects solid, obtains title product 1- (4- pyridylmethyls) piperazine hydrochloride 51c (1.50 g, white solid), yield： 97.0%.
3rd step
4- [[7- [4- (4- pyridylmethyls) piperazine -1- carbonyls] -2, 3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone is by 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (100 mg, 0.31 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sequentially add 1- (4- pyridylmethyls) piperazine hydrochloride 51c (66 mg, 0.31 mmol), I-hydroxybenzotriazole (62 mg, 0.46 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (89 mg, 0.46 mmol) and triethylamine (93 mg, 0.93 mmol), reaction 12 hours.Add 30 mL water, filtering, filter cake is washed (10 mL) with water (10 mL), saturated ammonium chloride solution successively, with thin-layered chromatography with solvent system A purify gained filter cake, obtain title product 4- [[7- [4- (4- pyridylmethyls) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 51 (100 mg, white solid), yield： 67.0%.
MS m/z (ESI): 482.2 [M+l]
1H NMR (400 MHz, DMSO-^):δ 12.58 (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- [(l- methyl -3- piperidyls) methyl] -5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- formamides
50 52
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl]-N- (3- piperidine methyls) -2, (60 mg of 3- Dihydrobenzofuranes -7- carboxamide hydrochlorides 50,0.13 mmol) stirring under be dissolved in 20 mL dichloromethane, sequentially add triethylamine (0.2 mL, 1 mmol), 37% formalin (21 mg, 0.26 mmol) and sodium triacetoxy borohydride (54 mg, 0.26 mmol), react 12 hours.Add 20 mL water, divide liquid, collect organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, 10 mL water and potassium carbonate (500 mg are added in residue, 3.62 mmol), stirring 12 hours, (10 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product N- [(l- methyl -3- piperidyls) methyl] -5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, (30 mg of 3- Dihydrobenzofuranes -7- formamides 52, white solid), yield： 52.6%.
MS m/z (ESI): 433.2 [M+l]
1H NMR (400 MHz, OMSO-d6):δ 12.58 (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- dihydros -5H- [1,2,4] triazol [4,3-a] piperazine -7- carbonyl -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
The first step
2- (the fluoro- phenoxy groups of the bromo- 5- of 2-) ethanol
By 1- bromo- 2, fluoro- benzene 53a (10 g of 4- bis-, 51.80 mmol) stirring under be dissolved in 100 mL ethylene glycol, add 10 mL l- methylpyrrole protective embankment -2- ketone, potassium tert-butoxide (20.34 g are added portionwise, 181.30 mmol), 100 °C are reacted 7 hours.Add 100 mL water, it is extracted with ethyl acetate (120 mLx3), merge organic phase, (50 mLx2), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain title product 2- (the fluoro- phenoxy groups of the bromo- 5- of 2-) ethanol 53b (7.91 g, light yellow oil), yield： 64.9%.
Second step
1- is bromo-2-(2- bromine oxethyl)-4- fluoro- benzene
Under ice bath, by 2- (the fluoro- phenoxy groups of the bromo- 5- of 2-) ethanol 531> (7.91§, 33.65 mmol) it is dissolved in 80 mL dichloromethane protective embankments under stirring, sequentially add carbon tetrabromide (13.95 g, 42.06 mmol) and triphenyl phosphorus (13.24 g, 50.48 mmol), room temperature reaction 2 hours.Be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the fluoro- benzene 53c of the bromo- 2- of title product 1- (2- bromine oxethyls) -4- (10.09 g, colorless oil), yield： 100%.
3rd step
The fluoro- 2,3- Dihydrobenzofuranes of 6-
In dry ice acetone bath, by fluoro- benzene 53c (10.06 g of the bromo- 2- of 1- (2- bromine oxethyls) -4-, 33.76 mmol) stirring under be dissolved in 110 mL tetrahydrofurans, the just own protective embankment solution of the M n-BuLis of 14.2 mL 2.5 is added dropwise, -78 °C are reacted 2 hours, are gradually increased to room temperature.Under ice bath, 50 mL water are added dropwise, are extracted with ethyl acetate (100 mLx3), merge organic phase, washed (50 mL), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain fluoro- 2,3- Dihydrobenzofuranes 53d (3.86 g of title product 6-, colorless oil), yield： 82.8%.
4th step Fluoro- 2, the 3- Dihydrobenzofuranes -5- formaldehyde of 6-
Under ice bath, by 6- fluoro- 2,3- Dihydrobenzofuranes 53d (3.86 g, 28 mmol) stirring under be dissolved in Ν, in Ν-dimethylformamide (4.8 mL, 61.50 mmol), POCl3 (5.1 mL are added dropwise, 56 mmol), 85 °C are reacted 7 hours.Add in 30 mL frozen water, stir 10 hours.It is extracted with ethyl acetate (40 mLx3), merge organic phase, washed (30 mLx2), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain fluoro- 2,3- Dihydrobenzofuranes -5- formaldehyde 53e (2.38 g of title product 6-, white solid), yield： 51.2%.
5th step
Fluoro- 2, the 3- Dihydrobenzofuranes -5- formaldehyde of the bromo- 6- of 7-
It is dissolved under fluoro- 2, the 3- Dihydrobenzofuranes -5- formaldehyde 53e of 6- (1.50 g, 9 mmol) are stirred in 20 mL acetic acid, add sodium acetate (0.88 g, 10.80 mmol) and bromine (2.88 g, 18 mmol), react 15 hours.Sequentially add 20 mL saturated sodium bisulfite solutions and 20 mL saturated sodium bicarbonate solutions, it is extracted with ethyl acetate (50 mLx3), merge organic phase, (40 mL), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression is concentrated, and obtains fluoro- 2,3- Dihydrobenzofuranes -5- formaldehyde 53f (1.61 g of the bromo- 6- of crude title product 7-, light yellow solid), product is not purified directly to carry out next step reaction.
MS m/z (ESI): 256.9 [M+l]
6th step
(3Z) -3- [(bromo- 6- of 7- fluoro- 2, 3- Dihydrobenzofuranes -5- bases) methylene] isobenzofuran -1- ketone is by the bromo- 6- of crude product 7- fluoro- 2, 3- Dihydrobenzofuranes -5- formaldehyde 53f (1.35 g, 5.51 mmol) stirring under be dissolved in 30 mL tetrahydrofurans, add 3- dimethoxy Rocky base -3H- isobenzofuran -1- ketone 53g (1.34 g, 5.51 mmol, using known method " Jowr " fir/ of Medicinal Chemistry, 2008, 51 (20), 6581-6591 " is prepared), triethylamine (0.8 mL is added dropwise in controlling reaction temperature under 15 °C, 5.51 mmol), room temperature reaction 5 hours, reacted 12 hours under 50 °C.It is concentrated under reduced pressure, add 20 mL water, after stirring 30 minutes, filtering, filter cake uses water (10 mL), ether (10 mL), petroleum ether (20 mL) successively, vacuum drying, obtain crude title product (3Z) -3- [(bromo- 6- of 7- fluoro- 2,3- Dihydrobenzofuranes -5- bases) methylene] isobenzofuran -1- ketone 53h (1.28 g, gray solid), product is not purified directly to carry out next step reaction.
MS m/z (ESI): 361.9 [M+l]
7th step
4- [(the bromo- 6- of 7- fluoro- 2,3- Dihydrobenzofuranes -5- bases) methyl] -2H- phthalazines -1- ketone is by crude product (3Z) -3- [(the bromo- 6- of 7- fluoro- 2, the 3- Dihydrobenzofuranes -5- bases) methylene] -one of isobenzofuran -1 53h
It is dissolved under (100 mg, 0.28 mmol) stirring in 15 mL hydrazine hydrates, 100 °C are reacted 7 hours.Ice bath is cooled down, filtering, filter cake is washed (10 mL) with water (10 mL), ether successively, vacuum drying, obtain title product 4- [(the bromo- 6- of 7- fluoro- 2,3- Dihydrobenzofuranes -5- bases) methyl] -2H- phthalazines -1- ketone 53i (60 mg, white solid), yield： 57.1 %.
MS m/z (ESI): 376.0 [M+l]
8th step The fluoro- 5- of 6- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- formic acid
Under -78 °C, by 4- [(the bromo- 6- of 7- fluoro- 2,3- Dihydrobenzofuranes -5- bases) methyl] -2H- phthalazines -1- ketone 53i (100 g, 0.27 mmol) stirring under be dissolved in 5 mL tetrahydrofurans, the hexane solution of the M n-BuLis of 0.3 mL 2.5 is added dropwise, reaction 40 minutes, carbon dioxide replacement three times is reacted at room temperature 1 hour under carbon dioxide atmosphere.Add 5 mL water, it is concentrated under reduced pressure, add 10 mL ethyl acetate and 10 mL water, divide liquid, collect aqueous phase, it is 2 that 1 M hydrochloric acid, which is added dropwise, to aqueous phase pH, is extracted with ethyl acetate (15 mLx3), merges organic phase, washed with saturated nacl aqueous solution (10 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain the fluoro- 5- of title product 6- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- formic acid 53j (40 mg, white solid), yield： 44.0%.
