CN110272419A - Dihydro pyrido phthalazinone derivatives, preparation method and application - Google Patents

Dihydro pyrido phthalazinone derivatives, preparation method and application Download PDF

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Publication number
CN110272419A
CN110272419A CN201810216030.4A CN201810216030A CN110272419A CN 110272419 A CN110272419 A CN 110272419A CN 201810216030 A CN201810216030 A CN 201810216030A CN 110272419 A CN110272419 A CN 110272419A
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base
dihydro
fluoro
fluorophenyl
phthalazines
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罗会兵
周华勇
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Shanghai Allist Pharmaceuticals Inc
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Shanghai Allist Pharmaceuticals Inc
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Priority to CN201810216030.4A priority Critical patent/CN110272419A/en
Priority to PCT/CN2019/078089 priority patent/WO2019174607A1/en
Priority to CN201980018770.XA priority patent/CN111868060B/en
Publication of CN110272419A publication Critical patent/CN110272419A/en
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    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/5025—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with heterocyclic ring systems
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    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/536—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines ortho- or peri-condensed with carbocyclic ring systems
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    • 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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    • 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
    • C07D491/10—Spiro-condensed systems
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    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The present invention relates to dihydro pyrido phthalazinone derivatives, preparation method and application shown in the following general formula (I), R in formula1、R2、R3, m, n, ring A and ring B be defined as in the description.Dihydro pyrido phthalazinone derivatives of the present invention have good PARP inhibitory activity, can be used to treat or prevent the disease improved because inhibiting PARP active.

Description

Dihydro pyrido phthalazinone derivatives, preparation method and application
Technical field
The present invention relates to one kind be able to suppress poly- (ADP- ribose) polymerase activity dihydro pyrido phthalazinone derivatives, Preparation method and pharmaceutical composition comprising the derivative and the derivative are in preparation for treating or preventing because inhibiting PARP activity and the application in terms of the drug of improved disease.
Background technique
Poly- (ADP- ribose) polymerase, also referred to as poly- (ADP- ribose) synzyme, poly- ADP- ribosyltransferase, is generally claimed For PARP.PARP family includes about 18 kinds of albumen, such as PARP-1, PARP-2, PARP-3, end anchor enzyme -1, holds anchor enzyme -2, dome PARP, TiPARP etc..PARP, which passes through its identification and is integrated to the ability of the single-stranded or double-stranded chain rupture of DNA rapidly, participates in DNA damage Signal transduction (Biochem J (1999) 342:249-268).The relevant function of a variety of DNA of its participation, including gene magnification, Telomere length and chromosome stability are repaired and are influenced in cell division, differentiation, apoptosis, DNA base excision (Nature Gen (1999) 23:76-80), this makes PARP inhibitor become the target for a variety of diseases.
For example, the fracture of DNA- chain and cell can be caused under the effect of PARP inhibitor in the cell handled through alkylating agent That kills dramatically increases (Nature (1980) 283:593-596；Radiat Res (1985) 101:4-14)；Radiotherapy and very much Treatment method is worked by radiation-indued DNA damage, so that PARP inhibitor can be used as the chemistry and radiosensitizer for the treatment of of cancer (US5032617, US5215738 and US5041653)；PARP inhibitor can be used for antiviral therapy and treatment of cancer (WO91/ 18591)；BRCA1 and/or BRCA2 mutation is fully realized (Exp Clin with being associated with for breast cancer in the art (2002) 21 (suppl 3): 9-12 of Cancer Res), the carrier being mutated in BRCA1 and/or BRCA2 is also at ovary, forefront In the elevated risk of gland and pancreatic cancer, PARP inhibitor has been found the specificity that can be used for BRCA1 and BRCA2 defect tumour Kill (Nature (2005) 434:913-916 and 917-921；Cancer Biol Ther (2005) 4:934-936)；PARP suppression Preparation can be used for treating neuropathic conditions, such as apoplexy, wound and Parkinson's disease；PARP inhibitor is also shown for treating urgency Property and astrocytoma (Pharmacol Res (2005) 52:34-43)；PARP inhibitor can be used for treating certain angiosises, purulence Toxicogenic shock, ischemia injury and neurotoxicity (Biochim Biophys Acta (1989) 1014:1-7；J Clin Invest (1997) 100:723-735)；PARP inhibitor can be used for treating inflammatory disease (Pharmacol Res (2005) 52: 72-82 and 83-92), for example, arthritis, gout, inflammatory bowel disease etc.；PARP inhibitor can be used to treat or prevent autoimmunity Disease, such as type-1 diabetes mellitus and diabetic complication (Pharmacol Res (2005) 52:60-71)；PARP inhibitor can be used to Treat or prevent retroviral infection (US5652260), retinal damage (Curr Eye Res (2004) 29:403), skin The skin injury (US5589483 and Biochem Pharmacol (2002) 63:921) etc. that aging and UV induce.
