CN102666539A - 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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CN102666539A
CN102666539A CN2011800046090A CN201180004609A CN102666539A CN 102666539 A CN102666539 A CN 102666539A CN 2011800046090 A CN2011800046090 A CN 2011800046090A CN 201180004609 A CN201180004609 A CN 201180004609A CN 102666539 A CN102666539 A CN 102666539A
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protective embankment
heterocyclic radical
heteroaryl
aryl
embankment base
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邓炳初
李心
王斌
李相勤
陈阳
陈雪江
张蕾
宋敏
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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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    • 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
    • C07D498/12—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 three hetero rings
    • C07D498/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
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    • A61P35/00—Antineoplastic agents
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic 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
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—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

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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, a pharmaceutical composition containing the derivative, and a use thereof as a therapeutic agent and especially 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 a kind of formula（I new phthalazines S analog derivatives shown in), 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, is constituted】The superfamily of 8 kinds of cell ribozymes and cytoplasm enzyme.This poly- adenosine diphosphate-ribosylation can adjust catalytic activity and the egg matter interphase 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).
The activity of PARP- 1 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, lacking tumour (such as tumor of breast and ovary of (such as BRCA-1 or BRCA-2) for DNA Related to repair gene Cancer), show the extreme sensitivity to the inhibitor of PARP- 1, this show PARP inhibitor Zuo Wei Unit agent treat it is this be referred to as triple negative breast cancer in terms of potential use（Referring to Plummer, E. R. C rr. Opin. Pharmacol. 2006,6,364; Ratnam, et al; Clin. Cancer Res. 2007,13, 1 383).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 stage Ji hair 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+, it 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, 2007,20,171-1 81) 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, 1 78.).
Have been disclosed that a series of patent application of phthalazines ketone PARP inhibitor, including WO2002036576, WO2004080976 and WO200602 are drawn at present.
Although the PARP inhibitor of a series for the treatment of tumour has been disclosed 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
In order to overcome the deficiencies in the prior art part, 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.
Its-in-
A and B form ring protective embankment base, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl appoint to select into a Walk independently of one another is selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more8、 -OC(0)R8、 -0(CH2)pC(0)ORs、 -C(0)R8、 -NHC(0)R8、 -NR9R'。、 -OC(0)NR9R' ° or-C (0) NR9R10Substituent replaced；
R1 、 R2、 R3Or R4It is each independently selected from hydrogen atom, halogen, hydroxyl, protective embankment base, cyano group, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR8、 -C(0)R8Or-C (0) NR9R1Q, wherein described protective embankment base or alkoxy it is each it is individually optional enter a Walk replaced by one or more substituents selected from halogen, hydroxyl, protective embankment base or protective embankment epoxide；
R5Selected from hydrogen atom, hydroxyl, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、 -C(0)R8Or-C (0) NR9R1(), replaced wherein described alkyl appoints to select into a Walk by one or more substituents for selecting halogen, hydroxyl, protective embankment base or protective embankment epoxide；
R6And R7It is each independently selected from hydrogen atom, protective embankment base, hydroxyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -NHC(0)R8、 -NR9R] 0、 -OC(0)NRQR10Or-C C Ni^R1°, or R6And R7- rise form oxo；
Annular atom D or E are each independently selected from C or N atoms：
When n is 1, D and E, which are connected with each other, is connected into 6 10 yuan of rings X, meet valence bond theory when cyclic, 6 10 described yuan of rings X are selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl appoint to select into a Walk independently of one another is selected from protective embankment base, halogen, hydroxyl, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, benzyl, oxo ,-OR by one or more8、 -C(0)ORs、 -OC(0)Rs、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR^10, -OC(0)NR9R10Or-C (0) NR9R1QSubstituent replaced, wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl, heteroaryl or benzyl appoint independently of one another select into a Walk by it is one or more be selected from alkyl, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8> -NR9RI()、 -OC(0)NR9R'.Or-C (0) NR9R'.Substituent replaced；
When n is 2, D and E are connected with each other and are connected into 5 10 yuan of rings X, valence bond theory are met when cyclic, 5 10 described yuan of rings X are selected from ring protective embankment base, heterocyclic radical or heteroaryl, wherein described cycloalkyl, heterocyclic radical or miscellaneous Each independently Ren of aryl is selected into Yi Walk and is selected from alkyl, halogen, hydroxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, benzyl, oxo ,-OR by one or more8、 -C(0)OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 - C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9R10、 -OC(0)NR9R10Or-C (0) NR9R10Substituent replaced, wherein alkyl, cycloalkyl, heterocycle very, aryl, heteroaryl or benzyl be optionally further selected from protective embankment base, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR by one or more independently of one another8、 -OC(0)R8、 - 0(CH2)pC(0)OR8、 - C(0)R8、 - S(0)mR8、 -NHC(0)R8, -NR9R1Q、 -OC(0)NR9R1DOr-C (0) NR9R1DSubstituent replaced；
R8Selected from hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl, replaced wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl appoints to select independently of one another into a Walk by one or more substituents selected from protective embankment base, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
R9Or RIQHydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, is replaced wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl appoint to select independently of one another into a Walk by one or more substituents selected from protective embankment base, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
Or, R9And R1QWith the nitrogen-atoms formation heterocyclic radical being connected, contain one or more N, 0 or S (0) ^ atoms in wherein described heterocyclic radical, and the heterocyclic radical times is selected and replaced into a Walk by one or more substituents selected from alkyl, halogen, hydroxyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
M is 0,1 or 2;
N is 1 or 2；And
P is 0,1 or 2.
The preferred scheme of the present invention, a kind of formula（I compound or its pharmaceutically useful salt described in), including formula (II：) described in compound or
( Π )
Wherein-
A and B form cycloalkyl, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl appoint to select into a Walk independently of one another is selected from alkyl, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -NHC(0)R8、 -N 9R10. -OC(0)NR9R1 ()Or-C (0) NR9R10Substituent replaced；
R1 、 R2、 R3Or R4Each Γ 3 independently select hydrogen atom, halogen, hydroxyl, alkyl, cyanogen, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl very ,-C (0) OR8、 -C(0)R8Or-C (0) NR9R1Q, wherein described alkyl or alkoxy each it is individually optional enter a Walk replaced by one or more substituents selected from halogen, hydroxyl, protective embankment base or alkoxy；
R5Selected from hydrogen atom, hydroxyl, alkyl, ring protective embankment, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、 -C(0)R8Or-C (0) NR9R1 (), the alkyl Ren described in its towel is selected to be replaced into Yi Walk by one or more substituents selected from halogen, hydroxyl, protective embankment base or protective embankment epoxide；
Annular atom D or E are each independently selected from C or N atoms；
D and E, which are connected with each other, is connected into 6 10 yuan of rings X, meet valence bond theory when cyclic, 6 10 described yuan of rings X are selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from alkyl, halogen, hydroxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, benzyl, oxo ,-OR by one or more independently of one another8、 -C(0)OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 - C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9R1G、 -OC(0)NR9Rl()Or-C (0) NR9RIGSubstituent replaced, wherein protective embankment base, cycloalkyl, heterocyclic radical, aryl, heteroaryl or benzyl independently of one another Ren select into Yi Walk by it is one or more be selected from alkyl, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9RIG、 -OC(0)NR9R1()Or-C (0) NR9Rl()Substituent replaced；
R8Selected from hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl, replaced wherein described alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl appoint to select independently of one another into a Walk by one or more substituents selected from protective embankment base, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
R9Or R1 GHydrogen atom, protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, is replaced wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl appoints to select independently of one another into a Walk by one or more substituents selected from alkyl, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
Or, R9And R1QHeterocyclic 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 optionally further replaces by one or more substituents selected from alkyl, halogen, hydroxyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
M is 0,1 or 2;And
P is 0,1 or 2.
The preferred scheme of the present invention, a kind of formula（I compound or its pharmaceutically useful salt described in), including the compound shown in formula (m) or its pharmaceutically useful salt：
( "I )
Wherein：
A and B form cycloalkyl, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein described ring protective embankment base, heterocyclic radical, aryl or heteroaryl appoints to select into a Walk independently of one another is selected from alkyl, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more8、 -OC(0)R8、 -0(C¾)pC(0)OR8、 C(0)R8、 -NHC(0)R8、 -NR9R10, -O C Nl^R1.Or-C (0) NR9R10Substituent replaced；
R' 、 R2、 R3Or R4It is each independently selected from hydrogen atom, halogen, hydroxyl, protective embankment base, cyano group, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR8、 -C(0)R8Or-C (0) NR9R1Q, wherein described protective embankment base or protective embankment epoxide it is each it is individually optional enter a Walk replaced by one or more substituents selected from halogen, hydroxyl, alkyl or protective embankment epoxide；
Y, Z, G and J are each independently selected from Ν atoms or C atoms；
Condition is, is Ν atoms when Y, Z, G or J are different, meanwhile, arbitrarily three connected annular atoms can not be Ν atoms simultaneously；
It is when bifurcation, Z, G and J are selected from the Ν atomic time, then unsubstituted；
When bifurcation, Z, G and J are selected from the C atomic time, then Ren is selected into Yi Walk and is selected from hydrogen atom, protective embankment base, halogen, hydroxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, benzyl, oxo ,-OR independently of one another by bifurcation, Z, G and J8, -C(0)OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9R10、 -OC(C NR9R1QOr-C (0) NR9R1(), wherein Ren is selected into Yi Walk by one or more selected from alkyl, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR independently of one another for protective embankment base, cycloalkyl, heterocyclic radical, aryl, heteroaryl or benzyl8、 -OC(0)R8、 -0(CH2)pC(0)OR8, -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9R1Q、 -OC(0)NR9R1QOr-C (0) NR9RI QSubstituent replaced； R8Selected from hydrogen atom, alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl, replaced wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl appoint to select independently of one another into a Walk by one or more substituents selected from protective embankment base, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
R9Or R1QHydrogen 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 alkyl, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylic by one or more independently of one another The substituent of acid esters is replaced；
Or, R9And R1()Heterocyclic 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 Ren selects and replaced into Yi Walk by one or more substituents selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, virtue, heteroaryl, carboxylic acid or carboxylate；
M is selected from 0,1 or 2;And
P is selected from 0,1 or 2.
The preferred scheme of the present invention, a kind of formula（II compound or its pharmaceutically useful salt described in), including formula（IV compound or its pharmaceutically useful salt shown in)：
( I )
A and B form ring protective embankment base, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein described 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, aryl, heteroaryl ,-C (0) OR by one or more independently of one another8、 -OC(0)R8、 -0(C¾)pC(0)OR8、 -C(0)R8、 -NHC(0)R8、 -NR9R10、 -OC(0)NR9R10Or-C (0) NR9R10Substituent replaced；
R1 、 R2、 R3Or R4It is each independently selected from hydrogen atom, halogen, hydroxyl, protective embankment base, cyano group, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR8、 -C(0)R8Or-C (0) NR9R1C), further replaced wherein described protective embankment base or alkoxy are each individually optional by one or more substituents selected from it elements, hydroxyl, alkyl or protective embankment epoxide；
R5Selected from hydrogen atom, hydroxyl, protective embankment base, cycloalkyl, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、 -C(0)R8Or-C (0) NR9R1Q, replaced wherein described protective embankment base appoints to select into a Walk by one or more substituents selected from halogen, hydroxyl, protective embankment base or alkoxy；
Y, Z, G and J are each independently selected from 0 atom, N (RU) or C (RU)(R12);
Condition is, is N (R ") when Y, Z, G or J are different, meanwhile, arbitrarily three connected annular atoms can not be l^R simultaneously11);
Meanwhile, Y, Z, J or G are selected from Iv R11) or C (R) (R12) when, two annular atoms of arbitrary neighborhood can form a ring protective embankment base, heterocyclic radical, aryl or heteroaryl；
R8Selected from hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl 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 by one or more independently of one another Element, base, alkoxy, ring protective embankment, heterocycle, virtue, heteroaryl, the substituent of carboxylic acid or carboxylate are replaced；
R9Or Rl()Hydrogen original, alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl Qi are each independently selected from, is replaced wherein described alkane ^, cycloalkyl, heterocyclic radical, virtue or heteroaryl appoints to select independently of one another into a Walk by one or more substituents selected from alkyl, ^ elements, hydroxyl, protective embankment epoxide, ring protective embankment base, heterocycle, aryl, heteroaryl, carboxylic acid or carboxylate；
Or, R9And RieHeterocyclic 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 Ren selects and replaced into Yi Walk by one or more substituents selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
R1 1And R12It is each independently selected from hydrogen atom, protective embankment base, halogen, hydroxyl, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, benzyl, oxo ,-OR8、 -C(0)OR8、 -OC(0)R8、 -0(C¾)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9R10、 -OC(0)NR9R1 ()Or-C (0) NR9R1 (), wherein Ren is selected into Yi Walk by one or more selected from protective embankment base, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR independently of one another for alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or benzyl8, -OC(0)R\ -0(C¾)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9RI0、 -OC(0)NR9R10Or-C (0) NR9R10Substituent replaced；
M is selected from 0, " or 2;And
P is selected from 0,1 or 2.
The preferred scheme of the present invention, a kind of formula（IV compound or its pharmaceutically useful salt described in), wherein-
A and B form ring protective embankment base, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein described ring protective embankment base, heterocyclic radical, aryl or heteroaryl appoints to select into a Walk independently of one another is selected from alkyl, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -NHC(0)R8、 -NR9R10、 -OC(0)NR9R10Or-C (0) NR9R10Substituent replaced；
R1 、 R R3Or R4It is each independently selected from hydrogen atom, halogen, hydroxyl, alkyl, cyano group, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR8、 -C(0)R8Or-C (0) NR9Rl(), wherein described protective embankment base or alkoxy each it is individually optional enter a Walk replaced by one or more substituents selected from halogen, hydroxyl, alkyl or protective embankment epoxide；
R5Selected from hydrogen atom, hydroxyl, alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、
-C(0)R8Or-C (0) NR9R1Q, replaced wherein described protective embankment base appoints to select into a Walk by one or more substituents selected from halogen, hydroxyl, protective embankment base or alkoxy；
Y, Z, G and J are each independently selected from Ο atoms, NiR1 1) or QRUXR12);
Wherein：
·!It is 0 atom or NiR11), G is R^XR12), Z is I^XR12), Y is 0 atom, N (R1 1) or C (R ") (R12); J foots C (R ") (R12), G is N (Rn) or C (Rn)(R12), Z is C (R ") (R12), Y is Q^XR12);J is CiRi'XR12), G is
Meanwhile, Y, Z, J or G are selected from N (R ") or C ")12) when, two annular atoms of arbitrary neighborhood can form ring protective embankment base, heterocyclic radical, aryl or a heteroaryl；
R8Selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, replaced wherein described a heatable brick bed base, cycloalkyl, heterocyclic radical, aryl or heteroaryl appoints to select independently of one another into a Walk by one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
R9Or RIGHydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are independently each selected, is replaced wherein described alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl appoint to select independently of one another into a Walk by one or more substituents selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
Or, R9And R1QHeterocyclic radical is formed with the nitrogen-atoms being connected, wherein containing one or more N, 0 or 8 (0) in described heterocyclic radical111Hetero atom, and the heterocyclic radical Ren selects and replaced into Yi Walk by one or more substituents selected from protective embankment base, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
RuAnd R12It is each independently selected from hydrogen atom, protective embankment base, halogen, hydroxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, benzyl, oxo ,-OR8、 -C(0)OR8、 -OC(0)R8、 -0(C¾)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9R10, - OC(0)NR9R1()Or-C (0) NR9R1(), wherein Ren is selected into Yi Walk by one or more selected from alkyl, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR independently of one another for alkyl, ring protective embankment base, heterocyclic radical, aryl, heteroaryl or benzyl8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9R10、 -OC(0)NR9R10Or-C (0) NR9R' ° of substituent is replaced；
M is selected from 0, " or 2;And
P is selected from 0,1 or 2.
The preferred scheme of the present invention, a kind of formula（I compound or its pharmaceutically useful salt described in), including a kind of formula（V compound or its pharmaceutically useful salt shown in)：
( V )
Wherein：
A and B form cycloalkyl, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein described Cycloalkyl, heterocyclic radical, each independently Ren of aryl or heteroaryl select into Yi Walk by it is one or more selected from protective embankment base,
^ elements, base, alkoxy, cycloalkyl, heterocycle, aryl, heteroaryl ,-C (0) OR8、 -0C(0)R8、 - 0(CH2)pC(0)OR8、 -C(0)Rs、 - NHC(0)Rs、 -NR9R'。、 -OC C NR9!^.Or-C (0) NR9R10Substituent replaced；
R1 、 I 2、 R3Or it is each independently selected from hydrogen atom, ^ elements, hydroxyl, alkyl, cyano group, alkoxy, ring protective embankment base, heterocyclic radical, aryl or heteroaryl ,-C (0) OR8、 -C(0)R8Or-C (0) NR9Rl(), wherein described protective embankment base or alkoxy it is each it is individually optional enter a Walk replaced by one or more substituents selected from halogen, hydroxyl, alkyl or protective embankment epoxide；
R5Selected from hydrogen atom, hydroxyl, alkyl, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、 -C(0)RsOr-C (0) NR9R1(), replaced wherein described protective embankment base appoints to select into a Walk by one or more substituents selected from halogen, hydroxyl, protective embankment base or protective embankment epoxide；
D and E are each independently selected from N or C atoms；
D and E, which are connected with each other, is connected into 5 10 yuan of rings X, meet valence bond theory when cyclic, 5 10 described yuan of rings X are selected from cycloalkyl, heterocyclic radical or heteroaryl, wherein described ring protective embankment base, heterocyclic radical or heteroaryl appoints to select into a Walk independently of one another is selected from protective embankment base, halogen, hydroxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, benzyl, oxo ,-OR by one or more8、 -C(0)OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9R1Q、 -OC(0)NR9RIGOr-C (0) NR9RI GSubstituent replaced, wherein protective embankment base, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl or benzyl independently of one another Ren select into Yi Walk by it is one or more be selected from protective embankment base, halogen, hydroxyl, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR R' 0、 -OC(0)NR9R10Or-C (0) NR9R1QSubstituent replaced；
R8Selected from hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl, replaced wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl appoints to select independently of one another into a Walk by one or more substituents selected from alkyl, halogen, hydroxyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
R9Or R1Gβ hydrogen atoms, alkyl, ring protective embankment base, heterocycle, aryl or heteroaryl are independently each selected, is replaced wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl appoints to select independently of one another into a Walk by one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
Or, R9And RieHeterocyclic 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 Ren selects and replaced into Yi Walk by one or more substituents selected from alkyl, halogen, hydroxyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
M is selected from 0,1 or 2;And
P is 0,1 or 2.
The preferred scheme of wood invention, a kind of formula（I compound or its pharmaceutically useful salt, wherein A and B described in) Aryl, preferably phenyl are formed 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 described in), its Cao R1Select hydrogen atom or Ι ^ elements, preferably hydrogen atom or fluorine atom.
The preferred scheme of the present invention, a kind of formula（I compound or its pharmaceutically useful salt described in), its Cao R1For halogen, preferably fluorine atom.
The preferred scheme of the present invention, a kind of formula（I compound or its pharmaceutically useful salt, wherein I described in)1、 R2、 R3Or R4It is each independently hydrogen atom.
The preferred scheme of the present invention, a kind of formula（I compound or its pharmaceutically useful salt, wherein R described in)2、 R3Or R4It is each independently hydrogen atom, R1For 1^ elements, preferably fluorine atom.
The preferred scheme of the present invention, a kind of formula（I compound or its pharmaceutically useful salt, wherein R described in)5For hydrogen atom.
The preferred scheme of the present invention, a kind of formula（) described in compound or its pharmaceutically useful salt, wherein R6Or R7It is each independently hydrogen atom, or R6And R7- play one oxo of formation.
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 high performance liquid chromatography.
The equivalent considered --- those skilled in the art will appreciate that being, compound（I the form of dynamic isomer) also may be present.Compound（I tautomeric form) may include but be not limited to by following formula（VI) the structure represented：
(VI) typical compound of the invention include, but are not limited to-
4- [[4- Mining -3- (6- oxos -3,3 ", and 4,5,7,7 α-hexahydro -1H- pyrrolo-es [3,4-cl pyridine -2- carbonyls)-phenyl] methyl] the small ketone of -2H- phthalein crops
4- [[3- | (8oR) -4- oxos-U, 6,7,8,8o- hexahydropyrrolo and Jie, 2- α] pyrazine -2- carbonyls] -4- fluoro-phenyls】Methyl] -2H- phthaleins prolixity -】-one
4- [[3- [aR) and -6- oxos-l, 3,4,7,8,8 ^- hexahydropyrrolos simultaneously [l, 2- α] pyrazine -2- carbonyls] -4- fluoro-phenyls] methyl] the small ketone of -2H- phthalein crops
Z factories
^ 。-
4- [[3- [1- benzyls -3,3,4,6,7,7Ω- hexahydro-2H- pyrrolo-es [3,2-c] pyridine-5- carbonyls]-4- fluoro-phenyls] methyl]-1 -one of-2H- phthalazines
o
4- [[the fluoro- 3- of 4- [】- 2//- pyrrolo- of hexahydro of-(3- picolyls) -3,3a, 4,6,7,7fl- [3,2-c | pyridine -5- carbonyls]-phenyl] methyl] -2/- phthalazines -1- ketone
0
0
8- [the fluoro- 5- of 2- [(- 1-yl of 4- oxo-3H- phthalazines) methyl] benzoyl]-6,7,9,9 α-tetrahydrochysene-1H- pyrazines simultaneously [2, l-c] [l, 4] oxazine-4- ketone
- fluorine _2,3,4a,5,7, 7a- hexahydropyrrolos simultaneously [3,4 -] Evil crop-6- carbonyls]-4- fluoro-phenyls] and methyl] the small ketone of-2H- phthalazines
63
4- [[the fluoro- 3- of 4- (2 epoxide -5,7- pyrrolin simultaneously [3,4-i/J pyrimidine -6- carbonyls) phenyl] methyl] -2H- phthalazines -1- ketone
o
64 」
4-[[3-[(4 i, 7 " and 5) -4- methyl-fluoro- 2,3,4a, 5,7,7a- hexahydropyrrolo simultaneously [3,4-6] [l, 4] Evil piperazine -6- treasures bases] -4- fluoro-phenyls] methyl] the small ketone of -2H- phthalein crops
「
2
、
65
4- [4- fluoro- 3- ((5^, 8^) -4,5 ", 6,7,8,8 "-hexahydropyrrolo simultaneously [3,4->] [1,2,3] triazol [1,5-^] [1,4] oxazine -7- carbonyls) benzyl] -2/- zhen piperazine -1- ketone
0
11
Bifurcation
1. !Shang,
- Ύ 0
、 ·、 . ·
0
) 'i ：
66 FFly：
4- [the fluoro- 3- of 4- ((5 " S, 8 5) -4,5a, the 6,7,8,8fl- hexahydropyrrolos simultaneously -one of [3,4-b] [l, 2,3] triazol [1,5-^ [1,4] oxazine -7- carbonyls) benzyl] -2H- phthalazines -1
Or its pharmaceutically useful salt.
Formula is prepared the present invention relates to one kind（I the method for compound or its pharmaceutically useful salt shown in), this method includes：
( IA ) (IB)
By formula (IA) compound optionally hydrolyse into carboxylic acid and formula (IB) compound or its salt in condensation reagent such as BTA-Ν, Ν, Ν ', in the presence of Ν '-tetramethylurea hexafluorophosphoric acid ester, reacted under alkalescence condition, obtain formula（I) compound；
Wherein：
RaSelected from halogen, hydroxyl or protective embankment epoxide；
A, B, D, E, ring X, n, R'R7Definition such as formula（I described in).
Formula is prepared the present invention relates to one kind（The method of compound or its pharmaceutically useful salt shown in Π), this method includes：
( HA ) (HB)
By formula (Π Α) compound optionally hydrolyse into carboxylic acid and formula (IIB) compound or its salt in condensation reagent such as BTA-Ν, Ν, Ν ', in the presence of Ν '-tetramethylurea hexafluorophosphoric acid ester, reacted under alkalescence condition, obtain formula（II) compound；
Wherein：
RaSelected from halogen, hydroxyl or protective embankment epoxide；
A, B, D, E, ring X, R1And R5Definition such as formula（II described in).
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：
( 1IA ) ( IIIB )
By formula (Π Α) compound optionally hydrolyse into carboxylic acid and formula (IIIB) compound or its salt in condensation reagent such as BTA-Ν, Ν, Ν ', in the presence of Ν '-tetramethylurea hexafluorophosphoric acid ester, reacted under alkalescence condition, obtain formula（III) compound；
Wherein：
RaSelected from halogen, hydroxyl or alkoxy；
A, B, Y, Z, J, G, R1Definition such as formula（III described in).
Formula is prepared the present invention relates to one kind（ IV：) shown in compound or its pharmaceutically useful salt method, this method includes：
( IIA ) (IVB)
By formula (Π Α) compound optionally hydrolyse into carboxylic acid and formula (IB) compound or its salt in condensation reagent such as BTA-Ν, Ν, Ν ', in the presence of Ν '-tetramethylurea hexafluorophosphoric acid ester, reacted under alkalescence condition, obtain formula（IV) compound；
RaSelected from halogen, hydroxyl or protective embankment epoxide；
A, B, Y, Z, J, G, R1And R5Definition such as formula（IV described in).
Formula is prepared the present invention relates to one kind（V the method for compound or its pharmaceutically useful salt shown in), this method includes：
( ΠΛ ) ( V B )
By formula (IIA) compound optionally hydrolyse into carboxylic acid and formula (VB) compound or its salt in condensation reagent such as BTA-Ν, Ν, Ν ', in the presence of Ν '-tetramethylurea hexafluorophosphoric acid ester, reacted under alkalescence condition, obtain formula（V) compound；
Wherein：
RaSelected from halogen, hydroxyl or alkoxy；
A, B, D, E, R1And R5Definition such as formula（V described in).
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 PA P method, and this method includes giving the formula for the effective therapeutic dose of patient for needing to treat（1) compound or its pharmaceutically useful salt.
The another aspect of wood invention is related to formula（I compound or its pharmaceutically useful salt shown in), are being prepared in cancer treatment procedure as assistant agent or for making tumour cell become the purposes of 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 the present invention 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 of the present invention as the medicine for suppressing PARP（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), in the purposes for 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 enters a Walk, it is selected from following Drug combination with treatment effective dose：Temozolomide (Temozolomide, TMZ), adriamycin, taxol (Taxol, Paclitaxel), cis-platinum (Cisplatin), carboplatin（Carbop】Atin), Dacarbazine（Dacarbazine), TPT（Topotecan), Irinotecan (Irinotecan) gemcitabine (Gemcitabine) or bevacizumab (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, adriamycin, taxol, cis-platinum, carboplatin, Dacarbazine, TPT, Irinotecan, gemcitabine or bevacizumab. It is related to the formula of the medicine as treating cancer in terms of the another ^ of the present invention（I compound or its pharmaceutically useful salt shown in), wherein described cancer be breast cancer, oophoroma, cancer of pancreas, prostate cancer, liver cancer or colon cancer, wherein described medicine enter a Walk its with treatment effective agent be selected from following Drug combination：Temozolomide, adriamycin, taxol, cis-platinum, carboplatin, Dacarbazine, TPT, Irinotecan, gemcitabine or bevacizumab.
Jin mono- Walk, the opposing party of the invention and be related to a kind of pharmaceutical composition, 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.The pharmaceutical composition prepare in cancer treatment procedure as assistant agent or for make tumour cell ionization good fortune is penetrated or chemotherapy become sensitive medicine in purposes.Purposes of the pharmaceutical composition in the medicine for preparing treating cancer, wherein described cancer is breast cancer, oophoroma, cancer of pancreas, prostate 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 or bevacizumab.Detailed description of the invention
Unless stated to the contrary, the term used in the specification and in the claims has following implications.
" baked 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 propyl, 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,】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..Low alkyl group 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 propyl, 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, 13- dimethylbutyls, 2- ethyl-butyls, 2- methyl amyls, 3- methyl amyls, 4- methyl amyls, 2, 3- dimethylbutyls etc..Protective embankment base can be substituted or unsubstituted, and when substituted, substituent can be with office What it is substituted on workable tie point, preferably one or more following groups, independently selected from protective embankment base, alkenyl, alkynyl, alkoxy, alkane sulphur, alkyl amino, halogen, mercaptan, hydroxyl, nitre, cyano group, ring protective embankment base, Heterocyclylalkyl, aryl, heteroaryl, cycloalkyloxy, heterocyclylalkoxy groups, cycloalkylthio, heterocycle protective embankment sulfenyl, oxo ,-OR8. -C(0)OR8、 -OC(0)R8、 - 0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9R'°. -OC(0)NR9R10Or-C (O) NR9Rl 0。
" ring protective embankment base " refers to saturation or part Bu Bao He Unit rings or polycyclic cyclic hydrocarbon substituent, it includes 3 to 20 carbon atoms, preferably includes 3 to 12 carbon atoms, and more preferably ring protective embankment basic ring includes 3 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 inferior loop coil protective embankment base, double loop coil protective embankment base bases or many spiro cycloalkyl groups according to the number of shared spiro-atom between ring and ring, is preferably single loop coil protective embankment base and double spiro cycloalkyl groups.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 spiro cycloalkyl group
" 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 10 yuan.Bicyclic, three rings, Fourth Ring or polycyclic fused ring protective embankment base can be divided into according to the number of composition ring, preferably bicyclic or three rings, comprising
" 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】0 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, and its Cao is ring protective embankment base with the ring that precursor structure links together, and non-limiting example includes indanyl, tetralyl, benzocyclohepta alkyl etc..Ring protective embankment base can be optionally substituted or unsubstituted, when substituted inch, substituent is preferably one or more following groups, independently selected from protective embankment base, alkenyl, alkynyl, protective embankment epoxide, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, ring protective embankment base, heterocycle alkane, aryl, heteroaryl, ring protective embankment epoxide, heterocyclylalkoxy groups, ring protective embankment sulfenyl, heterocycle alkylthio group, oxo ,-OR8、 -C(0)OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 - NR9R10、 -OC(0)NR9R10Or-C (O) NR9R10。
" alkenyl " refers to the protective embankment base as defined above that at least two carbon atoms and at least one carbon-to-carbon double bond are constituted.Such as vinyl, 1- acrylic, 2- acrylic, 1-, 2- or 3- cyclobutenyls etc..Alkenyl 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, protective embankment sulfenyl, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyano group, ring protective embankment base, Heterocyclylalkyl, aryl, heteroaryl, ring protective embankment epoxide, heterocycle protective embankment epoxide, ring protective embankment sulfenyl, heterocycle protective embankment sulfenyl ,-OR8、 -C(0)OR5、 -OC(0)R5、 -0(CH2)pC(0)OR5、 -C(0)R5、 -S(0)mR8、 -NHC(0)R5 -NR6R7、 -OC(0)NR6R7Or-C (0) NR6R7。
" alkynyl " refers to the alkyl as defined above that at least two carbon atoms and at least one carbon-to-carbon triple bond are constituted.Such as acetenyl, 1- propinyls, 2-propynyl, 1-, 2- or 3- butynyls etc..Alkynyl 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, cycloalkyloxy, heterocycle protective embankment epoxide, cycloalkylthio, heterocycle protective embankment sulfenyl ,-OR8、 -C(0)OR8、 -OC(0)R8、 -0(C¾)PC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9R10、 -OC(0)NR9R10Or-C (O) NR9R10。
" heterocyclic radical " refers to the unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent of saturation or part, it includes 3 to 20 annular atoms, wherein one or more annular atoms are selected from the hetero atom of nitrogen, oxygen or S (0) m (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 ring protective embankment base includes pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thio-morpholinyl, homopiperazine base etc..Polycyclic naphthene 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)mThe hetero atom of (wherein m 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.Loop coil protective embankment base is divided into by single spiroheterocyclic according to the number of shared spiro-atom between ring and ring Base, double spiro heterocyclic radicals or many spiro heterocyclic radicals, are preferably single loop coil protective embankment base and double spiro cycloalkyl groups.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.The non-limiting example of spiro cycloalkyl group 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)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.Bicyclic, three rings, Fourth Ring or polycyclic condensed hetero ring protective embankment base, more preferably preferably bicyclic or three rings, 5 yuan/5/6 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 bridged ring protective embankment base, 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 bridge ring alkyl is included：
The heterocyclic ring can be condensed on aryl, heteroaryl or cycloalkyl ring, wherein the ring being connected to precursor structure
Deng.Heterocyclic radical can be optionally substituted or unsubstituted, and when substituted, substituent is preferably one or many Individual following group, independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio group, alkyl amino, halogen, mercaptan, hydroxyl, nitro, cyanogen, ring protective embankment base, Heterocyclylalkyl, virtue, heteroaryl, ring protective embankment epoxide, heterocyclylalkoxy groups, cycloalkanes sulphur, heterocycle protective embankment sulfenyl, oxo ,-OR8, -C(0)OR8、 -0C(O)R8、
-0(CH2)PC(0)OR8、 -C(0)R8、 -S(0)MR8、 -NMC(0)R8、 -NR9R10、 - OC(0)NR9R10Or-C (O) NR9R
" 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, and its ring together is aryl rings, and 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, protective embankment sulfenyl, protective embankment base amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, heterocycle protective embankment base, aryl, heteroaryl, ring protective embankment epoxide, heterocyclylalkoxy groups, ring protective embankment sulfenyl, heterocycle protective embankment sulfenyl ,-OR8、 -C(0)OR8、 -OC(0)R8、 -0(CH2)PC(0)OR8、 -C(0)R8、 -S(0)MR8、 -NHC(0)R8、 -NR9R10, -OC(0)NR9RL F)Or-C (O) NR9R10。
" 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 cycloalkyl ring, wherein with precursor structure link together-
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, alkylthio group, protective embankment base amino, halogen, mercaptan, hydroxyl, nitro, cyano group, cycloalkyl, heterocycle protective embankment base, aryl, heteroaryl, cycloalkyloxy, heterocycle protective embankment epoxide, cycloalkylthio, heterocycle alkylthio group ,-OR8、 -C(0)OR8、 -OC(0)R8、 -0(CH2)PC(0)ORS、 -C(0)R8、 -S(0)MRS、 -NHC(0)R8、 -NR9RI0、 -O C^NRQR1.Or-C (O) NRL0。
" alkoxy " refers to-o- (alkyl) and-o- (unsubstituted cycloalkyl), and wherein alkyl is as defined above.Non-limiting example includes methoxyl group, ethyoxyl, propoxyl group, butoxy, ring propoxyl group, cyclobutoxy group, ring Amoxy, hexamethylene Gas bases etc..Alcoxyl can be optionally substituted or unsubstituted, when received for when, substituent is preferably one or more following groups, independently selected from for protective embankment base, alkenyl, alkynyl, alkoxy, alkylthio group, 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 ,-OR8, -C(0)OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9RI 0、 -OC(O)NR9Ri0Or-C (O) NR9R10。
" 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-C (0) OH.
" carboxylate " refers to-C (0) 0 (base of washing) 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 is replaced by protective embankment base of heterocyclic group and heterocyclic group not by alkyl-substituted situation.
" 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 alkene Li) 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, n and R8〜RI()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 adopts the following technical scheme that-one kind prepares formula（I the method for compound or its pharmaceutically useful salt shown in), this method includes：Formula is prepared the present invention relates to one kind（1) method of compound or its pharmaceutically useful salt shown in, this method includes：
( 1A ) (IB)
By formula (IA) compound optionally hydrolyse into carboxylic acid and formula (IB) compound or its salt in condensation reagent such as BTA-Ν, Ν, Ν ', in the presence of Ν '-tetramethylurea hexafluorophosphoric acid ester, reacted under alkalescence condition, obtain formula（I) compound；
Wherein-
RaSelected from halogen, hydroxyl or protective embankment epoxide；
A, B, D, E, ring X, η,！^〜7Definition such as formula（I described in).
One kind prepares formula（II the method for compound or its pharmaceutically useful salt shown in), this method includes：
( HA ) (HB)
By formula (Π Α) compound optionally hydrolyse into carboxylic acid and formula (Π Β) compound or its salt in condensation reagent such as BTA-Ν, Ν, Ν ', in Ν '-four in the presence of base urea hexafluorophosphoric acid ester, reacted under alkalescence condition, obtain formula（II) compound；
Wherein-
RaSelected from halogen-element, hydroxyl or protective embankment epoxide；
A, B, D, E, ring X, R1And R5Definition such as formula（II described in).