MS m/z (ESI):295.1 [M-46+1]
9th step
4- [[the fluoro- 7- of 6- [3- (trifluoromethyl) -6,8- dihydros -5H- [1,2,4] triazol [4,3-a] piperazine -7- carbonyl -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By the fluoro- 5- of 6- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 53j (30 mg, 0.09 mmol) stirring under be dissolved in 5 mL Ν, in Ν-dimethylformamide, sequentially add 3- trifluoromethyls -5, 6, 7, 8- tetrahydrochysenes-[1, 2, 4] triazol [4, 3-a] pyrazine hydrochloride (17 mg, 0.10 mmol, it is prepared using known method " patent WO2004080958 "), I-hydroxybenzotriazole (18 mg, 0.13 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (26 mg, 0.13 mmol) and triethylamine (36 mg, 0.35 mmol), reaction 15 hours.Add 20 mL water, it is extracted with ethyl acetate (50 mLx2), merge organic phase, successively with 1 M hydrochloric acid (20mL), saturated sodium bicarbonate solution (20 mL), saturated nacl aqueous solution washs (20 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product 4- [[the fluoro- 7- of 6- [3- (trifluoromethyl) -6, 8- dihydros -5H- [1, 2, 4] triazol [4, 3-a] piperazine -7- carbonyls -2, 3- Dihydrobenzofuranes -5- bases] methyl] 53 (28 mg of -2H- phthalazines -1- ketone, white solid), yield： 62.2 %.
MS m/z (ESI): 515.1 [M+1]
1H NMR (400 MHz, CDC13):δ 10.34 (s, 1 Η), 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- pyridylmethyls) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
The first step
4- (3- pyridylmethyls) piperazine -1- t-butyl formates
By pyridine -3- formaldehyde 54a (1.07 g, 10 mmol) stirring under be dissolved in 50 mL 1, in 2- dichloroethanes, piperazine -1- t-butyl formates (1.95 g, 10.50 mmol) are added, are reacted 30 minutes, under ice bath, sodium triacetoxy borohydride (4.23 g, 20 mmol) is added, is reacted at room temperature 12 hours.15 mL water are added, point liquid collects organic phase, successively with saturated sodium carbonate solution (5 mLx3), water (5 mL><3), saturated nacl aqueous solution washing (5 mLx3), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain title product 4- (3- pyridylmethyls) piperazine -1- t-butyl formates 54b (2.30 g, brown oil), yield： 83.0%.
MS m/z (ESI): 278.2 [M+l]
Second step
1-(3- pyridylmethyls) piperazine hydrochloride
It is dissolved in the methanol solution of the M hydrogen chloride of 10 mL 2, reacts 12 hours under 4- (3- pyridylmethyls) piperazine -1- t-butyl formates 54b (2.10 g, 7.58 mmol) is stirred.It is concentrated under reduced pressure, obtains brown solid, with methanol and petroleum ether (V/V=1:5) mixed solvent washing, obtains title product 1- (3- pyridylmethyls) piperazine hydrochloric acid 54c (1.30 g, white solid), yield： 81.0%.
3rd step
4- [[7- [the small carbonyl of 4- (3- pyridylmethyls) piperazines] -2, 3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone is by 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (200 mg, 0.62 mmol) stir dissolve under be dissolved in 5 mL N, in dinethylformamide, sequentially add 1- (3- pyridylmethyls) piperazine hydrochloride 54c (159 mg, 0.74 mmol), I-hydroxybenzotriazole (126 mg, 0.93 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (178 mg, 0.93 mmol) and triethylamine (313 mg, 3.10 mmol), reaction 12 hours.Add 50 mL water, (20 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, washed and put on the skin (5 mLx3) with water (5 mLx3), saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- (3- pyridylmethyls) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 54 (120 mg, white solid), yield： 40.2%.
MS m/z (ESI): 482.2 [M+l]
1H NMR (400 MHz, OMSO-d6):δ 12.58 (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- ketone
The first step
2- (t-butoxycarbonyl amino) acetic acid
By 2- amion acetic acids 55a (1 g, 13.30 mmol) stirring under be dissolved in 32 mL 1, in 4- dioxane solutions, sequentially add di-tert-butyl dicarbonate (4.36 g, 19.98 mmol) and sodium hydroxide (0.60 g, 15.99 mmol), react 12 hours.It is concentrated under reduced pressure, 20 mL water are added, are washed with ethyl acetate (40 mLx2), 1 M hydrochloric acid of dropwise addition to aqueous phase pH is 4, it is extracted with ethyl acetate (40 mLx2), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain title product 2- (t-butoxycarbonyl amino) acetic acid 55b (2.20 g, white solid), yield： 98.0%
MS m/z (ESI): 351.0 [2M+1]
Second step
N- [2- oxos -2- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- bases] ethyl] t-butyl carbamate
By 4- [[7- (piperazine -1- carbonyls) -2, 3- Dihydrobenzofuranes -5- bases] methyl] 4 (223 mg of -2H- phthalazines -1- ketone, 0.57 mmol) stirring under be dissolved in 20 mL N, in dinethylformamide, sequentially add 2- (t-butoxycarbonyl amino) acetic acid 55b (100 mg, 0.57 mmol), I-hydroxybenzotriazole (115 mg, 0.86 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (163 mg, 0.86 mmol) and triethylamine (173 mg, 1.71 mmol), reaction 12 hours.50 mL water are added, (30 mL are extracted with ethyl acetate><3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, and obtains title product N- [2- oxos -2- [4- [5- [(the small base of 4- oxo -3H- phthalazines) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- bases] ethyl] t-butyl carbamate 55c (221 mg, light yellow solid), yield： 70.6%.
MS m/z (ESI): 448.2 [M-100+1]
3rd step
4- [[7- [4- (2- glycyls) piperazine -1- carbonyls] -2; 3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone is by N- [2- oxos -2- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2; 3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- bases] ethyl] t-butyl carbamate 55c (221 mg; 0.40 mmol) stirring under be dissolved in the methanol solution of the M hydrogen chloride of 10 mL 1, react 12 hours.It is concentrated under reduced pressure; be added dropwise ammoniacal liquor to reaction solution ρ Η be 8; it is extracted with ethyl acetate (20 mLx3); merge organic phase; it is concentrated under reduced pressure; with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- (2- glycyls) piperazine -1- carbonyls] -2,3- dihydrobenzos Furans -5- bases] methyl] -2H- phthalazines -1- ketone 55 (100 mg, colorless oil), yield： 55.0%.
MS m/z (ESI): 448.2 [M+l]
1H NMR (400 MHz, CD3OD):δ 8.35 (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- methylaminos acetyl group) piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1-
The first step
2- (tertbutyloxycarbonyl (methyl) amino) methyl acetate
By 2- (t-butoxycarbonyl amino) acetic acid 55b (0.80 g, 4.57 mmol) stirring under be dissolved in 5 mL Ν, in Ν-dimethylformamide, sodium hydride and mineral oil mixture (548 mg, 60% are added, 22.80 mmol), under ice bath, react 1 hour, add iodine first protective embankment (1.94 g, 13.70 mmol), react at room temperature 12 hours.Add 10 mL water, extracted with dichloromethane (10 mLx2), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain title product 2- (tertbutyloxycarbonyl (methyl) amino) methyl acetate 56a (780 mg, colorless oil), yield： 84.0%.
MS m/z (ESI): 104.1 [M-100+1]
Second step
2- (tertbutyloxycarbonyl (methyl) amino) acetic acid
It is dissolved under 2- (tertbutyloxycarbonyl (methyl) amino) methyl acetate 56a (780 mg, 3.80 mmol) are stirred in 3.8 mL methanol, adds the M sodium hydroxide solutions of 3.8 mL 1, is reacted 12 hours.It is concentrated under reduced pressure, be added dropwise 1 M hydrochloric acid to aqueous phase pH be 4, it is extracted with ethyl acetate (10 mLx2), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain title product 2- (tertbutyloxycarbonyl (methyl) amino) acetic acid 56b (670 mg, colorless oil), yield： 92.0%.
MS m/z (ESI): 188.1 [M-l] 3rd step
N_ methyl _N_ [2- oxos _2_ [4_ [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- bases] ethyl] t-butyl carbamate
By 4- [[7- (piperazine -1- carbonyls) -2, 3- Dihydrobenzofuranes -5- bases] methyl] 4 (412 mg of -2H- phthalazines -1- ketone, 1.06 mmol) stirring under be dissolved in 10 mL N, in dinethylformamide, sequentially add 2- (tertbutyloxycarbonyl (methyl) amino) acetic acid 56b (200 mg, 1.06 mmol), I-hydroxybenzotriazole (215 mg, 1.59 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (304 mg, 1.59 mmol) and triethylamine (321 mg, 3.18 mmol), reaction 12 hours.50 mL water are added, (50 mL are extracted with ethyl acetate<3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain title product N- methyl-N- [2- oxos -2- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- bases] ethyl] t-butyl carbamate 56c (540 mg, white solid), yield： 90.0%.