Current published small molecule PARP inhibitor includes: WO1999/59973 disclosed condensed with 5 yuan of hetero-aromatic rings Indoles, WO2003/106430, WO2006/110816 that phenyl ring that amide replaces, amide disclosed in WO2001/85687 replace are public Acyl disclosed in benzoxazoles that amide disclosed in benzimidazole that the amide opened replaces, EP0879820 replaces, WO2008/84261 Benzopyrazoles that amine replaces, dihydro pyrido phthalazone disclosed in WO2010/17055 etc..
The small molecule PARP inhibitor listed includes Olaparib, WO2000/42040 disclosed in WO2004/80976 Niraparib disclosed in disclosed Rucaparib and WO2008/84261, three are used to treat oophoroma, specific structure It is as follows,
New small molecule PARP inhibitor is developed, more effectively for treating the disease by inhibiting PARP to improve, is Necessary for human.
Summary of the invention
The present invention provides a kind of dihydro pyrido phthalazinone derivatives, its pharmaceutically acceptable salt or alloisomerisms Body, this kind of compound have good PARP inhibitory activity, can be used in preparation treatment or prevention and change because inhibiting PARP active The drug of kind disease.
The present invention provides such as following formula (I) compound, its pharmaceutically acceptable salt or stereoisomer,
In formula:
Ring A is to pass through containing the nitrogenous alicyclic heterocyclic base or nitrogenous aromatic heterocyclic of 1~5 ring hetero atom selected from N, O or S N atom is connected with dihydro pyrido phthalazone parent nucleus on ring；
Ring B is aryl or aromatic heterocyclic；
R1Selected from hydrogen, C1-C6Alkyl, C1-C6Alkoxy, halogen, halogenated C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 3~ 7 yuan of naphthenic base ,-CN ,-OH ,-NO2Or-NR5R6；
R5、R6It is each independently selected from H, C1-C6Alkyl or halogenated C1-C6Alkyl；
R2It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-NH2, halogen, deuterium, deuterated C1- C6Alkyl ,-(CH2)qOH, 3~7 yuan of naphthenic base, Aryl is selected from C by 1~31-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-OH ,-NH2 Or the aryl that the substituent group of halogen replaces；
R3It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-OH ,-NH2Or halogen；
Q is 0,1,2 or 3；
N is 0,1,2,3 or 4；
M is 0,1,2 or 3.
The present invention provides the preparation methods of formula (I) compound.
The present invention provides intermediates 1, are used to prepare the compounds of this invention.
The present invention provides pharmaceutical compositions, including formula (I) compound of the present invention, its pharmaceutically acceptable salt or solid Isomers and pharmaceutically acceptable carrier, excipient or diluent.
The present invention provides formula (I) compound, its pharmaceutically acceptable salt or stereoisomer of the present invention or its medicine group Close application of the object in the drug that preparation treats or prevents the disease improved because inhibiting PARP active.