One kind prepares formula（III the method for compound or its pharmaceutically useful salt shown in), this method includes：
( IIA ) ( IIIB )
By formula (Π Α) compound optionally hydrolyse into carboxylic acid and formula (Π Ι Β) compound or its salt in condensation reagent such as benzene And in the presence of triazole-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester, reacted under alkalescence condition, obtain formula（III) compound；
Wherein：
RASelect halogen, hydroxyl or protective embankment epoxide；
A, B, Y, Z, J, G and R1Definition such as formula（III described in).
One kind prepares formula（IV this method includes：
( HA ) (IVB)
By formula (HA) compound optionally hydrolyse into carboxylic acid and formula (m) compound or its salt in the presence of condensation reagent such as BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester, reaction, obtains formula under alkalescence condition（IV) compound；
Wherein：
RASelected from halogen, hydroxyl or protective embankment epoxide；
A, B, Y, Z, J, G, R1And R5Definition such as formula（IV) described in Cao.
One kind prepares formula（V the method for compound or its pharmaceutically useful salt shown in), this method includes：
( HA ) ( V B )
By formula (Π Α) compound optionally hydrolyse into carboxylic acid and formula (VB) compound or its salt in condensation reagent such as BTA-Ν, Ν, Ν ', in the presence of Ν '-tetramethylurea hexafluorophosphoric acid ester, reacted under alkalescence condition, obtain formula（V) compound；
Wherein：
RASelected from halogen, hydroxyl or alkoxy；
A, B, D, E, R1And R5Definition such as formula（V described in).
Above-mentioned condensation reaction is optionally in carboxylic acid (including formula (IA) and formula (Π Α) compound) and amine（Formula (IB), formula (IIB), formula (IIIB；), formula (IVB) and formula (VB) compound) between carry out, carried out under condensation reagent and alkalescence condition, condensation reagent used is selected from Ν, Ν-dicyclohexylcarbodiimide, Ν, Ν-DIC, O- BTAs-Ν, Ν, Ν ', Ν '-tetramethylurea tetrafluoro boric acid ester (TBTU) etc., the preferably nitrogen of O- benzos three Azoles-Ν, Ν, Ν ', Ν '-tetramethylurea (TMU) tetrafluoro boric acid are cruel (TBTU);Alkalescence condition organic base or inorganic base are provided, and organic base is selected from such as diisopropylethylamine, pyridine, triethylamine, hexahydropyridine, N- φ bases piperazine, preferably DMAP, diisopropylethylamine；Solvent for use is selected from toluene, benzene, dichloromethane, tetrahydrofuran, Gas and imitates Ν, the mixture that Ν-dimethylformamide or above-mentioned solvent are constituted etc., preferably Ν, Ν-dimethylformamide；Reaction temperature is controlled at -80 °C to 100 °C, is preferably (TC to 60;General control was at 1 minute to 72 hours between reacting inch, preferably 15 minutes to 24 hours.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 10_6(ppm) unit is provided.NMR measure uses Bruker AVANCE-400 nuclear magnetic resonance spectrometers, and measure solvent is deuterated dimethyl sulfoxide (DMSO-t, deuterochloroform (CDC13), deuterated Cao alcohol (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 the 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 can be in ABCR GmbH ＆ Co. KG, Acros Organics, Aldrich Chemical Company, splendid remote chemistry is scientific and technological and goes out purchase up to companies such as auspicious chemicals.
Without specified otherwise in embodiment, reaction is carried out under blanket of nitrogen or argon atmospher.
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 rice of reaction process in embodiment has with thin-layered chromatography (TLC), the system of the used exhibition Ji agent of reaction： A:Dichloromethane protective embankment and Φ alcohol systems, B:Just own protective embankment and ethyl acetate system, C:Petroleum ether and ethyl acetate system, D:Acetone, the body trifoliate orange of solvent is more different than the polarity according to compound and is adjusted.
The system of eluant, eluent and the solvent system of thin-layered chromatography for the post eyebrow analysis that purifying compound is used include：A-. dichloromethane protective embankment and methanol system, B:N-hexane and ethyl acetate system, the volume ratio of solvent are adjusted according to the polarity difference of compound, can also add few:1：Triethylamine and the alkalescence such as acetic acid or acid reagent be adjusted.
Embodiment 1
4- [[the fluoro- 3- of 4- (6- oxos -3,3 α, 4,5,7,7 α-H- of hexahydro -1 pyrrolo-es [3,4-c] pyridine -2- carbonyls)-phenyl] first
Mono- Walk
1,2,3,4,5,7,7 α-octahydro pyrrolo- [3,4-c] pyridine -6- ketone
Under ice bath, by 5- oxos -1,3,3,4,6,6 β-hexahydro cyclopentano [c] pyrroles's -2- t-butyl formates la (1 g, 4.40 mmol) is dissolved in 10 mL concentrated hydrochloric acids, adds sodium azide (0.69 g, 10.60 mmol), react at room temperature 12 hours.It is concentrated under reduced pressure, it is 9 that saturated sodium bicarbonate solution, which is added dropwise, to reaction solution pH, and (100 mLx2) is extracted with dichloro Ψ protective embankments, merge organic phase, be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain U, 3,4,5,7,7 "-octahydro pyrrolo- [3,4-c] pyridine -6- ketone lb (0.20 g; sepia solid), yield: 35.0%.
MS m/z (ESI): 141.1 [M+l]
Bis- Walk
4- [[the fluoro- 3- of 4- (6- oxos-3,3fl, 4,5,7,7-hexahydropyrrolo simultaneously [3,4-c] pyridine-2- carbonyls)-phenyl] methyl]-2H- phthalazines-1- ketone
By the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid lc (150 mg, 0.50 mmol, it is prepared using known method " patent WO2004080976 ") it is dissolved in 10 mL Ν, in Ν-dimethylformamide, power mouthful enters BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (285 mg, 0.75 mmol), 1, 2, 3, 4, 5, 7, 7 α-octahydro pyrrolo- [3, 4-c] pyridine -6- ketone lb (85 nig, 0.60 mmol) and triethylamine (0.2 mL, 1 mmol), reaction 12 hours.Filtering, filtrate decompression concentrate, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 4- [[4- fluoro- 3- (6- oxos -3,3fl, 4,5,7,7 "-hexahydropyrrolo simultaneously [3; 4-c] pyridine -2- carbonyls)-phenyl] methyl] the small ketone 1 of -2H- phthalein crops (120 mg, light yellow solid), yield： 55.0%. MS m/z(ESi): 421.2 [M+l]
Ή NMR (400 MHz, DMSO-c/6):δ 12.60 (br. s, 1H), 8.24-8.26 (m, 1H), 7.96-7.99 (m, 1H), 7.82-7.89 (m, 2H), 7.50-7.70 (m, 1H), 7.38-7.42 (m, 2H), 7.18-7.21 (m, 1H), 4.31 (m, 2H), 3.72-3.76 (m, 1H), 2.88-3.36 (m, 4H), 1.95-2.34 (m, 311), 1.10-1.14 (m, 2H) embodiment 2
4- [[3- [(8) -4- oxos -1,3,6,7,8,8 "-hexahydropyrrolo simultaneously [1,2- "] pyrrole shout -2- carbonyls] -4- fluoro-phenyls] first
Mono- Walk
(2 Λ)-2- (methyl) pyrroles's-1-t-butyl formate of protective embankment
By [(2/)-pyrroles protective embankment -2- bases]-methanol 2a (4 g, 39.50 mmol) it is dissolved in 50 mL dichloromethane protective embankments, power mouthful enters triethylamine (ll mL, 80 mmol), under ice bath, di-tert-butyl dicarbonate (12.90 g, 59 mmol) is added, is reacted 3 hours.Be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain (2/ -2- (methylol) pyrroles protective embankment -1- t-butyl formates 2b (7.01 g, light yellow oil), yield： 88.0%. MS m/z (ESI+23): 224.2 [M+23]
Bis- Walk
(2i) -2- formylpyrrole protective embankment -1- t-butyl formates
Oxalyl chloride (0.8mL, 8 mmol) is dissolved in 5 mL dichloromethane protective embankments, reaction solution is cooled to -78, dimethyl sulfoxide (DMSO) (14mL is added dropwise, 14 mmol), after stirring 15 minutes, 3 mL (2i are added dropwise under -78 °C) -2- (methylol) B ratios cough up alkane -1- t-butyl formates 2b (400 mg, 2 mmol) dichloromethane solution, stirring adds triethylamine (2 mL after 15 minutes, 14 mmol), continue after stirring 15 minutes, be warming up to 0 reaction 15 minutes.Add 80mL petroleum ethers; it is washed with water (20mLx2); anhydrous sodium sulfate thousand is dry; filtering; filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system B purify obtained by residue, obtain formylpyrrole protective embankment -1- t-butyl formates 2c (349 mg; light yellow oil), yield： 87.7%.
MS m/z (ESI): 199.8 [M+l]
Tri- Walk
(2/) -2- [[(2- ethyoxyl -2- oxo-ethyls) aminomethyl] small t-butyl formates of pyrroles's protective embankment By (2) -2- formylpyrroles protective embankment -1 the tertiary 2c (500 mg, 2.50 mmol) of-Cao acid be dissolved in 30 mL：Chloromethanes Cao, adds glycine ethyl ester hydrochloride (526 mg, 3.80 mmol), and stirring adds sodium triacetoxy borohydride (1.59 g, 7.50 mraol) after 30 minutes, reacted 12 hours.Add 30 mL water, extracted with dichloromethane (30 mLx2), merge organic phase, washed with saturated nacl aqueous solution (15 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain (2W) -2- [[(2- ethyoxyl -2- oxo-ethyls) amino] first port] small t-butyl formate 2d (611 mg of pyrrolidines, light yellow oil), yield： 85.2%.
MS m/z (ESI): 287.2 [M+l]
Tetra- Walk
(8) -2,3,6,7,8,8a- hexahydro -1H- pyrrolo-es [1,2- α] pyrazine -4- ketone incite somebody to action (2/) -2- [[(2- ethyoxyl -2- oxo-ethyls) amino] methyl] pyrroles's protective embankment -1- t-butyl formates 2d (mmol of 611 mg, 2J 0) and 3 mL trifluoroacetic acids are dissolved in lO mL dichloromethane, react】2 hours.It is concentrated under reduced pressure, 40 mL dichloromethane are added, it is 12 13 that 1 M sodium hydroxide solutions, which are added dropwise, to reaction solution pH, divides liquid, aqueous phase is extracted (20 mLx3) with dichloromethane, merge organic phase, (15 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 A purify obtained by residue, obtain (8fli) -2,3,6,7,8,8fl- hexahydro -1H- pyrrolo-es [】, 2-] and pyrazine -4- ketone 2e (105 mg, brown oil), yield： 35.0%.
MS m/z (ESI): 141.1 [M+l]
Wu Walk
4- [[3- [(8 ^) -4- oxos -1,3,6,7,8,8 α-hexahydropyrrolo simultaneously [1,2- α] pyrazine -2- carbonyls] -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone
By the fluoro- 5- of 2- [(4- oxo -3H- phthalein crop -1- bases) methyl] benzoic acid】C (150 mg, 0.50 mmol) is dissolved in 6 mL Ν, Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (340 mg, 0.90 mmol), (8 " -2; 3; 6,7,8; 8 "-hexahydropyrrolo simultaneously [1,2- "】Pyrazine -4- ketone 2e (105 mg, 0.75 mmol) and Ν, Ν-diisopropylethylamine (260 L, 1.50 mmol), react 12 hours.20 mL water are added, (30 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, it is dry with anhydrous sodium sulfate thousand, filtering, filtrate decompression concentration, with silicon stock column chromatography with eluant, eluent system A purify obtained by residue, obtain 4- [[3- [(8 i) -4- oxos -1,3,6,7,8,8 α-hexahydropyrrolo simultaneously [1,2- "] pyrazine -2- carbonyls] -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone 2 (20 mg, light yellow solid), yield： 9.0%.
MS m/z (ESI): 421.1 [M+l ]
1H NM (400 MHz, CDC13):δ 10.45 (br. s, 1H), 8.47 (d, 1H), 7.79 (m, 2H), 7.76 (m, 1H), 7.35 (m, 2H), 7.29 (t, 1H), 4.28 (s, 2H), 4.05 (m, 1H), 3.85 (m, 1H), 3.69 (m, 2H), 3.52 (m, 2H), 2.64 (m, 1H), 2.04 (m, 2H), 1.87 (m, 2H) embodiment 3
4- [[3- [(8 α Λ)-6- oxos-1,3,4,7,8,8-hexahydropyrrolo simultaneously [1,2- α] pyrazine-2- carbonyls]-4- fluoro-phenyls] methyl]-2H- phthalazines-1- ketone
Mono- Walk
[(27) -5- oxo-pyrrolidine -2- bases] methyl mesylate
By (5i) -5- (methylol) pyrroles protective embankment -2- ketone 3a (4 g, 43.40 mmol) it is dissolved in 150 mL chloroforms, add triethylamine (35 mL, 260.40 mmol), stirred 10 minutes under ice bath, mesyl chloride (20 mL, 217 mmol) is added, is reacted at room temperature 3 hours.Add 100 mL dichloromethane protective embankments, washed (20 mL) with saturated sodium bicarbonate solution (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 [(2i) -5- oxo-pyrrolidine -2- bases] methanesulfonic acid first 3b (3.50 g, light yellow solid), yield： 42.0%.
MS m/z (ESI): 194.0 [M+l]
Bis- Walk
(5i) -5- [(benzyl (2- hydroxyethyls) amino) methyl] pyrroles protective embankment -2- ketone general [(2) -5- oxo pyrroles protective embankment -2- bases] methyl mesylate 3b (1 g, 5.17 mmol) and 2- benzylamino-ethanols (3 g, 20.68 mmol) add in microwave reaction pipe, reacted 40 minutes under 130'C microwave conditions.Add 20 mL dichloromethane and 20 mL water, divide liquid, aqueous phase is extracted (20 mLx2) with dichloromethane, merge organic phase, (20 mL), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression concentrate, with silica gel column chromatography with eluant, eluent system A purify obtained by residue, obtain (57) -5- [(benzyl (2- hydroxyethyls) amino) methyl】Pyrroles protective embankment -2- ketone 3c (640 mg, light yellow oil), yield： 50.0%.
MS m/z (ESI): 249.1 [M+l]
Tri- Walk
2- [benzyls _ [[(2i) -5- oxo pyrroles protective embankment -2- bases] methyl] amino] ethyl methane sulfonate general (5/) -5- [(base (2- hydroxyethyls) amino) methyl] pyrrolidin-2-one 3c (640 mg, 2.58 mmol) it is dissolved in 10 mL chloroforms, add triethylamine (0.8 mL, 5.15 mmol), under ice bath, mesyl chloride (0.4 mL, 5.15 mmol) is added, is reacted at room temperature 6 hours.20 mL saturated sodium bicarbonate solutions are added, point liquid, aqueous phase extracts (20 mLx2) with dichloromethane protective embankment, merge organic phase, filtering dry with anhydrous sodium sulfate thousand, filtrate decompression concentration obtains 2- [benzyls-[[(2/) -5- oxo-pyrrolidine -2- bases] methyl] amino] ethyl methane sulfonate 3d (180 mg, nothing Tetra- Walk
(8 "/- 2- benzyls -1,3,4,7,8,8^ hexahydropyrrolos simultaneously [1,2- α] pyrazine -6- ketone by 2- [Jie Ji-[[(2) -5- oxo-pyrrolidine -2- bases] if yls] amino] ethyl methane sulfonate 3d (180 mg, 0.55 nimol) it is dissolved in 10 mL acetonitriles, add sodium hydride and mineral oil mixture (30 mg, 60%, 0.72 mmol), react 4 hours.Pour into 30 mL frozen water, (20 mL are extracted with dichloromethane><3), merge organic phase, washed with saturation sodium solution (20 mL), anhydrous sodium sulfate thousand is dry, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain (8 α-2- benzyls-1,3,4,7,8,8-hexahydropyrrolo simultaneously [1,2- 〃] pyrazine-6- ketone 3e (90 mg, light yellow oil), yield： 71.0%.
MS m/z (ESI): 231.1 [M+l ]
Wu Walk
(8ai-2,3,4,7,8,8-hexahydropyrrolo simultaneously [1,2- β] pyrazine-6- ketone by (8 i) -2- benzyls -1,3,4,7,8,8 " simultaneously [1; 2- "] pyrazine -6- ketone 3e (90 mg, 0.39 mmol) is dissolved in 5 mL methanol-hexahydropyrrolo, adds 20 10% palladiums of mg/carbon and formic acid neodymium (172 mg, 2.74 mmol), back flow reaction 3 hours.Filtering, filter cake is washed with 10 mL methanol, filtrate decompression concentration, obtains (8ai) -2,3,4,7,8,8a- hexahydropyrrolos simultaneously [1,2- 7] pyrrole crop -6- ketone 3f (55 mg, colorless oil), yield： 100.0%.
MS m/z (ESI): 141.1 [M+l]
Liu Walk
4-[[3-[(8aJ) -6- oxos -1,3,4,7,8,8fl- hexahydropyrrolo simultaneously [1,2-a) pyrazine -2- carbonyls] -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone
By the fluoro- 5- of 2- [(4- oxo -3H- phthalein crop -1- bases）Methyl] benzoic acid lc (106 mg, 0.36 mmol) is dissolved in
10 mL DMF Cao, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (205 mg, 0.54 mmol), (8i/) -2, simultaneously [1,2- "] pyrazine -6- ketone 3f (55 mg, 0.39 mmol) and Ν, Ν-diisopropylethylamine (130 μ, 0.72 mmol) react 12 hours 3,4,7,8,8a- hexahydropyrrolos.It is concentrated under reduced pressure, gained residue is purified with solvent system A with thin-layered chromatography, 4- [[3- [(8^) -6- oxos-l, 3,4,7,8,8 is obtaineda- hexahydropyrrolo simultaneously [1,2-al pyrazine -2- carbonyls] -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone 3 (30 rag, light yellow solid), yield： 20.0%.
MS m/z (ESI): 421.1 [M+l J
Ή NMR (400 MHz, OMSO-d6):δ 12.59 (br. s, IH), 8.27 (d, IH), 7.98 (m, 3H), 7.45 (m, 3H), 4.62 (m, IH), 4.33 (s, 2H), 4.08 (m, IH), 3.75 (m, 1H), 3.52 (m, I H), 3.17 (m, IH), 2.89 (m, 4H), 2.27 (m, 2H) embodiments 4
4- [[3- [l- benzyls -3,3fl, 4,6,7,7fl- hexahydro -2H- pyrrolo-es [3,2-c] pyridine -5- carbonyls] -4- fluoro-phenyls] methyl] small ketone of -2H- phthalazines
Mono- Walk
3- (2- methoxyl group -2- oxo-ethyls) -4- oxo piperidine -1- t-butyl formates are by 4- oxo piperidine -1- t-butyl formates 4a (20 g, 100.50 mmol) it is dissolved in 180 mL tetrahydrofurans, tetrahydrofuran/just protective embankment in heptan/ethyl benzole soln (75 mL of 2 M lithium diisopropyl amidos are added at -78 times, 150 mmol), stirring 30 minutes, methyl chloroacetate (13 mL are added dropwise, 150 mmol), -78 times reactions 3 hours, are reacted at room temperature 12 hours.Add 100 mL water, it is extracted with ethyl acetate (200 mLx3), merge organic phase, (20 mL), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression concentrate, with silica gel pestle chromatography with eluant, eluent system B purify obtained by residue, obtain 3- (2- methoxyl group -2- oxo-ethyls) -4- oxo piperidine -1- t-butyl formates 4b (26.56 g, brown-red oil), yield： 97.2%.
MS m/z (ESI): 172.1 [M- 100+1]
Bis- Walk
4- hydroxyls -3- (2- hydroxyethyls) piperidines -1- t-butyl formates
By 3- (2- methoxyl group -2- oxo-ethyls) -4- oxo piperidine -1- t-butyl formates 4b (3 g, 11 mmol) it is dissolved in 30 mL tetrahydrofurans, add lithium borohydride (730 mg, 33 mmol), react 3 hours, react at room temperature 48 hours under 40 °C.Add 10 mL saturated ammonium chloride solutions, filtering, filtrate decompression concentration, adds 50 mL ethyl acetate, washed with saturated nacl aqueous solution (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with alumina column chromatography with eluant, eluent system A purify gained residue, obtain 4- hydroxyls -3- (2- hydroxyethyls) piperidines -1- t-butyl formates 4c (2.31 g, brown oil), yield： 85.8%.
Tri- Walk
4- mesyloxies -3- (2- Methansulfonyloxyethyls) piperidines -1- t-butyl formates are by 4- hydroxyls -3- (2- hydroxyethyls) piperidines -1- t-butyl formates 4c (500 mg, 2.04 mmol) it is dissolved in 15 mL dichloromethane protective embankments, add triethylamine (850 6.12 mmol), stirred 10 minutes under ice bath, mesyl chloride (380 4.89 mmol) is added, is reacted 1 hour.Washed with saturated ammonium chloride solution (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain 4- mesyloxies -3- (2- Methansulfonyloxyethyls) piperidines -1- t-butyl formates 4d (614 mg, light brown oily substance), yield： 75.0%.
Tetra- Walk 1-3,3 α, 4,6,7,7 "-hexahydro-2H- pyrrolo-es [3,2-c] pyridine-5- t-butyl formates
4- mesyloxies -3- (ethyl of 2- methylsulfonyls oxygen 3) piperidines -1- t-butyl formates 4d (305 mg, 0.76 mmol) are dissolved under benzylamine (407 mg, 3.80 mmol) Cao, 70 °C and reacted 2.5 hours.Add that 15 mL acetic acid second are cruel and the M i sodium hydroxide solutions of 2.5 mL 5, point liquid, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, it is residue obtained by A is purified to consult method with eluant, eluent to stop with oxidation mendelevium post color, obtain 1- benzyls-3,3,4,6,7,7-hexahydro-2H-M ratios cough up simultaneously [3,2-c] pyridine-5- t-butyl formates 4e (181 mg, light yellow oil), yield： 75.0%.
MS m/z (ESI): 317.2 [M+l ]
Wu Walk
1-benzyl-2,3,3,4,5,6,7,7 octahydro pyrrolo- [3,2-c] pyridine hydrochlorides are by 1- benzyls-3,3 Ο, 4,6,7,7 Ω-hexahydro-2H- pyrrolo-es [3,2-c] pyridine-5- t-butyl formates 4e (181 mg, 0.57 mmol) is dissolved in 2 mL dichloromethane tracks, add the M hydrogen chloride of 3 mL 2 ", 4- dioxane solutions are reacted 12 hours.It is concentrated under reduced pressure, obtains crude product 1- benzyls -2,3,3 α, 4,5,6,7,7 α-octahydro pyrrolo- [3,2-c] pyridine hydrochloride 4f (181 mg, light yellow oil), product is not purified directly to enter the lower Walk reactions of row.
Liu Walk
4- [[3- [1- benzyls -3,3,4,6,7,7 "-hexahydro -2H- pyrrolo-es [3,2-c] pyridine -5- carbonyls] -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone
The fluoro- 5- of 2- [(- 1-yl of 4- oxo-3H- phthaleins prolixity) methyl] benzoic acid lc (1 15 mg, 0.38 mmol) is dissolved in 6 mL Ν, Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (260 mg, 0.68 mmol), crude product 1- benzyls-2,3,3 α, 4,5,6,7,7-octahydro pyrrolo- [3,2-c] pyridine hydrochloride 4f (144 mg, 0.57 mmol) and Ν, Ν-diisopropylethylamine (350 L, 1.90 mmol), react 12 hours.20 mL water are added, are extracted with dichloromethane (20 mlX3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with open up Ji agent system A purify gained residue, obtain 4- [[3- [1-benzyl-3,3/, 4,6,7,7 Ω-hexahydro-2H- pyrrolo-es [3,2-c] pyridine-5- carbonyl 1-4- fluoro-phenyls] methyl]-2H- phthalazines-1- ketone 4 (38 mg, light yellow solid), yield： 20.0%.
MS nVz (ESI): 497.2 [M+l J
Ή NMR (400 MHz, CDC13):10.50 (br. s, 1H), 8.47 (d, 1H), 7.77 (m, 3H), 7.33 (m, 7H), 7.01 (m, 1H), 4.26 (s, 2H), 4.17 (m, 1H), 3.86 (m, 2H), 3.73 (s, 2H), 3.31 (m, 2H), 2.75 (m, 2H), 2.28 (s, 3H), 2.18 (s, 1H), 1.97 (s, 1H) embodiment 5
4- [[the fluoro- 3- of 4- [l- (3- picolyls)-3,3 ", 4,6,7,7-hexahydro-2H- pyrrolo-es [3,2- c] pyridine-5- carbonyls]-phenyl]
Mono- Walk
1-(3- pyridine Cao yls)-3,3,4,6,7,7 α-hexahydro-2H- pyrrolo-es [3,2-c] pyridine-5- t-butyl formates are by small t-butyl formate d (719 mg of 4- mesyloxies-3- (2- Methansulfonyloxyethyls) piperidines, 1 .79 mmol) it is dissolved in C- pyridines-3--methyl amine (968 mg, 8.95 mmol), reacted 2.5 hours under 70 °C.30 mL ethyl acetate are added, (20 mLx3) is washed with 5 M sodium hydroxide solutions, point liquid, organic phase anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with alumina column chromatography with eluant, eluent system A purify gained residue, obtain 1- (3- picolyls)-3,3 α, 4,6,7,7-hexahydro-2H- pyrrolo-es [3,2-C] pyridine -5- t-butyl formates 5a (200 mg, light yellow oil), yield： 35.7%.
MS m/z (ESI): 318.2 [M+l]
Ghost one lacks
L- (3- picolyls) -2,3,3fl, 4,5,6,7,7a- octahydros pyrrolo- [3,2-c] pyridine hydrochloride is by 1- (3- picolyls) -3,3 β, 4,6,7,7 α-hexahydro -2H- pyrrolo-es [3,2-c | pyridine -5- t-butyl formates 5a (200 mg, 0.63 mmol) is dissolved in 3 mL dichloromethane, 1, the 4- dioxane solutions of the M hydrogen chloride of 6 mL 2 are added, are reacted 12 hours.It is concentrated under reduced pressure, obtains crude product 1- (3- picolyls)-2,3,3,4,5,6,7,7-octahydro pyrrolo- [3,2-c] pyridine hydrochloride 5b (181 mg, light yellow oil), product is not purified directly to enter the lower Walk reactions of row.
3rd step
4- [[the fluoro- 3- of 4- [Hydrogen-2H- pyrrolo-es [3, the 2- c] pyridine-5- carbonyls of 1-(3- picolyls)-3,3fl, 4,6,7,7fl- six]-phenyl] methyl]-2H- phthalazines-1- ketone
By the fluoro- 5- of 2- [(the small base of 4- oxo -3H- phthalazines) methyl] benzoic acid lc (150 mg, 0.50 nimol) it is dissolved in 6 mL Ν, in Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (342 mg, 0.90 ramol), crude product (3- picolyls) -2, 3, 3 α, 4, 5, 6, 7, 7-octahydro pyrrolo- [3, 2- c] pyridine hydrochloride 5b (i60 mg, 0.63 mmol) and N, N- diisopropylethylamine (430 L, 2.50 mmol), reaction 2 hours.10 mL water are added, (15 mL are extracted with ethyl acetate>0) organic phase, is merged, it is dry with anhydrous sodium sulfate thousand, filtering, filtrate decompression concentration, with thin-layered chromatography with open up Ji agent system A purify obtained by residue, obtain 4- [[the fluoro- 3- of 4- [1- (3- picolyls) -3,3 β, 4,6,7,7 α-hexahydro -2H- pyrrolo-es [3,2-c] pyridine -5- carbonyls]-phenyl] methyl] 5 (20 mg of -2H- phthalazines -1- ketone, light yellow solid), yield： 8.0%.
MS m/z (ESI): 498.4 [M+l]
Ή NMR (400 MHz, CDC13):δ 10.90 br. s, IH), 8.59 (m, 2H), 8.47 (d, 1H), 7.75 (m, 3H), 7.31 (m, 4H), 7.06 (m, 1H), 4.27 (s, 2H), 4.14 (m, IH), 3.93 (m, 2H), 3.74 (m, IH), 3.30 (m, IH), 2.77 (m, IH), 2.54 (m, IH), 2.30 (m, 2H), 2.25 (m, IH), 1.92 (s, IH), 1.29 (m, 3H) Embodiment 6
8One [2- fluorine-5-[(- 1-yl of 4- oxo-3H- phthalazines) methyl] benzoyl]-6,7,9 ,-tetrahydrochysene-1H- pyrazines are simultaneously
Mono- Walk
4- Benzyloxycarbonylpiperazin -2- formic acid
By piperazine crop -2- formic acid 6a (4 g, 30.70 mmol) it is dissolved in 30 mL water, add 60 mL cupric sulfate pentahydrates (3.84 g, 15.35 mmol) the aqueous solution, 30 mL benzyl chloroformates (5.3 mL are added dropwise under ice bath, 36.90 mmol) 1,4- dioxane solutions.Control reacting liquid pH value to be more than 7 (when needing plus sodium acid carbonates), react at room temperature 12 hours.Filtering, filter cake is washed (10 mL) with frozen water (10 mL), ethanol (10 mL), ethyl acetate successively, solid is dried in vacuo, obtain crude product 4- Benzyloxycarbonylpiperazin -2- formic acid 6b (8 g, blue solid), product is not purified directly to enter the lower Walk reactions of row.
Bis- Walk
Piperazine -1,3- dioctyl phthalate-benzyl ester -3- methyl esters
Added in 100 mL eggplant-shape bottles under 30 mL methanol, ice bath, thionyl chloride (2.7 mL are added dropwise, 37.50 mmol), stirring 30 minutes, adds crude product 4- Benzyloxycarbonylpiperazin-2- formic acid 6b (1.98 g, 7.50 mmol), back flow reaction 3 hours, it is concentrated under reduced pressure, obtains crude product piperazine-1,3- dioctyl phthalate-1-benzyl ester-3- methyl esters 6c (4.20 g, yellow oil), product is not purified directly to carry out next step reaction.
MS m/z (ESI): 279.1 [M+l]
Tri- Walk
3- (light methyl) piperazine-1-benzyl formate
Small benzyl ester -3- methyl esters the 6c of crude product piperazine -1,3- dioctyl phthalate (4.20 g, 15 mmol) is dissolved in 20 mL tetrahydrofurans, under ice bath, lithium borohydride (0.65 g, 30 mmol) is added, reacts at room temperature 12 hours.LO mL acetone is added, is concentrated under reduced pressure, 20 mL water is added, (20 mL is extracted with dichloromethane><3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains 3- (methylol) piperazine -1- benzyl formates 6d (1.80 g, colorless oil), yield： 50.0%. MS m/z (ESI): 251.1 [M+l]
Tetra- Walk
- ψ the acid benzyl esters of 4- (2- chloracetyls) -3- (hydroxyl first) piperazine -1 are by 3- (methylol) piperazine prolixity -1- benzyl formates 6d (1.80 g; 7 mmol) it is dissolved in 30 mL dichloro Cao protective embankments; under ice bath; triethylamine (3 mL are added dropwise successively; 21 mmol) and l O niL chloracetyl chlorides (0.6 mL; 8.40 mmol) dichloromethane solution, react at room temperature 2 hours.Add 30 mL water; divide liquid; aqueous phase is extracted (50 mLx3) with dichloromethane; merge organic phase; river saturated sodium bicarbonate solution (20 mLx2), saturated nacl aqueous solution washing (20 mLx2) successively; anhydrous sodium sulfate drying; filtering; filtrate decompression is concentrated; with silica gel column chromatography with eluant, eluent system B purify gained residue; obtain 4- (2- chloracetyls) -3- (methylol) piperazine crop -1- benzyl formates 6c (650 mg, colorless oil), yield： 28.0%.
MS m/z (ESI): 327 [M+l]
5th step
4- oxos-6,7,9; 9 " simultaneously [2; 1-c] [the small benzyl formate 6e of 4- (2- chloracetyls)-3- (methylol) piperazines (650 mg, 2 mmol) is dissolved in 5 mL Ν to-tetrahydrochysene-1H- pyrroles crop by l, 4] oxazine-8- benzyl formates; in Ν-dimethylformamide; under ice bath, adds sodium hydride and mineral oil mixture (192 mg, 60%; 4 mmol), is reacted at room temperature 12 hours.20 mL water are added, (50 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, with thin-layered chromatography with solvent system B purify gained residue, obtain 4- oxos -6,7,9,-tetrahydrochysene -1H- pyrazines simultaneously [2, l-c] [l, 4] oxazine -8- benzyl formates 6f (180 mg, white solid), yield： 31.0%.
MS m/z (ESI): 291.1 [M+l ]
Liu Walk
1,6,7,8,9,9 " simultaneously [2; l-c] [l, 4] oxazine -4- ketone are by 4- oxos -6,7; simultaneously [2, l-c] [l; 4] oxazine -8- benzyl formates 6f (180 mg, 0.62 mmol) are dissolved in 20 mL methanol, adds 50 10% palladiums of mg/carbon to 9,9 α-tetrahydrochysene -1H- pyrazines; hydrogen is replaced three times, reacts 4 hours for-hexahydropyrazine.Filtering, filtrate decompression concentration, obtains crude product 1,6,7,8,9,9-hexahydropyrazine simultaneously [2, l-c | [l, 4] oxazine-4- ketone 6g (100 mg, colorless oil), product is not purified directly to be entered the lower Walk of row and reacts.
Qi Walk
8- [the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoyl] -6,7,9,9 α-tetrahydrochysene -1H- pyrazines are simultaneously
[2,1-C] [Isosorbide-5-Nitrae] oxazine -4- ketone
By the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid lc (150 mg, 0.50 mmol) it is dissolved in 5 mL DMFs, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (285 mg, 0.75 mmol), crude product 1,6,7,8,9,9 α-hexahydro pyrrole crop simultaneously [2, l-c] [l, 4] oxazine -4- ketone 6g (100 mg, 0.64 mmol) and N, N- diisopropylethylamine (0.2 mL, 1 mmol), reacts 12 hours.20 mL water are added, are extracted with dichloromethane (20 niLx3), merges organic phase, (20 mL is washed with saturated nacl aqueous solution><2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 8- [the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases）Methyl] benzoyl] -6,7,9,9 " H- of-tetrahydrochysene -1 pyrazines are simultaneously [2, l-c] [l, 4] Evil crop -4- ketone 6 (200 mg, color solid), yield: 92.0%
MS m/z (ESI): 437.1 [M+l]
Ή NMR (400 MHz, CDC13):{ the br. s of δ 10.45,111), 8.49-8.46 (m, I H), 7.81-7.70 (m, 3H) 7.39-7.34 (m, 2H), 7.10-7.03 (m, I H), 4.68-4.58 (m, 2H), 4.29 (s, 2H), 4.20-4.05 (m 3H), 3.74-3.38 (m, 4H), 3.21-3.18 (m, IH), 2.78-2.68 (m, IH) embodiment
4- [[3- (l, 3,3fl, 4,5 ,] -2 phthalein prolixity -1- ketone
The fluoro- 5- of 2- [(the small base of 4- oxo -3H- phthalein crops) methyl] benzoic acid l c (150 mg, 0.50 mmol) are dissolved in
20 mL N, in dinethylformamide, BTA-Ν, Ν are added, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (284 mg, 0.75 mmol), octahydro-isoindol (75 mg, 0.60 mmol) and Ν, Ν-diisopropylethylamine (0.2 mL, 1 mmol), reacts 12 hours.Be concentrated under reduced pressure, consulted with thin layer color method with solvent system A purify gained residue, obtain 4- [[3- (1,3,3,4,5,6,7,7 β-octahydro iso-indoles -2- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone 7
(76 mg, white solid), yield： 37.6%.
MS m/z (ESI): 406.2 [M+l]
Ή NMR (400 MHz, CDC13):δ 10.02 (br. s, IH), 8.51 (d, H), 7.82 (m, 3H), 7.60 (m, I H), 7.39 (m, I H), 7.07 (m, IH), 4.31 (s, 2H), 4.25 (m, IH), 3.74 (m, I H), 3.53 (m, 3H), 3.32 (m, IH), 3.20 (m, 2H), 3.16 (m, 2H), 2.35 (m, 2H), 1.57 (m, 2H) embodiment 8
4- [[3- (5,7- dihydros] -2H- phthalazines -1- ketone
By the fluoro- 5- of 2- [(the small base of 4- oxo -3H- phthalazines) methyl]-benzoic acid lc (150 mg, 0.50 mmol) it is dissolved in 10 mL N, dinethylformamide Cao, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (285 Mg, 0.75 mmol), 6,7- dihydro -5H- pyrrolo-es [3,4- Λ] pyridine hydrochloride (116 mg, 0.60 mmol) and Ν, Ν-diisopropylethylamine (350 2 mmol) react 12 hours.Add 30 mL water, extracted with dichloromethane (50 mLx3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with spreader system A purify gained residue, obtain (200 mg of 4- [[3- (5,7- pyrrolin simultaneously [3,4-6] pyridine -6- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone 8, white solid), yield： 〗00.0%.