MS m/z (ESI): 462.2 [M-100+1]
4th step
4- [[7- [4- (2- methylaminos acetyl group) the small carbonyl of piperazine] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- keto hydrochlorides
By N- methyl-N- [2- oxos -2- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] the small base of piperazine] ethyl] t-butyl carbamate 56c (540 mg, 0.96 mmol) stirring under be dissolved in the methanol solution of 10 mL I M hydrogen chloride, react 12 hours.It is concentrated under reduced pressure; obtain title product 4- [[7- [4- (2- methylaminos acetyl group) piperazine -1- carbonyls] -2; 3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- keto hydrochlorides 56 (370 mg, light yellow solid), yield： 83.5 %.
MS m/z (ESI): 462.2 [M+l]
1H NMR (400 MHz, OMSO-d6):δ 12.57 (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- pyridine radicals] methyl] piperazine-1- carbonyls]-2, 3- Dihydrobenzofuranes -5- bases] and methyl J-2H- phthalazines -1- ketone
The first step
4- [[6- (trifluoromethyl) -3- pyridine radicals] methyl] piperazine -1- t-butyl formates are by 6- (trifluoromethyl) P than pyridine -3- formaldehyde 57a (350 mg, 2 mmol) stirring under be dissolved in 5 mL 1, in the chloroethene protective embankments of 2- bis-, add piperazine -1- t-butyl formates (409 mg, 2.20 mmol), reaction 30 minutes, under ice bath, add sodium triacetoxy borohydride (848 mg, 4 mmol), react at room temperature 12 hours.Add 15 mL water, divide liquid, collect organic phase, washed (5 mLx3), anhydrous sodium sulfate drying, filtered with saturated sodium carbonate solution (5 mLx3), water (5 mLx3), saturated nacl aqueous solution successively, filtrate decompression is concentrated, obtain title product 4- [[6- (trifluoromethyl) -3- pyridine radicals] methyl] piperazine -1- t-butyl formates 57b (650 mg, yellow solid), yield： 94.0%.
Second step
1- [[6- (trifluoromethyl) -3- pyridine radicals] methyl] piperazine hydrochlorides are by 4- [[6- (trifluoromethyl) -3- pyridine radicals] methyl] piperazine -1- t-butyl formates 57b (0.60 g, 1.74 mmol) stirring under be dissolved in the methanol solution of the M hydrogen chloride of 3 mL 2, react 12 hours.It is concentrated under reduced pressure, obtains title product 1- [[6- (trifluoromethyl) -3- pyridine radicals] methyl] piperazine hydrochloride 57c (0.40 g, white solid), yield： 81.6%.
3rd step
4- [[7- [4- [[6- (trifluoromethyl) -3- pyridine radicals] methyl] piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By 5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 3b (200 mg, 0.62 mmol) stirring under be dissolved in 5 mL N, in dinethylformamide, sequentially add 1-[[6- (trifluoromethyl)-3- pyridine radicals] methyl] piperazine hydrochloride 57c (174 mg, 0.62 mmol), I-hydroxybenzotriazole (126 mg, 0.93 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (177 mg, 0.93 mmol) and triethylamine (188 mg, 1.86 mmol), reaction 12 hours.Add 30 mL water, it is extracted with ethyl acetate (30 mLx3), merge organic phase, water (10 mLx2) is used successively, saturated nacl aqueous solution washs (10 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain title product 4- [[7- [4- [[6- (trifluoromethyl) -3- pyridine radicals] methyl] piperazine -1- carbonyls] -2, 3- Dihydrobenzofuranes -5- bases] methyl] small (130 mg of ketone 57 of -2H- phthalazines, white solid), yield： 38.0%.
MS m/z (ESI): 550.2 [M+l]
1H NMR (400 MHz, DMSO- )：δ 12.58 (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- [fluoro- [7- [4- (1- methylaminos cyclobutyl carbonyl) piperazine -1- the carbonyls] -2,3- Dihydrobenzofuranes -5- bases] first of 6-
'
The first step
4- [the fluoro- 5- of 6- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] small t-butyl formate of piperazine
By the fluoro- 5- of 6- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- formic acid 53j (135 mg, 0.40 mmol) stirring under be dissolved in 15 mL N, in dinethylformamide, sequentially add piperazine -1- t-butyl formates (89 mg, 0.48 mmol), I-hydroxybenzotriazole (80 mg, 0.60 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (114 mg, 0.60 mmol) and triethylamine (120 mg, 1.20 mmol), reaction 12 hours.Add 15 mL water, it is extracted with ethyl acetate (30 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain title product 4- [the fluoro- 5- of 6- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- t-butyl formates 58a (160 mg, yellow oil), yield： 79.2%
MS m/z (ESI): 509.2 [M+l]
Second step
4- [fluoro- [the 7- (piperazine -1- carbonyls) -2 of 6-, 3- Dihydrobenzofuranes -5- bases) methyl] -2H- phthalazines -1- ketone is by 4- [the fluoro- 5- of 6- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- t-butyl formates 58a (160 mg, 0.31 mmol) stirring under be dissolved in 10 mL methanol, the methanol solution of the M hydrogen chloride of 3 mL 2 is added, is reacted 12 hours.It is concentrated under reduced pressure, add 10 mL dichloromethane, be added dropwise 10% sodium hydroxide solution to reaction solution ρ Η be 9, extracted with dichloromethane (30 mLx3), merge organic phase, washed with saturated nacl aqueous solution (15 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, and obtains title product 4- [fluoro- [7- (piperazine -1- carbonyls) -2, the 3- Dihydrobenzofuranes -5- bases] methyl of 6-] -2H- phthalazines -1- ketone 58b (100 mg, white solid), yield： 78.1 %.
MS m/z (ESI): 409.1 [M+l]
3rd step N- [l- [4- [the fluoro- 5- of 6- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] cyclobutyl]-N- Methyl-carbamic acid tert-butyl esters
By the 4- [fluoro- [7- (piperazine -1- carbonyls) -2 of 6-, 3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 58b (100 mg, 0.25 mmol) stirring under be dissolved in 10 mL N, in dinethylformamide, sequentially add 1- (tert-butoxycarbonyl (methyl) amino) cyclobutyl formate 37b (68 mg, 0.29 mmol), I-hydroxybenzotriazole (50 mg, 0.37 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (70 mg, 0.37 mmol) and triethylamine (74 mg, 0.74 mmol), reaction 12 hours.50 mL water are added, are extracted with ethyl acetate (50 mLx3), merges organic phase, washes paint (50 mL with saturated sodium bicarbonate solution (20 mL), saturated nacl aqueous solution successively><2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain title product N- [l- [4- [the fluoro- 5- of 6- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] the small carbonyl of piperazine] cyclobutyl]-N- Methyl-carbamic acid tert-butyl esters 58c (130 mg, yellow oil), yield： 83.3 %.
MS m/z (ESI): 520.2 [M-100+1]
4th step
4- [fluoro- [7- [4- (1- methylaminos cyclobutyl carbonyl) piperazine -1- the carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl of 6-] -2H- phthalazines -1- keto hydrochlorides
By N- [l- [4- [the fluoro- 5- of 6- [(4- oxo -3H- phthalazines -1- bases）Methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] cyclobutyl]-N- Methyl-carbamic acid tert-butyl ester 58c (130 mg, 0.21 mmol) stirring under be dissolved in 10 mL methanol, the methanol solution of the M hydrogen chloride of 3 mL 2 is added, is reacted 12 hours.It is concentrated under reduced pressure, add 10 mL dichloromethane, be added dropwise 10% sodium hydroxide solution to reaction solution pH be 9, extracted with dichloromethane (30 mLx3), merge organic phase, Strip (15 mL) is washed with saturated nacl aqueous solution, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue.Products obtained therefrom is dissolved in 10 mL methanol, add 0.5 mL concentrated hydrochloric acids, reaction 12 hours, it is concentrated under reduced pressure, obtain the title product 4- [fluoro- [7- [4- (1- methylaminos cyclobutyl carbonyl) piperazine -1- carbonyls] -2 of 6-, 3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- keto hydrochlorides 58 (75 mg, white solid), yield： 66.4%.