The present invention also provides formula (I) compound of the present invention, its pharmaceutically acceptable salt or stereoisomer or its medicines Compositions are in preparation for treating or preventing vascular diseases, septic shock, ischemia injury, reperfusion injury, Nervous toxicity Property, it is haemorrhagic shock, inflammatory disease, neurogenic disease, multiple sclerosis, diabetes with secondary effect, thin after cardiovascular surgery Application in the drug for the skin injury that acute treatment, retinal damage, skin aging or the UV of cellular toxicity induce.
The present invention also provides formula (I) compound of the present invention, its pharmaceutically acceptable salt or stereoisomer or its medicines Compositions are preparing the application in the drug for treating or preventing cancer.
The present invention also provides formula (I) compound of the present invention, its pharmaceutically acceptable salt or stereoisomer or its medicines Compositions are preparing the application in drug for treating or preventing cancer, the drug and ionising radiation, one or more Chemotherapeutics or combinations thereof is administered in combination.
The present invention also provides formula (I) compound of the present invention, its pharmaceutically acceptable salt or stereoisomer or its medicines Compositions include one or more cancer cells preparing the application in the drug for treating or preventing cancer, the cancer, The cancer cell has utilization homologous recombination (HR) the DNA plerosis double-strand break (DSB) for reducing or abolishing relative to normal cell Ability.
The present invention also provides formula (I) compound of the present invention, its pharmaceutically acceptable salt or stereoisomer or its medicines Compositions include one or more cancer cells preparing the application in the drug for treating or preventing cancer, the cancer, The cancer cell has thin relative to the ability using HR DNA plerosis DSB normal cell reduction or abolished, such as the cancer There is born of the same parents BRCA1 or BRCA2 to lack phenotype.
The present invention also provides formula (I) compound of the present invention, its pharmaceutically acceptable salt or stereoisomer or its medicines Compositions repair approach missing for treating or preventing homologous recombination (HR) dependent DNA double-strand break (DSB) in preparation Application in the drug of cancer.
Invention further provides formula (I) compound of the present invention, its pharmaceutically acceptable salt or stereoisomer or Its pharmaceutical composition is lacked in preparation for treating or preventing homologous recombination (HR) dependent DNA double-strand break (DSB) reparation approach Application in the drug of the cancer of mistake, the cancer include one or more cancer cells, and the cancer cell has relative to normal The ability using HR DNA plerosis DSB that cell is reduced or abolished.
Invention further provides formula (I) compound of the present invention, its pharmaceutically acceptable salt or stereoisomer or Its pharmaceutical composition is lacked in preparation for treating or preventing homologous recombination (HR) dependent DNA double-strand break (DSB) reparation approach Application in the drug of the cancer of mistake, the cancer include one or more cancer cells, and the cancer cell has relative to normal There is BRCA1 or BRCA2 to lack table for the ability using HR DNA plerosis DSB that cell is reduced or abolished, such as the cancer cell Type.
Cancer of the present invention includes but is not limited to breast cancer, oophoroma, carcinoma of endometrium, cervical carcinoma, lung cancer, prostate Cancer, cancer of pancreas, leukemia, gastric cancer, gallbladder cancer, liver cancer, head and neck cancer, the cancer of the esophagus, kidney, the cancer of the brain, leukaemia, colon cancer, intestinal tumor, Glioblastoma, lymthoma or melanoma.
The present invention provides a kind of method of disease for treating or preventing and improving because inhibiting PARP active, the method packets Include to the patients of needs apply a effective amount of formula (I) compound, its pharmaceutically acceptable salt or stereoisomer of the present invention or The pharmaceutical composition of formula (I) compound.
The present invention also provides a kind for the treatment of or prevention vascular diseases, septic shock, ischemia injury, Reperfusion injury Wound, neurotoxicity, haemorrhagic shock, inflammatory disease, neurogenic disease, multiple sclerosis, diabetes with secondary effect, angiocarpy The method for the skin injury that the acute treatment of cytotoxicity, retinal damage, skin aging or UV induce after operation, the method A effective amount of formula (I) compound, its pharmaceutically acceptable salt or stereoisomer of the present invention are applied including the patient to needs Or the pharmaceutical composition of formula (I) compound.