MS m/z (ESl): 401.1 [M+l]
Ή NMR (400 MHz, CDC13):δ 10.45 (br. s, 1 H), 8.56-8.43 (m, 2H), 7.82-7.62 (m, 4H), 7.53-7.35 (m, 2H), 7.31-7.1 8 (m; " H), 7.12-7.08 (m, IE), 5.01 (s, 2H), 4.67 (s, 2H), 4.30 (s, 2H) embodiment 9
4- [[3- (3,3fl, 4,6,7,7 "-hexahydro -2H- furans simultaneously [3,2- c] pyridine -5- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines
The first step
4- hydroxyls-3- (2- Methansulfonyloxyethyls) piperidines-1- t-butyl formates are by 4- hydroxyls-3- (2- hydroxyethyls) piperidines-1-t-butyl formate 4c (550 mg, 2.24 mmol) it is dissolved in 5 mL dichloromethane protective embankments, add N.N- diisopropylethylamine (0.8 mL, 4.48 mmol), stirred 10 minutes under ice bath, mesyl chloride (260 μ, 2.47 mmol) is added, is reacted at room temperature 2 hours.Washed (1 mL) with saturation chlorination cymbal solution, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with alumina column chromatography with eluant, eluent system A purify gained residue, obtain 4- hydroxyls -3- (2- Methansulfonyloxyethyls) piperidines -1- t-butyl formates % (50 mg, yellow oil), yield： 6.9%.
MS m/z (ESI): 224 [M- 100+1]
Bis- Walk
3,3fl, 4,6,7,7fl- hexahydro -2H- furans simultaneously [3,2-c] pyridine -5- t-butyl formates by small t-butyl formate 9a (800 mg of 4- hydroxyls -3- (2- Methansulfonyloxyethyls) piperidines, 2.50 mmol) it is dissolved in 10 mL tetrahydrofurans, under ice bath, sodium hydride and mineral oil mixture (119 mg, 60% are added, 3 mmol), react 3 hours.0.5 mL saturation chlorination cymbal solution is added, is concentrated under reduced pressure, gained residue is purified with eluant, eluent system A with alumina column chromatography, 3,3 α are obtained, 4,6,7,7 α-hexahydro -2H- furans simultaneously [3,2-C] pyridine -5- t-butyl formates 9b (200 mg, colorless oil), yield： 35.0%. MS m/z (ESI): 128.2 [M- 100+1 ]
Tri- Walk
2,3,3,4,5,6,7,7 "-octahydro furans simultaneously [3,2-c] pyridine hydrochloride by 3,3 ", 4,6,7, simultaneously [3,2- c] pyridine-5- t-butyl formates 9b (200 mg, 0.10 mmol) is dissolved in 2 ml to 7-hexahydro-2H- furans, in 1, the 4- dioxane solutions of 2 M hydrogen chloride, react 12 hours.It is concentrated under reduced pressure, obtains crude product 2,3,3,4,5,6,7,7-octahydro furans simultaneously [3,2-c] pyridine hydrochloride 9c (181 mg, light yellow oil), product is not purified directly to enter the lower Walk reactions of row.
MS m/z (ESI): 128.1 [M+l ]
Tetra- Walk
4- [[3- (3,3/, 4,6,7,7 β-hexahydro -2//- furans simultaneously [3,2-c] pyridine -5- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone
The fluoro- 5- of 2- [(the small base of 4- oxo -3H- phthalazines) methyl] benzoic acid lc (150 mg, 0.50 mmol) is dissolved in 5 mL Ν, Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (285 mg, 0.75 mmol), crude product 2,3,3 "; 4; 5,6,7; 7 "-octahydro furans simultaneously [3,2-c] pyridine hydrochloride 9c (76 mg, 0.60 mmol) and Ν, Ν-diisopropylethylamine (360 μ, 2 mmol), react 12 hours.20 mL water are added, are extracted with dichloromethane (20 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify gained residue, obtain 4- [[3- (3,3,4,6,7,7-hexahydro-2H- furans simultaneously [3,2-c] pyridine-5- carbonyls)-4- fluoro-phenyls] methyl]-2H- phthalazines-1- ketone 9 (40 mg, white solid), yield： 20.0%.
MS m/z (ESI): 408.2 [M+l]
Ή NMR (400 MHz, CDC13):δ 10.06 br. s, 1H), 8.45-8.47 (m, 1H), 7.73-7.79 (m, 3H), 7.27-7.32 (m, 2H), 7.00-7.05 (m, 1H), 5.57 (m, 1H), 4.27 (s, 2H), 4.21 (m, 1H), 3.71-3.74 (m, 2H), 2.28-2.33 (m, 4H), 1.26-1.30 (m, 4H) embodiment 10
- fluoro-5-[(4_ oxo -3H- phthalazines -1- bases) methyl] benzoyl] -5,6,8,8a- tetrahydrochysene -1H- oxazoles simultaneously [3,4-] pyrrole
Mono- Walk
Simultaneously the small benzyl formate 6d of 3- (methylol) piperazine (500 mg, 2 mmol) is dissolved in 30 mL 1, the chloroethene institutes of 2- bis- to -5,6,8,8 α of 3- oxos-tetrahydrochysene -1H- oxazoles by [3,4- "] pyrazine -7- benzyl formates Cao, adds Ν, different Inner ' the bases ethamine of Ν-two (mmol of 0.5mL 3) o adds triphosgene, and (1 50 °C of 1 n of 296mg react 12 hours.30 mL water are added, point liquid, aqueous phase extracts (50 mL with dichloromethane protective embankment><3), merge organic phase, washed with saturated nacl aqueous solution (25mLx2), anhydrous sodium sulfate thousand is dry, filtering, filtrate decompression is concentrated, and obtains crude product 3- oxos-5,68,8-tetrahydrochysene-1H- oxazoles simultaneously [3,4- α] pyrazine-7- benzyl formates 10a (551 nig, colorless oil), product is not purified directly to enter the lower Walk reactions of row.
MS m/7.(ESl): 277.1 [M+l]
Bis- Walk
1,567,88 β-Liu Qing Evil miaows simultaneously [3,4-o] pyrrole prolixity -3- ketone
By -5,6,8,8 α of crude product 3- oxos-tetrahydrochysene -1H- oxazoles simultaneously [34- α] pyrazine -7- benzyl formates 10a (mmol of 551 mg 2：) 50 mL methanol Cao are dissolved in, 100 10% palladiums of mg/carbon is added, hydrogen is replaced three times, is reacted 3 hours.Filtering, filtrate decompression concentration, obtains crude product 15,6,7,8,-six hydrogen oxazoles simultaneously [3,4-] pyrazine -3- ketone 10b (284 mg, colorless oil), and product is not purified directly to be entered the lower Walk of row and react.
Tri- Walk
- 5,6,8,8-Si Qing oxazoles are simultaneously by 7- [the fluoro- 5- of 2- [(the small base of 4- oxo-3H- phthalazines) methyl] benzoyl]
[3,4-] Π is than piperazine -3- ketone
By the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid lc (150 mg, 0.50 mmol) it is dissolved in 5 mL Ν, in Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (285 mg, 0.75 mmol), crude product 1,5,6,7,8,8 "-Liu Qing oxazoles simultaneously [3; 4- α] pyrazine -3- ketone 10b (150 mg; 1 mmol) and Ν, Ν-diisopropylethylamine (mmol of 0.2mL 1), reacts 12 hours.It is concentrated under reduced pressure; add 20mL water; extracted with dichloromethane (50mLx3); merge organic phase; washed with saturated nacl aqueous solution (20 mLx2); anhydrous sodium sulfate drying; filtering; filtrate decompression concentrate, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 7- [the fluoro- 5- of 2- [(the small base of 4- oxo -3H- phthalazines) methyl] benzoyl] -56; a- tetrahydrochysene -1H- oxazoles simultaneously [3; 4-a] pyrazine -3- ketone 10 (65 mg, white solid), yield： 31.0%
MS m/z(ESl): 423.1 [M+l]
]Η NMR (400 MHz, CDC13):δ 10.52 (br. s, lH), 8.51-8.49 (m, 1 H), 7.84-7.78 (m, 3H), 7.45-7.39 (m, 2H), 7.18-7.10 (m, 1H), 4.95-4.82 (m, 1H), 4.57-4.47 (m, 1H 4.35 (s, 2H), 4.12-3.54 (m, 5H), 3.21-3.15 (m, 2H) embodiment 1】
4- [[3- (1,2,34,4 α, 577 α-octahydro pyrrolo- [3,4-6] pyridine -6- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines -1-
Mono- Walk
6- [the fluoro- 5- of 2- [(- 1-yl of the phthalein of 4- oxos-3 prolixity) methyl] benzoyl]-3,4,4", the 5,7,7 " pyrrolo-es of-hexahydro -2
[3,4-6] pyridine -1- t-butyl formates
The fluoro- 5- of 2- [(the small base of 4- oxo -3H- phthalein crops) methyl] benzoic acid lc (150 mg, 0.50 mmol) is dissolved in
In 20 mL DMFs, BTA-Ν is added, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (284 mg, 0.75 mmol), octahydro-B ratios cough up simultaneously [3,4-6] pyridine -1- t-butyl formates (136 mg, 0.60 mmol) and Ν, Ν-diisopropylethylamine (0.2 mL, 1 mmol), react 12 hours.It is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain 6- [the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoyl] -3,4,4 α, 5,7,7/- hexahydro -2H- pyrrolo-es [3,4-6] pyridine -1- t-butyl formates 11a (58 mg, brown oil）, yield： 23.0%.
MS m/z (ESI): 407.2 [M- 100+1]
Bis- Walk
4- [[3- (1,2,3,4,4α, 5,7,7 α-octahydro pyrrolo- [3,4-6] pyridine -6- carbonyls) and -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone
By 6- [the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoyl] -3; 4; 4 β; 5,7,7 Ω-hexahydro -2H- pyrrolo-es [3; 4-6] small t-butyl formate 11a (58 mg of pyridine; 0.11 mmol) it is dissolved in Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 2 mL 2, react】2 hours.Be added dropwise saturated sodium bicarbonate solution to reaction solution pH be 9, (20 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, (20 mL), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression concentrate, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 4- [[3- (1,2,3,4,4,5,7,70- octahydro pyrrolo- [3,4-6] pyridine-6- carbonyls)-4- fluoro-phenyls] methyl] small (5 mg of ketone 11 of-2-phthalazines, white solid), yield： 10.9%.
MS m/z (ESI): 407.2 [M+l]
^ NMR (400 MHz, CDC13):δ 10.03 (br. s, 1H), 8.50 (d, 1H), 7.82 (m, 3H), 7.30 (m, 1H), 7.29 (m, 1H), 7.01 (m, 1 H), 4.31 (s, 2H), 4.16 (m, 1H), 3.76 (m, 4H), 3.25 (m, 3H), 3.07 (m, 2H), 2.70 (m, 1H), 2.09 (m, 2H) embodiment 12
4- [[3- (3,3 α, 4,6,7,7 β-hexahydro -2H- thiophene 5- carbonyls)-phenyl] methyl] -2H- phthalazines -1- ketone
Mono- Walk
6, the 7- tertiary fourths of dihydro -4H- thienos [3,2-c] pyridine -5- formic acid ' | by 4,5,6,7- tetra- Gas thienos [3,2-cl pyrrole 12a (1 g, 5.70 mmol) it is dissolved in 30 mL dichloromethane protective embankments, add Ν, the different W bases ethamine of Ν-two (3 mL, 1 7.10 mmol) and di-tert-butyl dicarbonate (3.10 g, 14.20 mmol), react 2 hours.Add 30 mL saturated ammonium chloride solutions, extracted with dichloromethane (50 mLx2), merge organic phase, washed with saturated nacl aqueous solution (25 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude product 6,7- dihydro -4H- thienos [3,2-c] pyridine -5- t-butyl formates 12b (1.40 g, colorless oil), the lower Walk reactions of the not purified row that directly spouts of product.
Bis- Walk
3,4,6,7,7 "-hexahydro -2H- thienopyridine -5- t-butyl formates are by crude product 6; and 7- dihydro -4H- thienos [3,2-c | pyridine -5- t-butyl formates 12b (500 mg, 2.10 mmol) is dissolved in 30 mL methanol; add 20% palladium dydroxide/carbon (1.62 g; 2.30 mmol), and hydrogen is replaced three times, and 50 °C are reacted 12 hours.Filtering, filtrate decompression concentration, obtains 3,3 α, 4,6,7,7 α-hexahydro -2H- thienos [3,2-c] pyridine -5- t-butyl formates 12c (50 mg, colorless oil), yield： 10.0%.
MS m/z (ESI): 188.1 [M-56+1 ]
Tri- Walk
2,3,3 α, 4,5,6,7,7-octahydro thieno [3,2-c] pyridine hydrochloride is by 3,3 α, 4,6,7,7 π-hexahydro-2H- thienos [3,2-c] pyridine-5- t-butyl formates 12c (200 mg, 0.82 mmol) it is dissolved in Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 3 mL 2, react 12 hours.It is concentrated under reduced pressure, obtains crude product 2,3,3 α, 4,5,6,7,7 β-octahydro thieno [3,2-c] pyridine hydrochloride 12d (118 mg, white solid), product is not purified directly enters the lower Walk reactions of row.
MS iz (ESI): 144.1 [M+l]
Tetra- Walk
4- [[3- (3,3 ", 4,6,7,7 "-hexahydro -2H- thienos [3,2-cl pyridine -5- carbonyls)-phenyl] methyl] -2H- phthalazines -1- ketone
The fluoro- 5- of 2- [(4- oxos-3H-phthalazines-1-yl) methyl] benzoic acid lc (150 mg, 0.50 mmol) is dissolved in 10 mL DMFs, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (285 mg, 0.75 mmol), crude product 2,3,3 "; 4; 5,6,7; 7/- octahydro thieno [3; 2-c] pyridine hydrochloride 12d (65 mg, 0.45 nimol) and Ν, Ν-diisopropylethylamine (260 μ; 1.50 mmol), reacts 12 hours.It is concentrated under reduced pressure, add 20 mL saturation neodymium chloride solutions, (50 mLx2) is extracted with dichloromethane protective embankment, merge organic phase, washed (50 mLx2), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain 4- [[3- (3,3/, 4,6,7-hexahydro-2H- thienos [3,2-c] pyridine-5- carbonyls)-phenyl] methyl] 12 (60 mg of-1 -one of-2H- phthalazines, white solid), yield： 28.0%.
One s (the letters of 0 ()-I 191 (Η ε ζ/.8 Worry Hs ￡:..
Romania 1
Mono- Walk
The bromo- 4- of 3- (2- hydroxyl-oxethyls)-1-t-butyl formates of pyrroles's protective embankment are by 2, small t-butyl formate 14a (9.50 g of 5- pyrrolin, 56.14 mmol, using known method " Organic Process Research ＆ Development; 2009; 13 (3); 63-^/0 " be prepared) it is 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 mLx2), 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-1-t-butyl formate of protective embankment 14b (12 g, rufous grease), yield： 72.3%.
MS m/z (ESI): 254 [M-56+1]
Second step
3- deserts-4- [2- (toluene-4- sulfonyloxies) ethyoxyl] pyrrolidines-1-t-butyl formates are by small t-butyl formate 14b (12 g of the bromo- 4- of 3- (2- hydroxyl-oxethyls) pyrrolidines, 38.69 mmol) it is dissolved in 100 mL toluene, add triethylamine (8.1 mL, 58.03 mmol) with 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 thousand is dry, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain the bromo- 4- of 3- [2- (toluene -4- sulfonyloxies) ethyoxyl] pyrroles protective embankment -1- t-butyl formates 14c (14.30 g, colorless oil), yield： 79.6%.
Tri- Walk
4- benzyls-2,3,4 α, 5,7, simultaneously [3,4-W [the bromo- 4- of 3- [2- (toluene-4- sulfonyloxies) ethyoxyl] P ratios are coughed up protective embankment-1-t-butyl formate 14c (14.30 g to 7-hexahydropyrrolo by l, 4] oxazine-6- t-butyl formates, 30.78 mmol) it is 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 -2,3,4fl, 5,7,7a- hexahydropyrrolos simultaneously [3,4-6] [1,4] oxazine -6- t-butyl formates 14d (7.50 g, light brown grease), yield： 76.0%
MS m/z (ESI): 319.2 [M+l]
Tetra- Walk
4- benzyls-3,4,5,6,7,7-hexahydro-2H- pyrrolo-es [3,4-W [l, 4] oxazines By 4- benzyls -2,3,5,7,7fl- hexahydros-pyrrolo- [3,4-6]【L, 4] Evil crop -6- t-butyl formates 14d (500 mg, 1.57 mmol) are dissolved in 10 mL dichloromethane protective embankment Cao, add 10 mL trifluoroacetic acids, react 2 small inch.Jian Ya Nong Shrink, add 10 mL saturated sodium bicarbonate solutions, are extracted with dichloromethane (20 mLx2), merge organic phase, (15 mLx2) is washed with saturated nacl aqueous solution, anhydrous sodium sulfate thousand is dry, filtering, filtrate decompression concentration, obtains crude product 4- benzyls -3,4 α, 5,6,7,7 " [3,4-W [l; 4] l piperazines 14e (340 mg, colorless oil), product is not purified directly to enter row lower Walk reaction to-hexahydro -2H- pyrrolo-es.
；
I is few '
4- [[3- (4- benzyls -2,3,4 ", 5,7,7/- hexahydropyrrolo simultaneously [3,4-6] [1,4] oxazine -6- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone
The fluoro- 5- of 2- [(4- oxo-3H- phthalazines-1- bases) methyl] benzoic acid lc (150 mg, 0.50 mmol) is dissolved in 5 mL Ν, Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (285 mg, 0.75 mmol), crude product 4- benzyls-3,4fl, 5,6,7,7-hexahydro-2H- pyrrolo-es [3,4->] [1,4] Evil crops 14e (220 mg, 1 mmol) and Ν, Ν-diisopropylethylamine (0.2 mL, 1 mmol) react 12 small inch.Add 20 mL water, (50 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, washed (20 mLx2), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain 4- [[3- (4- benzyls -2,3,4 α, 5,7,7 α-hexahydropyrrolo simultaneously [3,4-6] [1,4] oxazine -6- carbonyls) the fluoro- phenyl of -4-] methyl] the small ketone 14f of -2H- phthalein crops (200 mg, white solid), yield： 80.0%.
MS m/z (ESI): 499.2 [M+l]
Liu Walk
4- [[3- (and 3,4,5,7,7a, hexahydro -2H- pyrrolo-es [3,4- Λ] [Isosorbide-5-Nitrae] oxazine -6- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone
By 4- [[3- (4- benzyls-2,3,4 α, 5,7,7-hexahydropyrrolo simultaneously [3,4-6] [1,4] oxazine-6- carbonyls)-4- fluoro-phenyls] methyl]-2H- phthalazines-1- ketone 14f (200 mg, 0.40 mmol) it is dissolved in 30 mL methanol, add 20 mg 10% and harrow/carbon, hydrogen is replaced three times, 35 reactions 3 hours.Filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain 4- [[3- (3,4,4 β, 5,7,7 β-hexahydro -2H- pyrrolo-es [3,4- 6] [1,4] oxazine -6- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone;I4 (45 mg, white solid), yield： 27.0%. MS m/z (ESI): 409.1 [M+l]
'H NMR (400 MHz, CDC13):δ 10.51 (br. s, IH), 8.45-8.49 (m, IH), 7.70-7.81 (m, 3H), 7.37-7.41 (m, IH), 7.26-7.31 (m, IH), 6.99-7.06 (m, 1H), 4.28 (d, 2H), 3.95-4.10 (m, IH), 3.81-3.90 (m, IH), 3.67-3.78 (m, 2H), 3.47-3.64 (m, 3H), 3.22-3.36 (m, I H), 3.01-3.21 (m, IH), 2.64-2.75 (m, IH) embodiment 15
4- [[the fluoro- 3- of 4- [2- [(4- methoxyphenyls) methyl]-3,3fl, 4,6,7,7-hexahydro-1H- pyrrolo-es [3,4-c] pyridine-5- carbonyls] phenyl] methyl] small ketone of-2H- phthalazines
2- [[(4- methoxyphenyls) methyl] -3,3/, 4,5,7,7 Ω-hexahydro-IH- pyrrolo-es [3,4- c] pyridine -6- ketone will】, 2,3,4,5,7,7 "-octahydro pyrrolo- [3; 4-c] pyridine -6- ketone lb (300 mg; 2.14 mmol) is dissolved in 10 mL acetonitriles, adds 1- (bromomethyl) -4- methoxyl groups-benzene (644 mg, 3.21 mmol) and potassium carbonate (886 mg; 6.42 mmol), and 80 °C are reacted 4 hours.Filtering, filtrate decompression concentration, obtain 2- [[(4- methoxyphenyls) methyl] -3,3 ", 4,5,7,7 α-hexahydro -1H- pyrrolo-es [3,4-c] pyridine -6- ketone 15a (700 mg, brown solid), yield：Move .0%.
MS m/z (ESI): 261.1 [M+l]
Second step
2- [(4- methoxyphenyls) methyl] -1,3,3 ", 4,5,6,7,7 Ω-octahydro pyrrolo- [3,4-c] pyridine is by 2- [[(4- methoxyphenyls）Methyl]-3,3fl, 4,5,7,7-hexahydro-1H- pyrrolo-es [3,4-c] pyridine-6- ketone 15a (200 mg, 0.52 mmol) is dissolved in 12 mL tetrahydrofurans, add lithium aluminium hydride reduction (50 mg, 1.16 mmol), 70 °C are reacted 2 hours, and 50 °C are continued to react 12 hours.0.1 mL water and the sodium hydroxide solutions of 0.1 mL 10% are added, is centrifuged, supernatant liquor is concentrated under reduced pressure, and obtains 2- [(4- methoxyphenyls) methyl：H, 3,3fl, 4,5,6,7,7a- octahydro pyrrolo- [3.4-c] pyridine 15b (127 mg, light brown oily substance), yield： 67.1%.
MS m/z (ESI): 247.2 [M+l]
Tri- Walk
4- [[the fluoro- 3- of 4- [2- [(4- methoxyphenyls) methyl] -3,3 α, 4,6,7,7 "-hexahydropyrrolo simultaneously [3,4-C] pyridine -5- carbonyls] phenyl] methyl] -2H- phthalazines -1- ketone
By the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid lc (130 mg, 0.43 mmol) it is dissolved in 5mL Ν, in Ν-dimethylformamide, add the nitrogen miaow-Ν of benzo three, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (290 mg, 0.78 mmol), 2- [(4- methoxyphenyls) methyl] -1, 3, 3 ", 4, 5, 6, 7, 7 α-octahydro pyrrolo- [3, 4-c] pyridine 15b (127 mg, 0.52 mmol) standing grain Π Ν, Ν-diisopropylethylamine (0.2 mL, 1.29 mmol), reaction 12 hours.Add 15 mL water, it is extracted with ethyl acetate (15 mLx3), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 4- [[the fluoro- 3- of 4- [2- [(4- methoxyphenyls）Methyl] -3,3 ", 4,6,7,7 α-hexahydro -1H- pyrrolo-es [3,4-C] pyridine -5- carbonyls] phenyl] methyl] -2H- phthalazines -1- ketone 15 (21 mg, light yellow solid), yield： 9.5%.
MS m/z (ESI): 527.2 [M+l]
Ή NMR (400 MHz, CDC13): δ 10.6 {br. s, IH), 8.48 (d, IH), 7.72 (m, 3H), 7.27 (m, 3H), 7.01 (dd, IH), 6.92 (d, IH), 6.86 (m, 2H), 4.28 (s, 2H), 3.78 (m, 5H), 3.64 (m, 2H), 3.31 (m, 2H), 2.91 (m, 2H), 2.58 (m, 2H), 2.42 (m, 2H), 2.23 (m, 1 H), 1.90 (m, 1H) embodiments 16
4- [[4- Mining -3- (2- methyl -3,3 ", 4,6,7, the 7 Ω-H- of hexahydro -1 pyrrolo-es [3,4-c] pyridine -5- carbonyls) phenyl] methyl] -2H-
Yi Walk
6- oxos -3,3 α, 4,5,7,7 β-hexahydro -1H- pyrrolo-es " 3,4- c] pyridine -2- t-butyl formates are by 1,2; 3,4,5; 7,7 α-octahydro pyrrolo- [3,4- c] pyridine -6- ketone lb (300 mg; 2.14 nimoi) is dissolved in the mL bis- of i 2, and (methane Cao adds Ν, Ν-diisopropylethylamine (0.7 mL; 4.1 8 η κ η ο) and di-tert-butyl dicarbonate (560 mg, 2.57 mmol), reaction 12 hours.5 mL water are added, (10 mL are extracted with dichloromethane protective embankment><3), merge organic phase, washed with saturated nacl aqueous solution (30 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain 6- oxos -3,3 α, 4,5,7, the 7 α-H- of hexahydro -1 pyrrolo-es [3,4-c] pyridine -2- t-butyl formates 16a (406 mg, yellow solid）, yield： 78.9%.
Bis- Walk
2- methyl-l, 3,3,4,5,6,7,7fl- octahydro pyrrolo-es [3,4-c] pyridine is by 6- oxos -3,3a, 4,5,7,7fl- hexahydro -1H- pyrrolo-es [3,4- c] pyridine -2- t-butyl formates 16a (300 mg, 1.24 mmol) is dissolved in 15 mL tetrahydrofurans, adds lithium aluminium hydride reduction (194 mg, 5.24 mmol), 70 °C are reacted 2 hours, and 50 °C are continued to react 12 hours.0.5 mL water and 0.5 mL10% sodium hydroxide solutions are added, is centrifuged, supernatant liquor subtracts EE Nong Shrink, obtains 2- methyl -1,3,3 α, 4,5,6,7,7 α-octahydro pyrrolo- [3,4-c] pyridine 16b (130 mg, colorless oil), yield： 76.0%.
MS m/z (ESI): 141.2 [M+l]
Tri- Walk
The -one of 4- [[the fluoro- 3- of 4- (2- methyl-3,3 α, 4,6,7,7-hexahydro-1H- pyrrolo- [3,4-c] pyridine-5- carbonyls) phenyl] methyl]-2H- phthalazines-1
The fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid lc (260 mg, 0.89 mmol) is dissolved in 10 mL DMFs, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (600 mg, 1.60 mmol), 2- methyl isophthalic acids, 3,3 ￡ Isosorbide-5-Nitraes, 5,6,7,70- octahydros pyrrolo- [3,4] pyridine 161) (150.^, 1.10 mmol) and Ν, Ν-diisopropylethylamine (0.4 mL, 2.25 mmol), react 12 hours.Be concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain 4- [[the fluoro- 3- of 4- (and 2- methyl -3,3,4,6,7,7 α - Six a-lH- pyrrolo-es [3,4-C] pyridine -5- carbonyls) phenyl] first] -2/-phthalein prolixity -1- ketone 16 (83 mg, light yellow solid), yield： 19.2%.
MS m/z (ESI): 421.2 [M+l ]
Lan R (400 MHz, CD3OD):δ 8.37 (d, I H), 7.94 (d, I H), 7.85 (m, 2H), 7.47 (m, IH), 7.31 (m, 1 H), 7.15 (t, I H), 4.38 (s, 2H), 3.73 (m, IH), 3.42 (m, 111), 3.16 (m, I H), 2.91 (m, 2H), 2.56 (m, 2H), 2.40 (m, 2H), 2.32 (s, 3H), 2.10 (m, I H), 1.90 (m, IH), 1 .73 (m, IH) embodiment 17
4- [[3- [l (cyclopropyl carbonyl) -3,4,5,7,7 "-hexahydropyrrolo simultaneously [3,4- W pyridine -6- carbonyls] -4- fluoro-phenyls] first
By 4- [[3- (1,2,3,4,4 α, 5,7,7-octahydro pyrrolo- [3,4-6] pyridine-6- carbonyls)-4- fluoro-phenyls] methyl] 11 (100 mg of-1 -one of-2H- phthaleins crop, 0.25 mmol) it is dissolved in 5 mL dichloromethane protective embankments, add and cyclopropyl acyl chlorides (33 L are added under triethylamine (68 μ, 0.50 mmol), 0 °C, 0.37 mmol), react 1 hour.20 mL water are added, (20 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression Nong Shrink, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 4- [[3- [1 (cyclopropyl carbonyls)-3,4,5,7,7-hexahydropyrrolo simultaneously [3,4->] pyridine -6- carbonyls] -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone 17 (10 mg, white solid), yield： 8.6%.
MS m/z (ESI): 475.2 [M+l ]
Ή NMR (400 MHz, CDC13):δ 10.27 (hr. s, IH), 8.51 (d, IH), 7.82 (m, 3H), 7.41 (m, I H), 7.30 (m, 2H), 4.32 (s, 2H), 4.15 (m, IH), 3.86 (m, 2H), 3.68 (m, 2H), 3.53 (m, IH), 3.10 (m, IH), 3.01 (m, 1H), 2.32 (m, IH), 1.92 (m, 4H), 1.04 (m, 2H), 0.85 (m, 2H) embodiment 18
4- [[the fluoro- 3- of 4- (4- methyl-2,3,5,7,7-hexahydropyrrolo simultaneously [3,4-W [l, 4] oxazine-6- carbonyls)-phenyl] first
s/Dϋ O sooosId 9ίοίAV
¾^！^1N Lian ^：One (^ η (o Μ, 0Uusi.
S^ ^ Destroy s H!7 foretell a cun ￡ ι ￡ ζ 9.,.--------.- -- By 4- [[3- (l, 2,3,4,4 ", 5,7,7 "-octahydro pyrrolo- [3,4-W pyridine -6- carbonyls) -4- fluoro-phenyl] first] the small ketone 11 of-2-phthalazines (110 mg, 0.27 mmol) is dissolved in 10 mL DMFs, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (】52 mg, 0.40 mmol), the small t-butyl formate 19b (l of powder product pyrroles's protective embankment -2- formic acid】7 mg, 0.54 mmol) and Ν, Ν-diisopropylethylamine (0.】ML, 0.54 mmol), react 12 hours.Add 30 mL water, it is extracted with ethyl acetate (50 mLx3), merge organic phase, washed (50 mL) with saturation neodymium chloride solution (50 mL), saturation Gasization sodium solution successively, anhydrous sodium sulfate thousand is dry, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify gained residue, obtain 2- [6- [the fluoro- 5- of 2- [(4- oxo-3H- phthalein-1-bases of crop）Methyl] benzoyl]-3,4,4 ", 5,7,7-hexahydro-2H- pyrrolo-es [3,4- 6] pyridine-1- carbonyls] and pyrroles protective embankment-1- t-butyl formates 19c (100 mg, white solid), yield： 61.0%.
MS m/z (ESI): 604.3 [M+l]
Tri- Walk
4- [[4- fluorine (pyrrolidines-2- carbonyls)-3,4,4 ", 5,7,7-hexahydro-2H- pyrrolo-es [3,4-W pyridine-6- carbonyl phenyls] methyl]-2H- phthalazines-1- ketone
By 2- [6- [the fluoro- 5- of 2- [(4- oxo -3H- phthalein crop -1- bases）Methyl] benzoyl]-3; 4; 5,7,7fl- hexahydro-2H- pyrrolo-es [3; 4-] pyridine-1- carbonyls] pyrrolidines-1-t-butyl formate 19c (100 mg; 0.16 mmol) it is dissolved in Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 30 mL 2, react 12 hours.It is concentrated under reduced pressure, add 50 mL dichloromethane protective embankments, be added dropwise saturated sodium bicarbonate solution to reaction solution pH be 9, separate organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify gained residue, obtain 4- [[the fluoro- 3- of 4- [1- (pyrroles protective embankment-2- carbonyls)-3,4,4 α, 5,7,7-hexahydro-2H- pyrrolo-es [3,4-6] pyridine-6- carbonyls]-phenyl] methyl] 19 (32 mg of-2H- phthalazines-1- ketone, white solid), yield：38.6%。
MS mix (ESI): 504.2 [M+l]
Ή NM (400 MHz, CDC13):δ 8.39-8.48 (m, 1H), 7.70-7.86 (m, 3H), 7.28-7.45 (m, 2H), 7.00-7.10 (m, 1H), 4.28 (s, 2H), 3.72-3.85 (m, 1H), 3.56-3.71 (m, 3H), 3.40-3.55 (m, 2H), 2.95-3.15 (m, 1H), 2.44-2.71 (m, 1H), 2.00-2.34 (m, 3H), 1.69-1.97 (m, 9H) embodiment 20
4- [[the fluoro- 3- of 4- [l- [(4- methoxyphenyls) methyl] -3,3 α, 4,6,7,7 "-hexahydro -2H- pyrrolo-es [3,2-c] pyridine -5- carbonyls
Mono- Walk L-[(4-Cao phenyls）E i] -3,3 ", 4,6,7,7o- hexahydro -2H- pyrrolo-es [3,2-1'] pyridine-5- t-butyl formates are by 4- η hard and infertile acyloxy-3- (2- methylsulfonyl ^ bases ethyl) piperidines-1-t-butyl formate 4d (250 mg, 0.62 nimol) it is dissolved in the Hydrogen furans of 5 mL tetra-, add (4- methoxyphenyls) methylamine (256 mg, 1.87 mmol), react 20 minutes under 120 °C of microwave conditions.Room temperature is cooled to, 50 mL ethyl acetate is added, is washed (15 mLx3) with 5 M sodium hydroxide solutions, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain 1- [(4- methoxybenzenes are very) methyl]-3,3^, 4,6,7-hexahydro-2H- pyrrolo-es [3,2-c] pyridine-5- t-butyl formates 20a (170 mg, colorless oil), yield： 79.0%.
MS m/z (ESI): 347.2 [M+l]
Bis- Walk
L- [(4- methoxyphenyls) methyl] -2,3,3,4,5,6,7,7 "-octahydro pyrrolo- [3,2- c] pyridine hydrochloride is by 1- [(4- methoxybenzenes) methyl] -3; 3fl, 4,6; 7,7a- hexahydro -2H- pyrrolo-es [3,2-c] pyridine -5- t-butyl formates 20a (n0 mg; 0.38 mmol) are dissolved in L5 mL dichloromethane protective embankments, adds】.5 Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of mL 2, reacts 12 hours.It is concentrated under reduced pressure, obtains crude product 1- [(4- methoxyphenyls) methyl]-2,3,3 "; 4,5,6,7; 7-octahydro pyrrolo- [3,2-c] pyridine hydrochloride 20b (92 mg, light yellow oil), product is not purified directly to enter the lower Walk reactions of row
MS m/z (ESI): 247.1 [M+l]
Tri- Walk
4- [[the fluoro- 3- of 4- [hexahydro -2H- pyrrolo-es [3, the 2- c] pyridine -5- carbonyls of 1- [(4- methoxyphenyls) methyl] -3,3fl, 4,6,7,7fl-]-phenyl] methyl] -2H- phthalazines -1- ketone
By the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid lc (100 mg, 0.31 mmol) it is dissolved in 5 mL Ν, in Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (118 mg, 0.56 mmol), crude product 1- [(4- methoxyphenyls) methyl] -2, 3, 3 ", 4, 5, 6, 7, 7 "-octahydro pyrrolo- [3, 2-c] pyridine hydrochloride 20b (92 mg, 0.38 mmol) and Ν, Ν-diisopropylethylamine (270 0.94 mmol), reaction 12 hours.Add 20 mL water, it is extracted with ethyl acetate (15 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 4- [[the fluoro- 3- of 4- [1- [(4- methoxyphenyls）Methyl l-3,3fl, 4,6,7,7-hexahydro-2H- pyrrolo-es [3,2-c] pyridine-5- carbonyls]-phenyl] methyl】- 2H- phthalazines-ketone 20 (I3 mg, light yellow solid), yield： 7.0°/..