MS m/z (ESI): 520.2 [M+l]
1H wakes up R (400 MHz, DMSO-^):δ 12.53 (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- [(2i) -2- methylpyrrolidin- 2- carbonyls] piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- keto hydrochlorides
The first step
01-tert-butyl group-02- methyl-(2/) -2- methylpyrrole protective embankment -1,2- dicarboxylic acid esters are by (2i) -2- methylpyrrolidin- 2- methyl formate hydrochlorides 25e (1.38 g, 7.70 mmol) stirring under be dissolved in
In 30 mL Isosorbide-5-Nitraes-dioxane, the M sodium hydroxide solutions of 15 mL 1 and di-tert-butyl dicarbonate (2 g, 9.20 mrnol) are added, is reacted 12 hours.It is concentrated under reduced pressure, adds 20 mL water, be extracted with ethyl acetate (30 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains the title product 01- tert-butyl group -02- methyl-(2/) -2- methylpyrrolidin- 1,2- dicarboxylic acid esters 59a (1.50 g, white solid), yield： 83.3 %. MS m/z (ESI): 144.1 [M-100+1]
Second step
(2R)-1-tertbutyloxycarbonyl-2- methylpyrrole protective embankment-2- formic acid
By the 01- tert-butyl group -02- methyl-(2i) -2- methylpyrrole protective embankment -1,2- dicarboxylic acid esters 59a (1.50 g, 6.20 mmol) stirring under be dissolved in 20 mL methanol, add the M sodium hydroxide solutions of 30 mL 1, react 12 hours.Add 15 mL water, (20 mLx2) o is washed with dichloromethane protective embankment and collects aqueous phase, be added dropwise concentrated hydrochloric acid to aqueous phase pH be 3, it is extracted with ethyl acetate (30 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, and obtains title product (2i)-l- tertbutyloxycarbonyl -2- methylpyrrole protective embankment -2- formic acid 59b (0.85 g, light yellow solid), yield： 60.7%.
MS m/z (ESI): 228.1 [M+l]
3rd step
(2i)-2- [4- [the fluoro- 5- of 6- [(4- oxo-3H- phthalazines-1- bases) methyl]-2,3- Dihydrobenzofuranes-7- carbonyls] piperazine-1- carbonyls]-2- methyl-pyrrol-1-t-butyl formates of protective embankment
By the 4- [fluoro- [7- (piperazine -1- carbonyls) -2 of 6-, 3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 58b (100 mg, 0.25 mmol) stirring under be dissolved in 10 mL N, in dinethylformamide, (2i is sequentially added)-l- tertbutyloxycarbonyl -2- methylpyrrolidin- 2- formic acid 59b (67 mg, 0.29 mmol), I-hydroxybenzotriazole (50 mg, 0.37 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (70 mg, 0.37 mmol) and triethylamine (74 mg, 0.74 mmol), react 12 hours.50 mL water are added, are extracted with ethyl acetate (50 mLx5), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains title product (2i) -2- [4- [the fluoro- 5- of 6- [(the small base of 4- oxo -3H- phthalazines) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] the small carbonyl of piperazine] -2- methyl - Pyrrolidines -1- t-butyl formates 59c (140 mg, yellow oil), yield： 92.1 %.
MS m/z (ESI): 520.2 [M-100+1]
4th step
4- [[the fluoro- 7- of 6- [4- [(2i) -2- methylpyrrole protective embankment -2- carbonyls] piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- keto hydrochlorides
By (2i) -2- [4- [the fluoro- 5- of 6- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] -2- methyl-pyrrol protective embankment -1- t-butyl formates 59c (100 mg, 0.16 mmol) stirring under be dissolved in 10 mL methanol, the methanol solution of the M hydrogen chloride of 3 mL 2 is added, is reacted 12 hours.It is 9 that 1 M sodium hydroxide solutions, which are added dropwise, to reaction solution pH, is extracted with dichloromethane (30 mLx3), merges organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify obtained by residue.Products obtained therefrom is dissolved in the methanol solution of the M hydrogen chloride of 3 mL 2, is reacted 12 hours, is concentrated under reduced pressure, obtains title product 4- [[the fluoro- 7- of 6- [4- [(2/) -2- methylpyrrole protective embankment -2- carbonyls] piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- keto hydrochlorides 59 (25 mg, white solid), yield： 21.4%.
MS m/z (ESI): 520.2 [M+l]
1H NMR (400 MHz, DMSO-i/6):δ 12.55 (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- (l- amino ring fourth protective embankments carbonyl) piperazine -1- carbonyls] the fluoro- 2,3- Dihydrobenzofuranes -5- bases of -6-] methyl] -2H-
The first step
N- [l- [4- [the fluoro- 5- of 6- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls]-piperazine -1- carbonyls] ring fourth protective embankment] t-butyl carbamate
By the 4- [fluoro- [7- (piperazine -1- carbonyls) -2 of 6-, 3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 58b (25 mg, 0.61 mmol), 1- (t-butoxycarbonyl amino) cyclobutane formate 60a (16 mg, 0.73 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (21 mg, 0.11 mmol), I-hydroxybenzotriazole (15 mg, 0.11 mmol) and triethylamine (19 mg, 0.18 mmol) it is dissolved in 5 mL N, in dinethylformamide, reaction 15 Hour.Add 30 mL water, it is extracted with ethyl acetate (40 mLx3), merge organic phase, 1M hydrochloric acid (30 mL) is used successively, saturated sodium bicarbonate solution (30 mL), saturated nacl aqueous solution washs (30 mL), with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product N- [l- [4- [the fluoro- 5- of 6- [(4- oxo -3H- phthalazines -1- bases) methyl] -2, 3- Dihydrobenzofuranes -7- carbonyls]-piperazine -1- carbonyls] ring fourth protective embankment] t-butyl carbamate 60b (29 mg, white solid), yield： 78.4%. MS m/z (ESI): 506.2 [M-100+1]
Second step
4- [[7- [4- (l- amino cyclobutanecarbonyl) piperazine -1- carbonyls] fluoro- 2, the 3- Dihydrobenzofuranes -5- bases of -6-] methyl] -2H- phthalazines -1- ketone
5 mL methanol hydrochloride solutions are added to N- [l- [4- [the fluoro- 5- of 6- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls]-piperazine -1- carbonyls] ring fourth protective embankment] t-butyl carbamate 60b (29 mg, 0.48 mmol) in, react 12 hours.It is concentrated under reduced pressure, ammoniacal liquor is added dropwise into residue, it is 89 to adjust pH, it is extracted with ethyl acetate (10 mLx2), the organic phase of merging uses anhydrous sodium sulfate drying successively, filtering, decompression is lower to be concentrated, vacuum drying, obtain title product 4- [[7- [4- (1- amino cyclobutanecarbonyl) piperazine -1- carbonyls] -6- fluoro- 2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 60 (20.6 mg, white solid), yield： 84.6%.
MS m/z (ESI): 543.2 [M+l]
1H NMR (400 MHz, D20):δ 8.16-8.14 (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
4-[[7-[4-[(27) -2- methylpyrrolidin- 2- carbonyls] the small carbonyl of piperazine] -2,3- yls] -2H- phthalazines -1- ketone
The first step
(3 & 7a ) -7a- methyl -3- (trichloromethyl) -3, simultaneously [the small ketone of l, 2-c] oxazoles is by (3S, 7ai for 5,6,7- nafoxidines) -3- (trichloromethyl) -5,6,7, [the small ketone 61a of l, 2-c] oxazoles (24.40 g, 100 mmol) is dissolved in 500 mL tetrahydrofurans 7a- tetrahydrochysene -3H- pyrrolo-es, the tetrahydrofuran solution of 80 mL 2M diisopropylamino lithium is added dropwise under -78 °C, -78 times reactions 1 hour, are added dropwise 30 mL iodine first protective embankments, react 1 hour.150 mL water are added, (300 mLx2) is extracted with three chloromethane protective embankments, merge organic layer, dried, filtered with anhydrous magnesium sulfate, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain title product (3S, 7a) -7a- methyl -3- (trichloromethyl) -3,5,6,7- nafoxidines simultaneously [l, 2-c] oxazole -1- ketone 61b (21.50 g, weak yellow liquid), yield： 82.6%.
MS m/z (ESI): 260.0 [M+l]
Second step
(2R) -2- methylpyrrole protective embankment -2- methyl formates
By (3S, 7a/) -7a- methyl -3- (trichloromethyl) -3,5,6, simultaneously [l, 2-c] oxazole -1- ketone 61b (18 g, 70 mmol) are dissolved in 360 mL methanol 7- nafoxidines, stirring 30 minutes, is added dropwise 17 mL thionyl chlorides, back flow reaction 3 hours.It is concentrated under reduced pressure, adds 50 mL ethyl acetate, stir, filtering, filter cake vacuum drying obtains title product (2i) -2- methylpyrrolidin- 2- methyl formates 61c (10 g, white solid), yield： 80.2%.