The present invention also provides a kind of methods for treating or preventing cancer, and the method includes patient's applications to needs to have Formula (I) compound of the present invention, its pharmaceutically acceptable salt or the stereoisomer of effect amount or the pharmaceutical composition of formula (I) compound Object.
The present invention also provides a kind of method for treating or preventing cancer, the cancer includes one or more cancer cells, The cancer cell has the ability using HR DNA plerosis DSB for reducing or abolishing relative to normal cell, the method includes A effective amount of formula (I) compound, its pharmaceutically acceptable salt or stereoisomer of the present invention or formula are applied to the patient of needs (I) pharmaceutical composition of compound.
The present invention also provides a kind of method for treating or preventing cancer, the cancer includes one or more cancer cells, The cancer cell has thin relative to the ability using HR DNA plerosis DSB normal cell reduction or abolished, such as the cancer There is born of the same parents BRCA1 or BRCA2 to lack phenotype, and the method includes the patients to needs to apply a effective amount of formula (I) of the present invention Close the pharmaceutical composition of object, its pharmaceutically acceptable salt or stereoisomer or formula (I) compound.
The present invention also provides one kind by with ionising radiation, one or more chemotherapeutics or combinations thereof be administered in combination come The method for treating or preventing cancer, the method includes to needs a effective amount of formula (I) compound of the present invention of patient's application, its The pharmaceutical composition of pharmaceutically acceptable salt or stereoisomer or formula (I) compound.
The present invention also provides a kind for the treatment of or prevention homologous recombination (HR) dependent DNA double-strand breaks (DSB) to repair way The method of the cancer of diameter missing, the method includes the patients to needs to apply a effective amount of formula (I) compound of the present invention, its medicine The pharmaceutical composition of acceptable salt or stereoisomer or formula (I) compound on.
The present invention also provides a kind for the treatment of or prevention homologous recombination (HR) dependent DNA double-strand breaks (DSB) to repair way The method of the cancer of diameter missing, the cancer include one or more cancer cells, and the cancer cell has relative to normal cell The ability using HR DNA plerosis DSB for reducing or abolishing, the method includes the patients to needs to apply a effective amount of hair The pharmaceutical composition of bright formula (I) compound, its pharmaceutically acceptable salt or stereoisomer or formula (I) compound.
The present invention also provides a kind for the treatment of or prevention homologous recombination (HR) dependent DNA double-strand breaks (DSB) to repair way The method of the cancer of diameter missing, the cancer include one or more cancer cells, and the cancer cell has relative to normal cell There is BRCA1 or BRCA2 to lack phenotype, institute for the ability using HR DNA plerosis DSB for reducing or abolishing, such as the cancer cell The method of stating includes applying a effective amount of formula (I) compound, its pharmaceutically acceptable salt or solid of the present invention to the patient of needs The pharmaceutical composition of isomers or formula (I) compound.
Invention still further provides a kind of cancer cells for treating or preventing and there is BRCA1 or BRCA2 to lack phenotype The method of cancer, the method includes to needs a effective amount of formula (I) compound of the present invention of patient's application, it can pharmaceutically connect The pharmaceutical composition of salt or stereoisomer or formula (I) compound received.