MS m/z (ESI): 527.3 [M+l]
Ή NMR (400 MHz, CD3OD):δ 8.36 (d, IH), 7.93 (d, IH), 7.83 (m, 2H), 7.51 (m, IH), 7.43 (m, 2H), 7.28 (d, H), 7.17 (m, IH), 7.01 (m, 2H), 4.37 (s, 2H), 4.17 (m, 3H), 3.82 (s, 2H), 3.75 (m, IH), 3.08 (m, 2H), 2.42 (m, 2H), 2.19 (m, IH), 1.95 (m, IH), 1.30 (m, 5H) embodiment 21
4- [[the fluoro- 3- of 4- (5- methyl -3,3 ￡, 4,6,7,7c-hexahydro-lH- pyrrolo- [3,4-cl pyridine -2- carbonyls) phenyl] methyl] -2H- phthalazines-l- ketone
Mono- Walk
5- methyl -6- oxos -1,3,3 α, 4,7,7 α-hexahydropyrrolo simultaneously [3,4-c] pyridine -2- t-butyl formates by 6- oxos -3,3 ", 4,5; 7,7 "-hexahydro -1H- pyrrolo-es [3,4- | pyridine -2- t-butyl formates 16a (12.79 g
53.20 mmol) it is dissolved in 30 mL Ν, in Ν-dimethylformamide, sodium hydride and mineral oil mixture (2.34 g are added under ice bath, 60%, 58.50 mmol), stir 30 minutes, add iodine first protective embankment (10 mL, 15.90 mmol), react 3 hours.It is concentrated under reduced pressure, adds 20 mL frozen water, be extracted with ethyl acetate (20 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 5- methyl -6- oxos -1,3,3,4,7,7 α-hexahydropyrrolo simultaneously [3,4-c | a (6.35 g of pyridine -2- t-butyl formates 21, light yellow oil), yield： 47.1%.
MS m/z (ESI): 199.1 [M-56+1]
Second step
5- methyl-2,3,3a, 4,7,7tf- hexahydropyrrolos simultaneously [3,4-cJ pyridine-6- keto hydrochlorides are by 5- methyl-6- oxos-1,3,3,4,7,7-hexahydropyrrolo simultaneously [3,4-c] pyridine-2- t-butyl formates 21a (80 mg, 0.32 mmol) is dissolved in 2 mL dichloromethane, adds the 1 of the M hydrogen chloride of 2 mL 2,4- dioxane solutions, react 12 hours.It is concentrated under reduced pressure, obtains crude product 5- methyl -2,3,3a, the b (50 mg, white solid) of 4,7,7fl- hexahydro -1H- pyrrolo-es [3,4-c] pyridine -6- keto hydrochlorides 21, product is not purified directly to enter the lower Walk reactions of row.
Tri- Walk
5- methyl isophthalic acids, 2,3,3 β, 4,6,7,7 β-octahydro pyrrolo- [3,4-c] pyridine is by crude product 5- methyl -2,3,3fl, 4,7,7fl- hexahydropyrrolos simultaneously [3,4-c] pyridine -6- keto hydrochlorides 21 b (49 mg, 0.32 mmol) be dissolved in 5 mL tetrahydrofurans, add lithium aluminium hydride reduction (50 mg, 1.26 mmol), 70 °C are reacted 3 hours, and 50'C continues to react 12 hours.50 mL dichloromethane protective embankments, 0.5 mL water and the sodium hydroxide solutions of 0.5 mL 10% are added, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude product 5- methyl-l, 2,3,3a, 4,6,7,7fl- octahydros pyrrolo- [3,4-c] pyridine 21c (45 mg, colorless oil), product is not purified directly to enter the lower Walk reactions of row.
MS m/z (ESI): 141.1 [M+l]
Tetra- Walk
4- [[the fluoro- 3- of 4- (5- methyl -3,3a, 4,6,7,7a- hexahydro -1H- pyrrolo-es [3,4-c] pyridine -2- carbonyls) phenyl] methyl] small ketone of -2H- phthalazines
By the fluoro- 5- of 2- [(4- oxos -3//- phthalazines -1- bases) methyl] benzoic acid lc (90 mg, 0.29 mmol) it is dissolved in 5 mL Ν, in Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (195 Mg, 0.52 mmol), crude product 5- methyl isophthalic acids, 2,3,3 ", 4,6,7,7 α-octahydro pyrrolo- [3; 4-c] pyridine 21c (70 mg, 0.32 mmol) and Ν, Ν-diisopropylethylamine (150,0.86 mmol), react 12 hours.15 mL water are added, are extracted with ethyl acetate (15 mLx3), are merged：^ machine phases, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography to open up;^ agent systems A purifying gained residues, obtain 4- [[4- fluoro- 3- (5- methyl -3,3 "; 4,6,7; 7 "-hexahydro -1H- pyrrolo-es [3,4-c] pyridine -2- carbonyls) phenyl] methyl] -2H- phthalazines -1- ketone 21 (28 mg, light yellow solid), yield： 23.3%.
MS m/z (ESI): 421.2 [M+l ]
Ή NMR (400 MHz, CD3OD):δ 8.36 (d, IH), 7.94 (d, IH), 7.86 (m, 2H), 7.48 (s, IH), 7.37 (m, IH), 7.】6 (m, I H), 4.58 (s, 2H), 3.62 (m, IH), 3.55 (m, IH), 3.43 (m,】H), 3.26 (m, IH), 3.19 (m, IH), 2.77 (m, 3H), 2.59 (s, 1H), 2.54 (s, 3H), 2.49 (m, IH), 1.99 (m, IH), (1.81 m, IH) embodiment 22
4- [[4- fluorine 3-0 pyrimidine -2-bases -3,3 ", 4,5,7,7 "-hexahydro -2H- pyrrolo-es [3,4-c] pyridine -6- carbonyls) phenyl] first
By 4- [[3- (1,2,3,4,4 ", 5,7; 7-octahydro pyrrolo- [3; 4-W pyridine-6- carbonyls)-4- fluoro-phenyls] methyl]-2H- phthalazines-1- ketone 11 (HO mg, 0.25 mmol) is dissolved in 20 mL 1-METHYLPYRROLIDONEs, is added under 2- chlorine pyrimidine (40 mg; 0.38 mmol), 200 microwave conditions and is reacted 1 hour.It is concentrated under reduced pressure, add 80 mL ethyl acetate, saturated ammonium chloride solution (50 mL) is used successively, water (50 mL), saturated nacl aqueous solution washs (50 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain 4- [[4- fluorine 3- (1- pyrimidine -2-bases -3, 3 α, 4, 5, 7, 7-hexahydro-2H- pyrrolo-es [3, 4] pyridine -6- carbonyls) phenyl] methyl] 22 (35 mg of -2H- phthalazines -1- ketone, white solid), yield： 29.0%.
MS m/z (ESI): 485.2 [M+l]
Ή NMR (400 MHz, CDC13):(the br. s of δ 10.21, IH), 8.49-8.44 (m, IH), 8.35 (d, IH), 8.29 (d, IH), 7.79-7.71 (m, 3H), 7.41-7.35 (m, IH), 7.32-7.22 (m, IH), 7.07-6.98 (m, IH), 6.57-6.50 (m, IH), 4.28 (d, 2H), 3.71-3.65 (m, IH), 3.46-3.30 (m, 2H), 2.85 (m, 2H), 2.41-2.36 (m, 2H), 2.07-1.99 (m, 2H), 1.62-1.43 (m, 3H) embodiment 23 4- [[4- fluorine 3- (1- Cao -2- bases -3,3 ", 4,5,7,7 "-hexahydro -2//- pyrrolo- [3,4-c | pyridine -6- carbonyls) phenyl] first
By 4- [[3- (1,2,3,4,4 α, 5,7,7 "-octahydro pyrrolo- [3; 4- 6] pyridine -6- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone 11 (150 mg; 0.37 mmol) is dissolved in 20 mL 1, the chloroethene protective embankments of 2- bis-, and add 0.1 mL acetic acid and 40% formalin (53 μ; 0.75 mmol) o is stirred 2 hours; add sodium triacetoxy borohydride (160 mg, 0.75 mmol), react 48 hours.Add 50 mL dichloromethane protective embankments, saturated sodium bicarbonate solution (50 mL) is used successively, water (50 mL), saturated nacl aqueous solution washs (50 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, it is residue obtained by A is purified to be stopped with thin-layered chromatography with solvent, obtain 4- [[4- fluorine 3- (1- methyl-2- bases-3,3 α, 4,5,7,7 α-hexahydro-2H- pyrrolo-es [3,4-c] pyridine-6- carbonyls) phenyl] methyl]-1 -one of-2H- phthalazines 23 (35 mg, white solid）, yield： 22.6%.
MS m/z (ESi): 421.2 [M+l]
Ή NMR (400 MHz, CDC13): δ 10.25 (br. s, IH), 8.49-8.44 (m, IH), 7.80-7.71 (m, 3H), 7.45-7.39 (m, IH), 7.32-7.25 (m, III), 7.07-7.00 (m, IH), 4.28 (d, 2H), 3.66 (d, IH), 3.64-3.57 (m, IH), 3.45-3.36 (m, IH), 3.33-3.22 (m, IH), 2.81 -265 (m, IH), 2.36(s, 3H):2.17-2.09 (m, 2H), 1.87-1.75 (m, IH), 1.73-1.53 (m, 4H) embodiment 24
4- [[3- (and 3,4,6,7,9,9a- hexahydro-IH- pyrroles prolixity simultaneously [2, l-c] [l, 4] oxazine -8- carbonyls) -4- fluoro-phenyls " methyl:F-2H- phthaleins
The first step
L, 3,4,6,7,8,9,9fl- octahydro pyrazines simultaneously [2, l-c] [l, 4] oxazines
By 1,6,7,8,9,9 α-hexahydropyrazine simultaneously [2,1- c] [l, 4] Evil crop -4- ketone 6g (100 mg, 0.64 mmol) are dissolved in In 10 mL tetrahydrofurans, hydrogenation mendelevium lithium (50 mg, 1.28 mmol) is added, 40 °C are reacted 12 hours.30 mL dichloromethane and the sodium hydroxide solutions of 0.5 mL 10% are added, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains 1,3,4,6,7,8,9,9 "-octahydro pyrazine simultaneously [2,1-c] [l, 4] Evil make an uproar 24a (60 mg, yellow oil), yield： 66.6%.
Bis- Walk
4- " [3- (and 3,4,6,7,9 ,-six ift-lH- pyrazines simultaneously [2,1-6'] [】, 4] Evil make an uproar -8- carbonyls) and -4- fluoro-phenyls] methyl] -2H- phthalazines
The fluoro- 5- of 2- [(the small base of 4- oxo-3H- phthalazines) methyl] benzoic acid lc (150 mg, 0.51 mmol) is dissolved in 5 mL Ν, Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (319 mg, 0.84 mmol), 1,3,4,6,7,8,9,9-octahydro pyrrole crop simultaneously [2,1- c] [l, 4] oxazines 24a (60 mg, 0.42 mmol) and Ν, Ν-diisopropylethylamine (162 mg, 1.26 mmol), reacts 48 hours.Add 10 mL water, extracted with dichloromethane (25 niLx3), 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 4- [[3- (3,4,6,7,9,9-hexahydro-1H- pyrazines simultaneously [2,1- c] [l, 4] Evil crops-8- carbonyls)-4- fluoro-phenyls] methyl] 24 (10 mg of-2H- phthalazines-1- ketone, white solid), yield: 5.0%.
MS m/z (ESI): 423.2 [M+l]
Ή NMR (400 MHz, CDC13):δ 10.10 (br. s, 1H), 8.52-8.42 (m, 1H), 7.71-7.65 (m, 5H), 7.21-7.16 (m, 1H), 4.21 (s, 2H), 3.75-3.57 (m, 4H), 2.78-2.48 (m, 9H) embodiment 25
4- [[3 small ketone
The first step
2,3,3fl, 4,7,7-hexahydro-1H- iso-indoles
Under ice bath, by lithium aluminium hydride reduction (3.75 g, 132 mmol) it is added portionwise into 150 mL tetrahydrofurans, by 3,4,7,7fl- tetrahydrochysenes iso-indoles -1,3- ketone 25a (5 g, 33 mmol) is dissolved in 100 mL tetrahydrofurans, is slowly added dropwise into above-mentioned reaction solution.Finish nature to be warmed to room temperature, 40 °C are reacted 12 hours.Under ice bath, 20mL water and 40 g anhydrous sodium sulfates are added, filtering, filter cake washs (50 mLx2) with dichloromethane protective embankment, obtains crude product 2,3,3,4,7,7-six-1//- different Yin makes an uproar 25b (4 g, light yellow oil), and product is not purified directly to enter the lower Walk reactions of row.
Bis- Walk
1,3,4,7,7 hexahydro iso-indoles -2- t-butyl formates
By crude product 2,3,3ci, 4, the H- iso-indoles 25b of 7,7a- hexahydro -1 (5 g, 40 mmol) is dissolved in 100 mL tetrahydrofurans, add triethylamine (8.3 mL, 60 mmol), under ice bath, add di-tert-butyl dicarbonate (10 g, 45 mmol), room temperature reaction] 2 hours.150 niL water are added, are extracted with ethyl acetate (150 mLx3), merge organic phase, washed (100 mL), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, and obtains 1,3,3 α, 4,7,7 α-hexahydro iso-indoles -2- t-butyl formates 25c (8 g, orange Shan shape thing), yield： 89.6%.
Tri- Walk
5- hydroxyls -1,3,3,4,5,6,7,7β- octahydro iso-indoles -2- t-butyl formates are by 1,3,3 α, 4,7,7 α-hexahydro iso-indoles -2- t-butyl formates 25c (8 g, 36 mmol) it is dissolved in 80 mL tetrahydrofurans, under ice bath, the M of 36 mL 1 boron protective embankment tetrahydrofuran solution is added dropwise, finish nature to be warmed to room temperature, react 12 hours.20 mL methanol, the M sodium hydroxide solutions of 13.3 mL 3 and the hydrogen peroxide of 13.3 mL 30% are added under ice bath, 60 °C are reacted 1.5 hours.Room temperature is cooled to, is extracted with ethyl acetate (150 mLx3), merges organic phase, washed (100 mL), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, and obtains crude product 5- hydroxyls-1,3,3,4,5,6,7,7-octahydro iso-indoles-2- t-butyl formates 25d (10 g, light yellow oil), product is not purified directly to enter the lower Walk reactions of row.
4th step
6- oxos -3,3 Ω, 4,5,7,7 Ω-hexahydro -1H- iso-indoles -2- t-butyl formates are by crude product 5- hydroxyls -1,3,3 α, 4,5,6,7,7 α-octahydro iso-indoles -2- t-butyl formates 25d (2 g, 8.30 mmol) is dissolved in 70 mL dichloromethane protective embankments, adds Lv chromic acid Bi Ding Gun salt (2.86 g, 13.30 mmol) and 3 g diatomite, react 72 hours.Filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system B purify obtained by residual She's thing, obtain 6- oxos-3,3 α, 4,5,7,7-hexahydro-1H- iso-indoles-2- t-butyl formates 25e (700 mg, light yellow oil), yield 35.0%.
MS m/z (ESI): 184.1 [M-56+1]
Wu Walk
1,2,3,3,4,6,7,7 "-octahydro iso-indoles -5- ketone
By 6- oxo-3,3 α, 4,5,7,7-hexahydro iso-indoles-2- t-butyl formates 25e (700 mg, 2.93 mmol) is dissolved in Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 11 mL 2, reacts 14 hours.Be concentrated under reduced pressure, obtain crude product 1,2,3,3/, 4,6,7,7 α-octahydro iso-indoles -5- ketone 25f (600 mg, brown oil), product is not purified directly to enter row lower Walk reaction.
Liu Walk
4- [[4- fluorine 3- (6- oxos-3,3,4,5,7,7-hexahydro-1H- iso-indoles-2- carbonyls）- phenyl] methyl] the fluoro- 5- of crude product 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid lc (572 mg, 2 mmol) is dissolved in by -2H- phthalazines -1- ketone
In 5 mL DMFs, BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (1.10 are added G, 2.88 mmol), l, 2,3,3i, 4,6,7,7a- octahydro iso-indoles -5- ketone 25f (400 mg, 2.88 mmo】) and Ν, Ν-diisopropylethylamine (0.7 mL, 4 mmol), react 12 small inch.Be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain crude product 4- [[4- fluorine 3- (6- (generation -3,3,4,5,7,7 "-hexahydro -1H>Iso-indoles -2- carbonyls）- benzene] methyl] -2H- phthalazines -1- ketone 25g(1.20 g, brown oil), product is not purified directly to carry out next step reaction.
MS m/z (ESI): 420.2 [M+l ]
Qi Walk
4- [[3- (and 5- amino -1,3,3 "; 4,5,6; 7,7 β-octahydro iso-indoles -2- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone by crude product 4- [[the fluoro- 3- of 4- (and 6- oxos -3,3; 4,5,7; 7 "-hexahydro -1H- iso-indoles -2- carbonyls)-phenyl] methyl] small ketone 25g (100 mg of -2H- phthalazines, 0.24 mmol) it is dissolved in 5 mL methanol, add formic acid neodymium (30 mg, 0.48 mmol)0Stirring 2 hours, adds sodium triacetoxy borohydride (153 mg, 0.72 mmol), reacts 48 hours.Be concentrated under reduced pressure, with thin-layered chromatography with open up Ji agent system A purify gained residue, obtain 4- [[3- (5- amino -1,3,37,4,5,6,7,7α- octahydro iso-indoles -2- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone 25 (5 mg, white solid), yield： 5.0%.
MS m/z (ESI): 421.2 [M+l]
Ή NMR (400 MHz, CDC13):δ 10.01 br. s, 1H), 8.51 (d, 1H), (7.83 m, 3H), 7.40 (m, 2H), (7.08 m, 1H), 4.31 (s, 2H), (3.99 m, 2H), 3.74 (m, 2H), 3.53 (s, 2H), 2.46 (m, 3H), 1.66 (m, 3H) embodiment 26
4- [[3- [2- (Cvclopropvlmethvl)-3,3 α, 4,6,7,7-hexahydro-1H- pyrrolo- [3,4-c] pyridine-5- carbonyls]-4- fluoro-phenyls]
2- (Cvclopropvlmethvl)-3,3fl, 4,5,7,7-hexahydro-1H- pyrrolo- [3,4-c] pyridine-6- ketone
By l, 2,3,4,5,7,7fl- octahydro pyrrolo-es [3,4-c] pyridine -6- ketone lb (220 mg, 1.57 mmol) it is dissolved in 6 mL acetonitriles, sequentially add potassium carbonate (650 mg, 4.71 mmol) and 0.5 mL bromomethyl cyclopropanes (167 μ L, 1.73 mmol) acetonitrile solution, react 56 hours.Filtering, filtrate decompression concentration, obtains crude product 2- (Cvclopropvlmethvl)-3,3fl, 4,5,7,7-hexahydro-1H- pyrrolo-es [3,4-c] pyridine-6- ketone 26a (280 mg, light brown oily substance), product is not purified directly to carry out next step reaction.
MS m/z (ESI): 195.1 [M+l]
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ΖΖΖΪ00/ΐΐ0ΖΝ3Χ3<Ι carves 0 Ζ OAV Reaction 24 hours, adds triacetyl Gas bases sodium borohydride (100 mg, 0.45 mmol), back flow reaction 3 hours.15 mL water are added, (25 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, it is dry with anhydrous sodium sulfate thousand, filtering, filtrate decompression concentration, it is that A purifies gained residue to be stopped with layer chromatography with to open up Ji agent, obtains 4- [[4- fluoro- 3- (1- isopropyls -3,4,4fl, 5,7,7fl- hexahydro -2H- pyrrolo-es [3,4-] pyridine -6- carbonyls) benzene very] base] phthalazines -1- ketone 27 (8 mg, corpora flava）, yield： 10.0%.
MS m/z (ESl): 463.2 [M+l ]
Ή NMR (400 MHz, CDC13):δ 10.00 (br. s, 1H), 8.41-8.37 (m, 1H), 7.72-7.68 (m, 4H), 7.41 (m, 1H), 7.22-7.14 (m, 1 H), 4.20 (s, 2H), 2.94-2.19 (m, 9H), 1.81-1.62 (m, 6H), 0.92 (s, 3H), 0.91 (s, 3H) embodiment 28
4- [[￡ of 3- O rings propyl- 3,3fl, 4,6,7,7/- hexahydro -2H- pyrrolo-es [3,2-c] pyridine -5- carbonyls) -4- fluoro-phenyls] first
The first step
1- cyclopropyl -3,3fl, 4,6,7,7a- hexahydro -2H- pyrrolo-es [3,2- c] 4- mesyloxies -3- (2- Methansulfonyloxyethyls) piperidines -1- t-butyl formates 4d (818 mg, 2.04 mmol) is dissolved in 5 mL tetrahydrofurans by pyridine -5- t-butyl formates, adds cyclopropylamine (350 mg, 6.12 mmol), " react 30 minutes under 10 °C of microwave conditions.Be cooled to room temperature ,-be concentrated under reduced pressure, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain 1-cyclopropyl-3,, 4,6,7,7 hexahydropyrrolos simultaneously [3,2-cl pyridine-5- t-butyl formates 28a (90 mg, colorless oil）, yield： 16.6%.
MS m/z (ESI): 267.2 [M+l ]
Second step
1- cyclopropyl-2,3,3 α, 4,5,6,7,7 "-octahydro pyrrolo- [3,2-c | pyridine hydrochloride is by 1-cyclopropyl-3,3fl; 4,6,7; 7a- hexahydro-2H- pyrrolo-es [3,2-c] pyridine-5- t-butyl formates 28a (90 mg, 0.34 mmol) is dissolved in 2 mL dichloromethane protective embankments; add Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 2 mL 2, reacts 12 hours.It is concentrated under reduced pressure, obtains crude product 1- cyclopropyl -2,3,3α, 4,5,6,7,7 α-octahydro pyrrolo- [3,2-c] pyridine hydrochloride 28b (92 mg, light yellow oil), product is not purified directly to enter the lower Walk reactions of row.
3rd step
4- [[3- (1- cyclopropyl -3,3 α, 4,6,7,7 α-hexahydro -2H- pyrrolo-es [3,2-c] pyridine -5- carbonyls) -4- fluoro-phenyls] first Base] -2H- phthaleins make an uproar -1- ketone
The fluoro- 5- of 2- [(- 1-yl of 4- oxo-3H- phthalazines) methyl] benzoic acid lc (91 mg, 0.31 mmol) is dissolved in 5 mL Ν, Ν-dimethylformamide Cao, add BTA-Ν, Ν, Ν ', Ν '-Ρ methylurea hexafluorophosphoric acid esters (209 mg, 0.56 mmol), crude product 1- cyclopropyl-2,3,3fl, 4,5,6,7,7rt- octahydros pyrrolo- [3,2-c] pyridine hydrochlorate 28b (92 mg, 0.34 mmol) and Ν, Ν-diisopropylethylamine (265 L, 1.53 mmol), react 12 hours.20 mL water are added, be extracted with ethyl acetate (】5 mLx3), merge Nuisance machine phases, washed with saturated nacl aqueous solution (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 4- [[3- (1- cyclopropyl-3,3,4,6,7,7-hexahydro-2H- pyrrolo-es [3,2-c] pyridine-5- carbonyls)-4- fluoro-phenyls] methyl]-2H- phthalazines-1- ketone 28 (9 mg, light yellow solid), yield： 7.0%.
MS m/z (ESI): 447.2 [M+l]
Ή NMR (400 MHz, CD3OD):(the d of δ 8.36, 1H), 7.95 (d, 1H), 7.88 (m, 2H), 7.50 (m, 1H), 7.29 (m, 1H), 7.17 (m, 1H), 4.58 (s, 1 H), 4.39 (d, 2H), 4.16 (m, 1H), 3.75 (m, 1H), 3.03 (m, 2H), 2.51 (m, 2H), 2.32 (m, 1H), 2.20 (m, 2H), 1.97 (m, 2H), 1.59 (m, 1H), 0.85 (m, 2H), 0.73 (m, 1H), 0.64 (m, 1H) embodiment 29
4- [[3- [5- (Cvclopropvlmethvl) -3,3,4,6,7,7 α-hexahydro -1H- pyrrolo-es [3,4-c] pyridine -2- carbonyls] -4- fluoro-phenyls]
Mono- Walk
5- (Cvclopropvlmethvl) -6- oxos -1, 3, 3o, 4, 7, 7 "-hexahydropyrrolo simultaneously [3, 4- c] pyridine -2- t-butyl formates are by 6- oxos -3, 3, 4, 5, 7, 7 β-hexahydro -1H- pyrrolo-es [3, 4-c] pyridine -2- t-butyl formates 16a (300 mg, 1.25 mmol) it is dissolved in 8 mL N, in dinethylformamide, sodium hydride and mineral oil mixture (90 mg are added under ice bath, 60%, 2.25 mmol), stirring 30 minutes, add bromomethyl cyclopropane (240 μ, 2.50 mmol), continue to stir 30 minutes, it is warmed to room temperature reaction 3 hours.It is concentrated under reduced pressure, adds 20 mL water, be extracted with ethyl acetate (30 mLx2), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, and obtains crude product 5- (Cvclopropvlmethvl) -6- oxos -1,3,3 Ω, 4,7,7 α-hexahydropyrrolo simultaneously [3,4-c] pyridine -2- t-butyl formates 29a (400 mg, light brown oily substance）, product is not purified directly to enter the lower Walk reactions of row.
MS m/z (ESI): 239.1 [M-56+1]
Bis- Walk 5- (Cvclopropvlmethvl) -2,3,3 "; 4,7,7 "-hexahydropyrrolo simultaneously [3,4-] pyridine -6- keto hydrochlorides are by crude product 5- (cyclopropyl first) -6- oxos -13,4,7, the ^ pyrrolo-es [3 of 7^- six, 4-c] tertiary j ' the esters 29a of pyridine -2- formic acid (400 mg, 1.25 nimol) is dissolved in 6 mL dichloromethane protective embankments, adds the 1 of the M hydrogen chloride of 6 mL 2,4- dioxane solutions, reaction] 2 hours.Subtract ffi concentrations, obtain crude product 5- (Cvclopropvlmethvl) -2,3,3fl, 4,7,7 hexahydro -1H- pyrrolo-es [3,4-C] pyridine -6- keto hydrochlorides 29b (418 mg, yellow Shan shape thing), the lower Walk reactions of the not purified row that directly spouts of product.
The i of table two
5- (cyclopropyl ^ yls) -1,2,3,3,4,6,7,7 α-octahydro pyrrolo- [3,4-c] pyridine
By crude product 5- (Cvclopropvlmethvl) -2,33 α, 4,7,7 β-hexahydro -1H- pyrrolo-es [3,4-c] pyridine -6- ketone hydrochloric acid 29b (418 mg, 1.25 mmol) be dissolved in] in 0 mL tetrahydrofurans, add lithium aluminium hydride reduction (190 mg, 5 mmol), 70 °C are reacted 3 hours, and 50 °C are continued to react 12 hours.50 mL dichloromethane protective embankments, 0.5 mL water and the sodium hydroxide solutions of 0.5 mL 10% are added, is stirred 30 minutes, filtering, filtrate anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, and obtains crude product 5- (Cvclopropvlmethvl) -1,2,3,3 α, 4,6,7,7 α-octahydro pyrrolo- [3,4-c] pyridine 29c (225 mg, colorless oil), product is not purified directly to enter the lower Walk reactions of row.
Tetra- Walk
4- [[3- [5- (Cvclopropvlmethvl) -3,3 α, 4,6,7,7 β-hexahydro -1H- pyrrolo-es [3,4-cI pyridine -2- carbonyls] -4- fluoro-phenyls] methyl] small ketone of -2H- phthalazines
By the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid lc (300 mg, 1.13 mmol) it is dissolved in 5 mL Ν, in Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (760 mg, 2.34 mmol), crude product 5- (Cvclopropvlmethvl) -1, 2, 3, 3 ￡/, 4, 6, 7, 7 α-octahydro pyrrolo- [3, 4-c] pyridine 29c (225 mg, 1.25 mmol) and N, N- diisopropylethylamine (580 μ L, 3.39 mmol), reaction 12 hours.Add 15 mL water, it is extracted with ethyl acetate (25 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 4- [[3- [5- (Cvclopropvlmethvl) -3,3 β, 4,6,7,7 β-hexahydro -1H- pyrrolo-es [3,4-c] pyridine -2- carbonyls] -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone 29 (90 mg, light yellow solid), yield： 36.5%.
MS m/z (ESI): 461.2 [M+l ]
Ή NMR (400 MHz, CDC13):δ 10.51 br. s, IH), 8.46 (d, I H), 7.77 (m, 3H), 7.38 (m, 1H), 7.31 (m, 1H), 7.04 (m, IH), 4.64 (m, IH), 4.29 (d, 2H), 3.74 (m, IH), 3.68 (m, 1H), 3.42 (m, 2H), 3.01 (m, 2H), 2.55 (m, 4H), 1.89 (m, 2H), 1.66 (m, IH), 1.11 (m, IH), 0.69 (m, 2H), 0.36 (m, 2H) embodiment 30
4- [[3- (l, 2,3,34,6,7,7fl- octahydro pyrrolo- [3,4-c] pyridine -5- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines -1
", 3,3,4,5,6,7,7 "-octahydro pyrrolo- [3,4^] pyridine -2- t-butyl formates by 6- oxos -3,3 Ω, 4,5,7,7 "-hexahydro -】H- pyrrolo-es [3,4-] pyridine -2-1In tert-butyl acrylate 16a (50 mg, 0.21 mmol) the dissolving mL tetrahydrofurans of fourth 2, (TC adds borine tetrahydrofuran solution (1 mL, 1.04 mmol), reacts at room temperature 12 hours.The mL water of power 1 0.2 is dripped, is concentrated under reduced pressure, obtains crude product 1,3,3,4,5,6,7,7-octahydro pyrrolo- [3,4-C] pyridine -2- t-butyl formates 30a (20 mg, white solid), product without isolation Zhi connect for Xia Walk reaction.
MS m/z (ESI): 227.1 [M+l]
Bis- Walk
The -one of 4- [[3- (1,2,3,3 ", 4,6,7,7 "-octahydro pyrrolo- [3,4-c] pyridine -5- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines -1
By the fluoro- 5- of 2- [(4- oxo -3H- phthalein crop -1- bases) methyl] benzene IP acid lc (23 mg, 0.18 mmol) it is dissolved in 1 mL N, in dinethylformamide, add 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (51 mg, 0.27 mmol), I-hydroxybenzotriazole (12 mg, 0.089 mmol), l, 3, 3a, 4, 5, 6, 7, 7 "-octahydro pyrrolo- [3, 4-c] pyridine -2- t-butyl formates 30a (40 mg, 0.18 mmol) and triethylamine (49 μ L, 0.35 mmol), reaction 12 hours.Be concentrated under reduced pressure, with thin-layer chromatography chromatography with solvent system A purify gained residue.Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 5 mL 2 is added in gained residue, is reacted 12 hours.It is concentrated under reduced pressure, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain 4- [[3- (1,2,3,3 ", 4,6; 7; 7 α-octahydro pyrrolo- [3,4-c] pyridine -5- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalein crop -1- ketone 30 (20 mg, white solid）, yield： 27.4°/..
MS m/z (ESI): 407.2 [M+l]
1H NMR (400 MHz, CD3OD):δ 8.38 (d, I H), 7.98 (d, IH), 7.91-7.84 (m, 2H), 7.51-7.49 (m, 2H), 7.1S (t, IH), 4.40 (s, 2H), 4.27-4.13 (m, IH), 3.55-3.36 (m, 3H), 3.22-3.10 (m, 3H), 2.63-2.45 (m, 3H), 1.93-1.63 (m, 2H) embodiment 31
4- [[3- (5- dimethylaminos -1,3,3,4,5,6,7,7^- octahydro iso-indoles -2- carbonyls) -4- fluoro-phenyls " methyl] -2 phthaleins
By 4-[[amino -), 33 ", 4,5; 6; 7,7 "-hexahydro iso-indoles-2- carbonyls) the fluoro- benzene of-4-] base]-2H- phthaleins call out small ketone 25 (100 mg, 0.24 mmol) and are dissolved in 5 mh methanol, add 40% Cao aldehyde solution (24 μ, 0.26 mmol) and sodium triacetoxy borohydride (1 53 mg, 0.72 mmol), react 12 small inch.It is concentrated under reduced pressure, with thin-layer chromatography color method with solvent system A purify gained residue, obtain 4- [[3- (and 5- dimethylaminos -1,3,3 "; 4; 5,6,7; 7 octahydro iso-indoles -2- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines small ketone 31 (50 mg, white solid）, yield： 46.5%.
MS m/z (ESI): 449.2 [M+l]
'Η NM (400 MHz, CDC13):δ 10.53 (br. s, IH), 7.47 (m,), IH 7.80 (m, 3H), 7.33 (m, 2H), 7.05 (m,), IH 4.30 (m, 2H), 3.69 (m, 2H), 3.50 (m, 2H), 3.47 (m, IH), 2.66 (m, 6H), 2.23 (m, 2H), 2.16 (m, 2H), 1 .94 (m, 2H), 1.49 (m, 2H) embodiment 32
4- [[3- Π-(Cvclopropvlmethvl) -3,4,4α, 5,7,7-hexahydro-2H- pyrrolo-es [3,4-W pyridine-6- carbonyls]-4- is fluoro-
By crude product 4- [[3- (1,2,3,4,4 ", 5; 7; 7 β-octahydro pyrrolo- [3,4-6] pyridine -6- carbonyls) -4- fluoro-phenyls] methyl] the small ketone 11 of -2H- phthalazines (200 mg, 0.50 mmol) is dissolved in 50 mL acetonitriles; add potassium carbonate (140 mg; 1 mmot) and bromomethyl cyclopropane (100 mg, 0.75 mmol), 82 °C of reactions 3 hours.Filtering, filter cake is washed with 30 mL dichloromethane, filtrate decompression concentration, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain 4- [[3- [1- (Cvclopropvlmethvl)-3,4,4 α, 5,7,7-hexahydro-2H- pyrrolo-es [3,4-6] pyridine-6- carbonyls]-4- fluoro-phenyls] methyl] 32 (60 mg of-1 -one of-2H- phthalazines, white solid), yield： 28.3%.
MS m/z (ESI): 461.2 [M+l]
Ή NMR (400 MHz, CDC13):δ 8.48 (m, IH), 7.71 (m, 3H), 7.69 (m, 2H), 7.02 (m, I H), 4.28 (d, 211), 4.16 (d, 2H), 3.70 (d, 2H), 3.49 (m, 2H), 3.15 (m, IH), 2.69 (m, IH), 2.33 (m,), IH 1.76 (m, 2H), 1.70 (m, 2H), 1.44 (m,), IH 0.49 (m, 5H) embodiment 33
4- [[3- (l- ethyls -3,4,4 α, 5,7,7 α-hexahydro -2H- pyrrolo-es [3,4- δ] pyridine -6- carbonyls) -4- fluoro-phenyls] first Base]-
By 4- [[3- (], 2,3,4,4 ", 5,7,7 "-octahydro pyrrolo-es [3,4-?] pyridine -6- carbonyls) -4- fluoro-phenyls] methyl] small (100 mg of ketone 11 of -2H- phthalein crops, 0.25 mmol) it is dissolved in 30 mL acetonitriles, add potassium carbonate (70 mg, 0.50 mmol) and iodine second protective embankment (60 mg, 0.38 mmol), 75 °C are reacted 2 hours.Filtering, filter cake is washed with 30 mL dichloromethane, filtrate decompression concentration, it is residue obtained by A is purified to be stopped with thin-layer chromatography chromatography with solvent, obtain 4- [[3- (and ethyl-3,4,4 "; 5; 7,7 "-hexahydro-2H- pyrrolo-es [3,4- W pyridine-6- carbonyls)-4- fluoro-phenyls] methyl] 33 (31 mg of-1 -one of-2H- phthalazines, white solid), yield： 28.7%.