MS m/z (ESI): 144.2 [M+l]
3rd step
(2R)-2- methylpyrroles protective embankment-1,2- dioctyl phthalate-01-tertiary butyl ester-02- methyl esters is by (2i) -2- methylpyrrole protective embankment -2- methyl formates 61c (9 g, 50 mmol) it is dissolved in 180 mLl, 4- dioxane second protective embankments, add 75 mLI M sodium hydroxide solution and di-tert-butyl dicarbonate (13 g, 60 mmol), react 17 hours.It is concentrated under reduced pressure, adds l OO mL water, be extracted with ethyl acetate (100 mLx4), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains title product crude product (2i)-2- methylpyrrole protective embankment-1,2- dioctyl phthalate-01-tertiary butyl ester-02- methyl esters 61d (9.50 g, yellow oil), product is not purified to be directly used in the next step.
MS m/z (ESI): 144.1 [M-100+1]
4th step
(2R)-1-tertbutyloxycarbonyl-2- methyl-pyrrol protective embankment base-2- formic acid is by crude product (2i)-2- methylpyrrole protective embankment-1,2- dioctyl phthalate-01-tertiary butyl ester-02- methyl esters 61d (7.30 g, 30 mmol) are dissolved in 70 mL methanol, add 140 mLIM sodium hydroxide solutions, react 16 hours.Add 70 mL water, washed with dichloromethane protective embankment (100 mLx2), merge aqueous phase, it is 23 that concentrated hydrochloric acid, which is added dropwise, to aqueous phase ρ Η, is extracted with ethyl acetate (150 mLx3), merges organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains title product crude product (2i)-l- tertbutyloxycarbonyl -2- methyl-Pi coughs up protective embankment base -2- formic acid 61e (5.70 g, off-white powder), product is not purified to be directly used in the next step.
MS m/z (ESI): 228.1 [M-l]
5th step
(2i) -2- methyl -2- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazines Piperazine -1- carbonyls] pyrrolidines -1- t-butyl formates
By (2i)-2- methyl-2- [4- [5- [(4- oxo-3H- phthalazines-1- bases) methyl]-2,3- Dihydrobenzofuranes-7- carbonyls] piperazine-1-carbonyl] 4 (1.28 g of-1-t-butyl formate of pyrroles's protective embankment, 3 mmol) it is dissolved in 50 mL N, in N- diformazan formamides, crude product (2i is sequentially added)-l- tertbutyloxycarbonyl -2- methyl-pyrrol protective embankment base -2- formic acid 61e (824 mg, 3.60 mmol), I-hydroxybenzotriazole (608 mg, 4.50 mmol), 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (860 mg, 4.50 mmol) and triethylamine (879 mg, 8.70 mmol), react 48 hours.It is concentrated under reduced pressure, adds 10 mL dichloromethane, be washed with water (20 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains title product crude product (2i) -2- methyl -2- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] pyrrolidines -1- t-butyl formates 61f (1.70 g, yellow solid), product is not purified to be directly used in the next step.
MS m/z (ESI): 502.2 [M+l]
6th step
4-[[7-[4-[(2i2- methylpyrrolidin- 2- carbonyls] piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone
By crude product (2i) -2- methyl -2- [4- [5- [(4- oxo -3H- phthalazines -1- bases) methyl] -2,3- Dihydrobenzofuranes -7- carbonyls] piperazine -1- carbonyls] pyrroles protective embankment -1- t-butyl formates 61f (1.50 g, 2.50 mmol) it is dissolved in 15 mL dichloromethane protective embankments, add trifluoroacetic acid (1.5 mL, 20 mmol), react 16 hours.1M sodium hydroxide solutions (800 mg, 20 mmol) are added, (50 mL are extracted with dichloromethane protective embankment><3) organic phase, is merged, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains title product 4- [[7- [4- [(2i) -2- methylpyrrole protective embankment -2- carbonyls] piperazine -1- carbonyls] -2,3- Dihydrobenzofuranes -5- bases] methyl] -2H- phthalazines -1- ketone 61 (1.10 g, yellow solid), yield 88.0%. MS m/z (ESI): 502.2 [M+l]
lH NMR (400 MHz, DMSO-^):δ 12.57 (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
The PARP-1 enzyme assays of example 1 are tested
Following body outer screening test is the inhibitory action for determining the compounds of this invention for PARP- enzymatic activitys.Experiments described below determines inhibitory action of the invention compound to PARP enzymatic activitys by using homologous poly- (adenosine diphosphate (ADP)-ribose) the poly enzyme level kits (TREVIGEN HT F homogeneous PARP Inhibition Assay Kit, article No. No4690-096-K) of TREVIGEN HT F.Test needs to consume NAD+ based on the PARP DNA repair processes participated in, NAD+ is used for the molecule that the substrate of unstressed configuration activity is catalyzed into high fluorescence activity in another reaction simultaneously, therefore by determining the enhancing degree of fluorescence signal, the level of NAD+ in reaction system can be learnt, so as to calculate inhibition level of the test compound to PARP enzymatic activitys.
The detailed operation of experiment and the preparation of reagent used, such as reaction mixture (reaction mix), circulation are anti- Mixed liquor (cycling mix) and buffer solution (buffer) etc. are answered, homologous poly- (adenosine diphosphate (ADP)-ribose) the poly enzyme level kit specifications of TREVIGEN HT F are can refer to.
Experimental procedure is summarized as follows：Test compound is dissolved in dimethyl sulfoxide (DMSO), and concentration needed for experiment is then diluted to lx buffer solutions.25 μ are added into the orifice plate of round bottom 96 first, 200 nM, NAD+ solution is subsequently added 1 μ L test compounds solution and sets multiple holes to compare.Backward each hole in add the reaction mixture that 25 μ L contain DNA, PARP enzymes and reaction buffer.After incubating 30 minutes at room temperature, 50 circular response mixed liquors, at room temperature lucifuge, incubation 15 40 minutes are added into each hole.50 terminate liquids are subsequently added, the fluorescent value in each hole is read on ELIASA（Ex544 nm, Em590 nm).Compound can be calculated by NAD+ calibration curve equations
Chemical combination
Conclusion Aobvious inhibitory activity.The cell growth inhibition assay of example 2
Following experiment is used to determine proliferation inhibition activity of the compound of the present invention to the breast carcinoma cell strain MDA-MB-436 cells of three negative phenotypes under in vitro conditions.
In vitro cell experiment as described below can determine proliferation inhibition activity of the test-compound to the breast cancer cell of three negative phenotypes, and the inhibitory activity of compound can be represented with ICso values.
Experimental program is summarized as follows：First using the additional 10%FBS of DMEM F12 (being purchased from Gibco) as complete medium, MDA-MB-436 cells are inoculated with suitable cell density (3000/mL of e.g. medium) In on 96 well culture plates, under 37 °C, 5% carbon dioxide conditions, the overnight incubation in constant incubator.Test compound uses dmso solution, the concentration needed for being then diluted to experiment with the culture medium without FBS first.It is the fresh culture for adding a series of gradient concentration test-compounds (generally 7 or 9 concentration points) solution by original culture medium Geng Change after after cell attachment.Hereafter, by Tissue Culture Plate in 37 °C, 5 %C02Under the conditions of continue cultivate 72 hours.After 72 hours, using CCK8 (Cell Counting Kit-8, article No.：CK04, is purchased from Dojindo) method determines the inhibitory activity bred for cell of compound.
The IC of compound5QValue can be drawn by test-compound under various concentrations for the suppression numerical computations that cell is bred.
Conclusion:Preferred compound of the present invention has obvious inhibitory activity to MDA-MB-436 Carbazole alkaloids propagation.Pharmacokinetic Evaluation
The pharmacokinetics test of the embodiment of the present invention 22,25 of test case 1 and 33 compounds
1st, make a summary
Using SD rats as animal subject, determine rat intravenous injection using LC/MS/MS methods and give after embodiment 22,25 and 33 compounds not drug concentration in blood plasma in the same time.Pharmacokinetics behavior of the compounds of this invention in rat body is studied, its characteristics of pharmacokinetics is evaluated.
2nd, testing program
2.1 test drug
Embodiment 22,25 and 33 compounds
2.2 experimental animal Healthy adult SD rat 12, male and female half and half, purchased from the western pul-Bi Kai experimental animals Co., Ltd in Shanghai, animal productiong licensing number：SCXK (Shanghai) 2003-0002.
2.3 medicines are prepared
Appropriate amount of drug is weighed, the rear 0.5 % sodium carboxymethylcelluloses that add are configured to 1.5 mg/mL suspensions.
2.4 administration
It is injected intravenously respectively after healthy adult SD rat 12, male and female half and half, overnight fasting, dosage is 15.0 mg/kg, the mL/kg of administered volume 10.
2.5 sample collection
2 minutes, 15 minutes, 0.5,1.0,2.0 before being administered and after administration, 3.0,4.0,6.0,8.0,12.0, by eye socket 0.2 mL of blood sampling, it is placed in heparinised tubes, 3500 revs/min, centrifuges 20 minutes separated plasmas within 24.0 hours, in one 20 °C of preservation.
3rd, operate
Each 20 μ of rat blank blood plasma at each moment after medicine is drawn, the μ of inner mark solution 50, the μ L of methanol 140 is added, vortex mixed 3 minutes after mixing are centrifuged 10 minutes（13500 revs/min), take the μ of supernatant 20 to carry out LC-MS/MS analyses.Main pharmacokinetic parameter is calculated using the softwares of DAS 2.0.
4th, pharmacokinetic parameter result
The pharmacokinetic parameter of the compounds of this invention is following-
Conclusion：Preferably, pharmacokinetic property is obviously improved-tumor-inhibiting action evaluation to compound medicine of embodiment of the present invention codes or data
Test case 2 tests tumor-inhibiting action of the compounds of this invention to mouse
1. experiment purpose
Using BALB/cA-nude nude mices as animal subject, evaluate after the compounds of this invention and Temozolomide (TMZ) administering drug combinations to human colon carcinoma SW620 or the curative effect of people triple negative breast cancer cell MDA-MB-436 transplantable tumor transplantable tumor nude mouses.
2. test medicine
The compound of embodiment 25 3. experimental animal
BALB/cA-nude nude mouses, SPF, 16-20g,, purchased from the western pul in Shanghai must the triumphant limited duty of experimental animal ' appoint company.Quality certification number：SCXK (Shanghai) 2008-0016.
4. experimental procedure ' 4.1 nude mouse laboratory environment is adapted to three days.
The right flank subcutaneous vaccination colon cancer SW620 cells of 4.2 nude mouses, treat tumour length to 339 ± 132 mm3Animal is grouped to (d0) at random afterwards.
The right flank subcutaneous vaccination MDA-MB-436 cells of nude mouse, tumour growth 53 days is long to 360 ± 49 mm3Animal is grouped to (D0) at random afterwards.
4.3 dosages and dosage regimen see the table below.23 knurl volumes are surveyed weekly, claim mouse weight, record data.Gross tumor volume（V) calculation formula is：
V= l/2xaxb2
Wherein：A, b represent length and width respectively.
Tumour inhibiting rate (%)=^-7 ^ (%)
Wherein：T, C be respectively experiment at the end of experimental group (testing compound) and blank control group gross tumor volume.
5. dosage, dosage regimen and experimental result
Conclusion：Tumour inhibiting rate % data areas are represented： "+"： 40%〜60% ； "++"： 60%〜80% ；" +++,: 80%〜100%.Present invention compound to be measured has good tumour inhibiting rate to colon cancer SW620 cells and/or people's triple negative breast cancer MDA-MB-436 cells with TMZ combinations, most of to be higher than 60%.

Claims (1)

  1. Claims:
    1st, a kind of formula（I compound or its pharmaceutically useful salt shown in):
    ( I )
    Wherein：
    A and B form ring protective embankment base, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein the cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10Rn -OC(O)NR10R1 -NHC(O)NR10Ru、 -C(O)(CH2)mNR10RnOr-S (0)mR9Substituent replaced；
    E is formula-(CH2)nl-Q„2-(CH2)n3-;
    Wherein nl, n2 and n3 are respectively selected from 0,1,2 and 3, and nl, n2 and n3 summation are that 1,2 or 3, Q are selected from 0, S, NH or C (O);
    R1Selected from hydrogen atom, alkyl, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl or heteroaryl； R2、 R3And R4It is each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, alkyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10Rn -OC(O)NR10Rn -NHC(O)NR10Rn , -C(O)(CH2)mNR10RuOr-S (0)mR9, wherein described alkyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional to be further selected from halogen, hydroxyl, protective embankment base, alkoxy ,-C (0) OR by one or more9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR^R11 ^ -OC(O)NRI0Rn > -NHC(O)NR10Ru , - OXCH mNR^R11Or-S (0)mR9Substituent replaced；
    R5And R6It is each independently selected from hydrogen atom, hydroxyl, alkyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -C(0)R9Or-QOXCH^NR^R11, further replaced wherein described protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional by one or more substituents selected from halogen, hydroxyl, alkyl or alkoxy, or R5And R6- rise form oxo；
    R7And R8It is each independently selected from hydrogen atom, hydroxyl, alkyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -ΝΚ10ΚΠ -OC(O)NR10Rn -NHC(O)NR10Rn , - OXCH^NR1^11Or-S (0)mR9, wherein described protective embankment base, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl or heteroaryl each it is individually optional further by it is one or more selected from halogen, hydroxyl, The substituent of protective embankment base or alkoxy is replaced, or R7And R8- rise form oxo；
    R9Selected from hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical by one or more independently of one another：Aryl, heteroaryl,
    Or-C ^NR11Substituent replaced；
    R1()Or R11Hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, alkyl, halogen, cyano group, alkoxy, ring protective embankment base, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more independently of one another12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)mNR13R14Or-S (0) mR12Substituent replaced；
    Or, R1QAnd R11Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, 0 or S (0) in described heterocyclic radicalmHetero atom, and the heterocyclic radical is optionally further selected from hydroxyl, alkyl, halo protective embankment base, halogen, cyano group, alkoxy, cycloalkyl, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)mNR13R14Or-S (0)mR12Substituent replaced, wherein protective embankment base, ring protective embankment base, benzyl, heteroaryl are optionally further replaced by one or more substituents selected from alkyl, haloalkyl, halogen, hydroxyl, alkoxy, heteroaryl or ring protective embankment base independently of one another；
    R12、 R13Or R14Hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another15、 -OC(0)R15、 -C(0)R15、 -NHC(0)R15、 -NR16R17、 -OC(0)NR16R17、 -NHC(0)NR16R17、 -C(0)(CH2)mNR16R17Or-S (0)mR15Substituent replaced；
    R15、 R16Or R17Hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl by one or more independently of one another；And
    M is 0,1 or 2.
    2nd, formula according to claim 1（I compound or its pharmaceutically useful salt shown in), including a kind of formula（II compound or its pharmaceutically useful salt shown in)：
    ( Π)
    Wherein-
    Α and Β form cycloalkyl, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein the cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10R"、 -OC(O)NR10Rn , -NHC(O)NR10Rn -C(O)(CH2)mNR10RnOr-S (0)mR9Substituent replaced；
    R1Selected from hydrogen atom, protective embankment base, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl or heteroaryl；
    R2、 R3And R4It is each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, protective embankment base, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9 -NR10Rn , -OC^NR^R1^ -NHC(O)NR10Rll -C(O)(CH2)mNR10RnOr-S (0)mR9, wherein described protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional to be further selected from halogen, hydroxyl, alkyl, protective embankment epoxide ,-C (0) OR by one or more9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10Rn -OC(O)NR10Rn, -NHC^NR^R11^ -C(O)(CH2)mNR10RnOr-S (0)mR9Substituent replaced；
    R5And R6It is each independently selected from hydrogen atom, hydroxyl, alkyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -C(0)R9Or-OXCH^NR^R11, further replaced wherein described protective embankment base, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each individually optional by one or more substituents selected from halogen, hydroxyl, protective embankment base or protective embankment epoxide, or R5And R6- rise form oxo；
    R7And R8It is each independently selected from hydrogen atom, hydroxyl, protective embankment base, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10Rn -OC(O)NR10Ru , -NHC(O)NR10Rn. - OXCH^NRWR11Or-S (0)mR9, further replaced wherein described protective embankment base, alkoxy, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional by one or more substituents selected from halogen, hydroxyl, alkyl or protective embankment epoxide, or R7And R8- rise form oxo；
    R9Selected from hydrogen atom, alkyl, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl, wherein described alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl independently of one another optionally further by it is one or more selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl,
    Or-C^NR^R11Substituent replaced；
    R1QOr R11Be each independently selected from hydrogen atom, alkyl, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl independently of one another optionally further by It is one or more to be selected from hydroxyl, alkyl, halogen, cyano group, alkoxy, ring protective embankment base, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)mNR13R14Or-S (0)mR12Substituent replaced；
    Or, R1QAnd R11Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, 0 or S (0) in described heterocyclic radicalmHetero atom, and the heterocyclic radical is optionally further selected from hydroxyl, protective embankment base, halo protective embankment base, halogen, cyano group, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)mNR13R14Or-S (0)mR12Substituent replaced, wherein protective embankment base, ring protective embankment base, benzyl, heteroaryl are optionally further replaced by one or more substituents selected from alkyl, halo protective embankment base, halogen, hydroxyl, protective embankment epoxide, heteroaryl or ring protective embankment base independently of one another；
    R12、 R13Or R14Hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another15、 -OC(0)R15、 -C(0)R15、 -NHC(0)R15、 -NR16R17、 -OC(0)NR16R17、 -NHC(0)NR16R17、 -C(0)(CH2)mNR16R17Or-S (0)mR15Substituent replaced；
    R15、 R16Or R17Hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl by one or more independently of one another；And
    M is 0,1 or 2.
    3rd, formula according to claim 1 or 2（I compound or its pharmaceutically useful salt, wherein R shown in)2For halogen.