MS m/z (ESI): 435.2 [M+l ]
]H NMR (400 MHz, CDC13):δ 8.38 (m, 1H), 7.89 (m, 3H), 7.44 (m, 2H), 7.20 (m, 1 H), 4.40 (s, 2H), 3.94 (m, 2H), 3.48 (m, 2H), 3.18 (m, 3H), 2.97 (m, 2H), 1.79 (m, 5H), 1.29 (m, 3H) embodiment 34
4- [[3- (5- ethyls -3,3 ", and 4,6,7,7fl- hexahydro -1H- pyrrolo-es [3,4-c | pyridine -2- carbonyls) -4- fluoro-phenyls] methyl
The first step
5- ethyl -6- oxos -1,3,4,7,7 Ω-hexahydropyrrolo simultaneously [3,4-C] the tertiary fourth of pyridine-2- formic acid is flushed with drink 6- oxos-3,3 α, 4,5,7,7-hexahydro-1H- pyrrolo-es [3,4-c] pyridine-2- t-butyl formates 16a (300 mg, 1.24 mmol) is dissolved in 5 mL DMFs, 0 °C adds sodium hydride (74 mg, 1.86 mmol), and 0 °C is reacted 0.5 hour, room temperature reaction 1.2 hours, iodine second protective embankment (252 iL, 3.12 mmol) is added, is reacted 3 hours.20 mL water are added, are extracted with ethyl acetate (20 mLx3), merge organic phase, washed (40 mL), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression Nong Shrink, obtain crude product 5- ethyl -6- oxos -1,3,3 α, 4,7,7/- hexahydropyrrolo simultaneously [3,4-c] pyridine -2- t-butyl formates 34a (365 mg, yellow liquid), product without isolation Zhi connect for Xia Walk reaction. MS m/z (ESI): 213.1 [M-56+1 ]
Bis- Walk
5- ethyls-2,3,3,4,7,7-hexahydro-1//- pyrrolo- [3,4-c] pyridine-6- keto hydrochlorides are by crude product 5- ethyl-6- oxos-1,3,34,7,7 " simultaneously [3,4-c] pyridine-2- t-butyl formates 34a (620 mg; 2.50 mmol) is dissolved in the Gas first protective embankments of 8 mL bis--hexahydropyrrolo; add Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 5 mL 6.5, is reacted 12 hours.Be concentrated under reduced pressure, obtain crude product 5- ethyls-2,3,3 α, 4,7,7-hexahydro-1H- pyrrolo-es [3,4-c] pyridine-6- keto hydrochlorides 34b (420 mg, yellow solid), product without isolation Zhi connect for Xia Walk reactions.
MS m/z (ESI): 213.1 [M-56+1 ]
Tri- Walk
5- ethyls-1,2,3,3 α, 4,6,7,7 α-octahydro pyrrolo- [3,4-c] pyridine is by crude product 5- ethyls-2,3,3,4,7,7-hexahydro -] H- pyrrolo-es [3,4-c] pyridine-6- keto hydrochlorides 34b (420 mg, 2.50 mmol) is dissolved in 25 mL tetrahydrofurans, and 0 °C adds tetrahydrochysene lithium (285 mg, 7.50 mmol), 70 °C are reacted 3 hours, and 50 °C are reacted 12 hours.The M sodium hydroxide solutions of 0.3 mL 5,0.7 mL water and 50 mL dichloromethane protective embankments are added, are filtered with basic alumina, filtrate decompression is concentrated, and obtains crude product 5- ethyls-1,2,3,3,4,6,7,7-octahydro pyrrolo- [3,4-c] pyridine 34c (432 mg, light brown oily substance), product without isolation Zhi connect for Xia Walk reaction.
Tetra- Walk
4- [[3- (5- ethyls -3,3fl, the H- of 4,6,7,7-hexahydro-1 pyrrolo-es [3,4-c] pyridine-2- carbonyls) and-4- fluoro-phenyls] methyl]-2H- phthalazines-1- ketone
The fluoro- 5- of 2- [(4- oxo-3H- phthalazines-1- bases) methyl] benzoic acid lc (620 mg, 2.08 mmol) is dissolved in 8 mL DMFs, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (1.41 g, 3.74 mmol), crude product 5- ethyls-1,2,3,3 β, 4,6,7,7-octahydro pyrrolo- [3,4-c】P reacts 12 hours than pyridine 34c (432 mg, 2.50 mmol) and Ν, Ν-diisopropylethylamine (1.1 mL, 6.24 mmol).Add 25 mL water, it is extracted with ethyl acetate (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (40 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain 4- [[3- (5- ethyls -3,3 α, 4,6,7,7/- hexahydro -1H- pyrrolo-es [3,4-cl pyridine -2- carbonyls) -4- fluoro-phenyls] methyl] 34 (260 mg of -2H- phthalazines -1- ketone, pale red solid), yield： 28.8%.
MS m/z (ESI): 435.2 [M+l]
Ή NMR (400 MHz, CDC13):δ 10.13 (br. s, 1H), 8.46 (d, 1H), 7.76 (m, 3H), 7.37 (m, 1H), 7.28 (m, 1H), 7.03 (t, 1H), 4.28 (d, 2H), 3.65 (m, 1H), 3.59 (m, 1H), 3.32 (m, 1H), 3.29 (m, 1H), 2.40 (m, 6H), 1.95 (m, 2H), 1.73 (s, 2H), 1.58 (m, 1H), 1.41 (m, 2H) embodiment 35
4- [[3- (4- ethyls -2,3,4 ", 5,7,7 "-hexahydropyrrolo simultaneously [3,4-b] [l, 4] oxazine -6- carbonyls) -4- fluoro-phenyls] methyl 2H- phthalazines -1- ketone
Mono- Walk
3,4,5,7,7 Ω-hexahydro-2H- pyrrolo-es [3,4-6] Jie, 4] Evil crop-6- t-butyl formates are by the α of 4- benzyls-2,3,4,5,7,7-hexahydropyrrolo simultaneously [3,4-6] [1,4] oxazine-6- t-butyl formates 14d (500 mg
1.57 mmol) 20 mL methanol Cao are dissolved in, 20 10% palladiums of mg/carbon is added, hydrogen is replaced three times, is reacted 12 hours.Filtering, filtrate decompression concentration, obtains 3,4,5,7,7 α-hexahydro -2H- pyrrolo-es [3,4-6] [1,4] oxazine -6- t-butyl formates 35a (230 mg, colorless oil), yield： 64.0%.
Bis- Walk
4- ethyls -2,3,4 α, 5, simultaneously [3,4-6] [Isosorbide-5-Nitrae] Evil prolixity -6- t-butyl formates are by 3 for 7,7 α-hexahydropyrrolo, 4,4 α, 5,7,7 β-hexahydro -2H- pyrrolo-es [3,4-W [l, 4] oxazine -6- t-butyl formates 35a (300 mg, 1.31 mmol) are dissolved in 10 mL acetonitriles, sequentially add potassium carbonate (543 mg, 3.93 mmol) and iodoethane (0.2 mL, 1.97 mmol), 80 °C are reacted 3 hours.Filtering, filter cake is washed with 30 mL acetonitriles, filtrate decompression concentration, obtains crude product 4- ethyls -2,3,5,7,7α- hexahydropyrrolo simultaneously [3,4- δ] [1,4] oxazine -6- t-butyl formates 35b (400 mg, yellow solid), product without isolation Zhi connect for Xia Walk reaction.
Tri- Walk
4- ethyls-3,4a, [Isosorbide-5-Nitrae] oxazines hydrochloride is by crude product 4- ethyls-2,3,4 for 5,6,7,7-hexahydro-2H- pyrrolo-es [3,4-6]a,5,7,70- hexahydropyrrolo simultaneously [3,4-6] [Isosorbide-5-Nitrae] oxazine -6- t-butyl formates 35b (400 mg, 1.31 mmol) is dissolved in 1, the 4- dioxane of the M hydrogen chloride of 20 mL 6.5, react 12 hourscBe concentrated under reduced pressure, obtain crude product 4- ethyls-3,5,6,7,7-hexahydro-2H- pyrrolo-es [3,4-6] [1,4] oxazine hydrochlorides 35c (400 mg, brown solid), product without isolation Zhi connect for Xia Walk reactions.
MS m/z (ESI): 157.1 [M+l]
4th step
The -one of 4- [[3- (4- ethyls -2,3,4fl, 5,7,7fl- hexahydropyrrolos simultaneously [3,4-W [l, 4] oxazine -6- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines -1
By the fluoro- 5- of 2- [(the small base of 4- oxo-3H- phthalazines) methyl] benzoic acid lc (250 mg, 0.84 mmol) it is dissolved in 5 mL Ν, Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea Liu Fu Pity acid esters (477 mg, 1.26 mmol), crude product 4- ethyls-3,4/, 5,6,7,7-hexahydro-2H- pyrrolo-es [3,4-6] [1,4] Evil crop hydrochloride 35c (400 mg, 1 mmol) and Ν, Ν-diisopropylethylamine (0.3 mL, 1.68 mmol), reacts 12 hours.30 mL water are added, (30 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, it is concentrated under reduced pressure, 50 mL ethyl acetate are added, are washed (40 mL) with saturated sodium bicarbonate solution (40 mL), saturated nacl aqueous solution successively, it is anhydrous Sodium sulphate dry, filtering, filtrate decompression concentration, with thin ^ chromatograph color method with open up Ji agent system A purify obtained by residue, obtain 4- [[3- (4- ethyls -2,3,4ί(, 5,7,7 " and-hexahydropyrrolo simultaneously [3,4-6] Π, 4] oxazine -6- Tang Juan) the fluoro- benzene of -4-] methyl] -2//phthalazines -1- ketone 35 (70 mg, white solid), yield： 5.5%.
MS m/z (ESI): 437.2 [M+l]
1H NMR (400 MHz, CDC13):δ 10.40 (br. s, I H), 8.48 (m, I H), 7.78 (m, 3H), 7.40 (m, I H), 7.29 (m, IH), 7.05 (m, IH), 4.29 (m, 2H), 3.66 (m, 10H), 2.59 (m, 2H), 1.17 (t 3H) embodiments 36
4- [[3- [4- (Cvclopropvlmethvl)-2,3,5,7,7-hexahydropyrrolo simultaneously [3,4-6] [l, 4] oxazine-6- carbonyls]-4- fluoro-phenyls]
The first step
4- (；Cvclopropvlmethvl) -2,3,4 α, 5,7, simultaneously [3,4- 6] [Isosorbide-5-Nitrae] oxazine -6- t-butyl formates are by 3 for 7 β-hexahydropyrrolo, 4,4 ￡, 5,7,7 α-hexahydro -2H- pyrrolo-es [3, [l, 4] oxazine -6- t-butyl formates 35a (330 mg, 1.45 mmol) are dissolved in 30 mL acetonitriles 4-W, sequentially add potassium carbonate (530 mg, 4.35 mmol) and the protective embankment of bromomethyl ring third (391 mg, 2.90 mmol), 82 reactions 3 hours.Filtering, filter cake is washed with 30 mL dichloromethane protective embankments, filtrate decompression concentration, obtain crude product 4- (Cvclopropvlmethvl)-2,3,4 α, 5,7,7-hexahydropyrrolo simultaneously [3,4-W [l, 4] Evil crop-6- t-butyl formates 36a (300 mg, white solid), product without isolation Zhi connect for Xia Walk reaction
Second step
4- (Cvclopropvlmethvl) -3,4 α, 5,6,7,7 Ω-hexahydro -2H- pyrrolo-es [3,4-] [1,4] oxazines hydrochloride is by crude product 4- (Cvclopropvlmethvl) -2,3,4,5,7,7fl- hexahydropyrrolos simultaneously [3,4-W [l, 4] oxazine -6- t-butyl formates 36a (300 mg, 1 mmol) Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 20 mL 6.5 is dissolved in, react 12 hours.It is concentrated under reduced pressure, obtains crude product 4- (Cvclopropvlmethvl) -3,5,6,7,7 α-hexahydro -2H- pyrrolo-es [3,4-6] [1,4] Evil crop hydrochlorides 36b (260 mg, colorless oil), product without isolation Zhi connect for Xia Walk reaction.
3rd step
4- [[3- [α of 4- (Cvclopropvlmethvl) -2,3,4,5,7,7 α-hexahydropyrrolo simultaneously [3,4- δ] [1,4] Evil crop -6- carbonyls] -4- fluoro-phenyls] methyl] -2H- phthalein crop -1- ketone
The c (300 mg, 1 mmol) of the fluoro- 5- of 2- [(the small base of 4- oxo -3H- phthalein crops) methyl] benzoic acid 1 is dissolved in 20 mL
In Ν, Ν-dimethylformamide, addition BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (570 mg, 1.50 mmol), crude product 4- (cyclopropyl first) -3,4,5,6,7,7 "-hexahydro -2//- pyrrolo- [3; 44] [1; 4] Evil crop hydrochlorides 36b (260 mg, 1 mmol) and Ν, Ν-diisopropylethylamine (0.5 η stops; 3 mmol), reaction 12 hours.Add 50 mL water, (50 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, it is concentrated under reduced pressure, add lOO mL ethyl acetate, saturated sodium bicarbonate solution (40 mL) is used successively, saturated nacl aqueous solution washs (40 mL), anhydrous sodium sulfate thousand is dry, filtering, filtrate decompression is concentrated, with thin-layer chromatography chromatography with solvent system A purify gained residue, to 4- [[3- [4- (cyclopropyl Cao) -2, 3, 5, 7, 7-hexahydropyrrolo simultaneously [3, 4-6] [1, 4] ^ piperazines -6- carbonyls] -4- Gas-phenyl] methyl] 36 (185 mg of -2H- phthalazines -1- ketone, β colors solid), yield： 40.0%.
MS m/z (ESI): 463.2 [M+l]
Ή NMR (400 MHz, CDC13): δ 8.48 (m, 1H), 7.78 (m, 3H), 7.39 (m, 2H), 7.05 (m, 1 H), 4.27 (s, 2H), 3.89 (m, 1H), 3.76 (m, 4H), 3.51 (m52H), (m, 2H) embodiment 37 of 3.12 (m, 1 H), 2.71 (m, 2H), 2.42 (m, 2H), 0.89 (m, 1 H), 0.50 (m, 2H), 0.16
4- [[3- [2- (2- amino-ethyls) -3,3 ", 4,6,7,7fl- hexahydropyrrolos simultaneously [3,4-c] pyridine -5- carbonyls] -4- fluoro-phenyls]
N- [2- [5- [2- fluoro -5- [(the small base of 4- oxo -3H- phthalazines) methyl] benzoyl] -3, 3 α, 4, 6, 7, 7 α-hexahydro -1H- pyrrolo-es [3, 4-c] pyridine -2- bases] ethyl] t-butyl carbamate is by 4- [[3- (1, 2, 3, 3 α, 4, 6, 7, 7 "-octahydro pyrrolo- [3.4-c] pyridine -5- carbonyls) -4- fluoro-phenyls] methyl] 30 (80 mg of -2H- phthalazines -1- ketone, 0.19 mmol) it is dissolved in 10 mL acetonitriles, sequentially add potassium carbonate (82 mg, 0.59 mmol), sodium iodide（15 mg, 0.098 mmol) and N- (2- chloroethyls) t-butyl carbamate (53 mg, 0.29 mmol), back flow reaction 4 hours, 50'C reactions 12 hours.Filtering; filter cake is washed with 20 mL dichloromethane; filtrate decompression concentrate, with thin-layer chromatography chromatography with solvent system A purify obtained by residue, obtain N- [2- [5- [2- fluoro -5- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoyl] -3; 3; 4,6,7; 7 "-hexahydro -1H- pyrrolo-es [3,4-c] pyridine -2- bases] ethyl] t-butyl carbamate 37a (30 mg, white solid), yield： 27.8%. MS m/z (ESI): 550.2 [M+l]
Second step
4- [[3- [2- (2- amino-ethyls) -3,3 α, 4,6,7,7 α-hexahydro -1H- pyrrolo-es [3,4-c] pyridine -5- carbonyls] -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone
By N- [2- [5- [2- fluoro-5- [(the small base of 4- oxo-3H- phthalazines) methyl] benzoyl]-3,3 α, 4,6,7,7-hexahydro - IH- pyrrolo-es [3,4-c] pyridine -2-] ethyl] amino Ψ tert-butyl acrylates 37a (30 mg, 0.054 mmol) is dissolved in 3 mL dichloromethane, adds the 1 of the M hydrogen chloride of 2 mL 6.5,4- dioxane solutions, react 12 hours.It is concentrated under reduced pressure, add 20 mL dichloromethane, the M sodium hydroxide solutions of 0.1 mL 5,3 mL methanol, and saturated solution of sodium carbonate make reaction solution ρ Η be 9, with anhydrous sodium sulfate drying, filtering, filtrate subtracts ^ concentrations, and river thin-layer chromatography chromatography purifies gained residue with Μ Ji agent systems Α, obtain 4- [[3- [2- (2- amino-ethyls) -3,3fl, 4,6,7,7i/- hexahydropyrrolos simultaneously [3,4-c] pyridine -5- carbonyls] and -4- fluoro-phenyls] first] -2/- phthalein crash -1- ketone 37 (15 mg, light yellow solid), yield： 62.5%.
MS m/z (ESI): 448.0 [M-l ]
Ή NMR (400 MHz, CDC13):δ 8.88 (s, IH), 8.28 (d, IH), 8.15 (m, 1H), 7.93 (m, I H), 7.13 (d, 1H), 7.06 (d, IH), 6.45 (m, IH), 3.95 (m, IH), 3.83 (s, 2H), 2.29 (m, 2H), 2.22 (m, 211), 1 .94 (m, 8H), 1.26 (m, 4H) embodiment 38
4- [[4- fluoro -3- [2- (2- hydroxyethyls) -3,3a, 4,6,7,7c/- hexahydro-IH- pyrrolo-es [3,4-c] pyridine -5- carbonyls] phenyl]
By 4- [[3- (1,2,3,3, 4,6,7,7 α-octahydro pyrrolo- [3,4-c] pyridine -5- carbonyls) and -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone 30 (100 mg, 0.21 mmol) is dissolved in 10 mL acetonitriles, sequentially adds potassium carbonate（101 mg, 0.74 mmol) and bromoethanol (46 mg, 0.37 mmol), react 24 hours.It is concentrated under reduced pressure, gained residue is purified with solvent system A with thin-layer chromatography chromatography, obtains 4- [[4- fluoro -3- [2- (2- hydroxyethyls) -3,3 ", 4,6,7,7 "-hexahydropyrrolos simultaneously [3,4-C] pyridine -5- carbonyls] phenyl] methyl] -2H- phthalazines -1- ketone 38 (20 mg, white solid), yield： 18.2%.
MS m/z (ESI): 451.2 [M+1]
Ή NMR (400 MHz, CD3OD):δ 8.37 (s, IH), 7.98 (t, IH), 7.88 (m, 2H), 7.48 (m, IH), 7.36 (d, IH), 7.16 (t, IH), 4.59 (m, IH), 4.39 (s, 2H), 4.10 (s, 2H), 3.84 (m, 2H), 3.66 (m, 2H), 3.43 (m, IH), 3.39 (m, 2H), 3.20 (m, 2H), 2.68 (m, 2H), 1.94 (m, 2H), 1.76 (m, 2H), 1.66 (m, IH) embodiment 39
4- [[3- [(4a, 7aS)-l, 2,3,4,4fl, 5,7,7a- octahydro pyrrolo-es [3,4-W pyridine -6- carbonyls] -4- fluoro-phenyl J methyl] -2H- phthalazines -1- ketone
Mono- Walk
6- benzyl-pyrroles simultaneously [3,4-] pyridine -5,7- diketone
Pyridine -2,3- dioctyl phthalate 39a (10 g, 59.80 mmol) is dissolved in 20 mL acetic anhydrides, 110 °C of reactions
4 hours, it is concentrated under reduced pressure, obtains white solid furans simultaneously [3,4-6] pyridine -5,7- diketone.
0 °C by furans, simultaneously [3,4- 6] pyridine -5,7- diketone is dissolved in 10 mL benzylamines, and 180 °C are reacted 0.5 hour, 110 °C of 20 mL acetic anhydrides of addition, and 110 °C are reacted 2 hours.Ice bath is cooled down, and is added ethanol and is tied product again, there is white solid precipitation, filter, filter cake is washed with ethanol, obtains 6- benzyl-pyrroles and pyridine -5,7- diketone 39b (7 g, white solid), yield： 49.2%.
Bis- Walk
6- benzyls -1,2,3,4,4 α, 7 α-hexahydropyrrolo simultaneously [3,4-6] pyridine -5,7- diketone is by 6- benzyl-pyrroles simultaneously [3,4-W pyridine -5,7- diketone 39b (11 g, 46.20 mmol) is dissolved in 200 mL methanol, add 1.10 10% palladiums of g/carbon, hydrogenation instrument hydrogenation 12 hours.Filtering, filter cake is washed with 100 mL methanol, filtrate decompression concentration, with alkali alumina column chromatography with the separating obtained residues of eluant, eluent system A, obtain 6- benzyls-l, 2,3,4,4ii, 7fl- hexahydropyrrolo simultaneously [3,4- 6] pyridine -5,7- diketone 39c (10 g, light yellow oil）, yield： 89.2%.
MS m/z (ESI): 245.1 [M+l]
Tri- Walk
6- benzyls-1,23,4,4 ", 5,7,7-octahydro pyrrolo- [3,4-6] pyridine is by 6- benzyls-l, 2,3,4,4fl, 7fl- hexahydropyrrolo simultaneously [3,4->] pyridine -5,7- diketone 39c (5 g, 20 mmol) is dissolved in 120 mL tetrahydrofurans, 0 °C is added portionwise Lithium Aluminium Hydride (7.60 g, 20 mmol), 75 °C of 6 small inch of reaction.Ice bath is cooled down, and adds 12.9 mL water and 100 mL dichloromethane, and 20% sodium hydroxide solution is added dropwise to there is white precipitate, filtering, filter cake is washed with 50 mL dichloromethane, filtrate decompression Nong Shrink, obtain crude product 6- benzyls-l, 2,3,4,4a, 5,7,7fl- octahydro pyrrolo- [3,4-6] pyridine 39d (4 g, light yellow oil), product without isolation Zhi connect for Xia Walk reaction.
MS m/z (ESI): 217.2 [M+l]
Tetra- Walk
(4 ＆7 6- benzyls -1,2,3,4,4 Ω, 5,7,7 Ω-octahydro pyrrolo- [3,4-b] pyridine By molten mL N, N- the diformazan Cao acid amides towel of Τ 5 of D (-)-tartaric acid (1.38 g, 9.20 mmol), 80 °C of stirrings are completely dissolved it, add 1 mL crude product 6- benzyls-1,2,3,4,5,7,7-Λ pyrrolo-es [3,4- 6] pyridine 39d (1 g, 4.60 mmol) Ν, Ν-dimethyl formamide solution, 80 °C stirring】5 minutes, solution was changed into blackish green, was cooled to 0 °C, stirred 1 hour, and no solid is separated out, and added 5 mL glycol monoethyl ethers, and Nuisance white solids are separated out.Filtering, 5 mLN of filter cake, the washing of N- diformazans formamide, 2 mL glycol monoethyl ethers are added, are stirred 10 minutes, filtering, filter cake is dissolved in 5 mL water, adds the sodium hydroxide solutions of 0.8 mL 45%, is stirred 10 minutes, extracted with methyl tertiary butyl ether(MTBE) (6 mLx5), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains (＆7 " 5) -6- benzyls--1; 2; 3,4,40; 5; 7,7 " (0.25 g of-octahydro pyrrolo- [3,4-6] pyridine 396, colorless oil), yield： 25.0%.
Wu Walk
(4aS, 75 6- benzyls-3,4,4fl, 5,7,7a- hexahydro-2H- pyrrolo-es [3,4-6] pyridine-1- t-butyl formates are by (4a＆7aS-6- benzyls-1,2,3,4,4 ο, 5,7,7-octahydro pyrrolo- [3,4-6 " pyridines 39e (120 mg; 0.56 mmol) is dissolved in 20 mL dichloromethane, adds DMAP (136 mg, 1.11 mmol) and di-tert-butyl dicarbonate (182 mg; 0.83 mmol), is reacted 4 hours.20 mL water are added, point liquid, aqueous phase is extracted (20 mLx3) with dichloromethane, merge organic phase, (40 mL) is washed with saturated nacl aqueous solution, anhydrous sodium sulfate thousand is dry, filtering, filtrate decompression concentration, obtains (4aS, 7aS -6- benzyls -3,4,4 α, 5,7,7α- hexahydro -2H- pyrrolo-es [3,4-6] pyridine -1- t-butyl formates 39f (150 mg, light yellow liquid), yield： 85.4%.
MS m/z (ESI): 317.2 [M+l]
Liu Walk
(the α of 4 α ＆7 2,3,4,4,5,6,7,7 α-octahydro pyrrolo- [3,4-6] pyridine-1- t-butyl formates are by (4,7 S)-6- benzyls-3,4,4/, 5,7, [the small t-butyl formate 39f of 3,4-W pyridines (150 mg, 0.47 mmol) is dissolved in 10 mL methanol 7-hexahydro-2H- pyrrolo-es, 15 10% palladiums of mg/carbon is added, hydrogen is replaced three times, is reacted 12 hours.Filtering, filter cake is washed with 20 mL methanol, filtrate decompression concentration, obtains (＆7 α 5) -23,4,4 α, 5,6,77 ￡-octahydro pyrrolo- [3,4-6] pyridine -1- t-butyl formates 39g (100 mg, light yellow liquid), yield： 93.5%.
Qi Walk
(4ί＆7 α)-6- [the fluoro- 5- of 2- [(- 1-yl of 4- oxo-3H- phthalazines) methyl] benzoyl] "-hexahydro-2H- pyrrolo-es [3,4- of-3,4,5,7,7C] pyridine-t-butyl formate
By the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid lc (132 mg, 0.44 mmol) it is dissolved in 2 mL Ν, in Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (251 mg, 0.66 mmol), (4 ＆7 " 5) -2, 3, 4, 4 α, 5, 6, 7, 7 α-octahydro pyrrolo- [3, 4-6] pyridine -1- t-butyl formates 39g (100 mg, 0.44 mmol) and Ν, Ν-diisopropylethylamine (0.2 mL, 0.88 mmol), reaction 12 hours.It is concentrated under reduced pressure; with thin-layer chromatography chromatography with solvent system A purify gained residue; obtain (4 ＆7^) -6- [the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoyl] -3,4,4 α; 5; 7,7 α-hexahydro -2H- pyrrolo-es [3,4-c] pyridine -1- t-butyl formates 39h (40 mg; white solid), yield： 17.9%.
Ba Walk 4- [[3- [(4 " S, 7 " 5)-l, 2,3,4,4fl, 5,7,7fl- octahydro pyrrolo- [3,4-] pyridine -6- carbonyls] -4- fluoro-phenyls] methyl] the small ketone of -2//- phthalazines
By (4fl＆7a) -6- [the fluoro- 5- of 2- [(4- oxo -3H- phthalein crash small bases）Methyl] benzene Cao acyl groups] -3,4,4 ", 5; 7,7 α-six -2H- pyrrolo-es [3,4-c] pyridine -1- t-butyl formates 39h (50 mg; 0.099 mmol) are dissolved in 1, the 4- dioxane solutions of the M hydrogen chloride of 5 mL 6.5, react 4 hours.Subtract Hi concentration, add 1 mL ammonia ZK, be concentrated under reduced pressure, with thin-layer chromatography chromatography with open up Ji agent system Α purify obtained by residue, obtain 4- [[3- [(45', 7 1,2,3,4,4,5,7,7 α-octahydro pyrrolo- [3,4->] pyridine-6- carbonyls]-4- fluoro-phenyls] methyl]-1 -one 39 (5 mg, light yellow solid) of-2H- phthalazines, yield： 〗2.5%.
MS m/z (ESI): 407.2 [M+l]
Ή NMR (400 MHz, CDC13):The .30 of δ 11 (br. s, 1H), 8.47 (m, 1H), 7.76 (m, 3H), 7.40 (m, 1H), 7.27 (m, 1H), 7.04 (m, 1H), 4.27 (η ι, 2H), 3.70 (m, 2H), 3.50 (m, 2H), 3.20 (m, 2H), 2.25 (m, 1H), 2.00 (m, 2H), 1.63 (m, 2H) embodiment 40
4- [[the fluoro- 3- of 4- [2- (2- pyridylmethyls) -3,3α, 4,6,7,7 α-hexahydro -1H- pyrrolo-es [3,4-c] pyridine -5- carbonyls】Phenyl]
By 4- [[3- (l, 2,3,3 " .4,6,7,7a- octahydro pyrrolo-es [3,4-C] pyridine -5- carbonyls) -4- fluoro-phenyls] methyl] 30 (80 mg of -2H- phthalazines -1- ketone, 0.19 mmol) it is dissolved in 10 mL 1,2- dichloroethanes, add pyridine-2-formaldehyde (32 mg, 0.30 mmol), back flow reaction 1 hour.Room temperature is cooled to, atmosphere base sodium borohydride (25 nig, 0.39 mmol) is added, reacted 12 hours.15 mL saturated ammonium chloride solutions are added, (15 mL are extracted with dichloromethane>2) organic phase, is merged, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 4- [[the fluoro- 3- of 4- [2- (2- pyridylmethyls) -3,3,4,6,7,7 α-hexahydropyrrolo simultaneously [3,4- c] pyridine -5- carbonyls] phenyl] methyl] 40 (27 mg of -2H- phthalein crop -1- ketone, white solid), yield： 27.8%.
MS m/z (ESI): 498.2 [M+l ]
Ή NMR (400 MHz, CDC13):δ 8.65 (d, 1H), 8.44 (d, 1H), 7.74 (m, 5H), 7.30 (m, 3H), 7.01 (m, 2H), 4.31 (s, 2H), 4.27 (s, 2H), 3.40 (m, 2H), 3.12 (m, 2H), 2.75 (m, 2H), 2.56 (m, 2H), 1.90 (m, 2H), 1.71 (m, 2H) embodiment 41
4-[[3-[(4ai,7" )-l, 2,3,4,4a, 5,7,7a- octahydro pyrrolo- [3,4-6] pyridine -6- carbonyls] -4- fluoro-phenyls] first
Mono- Walk
(4β , 7 ^) -6- benzyls -1, 2, 3, 4, 4, 5, 7, 7 α-octahydro pyrrolo- [3, 4-6] pyridine is by L (+)-tartaric acid (1.38 g, 9.20 mmol) it is dissolved in 4 mL Ν, in Ν-dimethylformamide, 80 °C of stirrings are completely dissolved it, add 1 mL crude product 6- benzyls -1, 2, 3, 4, 4 α, 5, 7, 7-octahydro pyrrolo- [3, 4-6] pyridine 39d (1 g, 4.60 mniol) Ν, Ν-dimethyl formamide solution, 80 stir and impeach 15 minutes, it is stirred at room temperature 1 hour, add 6 mL glycol monoethyl ethers, there is white solid precipitation.Filtering, filter cake is with 5 mL N, dinethylformamide is washed, 2 mL glycol monoethyl ethers are added in filter cake, stirring 10 minutes, filtering, filter cake is dissolved in 5 mL water, add the sodium hydroxide solutions of 0.8 mL 45%, stirring 5 minutes, extracted with methyl tertiary butyl ether(MTBE) (6 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain (4oR, 7oR) -6- benzyls -1, 2, 3, 4, 40, 5, 7, 7 "-octahydro pyrrolo- [3, 4-6] pyridine 413 (120 11, colorless oil), yield： 12.0%.
Bis- Walk
(4 ,7« ) -6- benzyls -3,4,4Ω, the small t-butyl formate of 5,7,7-hexahydro-2H- pyrrolo-es [3,4-b] pyridine is by (4ai, 7 ")-6- benzyls-1,2,3,4,4 ", 5; 7; 7-octahydro pyrrolo- [3,4-6] pyridine 41a (700 mg, 3.20 mmol) is dissolved in 10 mL dichloromethane; add triethylamine (L4 mL; 9.60 mmol) and di-tert-butyl dicarbonate (1.05 g, 4.80 mmol), react 12 hours.Reaction solution is with saturated ammonium chloride solution Xian Di (10 mL), and anhydrous sodium sulfate does ^！, filtering, filtrate decompression concentration, with the clear and bright column chromatography of silicon with eluant, eluent system A purify obtained by residue, obtain (4a, 7) and -6- benzyls -3,4,4fl, 5,7, the 7t/- small t-butyl formate 41b of hexahydro -2H- pyrrolo-es [3,4-6] pyridine (l g, yellow solid), yield： 98.9%.
MS m/z (ESI): 317.2 [M+l]
Tri- Walk
(4 /, 7i^) and-2,3,4,4fl, 5,6,7,7a- octahydro pyrrolo- [3,4-6] pyridine-1- t-butyl formates are by (aRJaR)-benzyl-3,4,4a, 5,7,7 α-hexahydro-2H- pyrrolo-es [3,4-6] pyridine-1-t-butyl formate
41b (1 g, 3.16 nimol) is dissolved in 20 mL methanol, adds 0.10 10% palladiums of g/carbon, and hydrogen is replaced three times, is reacted 12 hours.Filtering, filtrate decompression concentration, obtains crude product (4a^, 7i^) -2,3,4,4fl, 5,6,7,7fl- octahydros pyrrolo- [3,4-6] pyridine -1- t-butyl formates 41c (800 mg, white solid), product is not purified directly to enter the lower Walk reactions of row. MS m/z (ESI): 226.9 [ +l]
(4" 7fl7) _ 6- [the fluoro- 5- of 2- [(- 1-yl of 4- oxo-3H- phthalazines) methyl] benzoyl]-3,4,4 ", 5,7,7 "-hexahydros
- 2//- pyrrolo- [3,4-C] the tertiary Ding Xi I of pyridine acid
By 2 mouse-5- [(- 1-yl of 4- oxo-3H- phthalazines) methyl] benzene " Π acid lc (1.05 g; 3.53 mmol) is dissolved in 20 mL N; in dinethylformamide; add BTA-Ν; Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (2 g; 5.29 mmol), crude product (4a/,7ai) -2,3,4,4a, the small Cao tert-butyl acrylates 41c of 5,6,7,7a- octahydro pyrrolo-es [3,4- δ] pyridine (800 mg, 3.53 mmol) and DIPEA（1.3 mL, 7.06 mmol), react 12 hours.It is concentrated under reduced pressure, add 40 mL water, (40 mLx3) is extracted with dichloromethane protective embankment, merge excuse machine phase, (30 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 A purify obtained by residue, obtain (4 i,7a/) -6- [the fluoro- 5- of 2- [(4- oxos -3H- phthalazines-yl) methyl] benzoyl] -3,4,4; 5,7,7 "-hexahydro -2H- pyrrolo-es [3; 4-c] pyridine-- t-butyl formate 41d (1.20 g, yellow solid), yield： 70.8%.
MS m/z (ESI): 407.1 [M-100+1]
Wu Walk
, 2,3,4,4,5,7,7 α-octahydro pyrrolo- [3,4-6] pyridine -6- carbonyls] and -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone
Will (4 " 7 α/) -6- [the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases）Methyl] benzoyl] -3,4,4 ", 5; 7,7 α-hexahydro -2H- pyrrolo-es [3,4-c | pyridine -1- t-butyl formates 41d (1.20 g; 2.36 mmol) is dissolved in Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 20 mL 6.5, is reacted 12 hours.It is concentrated under reduced pressure, adds 20 mL dichloromethane protective embankments, ammoniacal liquor to solid is added dropwise and is completely dissolved.With anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layer chromatography chromatography with open up Jian agent systems A purify gained residue, obtain 4- [[3- [(4,7aW)-l, 2,3,4,4fl, 5,7,7-octahydro pyrrolo- [3,4-6] pyridine-6- carbonyls]-4- fluoro-phenyls] methyl]-2H- phthalazines-1- ketone 41 (360 mg, light yellow solid), yield： 37.5%.
MS m/z (ESI): 407.2 [M+l]
Ή NMR (400 MHz, DMSO-^):δ 12.60 (br. s, H), 8.24-8.26 (m, IH), 7.81-7.95 (m, 3H), 7.41-7.46 (m, 2H), 7.21-7.26 (ra, IH), 4.33 (s, 2H), 3.54-3.65 (m, 3H), 3.41-3.44 (m, IH), 3.13-3.17 (m, 3H), 2.77-3.06 (m, 1 H), 1.44-1.69 (m, 4H) embodiment 42
4- [[3- [l- (2- amino-ethyls) -3,4,4,5,7,7 α-hexahydro -2H- pyrrolo-es [3,4-6] pyridine -6- carbonyls] -4- fluoro-phenyls] first -one
Mono- Walk
N- (2- bromoethyls) t-butyl carbamate
By 2- bromine ethylamine hydrobromides 42a (11 g, 53.60 mmol) it is dissolved in 120 niL methanol, add triethylamine (40 mL, 161 mmol) and di-tert-butyl dicarbonate (23.40 g, 107 mmol), 60 °C are stirred 30 minutes, are reacted at room temperature 12 hours.It is concentrated under reduced pressure, add 150 mL ethyl acetate, 80 mL l M hydrochloric acid are added dropwise, divide liquid, organic phase washed with water (40 mL), saturated sodium bicarbonate solution (40 mL), saturated nacl aqueous solution washing (40 mL), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain N- (2- bromoethyls) t-butyl carbamate 42b (10.50 g, colorless oil), yield： 85.7%. MS m/z (ESI+23): 170.1 [M-56+1]
Bis- Walk
N- [2- [6- [the fluoro- 5- of 2- [(4- oxo -3H- phthalein crop -1- bases) methyl] benzoyl is very] -3,4,4 ", 5,7,7 α-hexahydro -2H- pyrrolo-es [3,4-6] pyridine -1- bases] ethyl] t-butyl carbamate
By 4- [[3- (1,2,3,4,4 ", 5; 7; 7-octahydro pyrrolo- [3,4-W pyridine-6- carbonyls)-4- fluoro-phenyls] methyl]-2H- phthalein crop-1- ketone 11 (210 mg, 0.50 mmol) is dissolved in 50 mL acetonitriles; add N- (2- bromoethyls) t-butyl carbamate 42b (168 mg; 0.75 mmol) and potassium carbonate (350 mg, 2.50 mmol), back flow reaction 7 hours.Filtering; filtrate decompression is concentrated; with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain N- [2- [6- [the fluoro- 5- of 2- [(- 1-yl of 4- oxo-3H- phthalazines) methyl] benzoyl]-3,4; 4 α; 5,7,7-hexahydro-2H- pyrrolopyridine-1- bases] ethyl] t-butyl carbamate 42c (150 mg; white solid), yield： 54.5%.
3rd step
4- [[3- [1-(2- amino-ethyls)-3,4, ^, 5,7,7-hexahydro-2H- pyrrolo-es [3,44] pyridine-6- carbonyls]-4- fluoro-phenyls] methyl]-2H- phthalazines-1- ketone
By N- [2- [6- [the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases）Methyl] benzoyl] -3; 4; 4 α; 5,7,7 α-hexahydro -2H- pyrrolo-es [3; 4-W pyridines-yl] ethyl] t-butyl carbamate 42c (150 mg; 0.27 mmol) it is dissolved in Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 2 mL 2, react 12 hours.It is concentrated under reduced pressure, add 50 mL dichloromethanes protective embankments and 20 mL saturated sodium carbonate solutions, divide liquid, collect organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify gained residue, obtain 4- [[3- [1- (2- amino-ethyls)-3,4,4,5,7,7 α-hexahydro-2H- pyrrolo-es [3,4-6] pyridine-6- carbonyls]-4- fluoro-phenyls] methyl] 42 (35 mg of-1 -one of-2H- phthalazines, white solid), yield： 28.7%.
MS m/z (ESI): 450.1 [M+l]
Ή NM (400 MHz, CDC13): δ 8.31 (m, IH), 7.88 (m, 3H), 7.52 (m, 2H), 7.23 (m, IH), 4.35 (s, 2H), 3.44 (m, 4H), 3.22 (m, 3H), 3.01 (m, 2H), 2.58 (m, IH), 2.28 (m, IH), 1.45 (m, 5H) embodiment 43
4- [[the fluoro- 3- of 4- [l- (3- pyridylmethyls) -3,4,45,7,7 "-hexahydro -2H- pyrrolo-es [3,4-] pyridine -6- carbonyls] phenyl]
By 4- [[3- (1,2,3,4,4 ", 5; 7; 7 α-octahydro pyrrolo- [3,4-W pyridine -6- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalein prolixity -1- ketone 11 (150 mg, 0.37 mmol) is dissolved in 10 mL 1; in 2- dichloroethanes; add pyridine -3- formaldehyde (47.40 mg, 0.44 mmol) and acetic acid (0.1 mL, 0.002 mmol); react 5 small inch, sodium triacetoxy borohydride (234 mg, 1.11 mmol) is added, is reacted 12 hours.Add 30 mL water, (50 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, washed with saturated nacl aqueous solution (50 mL), anhydrous sodium sulfate thousand is dry, filtering, filtrate decompression concentration, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain 4- [[the fluoro- 3- of 4- [and 1- (3- pyridylmethyls)-3,4,4 "; 5; 7,7 "-hexahydro-2H- pyrrolo-es [3,4-6] pyridine-6- carbonyls] phenyl] methyl] 43 (80 mg of-1 -one of-2H- phthalazines, white solid), yield： 43.7%.
MS m/z (ESI): 498.2 [M+l ]
1H NMR (400 MHz, CDC13):δ 11.21 (br. s, IH), 8.63 (m, 3H), 7.80 (m, 4H), 7.33 (m, IH), 7.30 (m, 2H), 7.09 (m,), IH 4.32 (m, 2H), 4.32 (m, 2H), 3.96 (m, I H), 3.68 (m, 3H), 3.41 (m, 2H), 3.17 (m, 2H), 2.68 (m, IH), 2.51 (m, IH), 2.24 (m,), IH 1.68 (m, 5H) embodiment 44
4- [[3- (1,2,3,4,40, 5,7,7 α-octahydro pyrrolo- [3,4-6] pyridine -6- carbonyls) and phenyl] methyl] -2H- phthalazines -1- ketone
6- [3- [(4- oxo -3H- phthalein crop -1- bases) methyl] benzoyl] -3,4,5,7,7a- hexahydro -2H- pyrrolo-es
[3,4-6] pyridine -1- t-butyl formates
By 3- [(- 1-yl of 4- oxo-3H- phthaleins prolixity) methyl] benzoic acid 44a (300 mg, 1.07 mmoh are respectively obtained using known method " patent WO2004080976 " system) dissolving Γ 20 mL N, in dinethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethyl very takes hexafluorophosphoric acid ester (528 mg, 1.61 mmol), octahydro-pyrrolo- [3, 4-6] pyridine-1-t-butyl formate (242 mg, 1.07 mmol) and Ν, Ν-diisopropylethylamine (0.6 mL, 3.21 mmol), reaction 12 hours.Be concentrated under reduced pressure, with thin-layered chromatography with open up Ji agent system A purify gained residue, obtain 6- [3- [(the small bases of 4- oxo -3H- phthalazines）Methyl] benzene I acyl groups] -3,4,4 ", 5,7,7 α-hexahydro -2H- pyrrolo-es [3,4- 6] pyridine -1- t-butyl formates 44b (400 mg, white solid), yield： 76.6%.
MS m/z (ESI): 389.2[M-100+1]
Second step
4- [[3- (1,2,3,4,4 ", 5,7,7 α-octahydro pyrrolo- [3,4-6] pyridine -6- carbonyls) phenyl] methyl] the small ketone of -2H- phthalein crops
By 6- [the fluoro- 5- of 2- [(the small base of 4- oxo-3H- phthalazines) methyl] benzoyl]-3; 4; 4 α; 5,7,7-hexahydro-2H- pyrrolo-es [3; 4-6] pyridine-1-t-butyl formate 44b (400 mg; 0.82 mmol) it is dissolved in Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 2 mL 2, react 12 hours.Be added dropwise saturated sodium bicarbonate solution to reaction solution pH be 9, (20 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, washed (20 mLx2), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain 4- [[3- (1,2,3,4,5,7,7 β-octahydro pyrrolo- [3,4- W pyridine -6- carbonyls) phenyl] methyl] -2H- phthalazines -1- ketone 44 (80 mg, white solid), yield： 25.1%.
MS m/z (ESI): 389.2 [M+l]
!H NMR (400 MHz, CDC13):δ 10.37 (br. s, 1H), 8.50 (m, 1H), 7.78 (m, 3H), 7.54 (m, 4H), 4.36 (s, 2H), 3.77 (m, 4H), 2.67 (m, 1H), 2.23 (m, 2H), 1.65 (m, 5H) embodiment 45
4- [[3- (5,7- dihydro pyrroles base] -2H- phthalazines -1- ketone
By 3- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid 44a (212 mg, 0.76 mmol) it is dissolved in 10 mL Ν, in Ν-dimethylformamide, BTA-Ν, Ν are added, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (375 mg, 1.14 mmol), 6,7- dihydro -5H- pyrrolo-es [3,4-6] pyridine（100 mg, 0.83 mmol) and DIPEA (0.4 mL, 2.28 mmol), react 12 hours.30 mL water are added, (50 mL 3) is extracted with dichloromethane, Merge organic phase, washed with saturated nacl aqueous solution (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, gone with thin layer color with solvent system A purify gained residue, obtain 4- [[3- (5,7- pyrrolin simultaneously [3,4- Λ] pyridine -6- carbonyls very) phenyl] first] small (99 mg of ketone 45 of -2//- phthalein crop, solid), yield： 34.0
%。
MS m/z (ESI): 383.1 [M+1]
Ή NMR (400 MHz, CDC13):δ 10.1 1 (br. s, 1H), 8.56 (m, 2H), 7.81 (m, 4H), 7.55 (m, 3H), 7.30 (m, 2H), 5.06 (s, 2H), 4.80 (s, 2H), 4.39 (s, 2H) embodiment 46
4-[[3-(1 ,3,3α, 4,5,6,7,7 ζ-octahydro pyrrolo- [3,4-c] pyridine -2- carbonyls) and -4- fluoro-phenyls] methyl] -2H- phthalazines -1
The first step
The 05- benzyl 02- tert-butyl groups 3,3 β, 4,6,7,7/- hexahydro -1H- pyrrolo-es [3,4-c] pyridine -2,5- dicarboxylic acid esters by 1,3,4,5,6,7,7 α-octahydro pyrrolo- [3,4-c | pyridine -2- t-butyl formates 30a (200 mg, 0.89 mmol) is dissolved in 5 mL dichloromethane protective embankments, adds triethylamine (369 L, 2.66 mmol) under 0 °C of c, benzyl chloroformate (189 μ, 1.33 mmol) is added dropwise, reacts at room temperature 12 hours.3 mL dichloromethanes protective embankments and 10 mL water are added, point liquid is collected organic phase, washed with saturated nacl aqueous solution (5 mL), anhydrous sodium sulfate drying, filters, filtrate decompression concentration obtains the 05- benzyl 02- tert-butyl groups 3,3 α, 4,6,7,7Ω- hexahydro -1H- pyrrolo-es [3,4-c] 2,5-Pyridinedicarboxylic acid ester 46a (250 mg, yellow oil), yield： 78.0%.
MS m/z (ESI): 261.1 [M-100+1]
Bis- Walk
L, 2,3,3fl, 4,6,7,7a- octahydro pyrrolo- [3,4-c] pyridine -5- benzyl formates trifluoroacetate is by 05- the benzyl 02- tert-butyl groups 3,3fl, 4,6,7,7a- hexahydro -1H- pyrrolo-es [3,4-c] pyridine -2,5- dicarboxylic acid esters
46a (250 mg, 0.69 mmol) is dissolved in trifluoroacetic acid (386 2.78 mmol), is reacted 0.5 hour.It is concentrated under reduced pressure, obtains crude product 1,2,3,3α, 4,6,7,7 α-octahydro pyrrolo- [3,4-c] pyridine -5- benzyl formate trifluoroacetic acids Salt 46b (260 mg, yellow Shan shape thing), product is not purified directly to carry out F Walk reactions.
Tri- Walk
2- [the fluoro- 5- of 2- [(the small base of 4- oxo -3H- phthalazines) methyl] benzoyl] -3,3 ", 4,6,7,7 "-hexahydropyrrolo simultaneously [3,4-c | pyridine -5- benzyl formates
By the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid lc (207 mg, 0.69 mmol) it is dissolved in 5 mL Ν, in Ν-dimethylformamide, add and foretell hydroxybenzotriazole (54 mg, 0.40 mmol), crude product 1, 2, 3, 3 α, 4, 6, 7, 7 α-octahydro pyrrolo- [3, 4-c] pyridine -5- Cao acid benzyl ester trifluoroacetate 46b (260 mg, 0.69 mmol) and 1-ethyl-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (199 mg, 1.04 mmol), reaction 12 hours.Be concentrated under reduced pressure, with thin-layer chromatography chromatography with solvent system A purify gained residue, obtain 2- [the fluoro- 5- of 2- [(the small bases of 4- oxo -3H- phthalazines）Methyl] benzoyl] -3,3 β, 4,6,7,7 β-hexahydro -1H- pyrrolo-es [3,4-c] pyridine -5- benzyl formates 46c (35 mg, yellow solid), yield： 9.3%.
MS m/z (ESI): 541.2 [M+l ]
Tetra- Walk
4- [[3- (1,3,3 ", 4,5,6,7,7 α-octahydro pyrrolo- [3,4-C] pyridine-2- carbonyls)-4- fluoro-phenyls] methyl]-1 -one of-2H- phthalazines
By 2- [the fluoro- 5- of 2- [(- 1-yl of 4- oxo-3H- phthalazines) methyl] benzoyl]-3,3α, 4,6,7,7 α-hexahydro -1H- pyrrolo-es [3,4-c] pyridine -5- formic acid section esters 46c (300 mg, 0.55 mmol) is dissolved in 10 mL methanol, adds 50 10% palladiums of mg/carbon, and hydrogen is replaced three times, is reacted 5 hours.Filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 4- [[3- (1,3,3 α, 4,5,6,7,7 "-octahydro pyrrolo- [3; 4-cJ pyridine -2- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines-ketone 46 (134 mg, white solid), yield： 60.0%. MS m/z (ESI): 407.2 [M+l]
Ή NMR (400 MHz, CD3OD):(the d of δ 8.38, 1H), 7.94 (m, 1H), 7.87 (m, 2H), 7.50 (m, 1H), 7.37 (m, 1H), 7.17 (dd, 1 H), 4.58 (m, 1 H), 4.39 (s, 2H), 3.74 (m, 1H), 3.60 (m, 1H), 3.45 (m, 1H), 3.24 (m, 1H), 3.20 (m, 2H), 3.17 (m, 1H), 2.73 (m, 1H), 2.64 (m, 1H), 2.05 (m, 1H), 1.88 (m, 1H), 1.67 (m, 1H) embodiment 47
Mono- Walk
2,3- bis- (bromomethyl) pyrazine
2,3- dimethyl pyrazines 47a (4 g, 0.037 mol) is dissolved in 100 mL carbon tetrachloride, N- bromines are added For succimide (19g, 0.1 1 mol) and azodiisobutyronitrile (0.60 g, 3.69 mmol), 80 °C of back flow reactions 6 hours, 50 °C are reacted 12 hours.Filtering, filter cake is washed (20 mL) with dichloromethane, and filtrate is washed (20 mLx2) with saturated sodium thiosulfate solution, filtrate decompression is concentrated, and obtains 2,3- bis- (bromomethyl) pyrrole crop 47b (6 g, yellow oil), yield： 66.0%.
MS m/z (ESI): 266.9 [M+l ]
Bis- Walk
6- trityl -5,7- pyrrolin simultaneously [tremnble by 3,4- W pyrroles
(bromomethyl) pyrazines of 2,3- bis- 47b (400 mg, 1.51 nimol) is dissolved in 20 mL Ν, in Ν-dimethylformamide, add 5 mL trityls amine (1.18 g, 4.52 mmol) Ν, Ν-dimethyl formamide solution.Under 0 °C, 1 mL DIPEAs are added, are reacted 1 hour.Add lOO niL water, it is extracted with ethyl acetate (100 mLx3), merges organic phase, washed (50 mLx2) with saturated ammonium chloride solution (50 mLx2), saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude product 6- trityls -5,7- pyrrolin simultaneously [3,4-6] pyrazine 47c (800 mg, brown solid), product is not purified directly to enter the lower Walk reactions of row. MS m/z (ESI): 363.1 [M+l]
Tri- Walk
6,7- dihydros -5//- pyrrolo- [3,4-6] pyrazine
By crude product 6- trityls -5,7- pyrrolin, simultaneously [3,4- δ] pyrazine 47c (250 mg, 0.69 mmol) is dissolved in the methanol solution of the M hydrogen chloride of 15 mL 2, is reacted 12 hours.It is concentrated under reduced pressure, obtains crude product 6,7- dihydro -5H- pyrrolo-es [3,4-6] pyrazine 47d (80 mg, brown oil), product is not purified directly to enter the lower Walk reactions of row.
Tetra- Walk
4- [[3- (5, 7- pyrrolin simultaneously [3, 4-6] pyrazine-6- carbonyls)-4- fluoro-phenyls] methyl]-2H- phthalazines-1 -one by the fluoro- 5- of 2- [(4- oxos-3H-phthalein crop-1- bases) methyl] benzoic acid lc (246 mg, 0.83 mmol) it is dissolved in 10 mL Ν, in Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (391 mg, 1.03 mmol), crude product 6, 7- dihydro -5H- pyrrolo-es [3, 4-6] pyrrole crop 47d (80 mg, 0.69 mmol) and Ν, Ν-diisopropylethylamine (178 mg, 1.38 mmol), reaction 12 hours.Subtract ffi concentrations, add 50 mL water, be extracted with ethyl acetate (50 mLx3), merge organic phase, (50 mL are washed with bubble and sodium chloride solution>2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 4- [[3- (5,7- pyrrolin simultaneously [3,4-6] pyrazine -6- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone 47 (42 mg, white solid), yield： 15.2%.
MS m/z (ESI): 402.1 [M+l]
Ή NMR (400 MHz, CDC13): δ 10.04 (br. s, 1H)58.44-8.49 (m, 3H), 7.73-7.80 (m, 3H), 7.40-7.42 (m, 2H), 7.11-7.15 (m, 1H), 5.06 (s, 2H), 4.73 (s, 2H), 4.31 (s, 2H) embodiment 48
4- [the fluoro- 3- of 4- (4,5,6,7,8,8-hexahydropyrrolo simultaneously [3,4-W [l, 2,3] triazol [1,5- [1,4] oxazine-7- carbonyls) benzyl]-2H- phthalein crop-1- ketone
Mono- Walk
4,5 α, 6,7,8,8 α-hexahydropyrrolo simultaneously [3,4- 6] [1,2,3] triazol [1,5- [l, 4] oxazines hydrochlorides are by 5i/, 6,8,8fl- nafoxidines simultaneously [3,44] [1,2,3] triazol [(the 4H)-t-butyl formate of 1,5- Isosorbide-5-Nitrae] oxazines -7
48a (1.20 g, 4.50 mmol are prepared using known method " patent WO2009071657 ") is dissolved in Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 20 mL 2, reacts 12 hours.It is concentrated under reduced pressure, obtains crude product 4,5fl, 6,7,8,8a- hexahydropyrrolos simultaneously [3,4-6] [1,2,3] triazol [1,5- [Isosorbide-5-Nitrae] Evil crop hydrochlorides 48b (1.10 g, brown solid), product is not purified directly to enter the lower Walk reactions of row.
Bis- Walk
4- [the fluoro- 3- of 4- (4,5fl, 6,7,8,8a- hexahydropyrrolo simultaneously [3,4-6] [1,2,3] triazol [1,5 [1,4] oxazine -7- carbonyls) benzyl] -2H- phthalazines -1- ketone
By the fluoro- 5- of 2- [(4- oxos -3H- "-l- bases) methyl] benzoic acid lc (300mg, 1 mmol) it is dissolved in 10 mL Ν, in Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (568 mg, 1.50 mmol), crude product 4, 5fl, 6, 7, 8, 8a- hexahydropyrrolos simultaneously [3, 4-] Π, 2, 3] triazol [1, 5- /] [1, 4] oxazine hydrochloride 48b (303 mg, 1.50 mmol) and Ν, Ν-diisopropylethylamine (0.6 mL, 3 mmol), reaction 12 hours.It is concentrated under reduced pressure, adds 50mL water, extracted with dichloromethane (50mLx3), merge organic phase, (50 mL), anhydrous sodium sulfate drying are washed with saturated nacl aqueous solution, filtering, filtrate decompression concentrate, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 4- [the fluoro- 3- (4 of 4-, 5a, 6,7,8,8rt- hexahydropyrrolos simultaneously [3,4-6] [1,2,3] triazol [1,5- [1,4] Evil crop -7- carbonyls) benzyl] -2H- phthalazines -1- ketone 48 (320mg, white solid), yield： 71.7%.
MSm/z (ESI): 447.1 [M+l]
Ή NMR (400 MHz, DMSO-i6):δ 12.59 br. s, IH), 8.25-8.27 (m,), IH 7.82-7.98 (m, 3H), 7.67 (s, IH), 7.46-7.48 (m, 2H), 7.28-7.29 (m, IH), 5.29-5.33 (m, IH), 5.02-5.08 (m,), IH 4.36-4.57 (m, IH), 4.35 (s, 2H), 4.15-4.34 (m,), IH 3.95-4.05 (m, IH), 3.59-3.63 (m, 2H), 3.13-3.15 (m, IH) embodiment 49
4- [[the fluoro- 3- of 4- (2- methyl -5,7- dihydros pyrrole-carbonyl) phenyl] methyl] small ketone of -2H- phthalein crops
By the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid l c (600 mg, 2.04 mmol) it is dissolved in 15 mL N, in N- dimethyl Cao acid amides, add the Destroy azoles-Ν of benzo three, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (1.39 g, 3.67 mmol), 2- methyl -6,7- dihydro -5H- pyrrolo-es [3,4- pyrimidines 49a (304 mg, 2.25 mmol, are prepared using known method " patent WO2006127530 ") and Ν, Ν-diisopropylethylamine（1.8 mL, 10.20 mmol), react 12 small inch.Be concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain4- [[4- fluorine _ 3- (2- methyl -5,7- pyrrolin simultaneously [3,4- pyrimidine -6- carbonyls) phenyl] methyl] -2H- phthalazines -1- ketone 49 (】00 mg, white solid), yield： 11.8%.
MS m/z (ESI): 416.1 [M+l]
Ή NMR (400 MHz, CDC13):δ 10.16 (br. s, 1H), 8.65 (s, 1H), 8.47 (d, 1H), 7.78 (m, 3H), 7.39 (m, 2H), 7.12 (t, 1H), 4.96 (m, 2H), 4.70 (m, 1H), 4.63 (m, 1H), 4.30 (m, 2H), 2.73 (s, 3H) embodiment 50
4-[[the fluoro- 3- of 4- [5- (3- pyridylmethyls)-3,3a, 4,6,7,7fl- hexahydropyrrolos simultaneously [3,4-c] pyridine-2- carbonyls] phenyl]
By 4- [[3- (l, 3,3fl, 4,5,6,7,7fl- octahydros pyrrolo- [3,4-cj pyridine -2- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines-ketone 46 (90 mg, 0.22 mmol) is dissolved in 15 mL 1, in 2 dichloroethanes, add pyridine -3- formaldehyde (36 mg, 0.33 mmol), back flow reaction 1.5 hours.Room temperature is cooled to, sodium cyanoborohydride (28 mg, 0.44 mmol) is added, reacted 12 hours.Add 20 mL saturated ammonium chloride solutions, extracted with dichloromethane (20 mLx2), merge organic phase, washed (20 mLx2), anhydrous sodium sulfate drying, filtered with saturated nacl aqueous solution, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain 4- [[the fluoro- 3- of 4- [5- (3- pyridylmethyls) -3,3, 4,6,7,7α- hexahydro -1H- pyrrolo-es [3,4-c] pyridine -2- carbonyls] phenyl] methyl] -2H- phthalazines -1- ketone 50 (31 mg, white solid), yield： 28.4%.
MS m/z (ESI): 498.2 [M+l]
Ή NMR (400 MHz, CD3OD):6 8.67 (d, 1H), 8.56 (t, 1 H), 8.36 (d, 1H), 8.04 (m, 1H), 7.97 (d, 1H), 7.87 (m, 2H), 7.49 (m, 3H), 7.16 (t, 1H), 4.40 (s, 2H), 4.08 (s, 2H), 3.66 (m, 2H), 3.58 (m, 1H), 3.40 (m, 2H), 2.96 (m, 4H), 2.04 (m, 1H), 1.88 (m, 1H), 1.63 (m M) embodiment 51
4-[【The fluoro- 3- of 4- [2- (3- pyridylmethyls) -3,3α, 4,6,7,7 α-hexahydro-I H- pyrrolo-es [3,4-c] pyridine -5- carbonyls] and phenyl]
By 4- [[3- (1,2,3,3 ", 4,6; 7; 7 "-octahydro pyrrolo- [3,4-c] pyridine -5- carbonyls) -4- fluoro-phenyls " methyl] -2H- phthaleins small ketone 30 (100 mg, 0.25 mmol) of making an uproar is dissolved in 20 mL 1; in 2 dichloroethanes; add Nicotinicum Acidum (50 mg, 0.44 mmol), back flow reaction 3 hours.Room temperature is cooled to, sodium cyanoborohydride (50 mg, 0.61 mmo are added】), react 12 hours.15 mL saturated ammonium chloride solutions are added, (20 mLx2) is extracted with dichloromethane protective embankment, merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 4- [[the fluoro- 3- of 4- [2- (3- pyridylmethyls) -3,4,6,7,7 Ω-hexahydro -1H- pyrrolo-es [3,4-C] pyridine -5- carbonyls] phenyl] methyl] -2H- phthalazines -1- ketone 51 (21 mg, light yellow solid), yield: 17.3%.
MS m/z (ESI): 498.2 [M+l ]
Ή NMR (400 MHz, CDC13):δ 8.62 (s, 1H), 8.54 (s, IH), 8.47 (d, IH), 7.75 (m, 3H), 7.27 (m, 4H), 7.01 (m, IH), 4.29 (s, 2H), 3.77 (s, 2H), 3.64 (s, 2H), 3.52 (m, IH), 3.30 (m, 2H), 2.82 (m, 2H), 2.55 (m, 2H), 2.42 (m, 2H), 2.23 (m, I H) embodiment 52
4-[[3-[(4 ,7ai)-l- methyl -3,4,4 ", 5,7,7- hexahydro -2H- pyrrolo-es [3,4-6] pyridine -6- carbonyls] the fluoro- benzene of -4-
Mono- Walk
(4aW,7a )-6- benzyl-1-methyl-3,4,4 Ω, 5,7,7/- hexahydro-2H- pyrrolo-es [3,4-6] pyridine general (4^, 7 "-6- benzyls-1,2,3,4,4 ", 5,7,70- octahydro pyrrolo- [3,4-6] pyridine 41a (2.30 g, 10.60 Mmol 50 bis- chloroethene protective embankment Cao of mL l, 2-) are dissolved in, 37% ψ solution (2.6 mL are added, 31 .90 mmol), react 2 hours, add triacetoxy borohydride sodium chloride (1 1.20 g, 53 mmol), react 12 hours.It is 8 that 1 M sodium hydroxide solutions, which are added dropwise, to reaction solution pH, and the Gas methane of river two extracts (40 mL>O), organic phase is merged, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration obtains crude product (4a ?,7a/) -6H l- ^ -3,4,5,7,7 "-hexahydro -2H- pyrrolo-es [3,4-6] pyridine 52a (2.30 g, light yellow oil), product is not purified directly to enter row lower Walk reaction.
MS m/z (ESl): 231.2 [M+1 ]
Bis- Walk
(4α/,7α ) -1- first very -2,3,4,4 ", 5,6,7,7 α-octahydro pyrrolo- [3,4-6】Pyridine is by crude product (4a 7aW) -6- benzyl -1- methyl -3,4,4a, 5,7,7a- hexahydro -2H- pyrrolo-es [3,4-6] pyridine 52a
(2.30 g, 10 mmol) are dissolved in 20 mL methanol, add 0.23 10% palladiums of g/carbon, and hydrogen is replaced three times, is reacted 12 hours.Filtering, filtrate decompression concentration, obtain crude product (the small methyl-2,3 of 4^, 7 ", 4,4,5,6,7,7-octahydro pyrrolo- [3,4-/>] pyridine 52b (1.10 g, yellow ex vivo), product is not purified directly to enter the lower Walk reactions of row.
MS m/z (ESI): 141.1 [M+1]
Tri- Walk
4-[[3-[(4α/,7α/)-1- methyl-3,4,4 α, 5,7,7 "-hexahydro-2H- pyrrolo-es [- 6- the carbonyls of 3,4- W pyrroles 1]-4- fluoro-phenyls] methyl]-1 -one of-2H- phthalazines
By the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid lc (2.30 g, 7.80 mmol) it is dissolved in 40 mL N, in dinethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (4.40 g, 1 .70 mmol), crude product (4c^, 7 "/- methyl -2, 3, 4, 4 α, 5, 6, 7, 7 α-octahydro pyrrolo- [3, 4-6] pyridine 52b (1.10 mg, 7.80 mmol) and Ν, Ν-diisopropylethylamine (4.3 mL, 23.40 mmol), reaction 12 hours.Be concentrated under reduced pressure, add 40 mL water, (40 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, washed (30 mLx2) with saturated sodium bicarbonate solution (30 mLx2), saturated nacl aqueous solution successively, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with alumina column chromatography with eluant, eluent system A purify gained residue Jin mono- Walk thin-layered chromatography with solvent system A purify obtained by residue, obtain 4- [[3- [(i, 7) and-l- methyl -3,4,4fl, 5,7,7a- hexahydro-2H- pyrrolo-es [3,4-0] pyridine-6- carbonyls-fluoro-phenyls " and methyl] the small ketone 52 of-2-phthalazines (1.10 g, white solid), yield： 33.6%.
MS m/z (ESI): 421.2 [M+1]
]U NMR (400 MHz, CDC13): δ 10.55 (br. s, IH), 8.46 (d, 】H), 7.74-7.78 (m, 4H), 7.29-7.31 (m, 1H), 7.00-7.05 (m, IH), 4.28 (s, 2H), 3.67-3.96 (m, 2H), 3.31-3.49 (m, 2H), 2.79-2.94 (m, I H), 2.56 (s, 3H), 2.22 (m, IH), 1.26-1.85 (m, 6H) embodiment 53
4- [[3- [(4 " ＆ 7 β 5)-1-methyl-3,4,4,5,7,7 hexahydro-2H- pyrrolo-es [3,4-6] pyridine-6- carbonyls]-4- fluoro-phenyls] methyl] small ketone of-2H- phthalazines
Mono- Walk
The small methyl -3,4 of (4a5,7a5) -6- benzyls, 4,5,7,7 (- hexahydro -2H- pyrrolo-es [3,4-6] pyridine is by (4fl＆7fl5) -6- benzyls -1,2,3,4,4 α, 5,7,7 ο-octahydro pyrrolo- [3,4-W pyridine 39e (1 .17 g, 5.40 mmol) it is dissolved in 25 mL l, in the chloroethene protective embankments of 2- bis-, 37% formalin (1.3 mL, 16.20 mmol) is added, reaction 2 hours, triacetyl oxygen S sodium borohydrides (5.70 g, 27 mmol) are added, are reacted 12 hours.It is 8 that 1 M sodium hydroxide solutions, which are added dropwise, to reaction solution pH, extracts (40 mLx3) with dichloromethane protective embankment, merges organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain crude product (4a5,7aS 6- benzyl-1- methyl-3,4,5,7,7-hexahydro-2/7- pyrrolo-es [3,4- W pyridines 53a (1 g, light yellow oil), product is not purified directly to carry out next step reaction.
Bis- Walk
(4 ＆7 α 5) -1- methyl -2,3,4,4 β, 5,6,7,7 α-octahydro pyrrolo- [3,4-6] pyridine is by crude product (4a^, 7a^-6- benzyl -1- methyl -3,4,4,5,7,7 α-hexahydro -2H- pyrrolo-es [3,4-6] pyridine 53a (1 g, 4.30 mmol) is dissolved in 10 mL methanol, 0.10 10% palladiums of g/carbon is added, hydrogen is replaced three times, is reacted 12 hours.Filtering, filtrate decompression concentration, obtains crude product (4 ＆7 5) small methyl -2,3,4,5,6,7,7 α-octahydro pyrrolo- [3,4-6] pyridine 53b (0.60 g, light yellow oil), product is not purified directly to enter the lower Walk reactions of row. MS m/z (ESI): 141.1 [M+l ]
Tri- Walk
4- [[3- [(4flS, 7oS)-l-methyl -3,4,4,5,7,7fl- hexahydro -2H- pyrrolo-es [3,4-6] pyridine -6- carbonyls] -4- fluoro-phenyls] methyl] -2H- phthalein crop -1- ketone
By the fluoro- 5- of 2-, [(4- oxo -3H- phthalazines -1- bases) methyl i benzoic acid le (1.27 g, 4.27 mmol) is dissolved in 10 mL Ν, Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (2.40 g, 6.40 mmol), crude product (4aS, 7a-l- methyl -2,3,4,4 β, 5,6,7,7 α-octahydro pyrrolo- [3,4-6] pyridine 53b (0.60 g, 4.27 mmol) and N, N- diisopropylethylamine (2.4 mL, 12.80 mmol), reaction】2 hours.It is concentrated under reduced pressure, add 40 mL water, extracted with dichloromethane (40 mLx3), merge organic phase, saturated sodium bicarbonate solution (30 mLx2) is used successively, saturated nacl aqueous solution washs (30 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with alumina column chromatography with eluant, eluent system A purify gained residue, Jin mono- Walk thin-layered chromatography purifies gained residue to open up Ji agent system A, obtain 4- [[3- [(4a＆7aS)-l-methyl -3, 4, 4, 5, 7, 7-hexahydro-2H- pyrrolo-es [3, 4-b] pyridine -6- carbonyls] -4- fluoro-phenyls " methyl] -2H- phthalazines-(0.60 g of ketone 53, white solid), yield： 33.3%. MS m/z (ESI): 421 .2 [M+l ]
Ή NMR (400 MHz, CDC13):δ 10.67 (br. s, 111), 8.45 (d, I H), 7.74-7.81 (m, 4H), 7.29-7.30 (m, IH), 7.00-7.05 (m,), IH 4.29 (s, 2H), 3.66-3.99 (m, 2H), 3.31-3.46 (, 2H), 2.81-2.96 (m,), IH 2.56 (s, 3H), 2.23 (m,), IH 1.26-1.86 (m, 6H) embodiment 54
4- [[the fluoro- 3- of 4- [2- (trifluoromethyl)-5,7--pyrimidine-6- carbonyls] phenyl] methyl]-2H- phthalazines-1-
By the fluoro- 5- of 2- [(the small base of 4- oxo -3H- phthalazines) methyl] benzoic acid lc (250 mg, 0.87 mmol) it is dissolved in 10 mL N, in dinethylformamide, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (989 g, 2.61 mmol), 2- (trifluoromethyl) -6, 7- dihydro -5H- pyrrolo-es [3, 4- pyrimidines 54a (200 mg, 1.04 mmol, it is prepared using known method " patent WO2006127530 ") and Ν, Ν-diisopropylethylamine (756 μ L, 4.35 mmol), reaction 12 hours.It is concentrated under reduced pressure, with thin-layered chromatography with solvent system A purify gained residue, obtain 4- [[the fluoro- 3- of 4- [2- (trifluoromethyl) -5,7- pyrrolin simultaneously [3,4-d pyrimidine -6- carbonyls] phenyl] methyl] 54 (35 mg of -2H- phthalazines -1- ketone, yellow solid), yield： 8.6%.
MS m/z (ESl): 470.1 [M+l]
1H NMR (400 MHz, CDC13): δ 10.69 {br. s, IH), 8.71 (d, IH), 8.46 (m, 1H>, 19 (m, 3H 7.42 (m, 2H), 7 -] 3 (t, IH), 5.07 (m, 2H), 4.77 (m, 2H) 4.32 (s, 2H) embodiment 55
The -one of 4- [[the fluoro- 3- of 4- (hydrogen-baseds of l- oxidations -5,7- two) phenyl] methyl] -2H- phthalazines -1
ίλ N
N HCI
HCI O
8a ,5a 55b 55c
It is few
5,7- pyrrolin simultaneously [3,4-6] pyridine -6- t-butyl formates
By 6,7- dihydro -5H- pyrrolo-es [3,4-6] pyridine hydrochloride 8a (313 g, 2 mmol) it is dissolved in 30 mL methanol, add triethylamine (l mL, 7 mmol), under ice bath, di-tert-butyl dicarbonate (655 mg, 3 mmol) is added, is reacted at room temperature 6 hours.It is concentrated under reduced pressure, obtains crude product 5,7- pyrrolin simultaneously [3,4-6] pyridine -6- t-butyl formates 55a (450 mg, colorless oil), product is not purified directly to enter the lower Walk reactions of row.