    4th, formula according to claim 1（I compound or its pharmaceutically useful salt shown in), including a kind of formula（III compound or its pharmaceutically useful salt shown in)：
    (IH)
    Wherein： A and B form ring protective embankment base, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein the ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, protective embankment base, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10RN > -OC(O)NR10R1 -NHC(O)NR10RN , -C(O)(CH2)MNR10RNOr-S (0)MR9Substituent replaced；
    R1Selected from hydrogen atom, alkyl, hydroxyl or alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl； R3And R4It is each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, protective embankment base, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10RN , -OC(O)NR10R1 -NHC(O)NRI0RN , -C(O)(CH2)MNR10RNOr-S (0)MR9, wherein described alkyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional to be further selected from halogen, hydroxyl, alkyl, alkoxy ,-C (0) OR by one or more9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10R' -OC(O)NR10RU、 -NHC(O)NR10RU、 -C(O)(CH2)MNR10R11Or-S (0)MR9Substituent replaced；
    R5And R6It is each independently selected from hydrogen atom, hydroxyl, protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -C(0)R9Or-OXCH^NR^R11, further replaced wherein described protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional by one or more substituents selected from halogen, hydroxyl, protective embankment base or protective embankment epoxide, or R5And R6- rise form oxo；
    R7And R8It is each independently selected from hydrogen atom, hydroxyl, alkyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR^R11 ^ -OC^NR^R1^ -NHC(O)NR10RN , (OXCH^NRWR11Or-S (0)MR9, further replaced wherein described protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional by one or more substituents selected from halogen, hydroxyl, alkyl or alkoxy, or R7And R8- rise form oxo；
    R9Selected from hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from protective embankment base, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-NR^R^-CX C NR^R by one or more independently of one another11Or (C NR^R11Substituent replaced；
    R1()Or R11Hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, alkyl, halogen, cyano group, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more independently of one another12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、
    -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)MNR13R14Or-S (0)MR12Substituent replaced；
    Or, R1QAnd R11Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, 0 or S (0) in described heterocyclic radicalMHetero atom, and the heterocyclic radical is optionally further selected from hydroxyl, protective embankment base, halo protective embankment base, halogen, cyano group, alkoxy, ring protective embankment base, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)mNR13R14Or-S (0)mR12Substituent replaced, wherein protective embankment base, ring protective embankment base, benzyl, heteroaryl independently of one another optionally further by it is one or more be selected from alkyl, halo protective embankment base, halogen, hydroxyl, protective embankment epoxide：Heteroaryl or the substituent of cycloalkyl are replaced；
    R12、 R13Or R14Hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, alkyl, halogen, cyano group, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another15、 -OC(0)R15、 -C(0)R15、 -NHC(0)R15、 -NR16R17、 -OC(0)NR16R17、 -NHC(0)NR16R17、 -C(0)(CH2)mNR16R17Or-S (0)mR15Substituent replaced；
    R15、 R16Or R17Hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl by one or more independently of one another；And
    M is 0,1 or 2.
    5th, the formula according to any one of claim 1 ~ 4（I compound or its pharmaceutically useful salt, wherein R shown in)3And R4It is each independently selected from hydrogen atom or halogen, R5、 R6、 R7And R8For hydrogen atom.
    6th, formula according to claim 4（I compound or its pharmaceutically useful salt shown in), including a kind of formula（IV compound or its pharmaceutically useful salt shown in)：
    (IV)
    Wherein-
    A and B form ring protective embankment base, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected；
    R1Selected from hydrogen atom；
    R3And R4It is each independently selected from hydrogen atom or halogen；
    R1QOr R11Hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, alkoxy, cycloalkyl, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more independently of one another12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)mNR13R14Or-S (0)mR12Substituent replaced；
    Or, R1QAnd R11Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one in described heterocyclic radical Individual or multiple N, O or S (0)mHetero atom, and the heterocyclic radical is optionally further selected from hydroxyl, protective embankment base, halo protective embankment base, halogen, cyano group, alkoxy, ring protective embankment base, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R'\ -NHC(0)NR13R14、 -C(0)(CH2)mNR13R14Or-S (0)mR12Substituent replaced, wherein alkyl, ring protective embankment base, benzyl, heteroaryl are optionally further replaced by one or more substituents selected from alkyl, halo protective embankment base, halogen, hydroxyl, protective embankment epoxide, heteroaryl or ring protective embankment base independently of one another；
    R12、 R13Or R14Hydrogen atom, alkyl, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another15、 -OC(0)R15、 -C(0)R15、 -NHC(0)R15、 -NR16R17、 -OC(0)NR16R17、 -NHC(0)NR16R17、 -C(0)(CH2)mNR16R17Or-S (0)mR15Substituent replaced；
    R15、 R16Or R17Hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl or heteroaryl by one or more independently of one another；And
    M is 0,1 or 2.
    7th, the formula according to any one of claim 1 ~ 6（I compound or its pharmaceutically useful salt shown in), wherein A and B form aryl, preferably phenyl together with the carbon atom being connected.
    8th, the formula according to any one of claim 1 ~ 6（I compound or its pharmaceutically useful salt, wherein R shown in)1For hydrogen atom.
    9th, the formula according to claim 4 or 6（I compound or its pharmaceutically useful salt, wherein R shown in)1QAnd R11Heterocyclic radical is formed with the nitrogen-atoms being connected, wherein described heterocyclic radical is optionally further by one or more-C (0) R12Substituent replaced.
    10th, compound according to claim 9 or its pharmaceutically useful salt, wherein R12Selected from protective embankment base, ring protective embankment base or heterocyclic radical, wherein described protective embankment base, cycloalkyl or heterocyclic radical are optionally further selected from halogen, protective embankment base or-NR by one or more16R17Substituent replaced.
    11st, the formula according to any one of claim 1 10（I compound or its pharmaceutically useful salt shown in), the wherein compound is：
    117
    Formula (Ι Π Α) compound is optionally further hydrolyzed and formula NHR^R11Reaction, obtains logical formula (III) compound;Wherein： A, B, R1 , R3〜R8、 R1Q、 R11Definition as claimed in claim 4；
    R18Selected from hydrogen atom or protective embankment base. '
    13rd, the compound or its pharmaceutically useful salt shown in a kind of formula (IIIA):
    (HIA)
    Wherein：
    A and B form ring protective embankment base, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein the ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from halogen, hydroxyl, cyano group, nitro, protective embankment base, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10RN . -OC(O)NR10RN -NHC(O)NR10RU、 -C(O)(CH2)MNR10R11Or-S (0)MR9Substituent replaced；
    R1Selected from hydrogen atom, alkyl, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl or heteroaryl； R3And R4It is each independently selected from hydrogen atom, halogen, hydroxyl, cyano group, protective embankment base, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10RN , -OC^NR^R1^ -NHC(O)NR10RN > -C(O)(CH2)MNR10RNOr-S (0)MR9, wherein described protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional to be further selected from halogen, hydroxyl, protective embankment base, protective embankment epoxide ,-C (0) OR by one or more9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10RN , -OC(O)NR10RN -NHC(O)NR10RN、 -C(O)(CH2)MNR10RNOr-S (0)MR9Substituent replaced；
    R5And R6It is each independently selected from hydrogen atom, hydroxyl, protective embankment base, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -C(0)R9Or-OXCH^NR^R11, further replaced wherein described alkyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional by one or more substituents selected from halogen, hydroxyl, protective embankment base or protective embankment epoxide, or R5And R6- rise form oxo；
    R7And R8It is each independently selected from hydrogen atom, hydroxyl, alkyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR9、 -OC(0)R9、 -C(0)R9、 -NHC(0)R9、 -NR10RU , -OC(O)NR10RN , -NHC(O)NR10RN - OXCH^NRWR11Or-S (0)MR9, further replaced wherein described alkyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each individually optional by one or more substituents selected from halogen, hydroxyl, protective embankment base or alkoxy, or R7And R8- rise form oxo；
    R9Selected from hydrogen atom, alkyl, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl, wherein described Protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-NR^^'.-OC^NR' by one or more independently of one another1Or-QC^NRWR11Substituent replaced；
    R1QOr R11Hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more independently of one another12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NRI3R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)mNR13R14Or-S (0)mR12Substituent replaced；
    Or, R1.With R " heterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, 0 or 8 (0) in described heterocyclic radical1Hetero atom, and the heterocyclic radical is optionally further selected from hydroxyl, protective embankment base, halo protective embankment base, halogen, cyano group, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, benzyl, heteroaryl ,-C (0) OR by one or more12、 -OC(0)R12、 -C(0)R12、 -NHC(0)R12、 -NR13R14、 -OC(0)NR13R14、 -NHC(0)NR13R14、 -C(0)(CH2)mNR13R14Or-S (0)mR12Substituent replaced, wherein protective embankment base, cycloalkyl, benzyl, heteroaryl are optionally further replaced by one or more substituents selected from protective embankment base, halo protective embankment base, halogen, hydroxyl, protective embankment epoxide, heteroaryl or ring protective embankment base independently of one another；
    R12、 R13Or R14Hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, benzyl or heteroaryl are each independently selected from, wherein described alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, protective embankment base, halogen, cyano group, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one another15、 -OC(0)R15、 -C(0)R15、 -NHC(0)R15、 -NR16R17、 -OC(0)NR16R17、 -NHC(0)NR16R17、 -C(0)(CH2)mNR16R17Or-S (0)mR15Substituent replaced；
    R15、 R16Or R17Hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further selected from hydroxyl, alkyl, halogen, cyano group, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl or heteroaryl by one or more independently of one another；
    R18Selected from hydrogen atom or alkyl；And
    M is 0,1 or 2.