Bis- Walk
1- oxidations -5,7- pyrrolin simultaneously [3,4-W pyridine -6- t-butyl formates are by crude product 5,7- pyrrolin simultaneously [3,4-6] pyridine -6- t-butyl formates 55a (330 mg, 1.50 mmol) is dissolved in 20 mL dichloromethane protective embankment Cao, add | chloroperoxybenzoic acid (345 mg, 2 mmol), react 16 hours.Add 50 mL saturated sodium carbonate solutions, extracted with dichloromethane (50 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, obtain crude product 1- and aoxidize -5,7- pyrrolin simultaneously [3,4-b] pyridine -6- t-butyl formates 55b (250 mg, white solid), product is not purified directly to enter the lower Walk reactions of row.
3rd step
Oxidation -6,7- dihydro -5H- pyrrolo-es [3,4-6] pyridine hydrochloride
- 5,7- pyrrolin will be aoxidized, and simultaneously [3,4-] pyridine -6- t-butyl formates 55b (931 mg, 4 mmol) is dissolved in the 1 of the M hydrogen chloride of 20 mL 2,4- dioxane solutions, is reacted 16 hours.It is concentrated under reduced pressure, obtains crude product 1-oxidation-6,7- dihydro-5H- pyrrolo- [3.4-6] pyridine hydrochloride 55c (690 mg, white solid), product is not purified directly enters the lower Walk reactions of row.
Tetra- Walk
4- [[the fluoro- 3- of 4- (1- oxidations -5, 7- pyrrolin simultaneously [3, 4-6] pyridine-6- carbonyls) phenyl] methyl]-2H- phthalazines-1- ketone is by the fluoro- 5- of 2- [(4- oxo-3H- phthaleins crash-1-yl) methyl] benzoic acid lc (300 mg, 1 mmol) it is dissolved in 20 mL Ν, in Ν-dimethylformamide, add BTA-Ν, Ν, Ν ', cruel (570 mg of Ν '-tetramethylurea hexafluorophosphoric acid, 1.50 mmol), crude product 1- oxidations -6, 7- dihydro -5H- pyrrolo-es [3, 4-6] pyridine hydrochloride 55c (175 mg, 1 mmol) and N, N- diisopropylethylamine (0.5 raL, 3 mmol), reaction 18 hours.It is concentrated under reduced pressure, adds 80 mL saturated sodium carbonate solutions, (50 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, it is concentrated under reduced pressure, adds 100 mL ethyl acetate, wash (30 mL with water (30 mLx2), saturated nacl aqueous solution successively><2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 4- [[4- Fluoro- 3- (l-oxidation-5,7- pyrrolin simultaneously [3,44] pyrrole-6- carbonyls) phenyl] methyl]-1 -one 55 (60 mg, white asks body) of-2 phthalazines, yield： 14.4%.
MS m/z (ESI): 417.1 [M+l]
'Η NMR (400 MHz, CDC13):δ 1 0.27 (br. s, IH), 8.55-8.45 (m, 2H), 7.79-7.76 (m, 3H), 7.74-7.66 (m, 111), 7.40-7.37 (m, 2H), 7.14-7.12 (m, IH), 7.11-7.09 (m, I H), 5.02 (s, 2H), 4.68 (s, 2F1), 4.31 (s, 2H) embodiment 56
1 -one
By the fluoro- 5- of 2- [(- 1-yl of 4- oxo-3H- phthalazines) methyl] benzoic acid lc (250 mg, 0.87 mmol) it is dissolved in 10 mL N, in dinethylformamide, BTA-Ν, Ν are added, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (593 mg, 1.57 mmol), 6,7- dihydro-5H- pyrrolo-es [3,4-] pyrimidine hydrochloride 56a (】35 mg, 1.04 mmol, are prepared using known method " patent WO2006127530 ") and DIPEA (756 μ L, 4.35 mmol), react 12 hours.It is concentrated under reduced pressure, add 20 mL water, it is extracted with ethyl acetate (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentrate, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 4- [[3- (5,7- pyrrolin simultaneously [3,4- pyrimidine -6- carbonyls) -4- fluoro-phenyls] methyl] -2H- phthalazines -1- ketone 56 (36.72 mg, white solid), yield： 10.5%.
MS m/z (ESI): 402.1 [M+l]
1H NMR (400 MHz, CD3OD):δ 9.05 (d, IH), 8.64 (d, IH), 8.36 (d, IH), 7.90 (s, IH), 7.86 (m, 2H), 7.51 (m, 2H), 7.23 (t, IH), 5.18 (s, IH), 5.03 (s, IH), 4.75 (s, I H), 4.67 (s, IH), 4.42 (s, 2H) embodiments 57
4-[[the fluoro- 3- of 4- [5- [[6- (trifluoromethyl)-3- pyridine radicals] methyl]-3,3 Ω, 4,6,7,7 β-hexahydro-I H- pyrrolo-es [3,4-c] pyridine-2- carbonyls] phenyl] methyl]-1 -one of-2H- phthalazines
46 57
By 4- [[3- (】, 3,3 "; 4,5,6; 7; 7-octahydro pyrrolo- [3,4-c] pyridine-2- carbonyls)-4- fluoro-phenyls] methyl] tremnble small ketone 46 (80 mg, 0.20 mmol) of-2H- phthaleins be dissolved in 15 niL 1; 2 two chloroethene protective embankment Cao; add 6- (trifluoromethyl) pyridine-3- formaldehyde (63 mg, 0.35 mmol), back flow reaction 2 hours.Room temperature is cooled to, sodium cyanoborohydride (32 mg, 0.50 mmol) is added, reacted 12 hours.Add 20 mL saturated ammonium chloride solutions, it is extracted with ethyl acetate (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (15 mLx2), anhydrous sodium sulfate thousand is dry, filtering, filtrate decompression is concentrated, with thin/S chromatographies with solvent system A purify gained residue, obtain 4- [[the fluoro- 3- of 4- [5- [[6- (trifluoromethyl) -3- pyridine radicals] methyl] -3, 3a, 4, 6, 7, 7a- hexahydro -1H- pyrrolo-es [3, 4-cl pyridine -2- carbonyls] phenyl] methyl] 57 (17 mg of -2H- phthalazines -1- ketone, white solid), yield： 15.3%.
MS m/z (ESI): 566.2 [M+l]
Ή NMR (400 MHz, DMSO-^):δ 12.62 (s, 1H), 8.70 (d, 1H), 8.26 (d, 1H), 7.95-7.75 (m, 6H), 7.47-7.27 (m, 2H), 4.64 (s, 2H), 3.58 (s, 2H), 3.56-3.36 (m, 2H), 3.35-3.17 (m, 2H), 2.98-2.93 (m, 1H), 2.33 (br, 2H), 2.14 (br, 2H), 1.70 (s, 1H), 1.50 (br, 2H) embodiment 58
4- [[the fluoro- 3- of 4- [2- [(2- methyl -3- pyridine radicals) epoxide] -5,7_ pyrrolin and pyrimidine -6- carbonyls] phenyl] methyl] -2H- phthalazines-I -one
Mono- Walk
2- methyl isothiourea iodates
Thiocarbamide (122 g, 1.61 mmol) is dissolved in 814 mL methanol Cao, iodomethane (114 mL, 1.83 mmol), back flow reaction 0.5 hour is added dropwise.It is concentrated under reduced pressure, the residue mL ether of ffl 200 and the washing of 100 mL Cao alcohol successively is concentrated under reduced pressure, obtains 2- methyl isothiourea iodates 58a (325 g, color lofty body), yield： 92.8%.
One |
One, is few
2- first mercapto -5//- pyrroles [3,4- pyrimidines -6 (7/-Cao acid uncle ' ester is by 3- oxo-pyrrolidine -1- Cao tert-butyl acrylates (1 g, 5.4 mmol) it is dissolved in 1, in 1- dimethoxy-Ν, Ν-dimethyl methylamine (6.6 mL, 49.36 mmol), backflow 2 hours, it is concentrated under reduced pressure, residue washs (20 mLx3) with iK hexanes, obtains yellow solid.
Above-mentioned yellow solid is dissolved in 40 mL ethanol, 2- methylthioureas 58a (2.35 g, 10.80 mmol) and caustic alcohol (0.55 g, 8.10 mmol), back flow reaction 5 hours, 50 °C of reactions are sequentially added！2 small inch, then back flow reaction 4 hours.Add 30 mL saturated nacl aqueous solutions, it is extracted with ethyl acetate (30 mLx3), merge organic phase, with anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain 2- first sulfydryl -5H- pyrroles [3,4-ifj pyrimidines -6 (7/)-t-butyl formate 58b (500 mg, white solid), yield： 34.7%.
MS m/z (ESI): 268.1 [M+l ]
Tri- Walk
2- mesyls -5; 7- pyrrolin simultaneously [3; 4-] pyrimidine -6- t-butyl formates are by 2- first sulfydryl -5H- pyrroles [3; 4-if] pyrimidine -6 (7/)-t-butyl formate 58b (100 mg, 0.37 mmol) is dissolved in 10 mL dichloromethane protective embankments, is cooled to 0 °C; 3 mL metachloroperbenzoic acids (193 mg are added dropwise; 0.78 mmol) dichloromethane solution, 0 reaction 1 hour, react at room temperature 15 hours.Add the mixed solvent (V/V=1/1) of 40 mL saturated sodium bisulfite solutions and saturated sodium bicarbonate solution; extracted with dichloromethane (40 mLx2); merge organic phase; with saturated common salt water washing (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 2- mesyls -5,7- pyrrolin simultaneously [3,4- pyrimidine -6- t-butyl formates 58c (90 mg; white solid), yield： 80.4%.
MS m/z (ESI): 300.1 [M+l ]
Tetra- Walk
2- [(2- methyl -3- pyridine radicals) epoxide] -5; 7- pyrrolin simultaneously [3; 4- pyrimidine -6- t-butyl formates are by 2- mesyls -5; 7- pyrrolin simultaneously [3; 4-c | pyrimidine -6- t-butyl formates 58c (100 mg; 0.33 mmol); 2- picoline -3- alcohol (36.50 mg; 0.33 mmol) and potassium carbonate (46.10 mg; 0.33 mmol) it is dissolved in 6 mLN; in dinethylformamide, 80 °C are reacted 1 hour.Add 20 mL water, it is extracted with ethyl acetate (30 mLx3), merge organic phase, with saturated common salt washing paint (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system B purify gained residue, obtain 2- [(2- methyl -3- pyridine radicals) epoxide] -5,7- pyrrolin simultaneously [3,4 ^ pyrimidine -6- t-butyl formates 58d (71.40 mg, white solid), yield： 65.1%. MS m/z (ESI): 329.1 [M+1 J
Wu Walk
2- [(2- methyl -3- pyridine radicals) epoxide] -6,7- dihydro -5H- pyrrolo-es [3,4-J] pyrimidine hydrochloride is by 2- [(2- methyl -3- pyridine radicals) epoxide] -5,7- pyrrolin simultaneously [3,4-] pyrimidine -6- t-butyl formates 58d (80 mg, 0.24 mmol) Ji solutions are in 5 mL dichloromethanes, and the 1 of the addition M hydrogen chloride of 5 mL 2.5,4- dioxane solutions, react 12 hours.It is concentrated under reduced pressure, obtain crude product 2- [(2- methyl -3- pyridine radicals) epoxide] -6,7- dihydro -5H- pyrrolo-es, 4-^] pyrimidine hydrochloride 58e (56 mg, pale solid), product without isolation Zhi connect for Xia Walk reaction.
MS m/z (ESI): 229.1 [M+1]
Liu Walk
The -one of 4- [[the fluoro- 3- of 4- [2- [(2- methyl -3- pyridine radicals) epoxide] -5,7- dichloros pyrrolo- [3,4-c/] pyrimidine -6- carbonyls] phenyl] methyl] -2H- phthalazines -1
By the fluoro- 5- of 2- [(- 1-yl of 4- oxo-3H- phthalazines) methyl] benzoic acid lc (70 mg, 0.23 mmol) it is dissolved in 8 mL N, in N- dimethyl Cao acid amides, add BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (160 mg, 0.41 mmol), crude product 2- [(2- methyl -3- pyridine radicals) epoxide] -6, 7- dihydro -5H- pyrrolo-es [3, 4-tf] pyrimidine hydrochloride 58c (56 mg, 0.24 mmol) and Ν, Ν-diisopropylethylamine (200 1.15 mmol), reaction 12 hours.Add】5 mL water, it is extracted with ethyl acetate (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain (51 mg of 4- [[the fluoro- 3- of 4- [2- [(2- methyl-3- pyridine radicals) epoxide]-5,7- pyrrolin simultaneously [3,4- pyrimidine-6- carbonyls] phenyl] methyl]-1 -one of-2H- phthalazines 58, white solid), yield-42.9%.
MS m/z (ESI): 509.1 [M+l]
1H NMR (400 MHz, OMSO-d6):δ 12.61 (s, 1H), 8.47 (d, 1H), 8.38 (d, I H), 8.26 (d, IH), 7.98 (s, IH), 7.93-7.73 (m, 2H), 7.60 (t, 1H), 7.55-7.35 (m, 2H), (s of 7.34-7.23 (m, 2H) 4.83,1H), 4.76 (s, 1H), 4.55 (s, IH), 4.51 (s, IH), 4.34 (d, 2H), 2.27 (s, 3H) embodiments 59
4- [[the fluoro- 3- of 4- (2- mesyl -5,7- pyrrolin and pyrimidine -6- carbonyls) phenyl] methyl] -2H- phthalazines is small
The first step
2- mesyls -6; 7- dihydro -5H- pyrrolo-es [3; Uj pyrimidine hydrochlorides are by 2- mesyls -5; 7- pyrrolin simultaneously [3; 4-t/] pyrimidine -6- t-butyl formates 58c (100 mg; 0.33 mmol) it is dissolved in Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 6 mL 2.5, react 18 hours.It is concentrated under reduced pressure, obtains crude product 2- mesyl -6,7- dihydro -5H- Pyrrolopyrimidin thiamine hydrochlorides 59a (78.80 mg, white solid), product is directly used in the next step without isolation.
Bis- Walk
4- [[the fluoro- 3- of 4- (2- mesyl -5,7- pyrrolin simultaneously [3,4- pyrimidine -6- carbonyls) phenyl] methyl] -2H- phthalein crop -1- ketone
By the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid lc (100 mg; 0.34 mmol) it is dissolved in 4 mL Ν; in Ν-dimethylformamide; add 1- ethyls-(3- dimethylaminopropyls) phosphinylidyne diimmonium salt hydrochlorate (95 mg; 0.50 mmol); 2- mesyls -6; 7- dihydro -5H- pyrrolo-es [3; 4-c/] pyrimidine hydrochloride 59a (78.80 mg; 0.34 mmol); I-hydroxybenzotriazole (54 mg, 0.40 mmol) and Ν, Ν-diisopropylethylamine（130 mg, 1.01 mmol), react 12 hours.It is concentrated under reduced pressure, 80 mL ethyl acetate is added, successively with water (20 mL><3), saturated nacl aqueous solution washing (20 mL); anhydrous sodium sulfate drying; filtering; filtrate decompression concentrate, with thin-layered chromatography with solvent system A purify obtained by residue, obtain 4- [[4- fluoro- 3- (2- mesyls -5; 7 pyrrolin simultaneously [3; 4- pyrimidine -6- carbonyls) phenyl] methyl] -2/-phthalazines -1- ketone 59 (60 11, white solid), yield： 37.5%. MS m/z (ESI): 480.1 [M+l]
!H NMR (400 MHz, CDC13): δ 8.89-8.73 (d, IH), 8.48-8.45 (m, IH), 7.81-7.76 (m, 3H):7.44-7.41 (m, 2H), 7.14 (t, IH), 5.13-5.11 (d, 2H), 4.85-4.80 (d, 2H), 4.32 (s, 2H), 3.38-3.34 (d, 3H) embodiment 60
4- [the fluoro- 3- of 4- (4,5,6,7,8,8fl- hexahydropyrrolos simultaneously (4- methyl)-[3,4-6] [1,2,3] triazol [l, 5-i J [l, 4] Evil crop -7- carbonyl ketone
The first step
Under 6- oxa- -3- azabicyclics [3.1.0] hexamethylene protective embankment -3- t-butyl formate ice baths, by 2, small t-butyl formate 14a (2 g of 5- pyrrolin, 11.80 mmol) it is dissolved in 40 mL dichloromethane, add metachloroperbenzoic acid (3.47 g, 14.10 mmol), react at room temperature 12 hours.Filtering, filter cake petroleum ether, filtrate is washed (20 mL) with saturated sodium bicarbonate solution (20 mLx3), saturated nacl aqueous solution successively, it is concentrated under reduced pressure, obtain crude product 6- oxa- -3- azabicyclics [3.1.0] hexamethylene protective embankment -3- t-butyl formates 60a (2 g, light yellow oil), product without isolation Zhi connect for Xia Walk reaction.
Bis- Walk
3- nitrine-4- hydroxyls-pyrroles puts out-1-t-butyl formate
Crude product 6- oxa- -3- azabicyclics [3.1.0] hexamethylene protective embankment -3- t-butyl formates 60a (2 g, 10.78 mmol) is dissolved in 40 mL first alcohol and waters (V/V=8:1) in the mixed solvent, adds ammonium chloride (1.26 g, 23.60 mmol) and sodium azide (2.10 g, 32.34 mmol), and 80 °C are reacted 7 hours.Add 30 mL saturated sodium bicarbonate solutions, it is extracted with ethyl acetate (50 mLx3), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude product 3- nitrine -4- hydroxy-pyrrolidine -1- t-butyl formates 60b (1.60 g, brown oil), product is directly used in the next step without isolation.
MS m/z (ESI): 129.1 [M- 100+1]
3rd step
3- nitrine -4- butyl- 2- alkynes oxygen-small the t-butyl formate of pyrroles's protective embankment
Under ice bath, crude product 3- nitrine -4- hydroxyl-P ratios are coughed up into alkane -1- t-butyl formates 60b (0.50 g, 2.19 mmol) it is dissolved in 10 mL tetrahydrofurans, add sodium hydride and mineral oil mixture (0.14 g, 60%, 3.28 mmol), reaction 30 minutes, the bromo- 2- butine of 1- (0.3 mL, 3.28 mmol) is added, is reacted at room temperature 12 hours.Add 10 mL water and 30 mL saturated ammonium chloride solutions, it is extracted with ethyl acetate (50 mLx3), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtains crude product 3- nitrine -4- butyl- 2- alkynes oxygen-pyrrolidines -1- t-butyl formates 60c (1.60 g, brown oil), product is directly used in the next step without isolation.
MS m z (ESI): 181.1 [M- 100+1]
Tetra- Walk
5 Ω, 6,8,8-nafoxidine simultaneously (4- methyl)-[3,4-6] [1,2,3] triazol [1,5-] [(tertiary fourth of 4H formic acid of 1,4] oxazines-7 Crude product 3- nitrine -4- butyl- 2- alkynes oxygen-pyrroles's protective embankment -1- t-butyl formates 60c (0.60 g, 2.10 mmol) is dissolved in 12 mL dimethylbenzene, 140 reactions 7 hours.It is concentrated under reduced pressure, obtains crude product 5,6,8,8 α-nafoxidine simultaneously (4- methyl)-[3,4-6] [1,2,3] triazol [1,5-] [(4H of Isosorbide-5-Nitrae] oxazines -7>T-butyl formate 60d (0.60 g, brown solid), product is directly used in the next step without isolation.
MS m/z (ESI): 281.2 [M+l]
5th step
4,5 Λ, 6,7,8,8-hexahydropyrrolo simultaneously (4- methyl)-[3,44] [1,2,3] triazol [1,5- J] [1,4] oxazines hydrochlorides are by crude product 5a, 6, S, 8a- nafoxidine simultaneously (4- methyl)-[3,4-] [1,2,3] triazol [l, 5-d] [l, (4H)-t-butyl formate 60d (600 mg of 4] oxazines-7,2.10 mmol) it is dissolved in Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 10 mL 2.5, react 4 hours.It is concentrated under reduced pressure, obtains crude product 4,5fl, 6,7,8,8a- hexahydropyrrolos simultaneously (4- methyl)-[3,4-] [1,2,3] triazol [1,5- /] [1,4] oxazine hydrochloride 60e (0.46 g, brown solid), product is not purified directly to enter the lower Walk reactions of row.
MS m/z (ESI): 181.1 [M+l]
Liu Walk
4- [the fluoro- 3- of 4- (4,5fl, 6,7,8,8-hexahydropyrrolo simultaneously (4- methyl)-[3,4-] [1,2,3] triazol [1,5-J] [Isosorbide-5-Nitrae] oxazine-7- carbonyls) benzyl]-2H- phthalazines-1- ketone
The fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid lc (275 mg, 0.93 mmol) is dissolved in
In 10 mL Ν, Ν-dimethylformamide, 4 are added, 5 Ω, 6,7,8,8 Ω-hexahydropyrrolo simultaneously (4- methyl)-[3,4-6] [1,2,3] triazol [1,5- Jie, 4] oxazine hydrochlorides 60e (300 mg, 1.38 mmol), BTA-Ν, Ν, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (523 mg, 1.38 mmol) and Ν, Ν-diisopropylethylamine (0.5 mL, 2.76 mmol), reacts 12 hours.It is concentrated under reduced pressure, extracted with dichloromethane (50mLx3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx2), anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain 4- [the fluoro- 3- (4 of 4-, 5 ", 6, 7, 8, 8a- hexahydropyrrolos simultaneously (4- methyl)-[3, 4-] [1, 2, 3] triazol [1, 5- [1, 4] oxazine -7- carbonyls) benzyl] 60 (170 mg of -2H- phthalazines -1- ketone, white solid), yield： 40.0%.
MS m/z (ESI): 461.1 [M+l]
Ή NMR (400 MHz, CDC13):δ 9.99 (s, 1H), 8.45-8.48 (m, 1H) .7.73-7.82 (m, 3H), 7.38-7.40 (m, 2H), 7.10-7.12 (m, 1H), 5.31-5.22 (m, 1H), 5.00-5.19 (m, 1H), 4.22-4.30 (m, 4H), 4.19-4.20 (m, 1H), 3.60-3.72 (m, 3H), (2.29 s, 3H) embodiment 61
4- [[the fluoro- 3- of 4- (hydrogen-baseds of 2- first sulfydryls -5,7- two) phenyl] methyl]-' 2/J- phthalazines -1- ketone
The first step
2- first sulfydryl -6,7- dihydros -5H- Pyrrolopyrimidins thiamine hydrochloride is by 2- first sulfydryl -5,7- pyrrolin simultaneously [3,4- pyrimidine -6- t-butyl formates 58b (100 mg.0.37 mmol) is dissolved in 4 mL dichloromethane protective embankments, add the 1 of the M hydrogen chloride of 3 mL 2.5,4- dioxane solutions, react 12 hours.Jian Ya Nong Shrink, obtain crude product 2- first sulfydryl -6,7- dihydro -5H- pyrrolo-es [3,4- pyrimidine hydrochloride 61a (45 mg, yellow solid), product without isolation Zhi connect for Xia Walk reaction.
Second step
4- [[the fluoro- 3- of 4- (2- first sulfydryls -5, 7- pyrrolin simultaneously [3, 4-] pyrimidine -6- carbonyls) phenyl] methyl] -2H- phthalazines -1- ketone is by the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid lc (100 mg, 0.37 mmol) it is dissolved in 5 mL Ν, in Ν-dimethylformamide, add crude product 2- first sulfydryl -6, 7- dihydro -5H- pyrrolo-es [3, 4-] pyrimidine hydrochloride 61a (62 mg, 0.37 mmol), I-hydroxybenzotriazole (230 mg, 0.61 mmol) and Ν, Ν-diisopropylethylamine (0.3 mL, 1.70 mmol), reaction 12 hours.Add 10 mL water, it is extracted with ethyl acetate (20 mLx3), merge organic phase, washed with saturated nacl aqueous solution (20 mLx2), anhydrous sodium sulfate thousand is dry, filtering, filtrate decompression is concentrated, with thin-layered chromatography with solvent system A purify gained residue, obtain (30 mg of 4- [[the fluoro- 3- of 4- (2- first sulfydryls -5,7- pyrrolin simultaneously [3,4- pyrimidine -6- carbonyls) phenyl] methyl] -2H- phthalazines -1- ketone 61, white solid), yield： 19.7%.
MS m/z (ESI): 448.1 [M+l]
'H NMR (400 MHz, DMSO-i 0):6 12.61 (s, 1H), 8.51 (d, 1 H), 8.25 (d, 1H), 7.97 (d, 1H), 7.96-7.79 (m, 1H), 7.78-7.73 (m, 1H), 7.56-7.36 (m, 2H), 7.36-7.17 (m, 1H), 4.75 (s, 2H), 4.52 (d, 2H), 4.35 (s, 2H), 2.52 (s, 3H) embodiment 62
[[[simultaneously [3,4- 6] [Isosorbide-5-Nitrae] oxazine -6- carbonyls] -4- is fluoro- for (4 S, 7) -4- methyl-fluoro- 23,4a, 5,7,7a- hexahydropyrrolo by 3- by 4-
The first step
(4aS, 7o -4- benzyls -3,4Ω, [3,4-W [(+)-tartaric acid (5.15 g, 34.36 mmol) is dissolved in 30 mL methanol 5,6,7,7 Ω-hexahydro -2H- pyrrolo-es by l, 4] oxazines, is heated to 60 °C, dropwise addition】0 mL 4- benzyls -3,4fl, [3,4- [Isosorbide-5-Nitrae] oxazines 14e (7,50 g, 34.36 mmol) methanol solution, is cooled to 49 °C to 5,6,7,7fl- hexahydro -2H- pyrrolo-es, reacts 30 minutes.It is cooled to 0 °C, filtering, 300 mL ethanol and methanol (V V=2 that solid is cooled down:1) mixed solvent is washed, obtained crude product is with 50 mL recrystallizing methanols, recrystallization mother liquor is concentrated under reduced pressure, gained residue is dissolved in 50 mL water, 6 M sodium hydroxide solutions of dropwise addition to reaction solution pH are 12, extracted with dichloromethane (100 mLx3), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate pressure concentration, obtains (4a＆7i/) -4- benzyls -3,4,5,6,7,7 α-hexahydro 2H- pyrrolo-es [3,4- W [l, 4] oxazines 62a (1.60 g, colorless oil）, yield： 42.6%.
Bis- Walk
(＆7^) -4- benzyls -2,3, simultaneously [3,4-6] [1,4] oxazine -6- t-butyl formates are by (＆7cii for 5,7,7 α-hexahydropyrrolo) -4- benzyl -3, [1,4] oxazines 62a (1.60 g, 7.30 mmol) is dissolved in 50 mL dichloromethane protective embankments 5,6,7,7 α-hexahydro -2H- pyrrolo-es [3,4-6], adds di-tert-butyl dicarbonate（2.40 g, 11 mmol) and triethylamine (2 mL, 14.60 mmol), react 12 hours.50 mL saturated ammonium chloride solutions are added, are extracted with dichloromethane (100 mLx3), merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain crude product (＆7^) -4- benzyls -2,3,4 α, 5,7,7 α-hexahydropyrrolo simultaneously [3,4- δ] [1,4] Evil crop -6- t-butyl formates 62b (3.07 g, colorless oil), product is directly used in the next step without isolation.
3rd step
(4 Ω ＆7) -3,4,4fl, 5,7,7 Λ-hexahydro -2H- pyrrolo-es [3,4-6] [1,4] oxazine -6- t-butyl formates are by crude product (4 α 5,7) -4- benzyls -2,3,4 Ω, 5,7,7 β-hexahydropyrrolo simultaneously [3,4-0] [1,4] oxazine -6- t-butyl formates 62b (3.07 g, 9.60 mmol) it is dissolved in 100 mL methanol, 300 10% palladiums of mg/carbon is added, hydrogen is replaced three times, is reacted 12 hours under 2 bar, filtering, filtrate decompression is concentrated, and obtains crude product (S, 7iJi) -3,4,4ii, 5,7,7c<- hexahydro -2H- pyrrolo-es [3,4-6] [Isosorbide-5-Nitrae] oxazine -6- t-butyl formates 62c (2 g, colorless oil), product without isolation Zhi connect for Xia Walk reaction.
Tetra- Walk
(½&7 i) -4- methyl -2,3,4 β, 5,7,7 β-hexahydropyrrolo simultaneously [3,4-6] [1 oxazine of Isosorbide-5-Nitrae _ 6- t-butyl formates are by crude product (＆7^) -3,4,5,7,7α- hexahydro -2H- pyrrolo-es [3,4-6![1.4] oxazine -6- t-butyl formates 62c (2 g; 8.76 mmol) it is dissolved in the chloroethene protective embankments of 100 mL bis-; add 37% formalin (1.40 g; 17.52 mmol); reaction 1 hour, is cooled to 0 °C, adds Sodium triacetoxyborohydride (4.64 g; 21.90 mmol), react at room temperature 12 hours.80 mL saturated sodium carbonate solutions are added, (100 mLx3) is extracted with dichloromethane protective embankment, merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, obtain crude product (4 S, 7oR) -4- methyl -2,3,4 β, 5,7,7 Ω-hexahydropyrrolo simultaneously [3,4-] [Isosorbide-5-Nitrae] oxazine -6- t-butyl formates 62d (1.80 g, colorless oil), product without isolation Zhi connect for Xia Walk reaction.
Wu Walk
(4fl&7ai)-4- methyl-3,4a, 5,6,7,7tz- hexahydro-2H- pyrrolo-es [3,4-] [], 4] oxazines hydrochlorides are by crude product (4 ＆7)-4- methyl-2,3,4a, 5,7,7-hexahydropyrrolo simultaneously [3,4-] [Isosorbide-5-Nitrae] oxazine-6- t-butyl formates 62d (1.80 g, 7.40 mmol) it is dissolved in Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 50 mL 4, react 12 hours.It is counter to be concentrated under reduced pressure, obtain crude product (4fl＆7fli) -4- methyl -3,4 α, 5,6,7,7 β-hexahydro -2H- pyrrolo-es [3,4-6] [Isosorbide-5-Nitrae] oxazine hydrochloride 62e (1.76 g, white solid), product is not purified directly to carry out next step reaction.
6th step
4- [[3- [(4aS, 7oR) -4- methyl-fluoro- 2,3,4a, 5,7,7a- hexahydropyrrolos simultaneously [3,4-] [1,4] oxazine -6- carbonyls] the fluoro- phenyl of -4-] methyl] -2H- phthalazines -1- ketone
By the fluoro- 5- of 2- [(4- oxo -3H- phthalazines -1- bases) methyl] benzoic acid lc (2.45 g, 8.20 mmol) it is dissolved in 60 mL N, in dinethylformamide, BTA-Ν, Ν are added, Ν ', Ν '-tetramethylurea hexafluorophosphoric acid ester (3.73 g, 9.80 mmol), Ν, Ν-diisopropylethylamine (4.7 mL, 28.7 mmol) and crude product（4 " ＆ 7)-4- methyl-3,4 β, 5,6,7,7-hexahydro-2H- pyrrolo- [3,4-W [l, 4] Evil crop hydrochlorides 62e (1.76 g, 8.20 mmol), reaction 12 hours.Add 100 mL saturated sodium carbonate solutions and 100 mL dichloromethane protective embankments, organic phase is separated, is concentrated under reduced pressure, 100 mL water is added in gained residue, it is extracted with ethyl acetate (100 mLx3), merge organic phase, (20 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 A purify obtained by residue, obtain 4-f [3- [(4 S;7) -4- methyl-fluoro- 2,3,4a, 5,7,7a- hexahydropyrrolo simultaneously [3,4-6] [Isosorbide-5-Nitrae] oxazine -6- carbonyls] -4- fluoro-phenyls] methyl] -2H- phthalazines -】-one 62 (2.80 g, white solid), yield： 80.9%.
MS m/z (ESI): 423.2 [M+l]
1H NMR (400 MHz, CDC13):δ 10.46 (s, 1H), 8.52-8.50 (m, 1 H), 7.82-7.80 (m, 3H), 7.44-7.42 (m, 1H), 7.36-7.34 (m, 1H), 7.09-7.06 (m, 1H), 4.33-4.31 (m, 2H), 4.18-4.07 (m, 1H), 3.95-3.65 (m, 5H), 3.53-3.46 (m, 2H), 3.33-3.18 (m, 2H), 2.49 (s, 3H) embodiment 63
4- [[the fluoro- 3- of 4- (2- methoxyl groups -5,7- diyl) phenyl j methyl] small ketone of -2H- phthalein crops
2- methoxyl group -5,7- pyrrolin simultaneously [3,4-ci] pyrimidine -6- t-butyl formates
By 2- mesyls -5; 7- pyrrolin simultaneously [3; 4-] pyrimidine -6- t-butyl formates 58c (50 mg; 0.17 mmol) it is dissolved in 4 mL methanol; reaction 10 minutes; add sodium hydride and mineral oil mixture (10 m.g; 60%; 0.22 mmol); reaction 3 hours, the mL water of drop power n 0.5, is concentrated under reduced pressure; 70 mL ethyl acetate are added, are washed with water (10 mL) and saturated nacl aqueous solution (15 mLx2).Merge organic phase, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, and obtains crude product 2- epoxides -5,7- pyrrolin simultaneously [3,4- pyrimidine -6- t-butyl formates 63a (30 mg, brown oil), product is directly used in the next step without isolation.
MS m/z (ESI): 252.1 [M+l]
Second step
2- methoxyl groups -6,7- dihydro -5H- pyrrolo-es [3,4-] pyrimidine hydrochloride is by 2- methoxyl groups -5,7- pyrrolin simultaneously [3,4- pyrimidine -6- t-butyl formates 63a (78 mg, 0.31 mmol) is dissolved in mL dichloromethane protective embankments, adds the 1 of the M hydrogen chloride of 2 mL 2.5,4- dioxane solutions, react 12 hours.Jian Ya Nong Shrink, obtain crude product 2- methoxyl groups -6,7- dihydro -5H- pyrrolo-es [3,4-] pyrimidine hydrochloride 63b (31 mg, white solid), product without isolation Zhi connect for Xia Walk reactions.
Tri- Walk
4- [[4- fluoro- 3- (2- methoxyl groups -5, 7- pyrrolin simultaneously [3, 4- pyrimidine-6- carbonyls) phenyl] methyl] and-2H- phthalazines-1 -one by the fluoro- 5- of 2- [(4- oxo-3H- phthalazines-1- bases) methyl] benzoic acid lc (90 mg, 0.30 mmol) it is dissolved in 8 mL Ν, in Ν-dimethylformamide, add crude product 2- methoxyl groups -6, 7- dihydro -5H- pyrrolo-es [3, 4- pyrimidine hydrochlorides 63b (50 mg, 0.31 mmol), water thing (210 mg of I-hydroxybenzotriazole one, 0.56 mmol) and Ν, Ν-diisopropylethylamine (0.3 mL, 1.55 mmol), reaction 12 hours.Add] 5 mL water, it is extracted with ethyl acetate (25 mLx3), merges organic phase, (20 mL are washed with saturated nacl aqueous solution<2), anhydrous sodium sulfate drying, filtering, filtrate decompression concentration, with thin-layered chromatography with solvent system A purify obtained by residue>Obtain the -one 63 (20 mg, white solid) of 4- [[the fluoro- 3- of 4- (2- methoxyl groups -5,7- pyrrolin simultaneously [3,4- pyrimidine -6- carbonyls) phenyl] methyl] -2H- phthalazines -1, yield： 11.5%.
MS m/z (ESI): 432.2 [M+l]
'H NMR (400 MHz, DMSO-i¾:δ 12.59 (s, 1H), 8.45 (d, 1H), 8.25 (d, I H), 7.97 (d, 1H), 7.99-7.79 (m, 1H), 7.78-7.64 (m, 1H), 7.57-7.37 (m, 2H), 7.35-7.17 (m, 1H), 4.73 (d, 2H), 4.49 (d, 2H), 4.35 (s, 2H), 3.89 (s, 3H) Embodiment 64
4-[[3-[(4 i, 7aS) and -4- methyl-fluoro- 2,3,4a, 5,7,7a- hexahydropyrrolos simultaneously [3,4- Ζ>] [Isosorbide-5-Nitrae] oxazine -6- carbonyls] -4- is fluoro-
Mono- Walk
(4ai, 7fl5 4- benzyls -3,4a, 5,6,7,7a- hexahydro -2H- pyrrolo-es [3,4-ft] [D- (-)-tartaric acid (5.15 g, 34.36 mmol) is dissolved in 30 mL methanol by l, 4] oxazines, it is heated to 60 °C, 10 mL 4- benzyls -3,4a, 5 are added dropwise, 6,7,7 "-hexahydro -2H- pyrrolo-es [3,4- Λ] (7; 4] oxazines 14e (7.50 g; 34.36 mmol) methanol solution, be cooled to 49 °C, react 30 minutes.It is cooled to 0 °C, filtering, 300 mL ethanol and methanol (V/V=2 that solid is cooled down:1) mixed solvent is washed, and recrystallization mother liquor is concentrated under reduced pressure by obtained crude product with 50 mL recrystallizing methanols, gained residue is dissolved in 50 mL water, it is 12 that 6 M sodium hydroxide solutions, which are added dropwise, to reaction solution pH, is extracted with dichloromethane (100 mLx3), merges organic phase, anhydrous sodium sulfate drying, filtering, filtrate pressure concentration, obtains (4,7 S) -4- benzyls -3,4,5,6,7,7 hexahydro -2H- pyrrolo-es [3,4-6] [Isosorbide-5-Nitrae] oxazines 64a (1.80 g, colorless oil), yield： 48.0%.