    14th, one kind prepares compound shown in formula according to claim 13 (Ι Π Α) or the method for its pharmaceutically useful salt, and this method includes：
    General formula compound b is changed into by general formula compound a is oxidized;
    b
    General formula compound b is changed into general formula compound c;
    Generalized C is changed into general formula compound mountain
    (ΙΠΑ)
    General formula compound d is changed into general formula compound (IIIA);
    Wherein A, B, R1, R3〜R8, R18Definition as claimed in claim 13, X is halogen.
    15th, a kind of pharmaceutical composition, it contains the formula according to any one of claim 1 11 for the treatment of effective dose（I compound or its pharmaceutically useful salt and pharmaceutically useful carrier or excipient shown in).
    16th, the formula according to any one of claim 1 11（I compound or its pharmaceutically useful salt shown in), purposes of the pharmaceutical composition according to claim 15 in the medicine for suppressing PARP is prepared.
    17th, the formula according to any one of claim 1 11（I compound or its pharmaceutically useful salt shown in), or pharmaceutical composition according to claim 15, it is used as the medicine for suppressing PARP.
    18th, a kind of suppression PARP method, this method includes giving the formula according to any one of claim 1 11 for the effective therapeutic dose of patient for needing to treat（I compound or its pharmaceutically useful salt shown in), or pharmaceutical composition according to claim 15.
    19th, the formula according to any one of claim 1 11（I compound or its pharmaceutically useful salt shown in), pharmaceutical composition according to claim 15 are being prepared in cancer treatment procedure as assistant agent or for making Tumour cell becomes the purposes in sensitive medicine to ionising radiation or chemotherapy.
    20th, the formula according to any one of claim 1 11（I compound or its pharmaceutically useful salt shown in), or pharmaceutical composition according to claim 15, it is used as the medicine in cancer treatment procedure as assistant agent or for making tumour cell become sensitive to ionising radiation or chemotherapy.
    21st, the formula according to any one of claim 1 11（I compound or its pharmaceutically useful salt shown in), purposes of the pharmaceutical composition according to claim 15 in the medicine for preparing treating cancer, wherein described cancer is preferably breast cancer, oophoroma, cancer of pancreas, prostate cancer, the carcinoma of the rectum, liver cancer or colon cancer.
    22nd, the formula according to any one of claim 1 11（I compound or its pharmaceutically useful salt shown in), or pharmaceutical composition according to claim 15, its as treating cancer medicine, wherein described cancer be selected from breast cancer, oophoroma, cancer of pancreas, prostate cancer, the carcinoma of the rectum, liver cancer or colon cancer.
    23rd, a kind of method for the treatment of cancer, this method includes giving the formula according to any one of claim 1 11 for the effective therapeutic dose of patient for needing to treat（I compound or its pharmaceutically useful salt shown in), or pharmaceutical composition according to claim 15.
    24th, the purposes according to claim 16,19 or 21 any one, wherein the medicine is further with treatment effective dose selected from following Drug combination：Temozolomide, adriamycin, taxol, cis-platinum, carboplatin, Dacarbazine, TPT, Irinotecan, gemcitabine and bevacizumab.
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Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102766135B (en) * 2012-07-09 2017-05-03 云南大学 Dihydrofuran indenoane-imidazole salts compound and preparation method thereof
CN106892926B (en) * 2012-10-16 2019-09-06 江苏盛迪医药有限公司 A kind of intermediate of DPP-IV inhibitor, preparation method and the method that DPP-IV inhibitor is prepared by it
HUE030613T2 (en) * 2012-12-31 2017-05-29 Cadila Healthcare Ltd Substituted phthalazin-1(2h)-one derivatives as selective inhibitors of poly (adp-ribose) polymerase-1
ES2861180T3 (en) 2013-03-13 2021-10-05 Forma Therapeutics Inc Derivatives of 2-hydroxy-1- {4 - [(4-phenyl) phenyl] carbonyl} piperazin-1-yl} ethan-1-one and related compounds such as fatty acid synthase inhibitors (FASN) for the treatment of cancer
KR101670126B1 (en) 2013-09-13 2016-10-27 일동제약(주) A novel phtalazinone derivatives and manufacturing process thereof
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EP3519051B1 (en) * 2016-09-27 2021-09-22 Beigene, Ltd. Treatment of cancers using combination comprising parp inhibitors
WO2018192576A1 (en) * 2017-04-21 2018-10-25 上海迪诺医药科技有限公司 Method for preparing parp inhibitor compound, and intermediate, amorphous form, solvate, pharmaceutical composition, and application thereof
CN108727391A (en) * 2017-04-21 2018-11-02 上海迪诺医药科技有限公司 PARP inhibitor compounds are amorphous and its preparation method and application
WO2019002344A1 (en) 2017-06-29 2019-01-03 Lonza Guangzhou Nansha Ltd. Method for preparation of alpha-methyl-l-proline
CN108341792B (en) * 2018-04-28 2021-09-17 苏州莱克施德药业有限公司 Preparation method of Volasertib intermediate 1-cyclopropyl methyl piperazine
TWI767148B (en) 2018-10-10 2022-06-11 美商弗瑪治療公司 Inhibiting fatty acid synthase (fasn)
CN113382633A (en) 2018-10-29 2021-09-10 福马治疗股份有限公司 Solid forms of (4- (2-fluoro-4- (1-methyl-1H-benzo [ d ] imidazol-5-yl) benzoyl) piperazin-1-yl) (1-hydroxycyclopropyl) methanone
CN115645370A (en) 2018-11-16 2023-01-31 江苏恒瑞医药股份有限公司 Pharmaceutical composition containing PARP inhibitor
CN111138335B (en) * 2020-01-14 2021-10-01 山东四环药业股份有限公司 Preparation method of optically active 2-methylproline
CA3176219A1 (en) 2020-04-21 2021-10-28 Kunhee LEE Crystalline forms of phthalazinone compound
CN111606842A (en) * 2020-05-27 2020-09-01 安徽中羰碳一工业技术有限责任公司 Preparation method of 2- (4-piperidyl) -2-propanol and hydrochloride thereof
CN114685374B (en) * 2020-12-28 2024-04-12 山东道合药业有限公司 Novel process for synthesizing Olaparib
CN112679411B (en) * 2020-12-31 2022-04-01 上海再启生物技术有限公司 Preparation method of chiral 5- (methylamino) hexahydrocyclopenta [ c ] pyrrole-2 (1H) -Boc methanesulfonate
CN112624981B (en) * 2021-03-09 2021-05-25 南京桦冠生物技术有限公司 Preparation method of 2-fluoro-5- [ (4-oxo-3H-2, 3-diazanaphthyl) methyl ] benzoic acid

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101048399A (en) * 2004-08-26 2007-10-03 库多斯药物有限公司 4-hetero aryl methyl substituted phthalazinone derivatives
EP1953147A1 (en) * 2005-11-21 2008-08-06 Japan Tobacco, Inc. Heterocyclic compound and medicinal application thereof
WO2009004356A1 (en) * 2007-07-05 2009-01-08 Astrazeneca Ab Phthalazinone derivatives as inhibitors of parp-1
CN101687855A (en) * 2007-04-10 2010-03-31 库多斯药物有限公司 Phthalazinone derivatives and their use as medicament to treat cancer

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101048399A (en) * 2004-08-26 2007-10-03 库多斯药物有限公司 4-hetero aryl methyl substituted phthalazinone derivatives
EP1953147A1 (en) * 2005-11-21 2008-08-06 Japan Tobacco, Inc. Heterocyclic compound and medicinal application thereof
CN101687855A (en) * 2007-04-10 2010-03-31 库多斯药物有限公司 Phthalazinone derivatives and their use as medicament to treat cancer
WO2009004356A1 (en) * 2007-07-05 2009-01-08 Astrazeneca Ab Phthalazinone derivatives as inhibitors of parp-1

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
SHIN-ICHI NAGAI，等: "Studies on the Chemical Transformations of Rotenoids. 6 Synthesis and Antitumor-Promoting Activity of [1]Benzofuro[2,3-d]pyridazines fused with 1,2,4-Triazole, 1,2,4-Triazine and 1,2,4-Triazepine", 《JOURNAL OF HETEROCYCLIC CHEMISTRY》 *

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