Bis- Walk
(4 , 7a5) and-4- benzyls-2,3,4,5,7,7-hexahydropyrrolo simultaneously [3,44] [Isosorbide-5-Nitrae：！Evil crop -6- t-butyl formates are by (4ai, 7 " 5) -4- benzyls -3,4 β, 5,6,7,7 β-hexahydro -2H- pyrrolo-es [3,4-6] [Isosorbide-5-Nitrae] oxazines 64a (1.80 g, 8.20 mmol) is dissolved in 40 mL dichloromethane protective embankments, add di-tert-butyl dicarbonate（2.70 g, 12.40 mmol) and triethylamine (2.3 mL, 16.40 mmol), react 12 hours.50 mL saturation chlorination money solution are added, are extracted with dichloromethane (100 mLx3), merge organic phase, anhydrous sodium sulfate thousand is dry, filtering, filtrate decompression concentration, obtain crude product (4^, 7^ 4- benzyls -2,3,4a, 5,7,7a- hexahydropyrrolos simultaneously [3,4-6] [Isosorbide-5-Nitrae] oxazine -6- t-butyl formates 64b (2.60 g, colorless oil), product without isolation Zhi connect for Xia Walk reaction.
Tri- Walk
(4ai, 7,fl5 3,4,4a, 5,7, [Isosorbide-5-Nitrae] oxazine-6- t-butyl formates are by crude product (4,75 4- benzyls-2,3,4 α for-2-pyrrolo- of 7a- hexahydros [3,4-0], 5,7,7 β-hexahydropyrrolo simultaneously [3,4-W [l, the 4 tertiary fourths of] oxazine-6- formic acid Ester 64b (2.60 g, 8.16 mmol) is dissolved in 60 mL methanol, adds 260 10% palladiums of mg/carbon, and hydrogen is replaced three times, is reacted 4 hours under 2 bar, filtering, and filtrate decompression concentration obtains crude product
Hexahydro -2H- pyrrolo-es [3,4-/>] [1,4] oxazine -6- t-butyl formates 64c (1.80 g, colorless oil), product is directly used in the next step without isolation.
Tetra- Walk
(½i, 7oS 4- methyl-2,3,4 α, simultaneously [3,4- 6] [Isosorbide-5-Nitrae] oxazine-6- t-butyl formates are by crude product (4fl for 5,7,7-hexahydropyrrolo, 7i75) and-3,4; 5,7-hexahydro-2H- pyrrolo-es [3,4- [1; 4] oxazine-6- t-butyl formates 64c (1.80 g, 7.88 mmol) is dissolved in the chloroethene protective embankments of 60 mL bis-, adds 37% formalin (1 mL; 11.80 mmol); reaction 1 hour, is cooled to 0 °C, adds Sodium triacetoxyborohydride (5 g; 23.60 mmol), react at room temperature 12 hours.Add 80 mL saturated sodium carbonate solutions, extracted with dichloromethane (100 mLx3), merge organic phase, anhydrous sodium sulfate drying, filtrate decompression concentration, obtain crude product (, 7rtS 4- methyl, simultaneously [3,4-6] [Isosorbide-5-Nitrae] oxazine -6- t-butyl formates 64d (2 g, colorless oil), product is directly used in the next step to 3,5,7,7 α-hexahydropyrrolo without isolation.
5th step
(4Ω , 7 Ω -4- methyl -3, [3,4-W [l, 4] oxazines hydrochlorides are by crude product (4o for 5,6,7,7a- hexahydro -2H- pyrrolo-es, 7aS-4- methyl-2,3,5,7,7-hexahydropyrrolo simultaneously [3,4- Α] [tertiary fourth tenth of the twelve Earthly Branches purport 64d (2 g of Isosorbide-5-Nitrae] oxazine-6- formic acid, 8.25 mmol) it is dissolved in Isosorbide-5-Nitrae-dioxane solution of the M hydrogen chloride of 50 mL 4, react 24 hours.It is concentrated under reduced pressure, obtains crude product (4fli, 7aS) and -4- methyl -3,4,5,6,7,7 α-six Gas pyrrolo-es [3,4-] [1,4] oxazine hydrochloride 64e (1.76 g, white solid), product is not purified directly to enter the lower Walk reactions of row.
6th step
4-[[3-[(½i, 7fl5) and -4- methyl-fluoro- 2,3,4a, 5,7,7a- hexahydropyrrolo simultaneously [3,4-6j [l, 4] oxazine -6- carbonyls] -4- fluoro-phenyls] methyl] the small ketone of -2H- phthalein crops
The fluoro- 5- of 2- [(the small base of 4- oxo -3H- phthalazines) methyl] benzoic acid lc (2.09 g, 7 mmol) is dissolved in 60 mL>In ^- dimethylformamides, BTA -1^^^'^- tetramethylurea hexafluorophosphoric acids ester (3.18 g, 8.40 mmol) is added, Ν, Ν-diisopropylethylamine (4 mL, 24.50 mmol) and (4,7 4- methyl -3,4tf, 5,6,7,7 "-hexahydro -2H- pyrrolo-es [3; 4-6] [1; 4] oxazine hydrochlorides 64e (1.52 g, 7 mmol), reaction 24 hours.Add 100 mL saturated sodium carbonate solutions and 100 mL dichloromethane protective embankments, separate organic phase, it is concentrated under reduced pressure, 100 mL water are added in gained residue, it is extracted with ethyl acetate (100 mLx3), merge organic phase, washed (20 ml 2) with bubble and sodium chloride solution, anhydrous sodium sulfate drying, filtering, filtrate decompression is concentrated, with silica gel column chromatography with eluant, eluent system A purify gained residue, obtain 4- [[3- [(4 7) -4- methyl-fluoro- 2, 3, 4a, 5, 7, 7a- hexahydropyrrolos simultaneously [3, 4-6] [1, 4] oxazine -6- carbonyls] -4- fluoro-phenyls] methyl] 64 (1 .50 g of -2H- phthalazines -1- ketone, white solid), yield： 50.8%.
MS m/z (ESI): 423.1 [M+1]
Ή NMR (400 MHz, CDC13):δ 10.46 (s, 1H), 8.52-8.50 (m, 1H), 7.82-7.80 (m, 3H), 7.44-7.42 (m, 1H), 7.36-7.34 (m, 1H), 7.09-7.06 (m, 1H), 4.33-4.31 (m, 2H), 4.18-4.07 (m, 1H), 3.95-3.65 (m, 5H), 3.53-3.46 (m, 2H), 3.33-3.18 (m, 2H), 2.49 (s, 3H) Embodiment 65
4_ [4_ fluorine _3_((5ί^,8ΰ;) -4,5 Ω, 6,7,8,8 "-hexahydropyrrolo simultaneously [3,4-6] [l, 2,3j triazol [】, 5- | [Isosorbide-5-Nitrae] oxazines
- 7- carbonyls) benzyl] -2H- phthalazines -1- ketone
0
By 4- [the fluoro- 3- (4,5 of 4-Ω, 6,7,8,8 Ω-hexahydropyrrolo simultaneously [3,4->] [1,2,3] triazol [1,5- [1,4] oxazine -7- carbonyls) benzyl] -2H- phthalazines -1- ketone 48 (550 mg, 1.23 mmol) through HPLC chiral separations purify, obtain 4- [fluoro- the 3- ((5^ of 4-, 8oR) and -4,5a, 6,7,8,8 ￡ i- hexahydropyrrolos simultaneously [3,4-6 " [1,2,3] triazol [1,5- [Isosorbide-5-Nitrae] sobs piperazine -7- carbonyls) benzyl] -2H- phthalazines -1- ketone 65 (240mg, white solid), yield： 99.9%.
MSm/z (ESI): 446.2 [M+l]
'HNMR (400 MHz, CD3OD-^):δ 8.35-8.38 (d, 1H), 7.82-7.96 (m, 3H), 7.63 (s, 1H), 7.46-7.53 (m, 1H), 7.44-7.45 (m, 1H), 7.20-7.45 (m, 1H), 5.27-5.35 (m, 1H), 5.06-5.15 (m, 1H), 4.57-4.61 (m, 1H), 4.40 (s, 2H), 4.13-4.16 (m, 2H), 3.49-3.74 (m, H) embodiment 66
4- [4- fluorine ^-^^^^^- ^,^, ^- hexahydropyrrolo and ^：^ ^ triazol ^- ^ oxazines
- 7 ketone
By 4- [the fluoro- 3- of 4- (and 4,5,6,7,8,8 α-hexahydropyrrolo simultaneously [3,4-6] [1,2,3] triazol [1,5-^ [and Isosorbide-5-Nitrae] oxazine -7- carbonyls) benzyl;1-2H- phthalazines -1- ketone 48 (550 mg, 1.23 mmol) is purified through HPLC chiral separations, obtains 4- [4- Fluoro- 3- ((5aS, 854,5a, 6,7,8,8-hexahydropyrrolo simultaneously [3,4-6] [1,2,3] triazol [1,5- [Isosorbide-5-Nitrae] oxazine-7- carbonyls) benzyl]-2H- phthalazines-1- ketone 66 (290 mg, white solid), yield： 99.9%.
MS m/z (ESI): 446.2 [M+l]
Ή NMR (400 MHz, CD3OD-^):δ 8.35-8.37 (d, 1H), 7.83-7.96 (m, 3H), 7.62 (s, 1H), 7.46-7.53 (m, 1H), 7.44-7.45 (m, 1H), 7.20-7.45 (m, 1H), 5.28-5.35 (m, 1H), 5.06-5.16 (m, 1H), 4.61-4.63 (m, 1H), 4.40 (s, 2H), 4.12-4.16 (m, 2H), 3.50-3.74 (m, 3H)
Test case：
Biological assessment
The PARP 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 is by using homologous poly- (last of the twelve Earthly Branches of adenosine diphosphate (ADP) 4 sugar) the poly enzyme level kits of TREVIGEN HT F（TREVIGEN HT F homogeneous PARP Inhibition Assay Kit, article No. No4690-096-K) determine inhibitory action of the invention compound to PARP enzymatic activitys.Test needs to consume NAD based on the PARP DNA repair processes participated in+, NAD+ be used to the substrate of unstressed configuration activity being catalyzed into the molecule of high fluorescence activity in another reaction simultaneously, therefore by determining the enhancing degree of fluorescence signal, can learn NAD in reaction system+Level, 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), circular response mixed liquor (cyding mix) and buffer solution (buffer) etc., can refer to homologous poly- (adenosine diphosphate (ADP)-ribose) the poly enzyme level kit specifications of TREVIGEN HT F.
Experimental procedure is summarized as follows：Test compound is dissolved in dimethyl sulfoxide (DMSO), and concentration needed for experiment is then diluted to b 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 contain DNA, PARP enzymes and reaction buffer.After incubating 30 minutes at room temperature, add under the conditions of 50 μ L circular response mixed liquors, lucifuge, incubate 15 40 minutes at room temperature into each hole.50 terminate liquids are subsequently added, the fluorescent value in each hole is read on ELIASA（Ex544 nm, Em590 nm).Inhibiting rate of the compound to PARP enzymatic activitys can be calculated by NAD+ calibration curve equations.The IC of compound5O values can be calculated by the inhibiting rate under various concentrations.
40 25
41 7
47 9.3
48 12
52 84
62 23
65 24The 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 use IC5QValue is represented.
Experimental program is summarized as follows：10% FBS (being purchased from Gibco) is added using DMEM F12 first and is used as complete medium, MDA-MB-231 and MDA-MB-436 cells are inoculated on 96 well culture plates with suitable cell density (3000/mL of e.g. medium), in 37 °C, 5% C02Under the conditions of, the overnight incubation in constant incubator.Test compound is dissolved with DMSO first, the concentration needed for being then diluted to experiment with the culture medium without FBS.After original culture medium after cell attachment, to be replaced by the fresh culture that adds a series of gradient concentration test-compounds (generally 7 or 9 concentration points) solution.Hereafter, by Tissue Culture Plate in 37,5% 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 compound5.It is worth the suppression numerical computations that can breed by test-compound under various concentrations for cell
30 0.77
33 0.11
34 0.11
36 0.34
39 0.12
40 0.098
41 0.013
45 0.21
47 0.057
48 0.007
49 0.13
51 0.14
52 0.022
54 0.042
55 0.002
56 0.072
58 0.026
60 0.003
61 0.002
62 0.031
65 0.017
66 0.005
Conclusion：Preferred compound of the present invention has obvious inhibitory activity to MDA-MB-436 Carbazole alkaloids propagation.Pharmacokinetic Evaluation
The pharmacokinetics test 1 of the embodiment of the present invention 8 of test case 1, embodiment 18 and the compound of embodiment 62, summary
Using SD rats as animal subject, determining rat using LC/MS/MS methods, drug concentration in blood plasma in the same time is given after the compound of embodiment 8, the compound of embodiment 18 and the compound of embodiment 62 not in gavage and intravenous injection respectively.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
The compound of embodiment 8, the compound of embodiment 18 and the compound of embodiment 62
2.2 experimental animal
Healthy adult SD rat 24, 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 2 gastric infusion groups：A certain amount of medicine is weighed, the mL of dimethyl sulfoxide (DMSO) 0.5 dissolvings are added, the rear physiological saline that adds is configured to 1.5 mg/mL to 10 mL;
It is injected intravenously administration group：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
Gastric infusion is distinguished after healthy adult SD rat 24, 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
Gastric infusion group：In before administration and 0.25,0.5,1.0 after administration, 1.5,2.0,3.0,4.0,5.0,7.0,9.0,12.0,24.0 hours by 0.2 mL of eye socket blood sampling, it is placed in heparinised tubes, 3500 revs/min, centrifuges 20 minutes separated plasmas, in one 20 °C of preservations, feed within 2 hours after administration.
It is injected intravenously administration group：2 minutes, 15 minutes, 0.5,1.0,2.0 before being administered and after administration, 3.0,4.0,6.0,8.0,12.0,24.0 hours eye socket 0.2 mL of blood sampling, are placed in heparinised tubes, 3500 revs/min, centrifuge 20 minutes separated plasmas, in one 20 °C of preservations.
3. operation
Each 20 μ of rat blank plasma at each moment after medicine is drawn, the μ of inner mark solution 50 is added, the μ L of methanol 140, vortex mixed 3 minutes after mixing are centrifuged 10 minutes（13500 revs/min), take 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 as follows：
Conclusion：Preferably, pharmacokinetic property is obviously improved compound medicine of embodiment of the present invention codes or data. Tumor-inhibiting action is evaluated
Test case 1 tests tumor-inhibiting action of the compounds of this invention to mouse
1. experiment purpose
Test the curative effect to human colon carcinoma SW620 transplantable tumor transplantable tumor nude mouses after the compounds of this invention and Temozolomide (TMZ) administering drug combinations.
2. test medicine
Embodiment compound
3. experimental animal
BALB/cA-nude nude mouses, SPF, 16-20g,, purchased from the western pul Bi Kai experimental animals Co., Ltd in Shanghai.Quality certification number：SCXK (Shanghai) 2008-0016.
4. experimental procedure
4.1 nude mouse laboratory environments are adapted to three days.
The right flank subcutaneous vaccination colon cancer SW620 cells of 4.2 nude mouses (5 X 106/ only), tumour growth 10 days is long to 339 ± 132 mm3Animal is grouped to (d0) at random afterwards.Dosage and dosage regimen see the table below.2-3 knurl volume is measured weekly, is weighed, record data.
Gross tumor volume（V) calculation formula is：
V = l/2xaxb2
Wherein a, b represent length and width respectively.
Tumour inhibiting rate (%)=(-)/.(%)
Wherein：T, C be respectively experiment at the end of experimental group (testing compound) and blank control group gross tumor volume.
5. dosage regimen, dosage and experimental result
3 42 -- (the intravenous injection of 1- embodiments 62）
50 10 42 +++ (gavage is oral by+TMZ）
30 42 +++ (gavage is oral for embodiment 65）
50 10 51 ++ (gavage is oral by+TMZ）
Conclusion：Tumour inhibiting rate % data areas are represented： "+"： 50%〜60% ； "++"： 60%〜80% ； " +++"： 80%〜100%.Present invention compound to be measured has good tumour inhibiting rate to colon cancer SW620 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 described ring protective embankment base, heterocyclic radical, aryl or heteroaryl is optionally further selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, (0) 01 by one or more independently of one another8、 -OC(0)R8、 -0(CH2)pC(0)ORs、 -C(0)R8、 -NHC(0)R8、 -NR9R'°、 -OC(0)NR9R'.Or-C (0) NR9R10Substituent replaced；
    R' 、 R2、 R3Or R4It is each independently selected from hydrogen atom, halogen, hydroxyl, protective embankment base, cyano group, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR8、 -C(0)R8Or-C (0) NR9Rl l), further replaced wherein described protective embankment base or alkoxy are each individually optional by one or more substituents selected from halogen, hydroxyl, alkyl or protective embankment epoxide；
    R5Selected from hydrogen atom, hydroxyl, alkyl, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、
    -C(0)RsOr (0^1^11(), wherein described protective embankment base optionally spouts, a Walk is replaced by one or more substituents selected from halogen, hydroxyl, protective embankment base or alkoxy；
    R6And R7It is each independently selected from hydrogen atom, protective embankment base, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR8、 -OC(0)R8、 -0(C¾)pC(0)OR8、 -C(0)R8、 -NHC(0)R8、 -NR9R10, -OC(O)NR9R!0Or-C (0) NR9R1Q, or R6And R7- rise form oxo；
    Annular atom D or E are each independently selected from C or N atoms；
    When n is 1, D and E, which are connected with each other, is connected into 6 10 yuan of rings X, meet valence bond theory when cyclic, 6 10 described yuan of rings X are selected from ring protective embankment base, heterocyclic radical, aryl or heteroaryl, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl appoint to select into a Walk independently of one another is selected from protective embankment base, halogen, hydroxyl, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, benzyl, oxo ,-OR by one or mores、 -C(0)OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)Rs、 -NR9R10、 -OC(0)NR9R10Or-C (0) NR9R1QSubstituent replaced, wherein described alkyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl or benzyl independently of one another optionally further by it is one or more be selected from protective embankment base, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)Rs、 -NR9R10、 -OC(0)NR9R1()Or, C (0) NRQR10Substituent replaced；
    When n is 2, D and E, which are connected with each other, is connected into 5 10 yuan of rings X, meet valence bond theory when cyclic, 5 10 described yuan of rings X are selected from cycloalkyl, heterocyclic radical or heteroaryl, wherein described ring protective embankment base, heterocyclic radical or heteroaryl are optionally further selected from protective embankment base, halogen, hydroxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, benzyl, oxo ,-〇 R by one or more independently of one anotherS、 -C(0)OR8、 -OC(0)R8、 -0(C¾)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9R10、 -OC(0)NR9R10Or-C (O) NR9Ri0Substituent replaced, wherein alkyl, ring protective embankment base, heterocyclic radical, aryl, heteroaryl or benzyl independently of one another Ren select into Yi Walk by it is one or more be selected from protective embankment base, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8 -NR9R1Q、 -OC(0)NR9R1QOr-C (0) NR9R1QSubstituent replaced；
    RsSelected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, replaced wherein described alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl appoint to select independently of one another into a Walk by one or more substituents selected from alkyl, halogen, hydroxyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate;
    R9Or!^ ° is each independently selected from hydrogen atom, protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl, is replaced wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl appoints to select independently of one another into a Walk by one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
    Or, R9And R1QHeterocyclic 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 optionally further replaces by one or more substituents selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
    M is 0,1 or 2;
    N is 1 or 2；And
    P is 0,1 or 2.
    2nd, formula according to claim 1（I compound or its pharmaceutically useful salt shown in), including formula（II compound described in) or
    Wherein：
    A and B form cycloalkyl, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) 0R by one or more independently of one anothers、 OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -NHC(0)Rs、 -NR Ri0, -O C Nl^R1.Or-C (0) NR9R' ° of substituent is replaced；
    R! 、 R2、 R3Or R4It is each independently selected from hydrogen atom, halogen, hydroxyl, protective embankment base, cyano group, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl or heteroaryl ,-C (0) OR8、 -C(0)R8Or-C (0) NR9R1Q, wherein described protective embankment base or alkoxy each it is individually optional enter a Walk replaced by one or more substituents selected from halogen, hydroxyl, alkyl or alkoxy；
    R5Selected from hydrogen atom, hydroxyl, alkyl, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、 -C(0)R8Or-C (0) NR9R1Q, wherein described alkyl optionally enters -- step is by one or more choosings) halogen, hydroxyl, the substituent of alkyl or protective embankment epoxide replace；
    Annular atom D or E are each independently selected from C or N atoms；
    D and E, which are connected with each other, is connected into 6 10 yuan of rings X, and valence bond theory, 6 10 described yuan of rings are met when cyclic
    X is selected from cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl appoint to select into a Walk independently of one another is selected from alkyl, halogen, hydroxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, benzyl, oxo ,-OR by one or mores、 -C(0)ORs、 -OC(0)R8、 -0(C )pC(0)OR8、 -C(0)Rs、 -S(0)mR8、 -NHC(0)R8、 -NR9R10, -OC(0)NR9R1()Or-C (0) NR9R1()Substituent replaced, wherein alkyl, ring protective embankment base, heterocyclic radical, aryl, heteroaryl or benzyl independently of one another Ren select into Yi Walk by it is one or more be selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、 -OC(0)R8、 -0(C¾)pC(0)OR8、 -C(0) 8 -S(0)mR8、 -NHC(0)Rs、 -NR9R1Q、 -OC(0)NR9R1GOr-C (0) NR9R1QSubstituent replaced；
    R8Selected from hydrogen atom, protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl, replaced wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl, heteroaryl appoint to select independently of one another into a Walk by one or more substituents for selecting Θ protective embankments base, halogen, hydroxyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
    R9Or R1QHydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are each independently selected from, is replaced wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl appoints to select independently of one another into a Walk by one or more substituents selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
    Or, R9And R1QWith the nitrogen-atoms formation heterocyclic radical being connected, contain one or more N, 0 or S (0) atom in wherein described heterocyclic radical, and the heterocyclic radical times is selected and replaced into a Walk by one or more substituents selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
    M is 0,1 or 2;And P is 0,1 or 2.
    3rd, formula according to claim 2（I compound or its pharmaceutically useful salt shown in), including the compound shown in logical formula (III) or its pharmaceutically useful salt：
    ( ΙΠ )
    Wherein-
    A and B form ring protective embankment base, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein described ring protective embankment base, heterocyclic radical, aryl or heteroaryl appoints to select into a Walk independently of one another is selected from alkyl, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more8、 -OC(0)R -0(CH2)pC(0)OR8、 -C(0)R8、 -NHC(0)R8、 -NR9Rl0、 -OC(〇)NR9R10Or-C (0) NR9R10Substituent replaced；
    R1 、 R\ R3Or R4It is each independently selected from hydrogen atom, halogen, hydroxyl, protective embankment base, cyano group, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR8、 -C(0)R8Or-C (0) NR9R10, wherein described alkyl or protective embankment epoxide each it is individually optional enter a Walk replaced by one or more substituents selected from L ' elements, hydroxyl, alkyl or alkoxy；
    Y, Z, G and Τ are each independently selected from Ν atoms or C atoms：
    Condition is, is Ν atoms when Y, Z, G or J are different, meanwhile, arbitrarily connected individual annular atom can not be Ν atoms simultaneously；
    It is when bifurcation, Z, G and J are selected from the Ν atomic time, then unsubstituted；
    When Y, Z, G and J are selected from the C atomic time, then Ren is selected into Yi Walk and is selected from hydrogen atom, protective embankment base, halogen, hydroxyl, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, benzyl, oxo ,-OR independently of one another by Y, Z, G and J8, -C(0)OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mRs、 -NHC(0)R8、 -NR9R10、 -0C(0)NR9RW or-C (0) NR9R1(), wherein Ren is selected into Yi Walk by one or more selected from alkyl, halogen, hydroxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR independently of one another for alkyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl or benzyls、 -OC(0)R8、 -0(C¾)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9Ri D、 -OC(0)NR9R1DOr-C (0) NR9R1QSubstituent replaced； R8Selected from hydrogen atom, alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate independently of one another； R9Or R1GHydrogen atom, protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate independently of one another；
    Or, 19With 111)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 optionally further replaces by one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
    M is selected from 0,1 or 2;And
    P is selected from 0,1 or 2.
    4th, formula according to claim 2（I compound or its pharmaceutically useful salt shown in), including the compound shown in logical formula (IV) or its
    Wherein-
    A and B form ring protective embankment base, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein described cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR by one or more independently of one anothers、 -OC(0)R8、 -0(CH2)pC(0)ORs、 -C(0)R8、 -NHC(0)Rs、 -NR9R10、 -O C NI^R1.Or-C (0) NR9R10Substituent replaced；
    R1 、 R R3Or R4It is each independently selected from hydrogen atom, halogen, hydroxyl, alkyl, cyano group, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl ,-C (0) OR8、 -C(0)R8Or-C (0) NR9R1(), further replaced wherein described protective embankment base or protective embankment epoxide are each individually optional by one or more substituents selected from halogen, hydroxyl, alkyl or protective embankment epoxide；
    R5Selected from hydrogen atom, hydroxyl, alkyl, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、
    -C(0)R8Or-C (0) NR9R1Q, wherein described alkyl is optionally further replaced by one or more substituents selected from halogen, hydroxyl, protective embankment base or protective embankment epoxide；
    Y, Z, G and J are each independently selected from 0 atom, WR11) or QR^XR12);
    Condition is, is N when Y, Z, G or J are different11), meanwhile, arbitrarily three connected annular atoms can not be N (R simultaneouslyU);
    Meanwhile, Y, Z, J or G are selected from N (R ") or CWXR12) when, two annular atoms of arbitrary neighborhood can be with Form a ring protective embankment base, heterocyclic radical, aryl or heteroaryl；
    R8Selected from hydrogen atom, protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl, wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl optionally spout independently of one another, a Walk is replaced by one or more substituents selected from alkyl, halogen, hydroxyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
    R9Or R1QHydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, wherein described protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from protective embankment base, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate independently of one another；
    Or, R9And R1QWith the nitrogen-atoms formation heterocyclic radical being connected, contain one or more N, 0 or 8 (0) in wherein described heterocyclic radical, hetero atom, and the heterocyclic radical Ren selects and replaced into Yi Walk by one or more substituents selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
    R11And R12It is each independently selected from hydrogen atom, protective embankment base, halogen, hydroxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, benzyl, oxo ,-OR8、 -C(0)OR8、 -OC(0)Rs、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mRs、 -NHC(0)R8、 -NR9R1G、 -OC(0)NR9R1GOr-C (0) NR9R1Q, wherein protective embankment base, cycloalkyl, heterocyclic radical, aryl, heteroaryl or benzyl are independently of one another optionally further by one or more selected from alkyl, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9R10, -0C(O)NR9R10Or-C (0) NR9R10Substituent replaced；
    M is selected from 0,1 or 2;And
    P is selected from 0,1 or 2.
    5th, formula according to claim 4（I compound or its pharmaceutically useful salt shown in), wherein：A and B form cycloalkyl, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein described 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 ,-C (0) OR by one or more independently of one anothers、 -OC(0)R8、 -0(C¾)pC(0)OR8、 -C(0)R8、 -NHC(0)R8、 -NR9R10、 -OC(0)NR9R10Or-C (0) NR9R10Substituent replaced；
    R1 、 R2、 R3Or R4It is each independently selected from hydrogen atom, halogen, hydroxyl, protective embankment base, cyano group, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl ,-C (0) OR8、 -C(0)R8Or-C (0) NR9RIG, further replaced wherein described alkyl or alkoxy are each individually optional by one or more substituents selected from halogen, hydroxyl, protective embankment base or alkoxy；
    R5Selected from hydrogen atom, hydroxyl, alkyl, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) ORs、 -C(0)RsOr-C (0) NR9R1Q, wherein described protective embankment base is optionally further replaced by one or more substituents selected from halogen, hydroxyl, protective embankment base or alkoxy； Y, Z, G and J are each independently selected from O atom, N (R ") or C (Rll)(R12);
    Wherein：
    J be O atom or N (R "), G be C (U)(R12), Z is C (RU)(R!2), Y is O atom, N (R! I) or C (R ") (R12);
    J is C^XR12), G is N (RU) or C (RU)(R12), Z is C (RU)(R12), Y is C (Rn)(R12);
    J is C (RU)( 12), G is C (Rn)(R12), Z is N (R ") or C (R! 1)(RJ2), Y is C (R】〗)(R12);Meanwhile, Y, Z, J or G are selected from N^11) or C (Rl l)(R12) when, two annular atoms of arbitrary neighborhood can form a cycloalkyl, heterocyclic radical, aryl or heteroaryl；
    R8Selected from hydrogen atom, protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described protective embankment base, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are optionally further replaced by one or more substituents selected from alkyl, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate independently of one another；
    R9Or R1GHydrogen atom, protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl are each independently selected from, is replaced wherein described alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl appoint to select independently of one another into a Walk by one or more substituents selected from protective embankment base, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
    Or, R9And R1QWith the nitrogen-atoms formation heterocyclic radical being connected, contain one or more N, 0 or SiC n^^ atoms in wherein described heterocyclic radical, and the heterocyclic radical appoint select into a Walk by one or more choosings alkyl, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate substituent replace；
    R11And R12It is each independently selected from hydrogen atom, alkyl, halogen, hydroxyl, cycloalkyl, heterocyclic radical, aryl, heteroaryl, benzyl, oxo ,-OR8、 -C(0)ORs、 -OC(0)R8、 -0(CH2)pC(0)OR8, -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9R1Q、 -OC(0)NR9R1QOr-C (0) NR9R1Q, wherein protective embankment base, ring protective embankment base, heterocyclic radical, aryl, heteroaryl or benzyl are independently of one another optionally further by one or more selected from alkyl, halogen, hydroxyl, protective embankment epoxide, cycloalkyl, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -NHC(0)R8、 -NR9R10, -OC(0)NR9RlOr C (0) NR9R10Substituent replaced；
    M is selected from 0,1 or 2;And
    P is selected from 0,1 or 2.
    6th, formula according to claim 1（I compound or its pharmaceutically useful salt shown in), including the compound shown in logical formula (V) or its pharmaceutically useful salt：
    ( V )
    Wherein：
    A and B form ring protective embankment base, heterocyclic radical, aryl or heteroaryl together with the carbon atom being connected, wherein described 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 ,-C (0) OR by one or more independently of one anothers、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -NHC(0)R8、 -NR9R10 -OC(0)NR9R1 () or-C (0) NR9R10Substituent replaced；
    R1 、 R2、 R3Or R4It is each independently selected from hydrogen atom, halogen, hydroxyl, alkyl, cyano group, alkoxy, cycloalkyl, heterocyclic radical, aryl or heteroaryl ,-C (0) OR8、 -C(0)R8Or-C (0) NR9R'G, wherein described protective embankment base or protective embankment epoxide each it is individually optional enter a Walk replaced by one or more substituents selected from halogen, hydroxyl, alkyl or protective embankment epoxide；
    R5Selected from hydrogen atom, hydroxyl, protective embankment base, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、 -C(0)RsOr-C (0) NR9Rifl, replaced wherein described protective embankment base appoints to select into a Walk by one or more substituents selected from halogen, hydroxyl, alkyl or alkoxy；
    D and E are each independently selected from N or C atoms；
    D and E, which are connected with each other, is connected into 5 10 yuan of rings X, meet valence bond theory when cyclic, 5 10 described yuan of rings X are selected from cycloalkyl, heterocyclic radical or heteroaryl, wherein described cycloalkyl, heterocyclic radical or heteroaryl appoint to select into a Walk independently of one another is selected from alkyl, halogen, hydroxyl, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, benzyl, oxo ,-OR by one or more8、 -C(0)OR8、 -OC(0)R8、 -0(CH2)pC(0)OR8、 -C(0)R8、 -S(0)mR8、 -NHC(0)R8、 -NR9R1Q、 -OC(0)NR9RIQOr-C (0) NR9Rll)Substituent replaced, wherein protective embankment base, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl or benzyl independently of one another optionally further by it is one or more be selected from alkyl, halogen, hydroxyl, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, oxo ,-C (0) OR8、 -OC(0)Rs、 -0(CH2)pC(0)OR8、 -C(0)R8> -S(0)mR8、 -NHC(0)R8、 -NR9R10、 -OC(0)NR9R10Or-C (0) NR9R1QSubstituent replaced；
    R8Selected from hydrogen atom, protective embankment base, cycloalkyl, heterocyclic radical, aryl or heteroaryl, replaced wherein described alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl appoint to select independently of one another into a Walk by one or more substituents selected from protective embankment base, halogen, hydroxyl, alkoxy, cycloalkyl, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
    ！^ or！^^ is each independently selected from hydrogen atom, alkyl, cycloalkyl, heterocyclic radical, aryl or heteroaryl, wherein described alkyl, ring protective embankment base, heterocyclic radical, aryl or heteroaryl are independently of one another optionally further by one or many The individual substituent selected from protective embankment base, halogen, hydroxyl, protective embankment epoxide, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate is replaced；
    Or, R9And R1QHeterocyclic 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 optionally further replaces by one or more substituents selected from alkyl, halogen, hydroxyl, alkoxy, ring protective embankment base, heterocyclic radical, aryl, heteroaryl, carboxylic acid or carboxylate；
    M is selected from 0,1 or 2;And
    P is 0,1 or 2.7th, the formula according to any one of claim 16（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 16（I compound or its pharmaceutically useful salt, wherein R shown in)1For hydrogen atom.
    9th, the formula according to any one of claim 16（I compound or its pharmaceutically useful salt, wherein R shown in)1For halogen, preferably fluorine atom.
    10th, the formula according to any one of claim 16（I compound or its pharmaceutically useful salt shown in), wherein R R2、 R3Or R4It is each independently hydrogen atom.
    11st, the formula according to any one of claim 16（I compound or its pharmaceutically useful salt, wherein R shown in)2、 R3Or R4It is each independently hydrogen atom, R1For halogen, preferably fluorine atom.12nd, the formula according to claim 1（I compound or its pharmaceutically useful salt, wherein R shown in)6Or R7It is each independently hydrogen atom, or R6And R7An oxo is formed together.
    13rd, the formula according to any one of claim 1 12（I compound shown in) or its is pharmaceutically useful
    Or
    14th, one kind prepares formula according to claim 1（I the method for compound or its pharmaceutically useful salt shown in), this method includes：
    ( IA ) (IB)
    By formula (IA) compound optionally hydrolyse into carboxylic acid and formula (IB) compound or its salt reaction response, formula is obtained（I) compound；
    Wherein： RaSelected from halogen, hydroxyl or protective embankment epoxide；
    A, B, D, E, ring X, n, 1^ 17Definition as described in the appended claim 1.
    15th, a kind of pharmaceutical composition, it contains the formula according to any one of claim 1 13 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 13（I compound or its pharmaceutically useful salt shown in), or 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 13（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 13 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 13（I compound or its pharmaceutically useful salt shown in), or purposes of the pharmaceutical composition according to claim 15 in preparation is as assistant agent in cancer treatment procedure or for making tumour cell become sensitive medicine to ionising radiation or chemotherapy.
    20th, the formula according to any one of claim 1 13（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 13（I compound or its pharmaceutically useful salt shown in), or purposes of the pharmaceutical composition according to claim 15 in the medicine for preparing treating cancer, wherein described cancer is 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 13（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 13 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, according to claim】6、 】Purposes described in 9 or 21 any one, wherein the medicine enter a Walk and treatment effective dose be selected from following Drug combination：Temozolomide, adriamycin, taxol, cis-platinum, carboplatin, Dacarbazine, TPT, Irinotecan, gemcitabine or bevacizumab.
CN2011800046090A 2010-08-09 2011-07-26 Phthalazinone derivative, and preparation method and pharmaceutical use thereof Pending CN102666539A (en)

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