The cancer of the ability using HR DNA plerosis DSB of the present invention for reducing or abolishing relative to normal cell is thin Born of the same parents lack the HR dependent DNA DSB repairing activity of one or more phenotypes, and the phenotype is selected from: ATM (NM-000051), RAD51 (NM-002875), RAD51L1 (NM-002877), RAD51C (NM-002876), RAD51L3 (NM-002878), DMCl (NM-007068), XRCC2 (NM7005431), XRCC3 (NM-005432), RAD52 (NM-002879), RAD54L (NM- 003579), RAD54B (NM-012415), BRCA1 (NM-007295), BRCA2 (NM-000059), RAD5O (NM-005732), MREI1A (NM-005590), NBSl (NM-002485), ADPRT (PARP-1), ADPRTL2 (PARP02), CTPS, RPA, RPA1, RPA2, RPA3, XPD, ERCC1, XPF, MMS19, RAD51, RAD51p, RAD51C, RAD51D, PTEN, DMC1, XRCCR, XRCC3, BRCA1, BRCA2, RAD52, RAD54, RAD50, MRE11, NB51, WRN, BLMKU70, RU80, ATM, ATRCHK1, CHK2, FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, RAD1 and RAD9.
In a preferred embodiment of formula (I) compound of the present invention, its pharmaceutically acceptable salt or stereoisomer In, the compound is formula (II) compound,
In formula:
Ring A is to pass through containing the nitrogenous alicyclic heterocyclic base or nitrogenous aromatic heterocyclic of 1~5 ring hetero atom selected from N, O or S N atom is connected with dihydro pyrido phthalazone parent nucleus on ring；
Ring B is aryl or aromatic heterocyclic；
R1Selected from hydrogen, C1-C6Alkyl, C1-C6Alkoxy, halogen, halogenated C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 3~ 7 yuan of naphthenic base ,-CN ,-OH ,-NO2Or-NR5R6；
R5、R6It is each independently selected from H, C1-C6Alkyl or halogenated C1-C6Alkyl；
R2It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-NH2, halogen, deuterium, deuterated C1- C6Alkyl ,-(CH2)qOH, 3~7 yuan of naphthenic base, Aryl is selected from C by 1~31-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-OH ,-NH2 Or the aryl that the substituent group of halogen replaces；
R3It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-OH ,-NH2Or halogen；
Q is 0,1,2 or 3；
N is 0,1,2,3 or 4；
M is 0,1,2 or 3.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is preferred real It applies in scheme, R1Selected from hydrogen, C1-C6Alkyl or halogen, more preferably halogen.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is preferred real It applies in scheme, ring B is phenyl or pyridyl group, R3It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkane Base ,-OH ,-NH2Or halogen, m 0,1,2 or 3.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is more preferable In embodiment, ring B is phenyl or pyridyl group, R3For halogen, m is 1 or 2.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is more preferable In embodiment, ring B is phenyl, R3For halogen, m is 1 or 2.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is preferred real It applies in scheme, ring A is nitrogenous monocycle alicyclic heterocyclic base, nitrogenous condensed ring alicyclic heterocyclic containing 1~5 ring hetero atom selected from N, O or S Base, nitrogenous bridged ring condensed ring alicyclic heterocyclic base, nitrogenous loop coil alicyclic heterocyclic base, nitrogenous bridged ring alicyclic heterocyclic base, nitrogenous loop coil condensed ring alicyclic heterocyclic Base or nitrogenous bridged ring loop coil alicyclic heterocyclic base are connected by N atom on ring with dihydro pyrido phthalazone parent nucleus；Wherein, R2Respectively Independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-NH2, halogen ,-(CH2)qOH, 3~7 yuan of naphthenic base,Aryl or by 1 ~3 are selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-OH ,-NH2Or the aryl that the substituent group of halogen replaces, q It is 0,1,2 or 3, n 0,1,2,3 or 4.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is preferred real It applies in scheme, ring A is nitrogenous monocycle alicyclic heterocyclic base, nitrogenous condensed ring alicyclic heterocyclic containing 1~5 ring hetero atom selected from N, O or S Base, nitrogenous bridged ring condensed ring alicyclic heterocyclic base or nitrogenous loop coil alicyclic heterocyclic base, pass through N atom on ring and dihydro pyrido phthalazone parent nucleus It is connected；Wherein, R2It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-NH2, halogen ,-(CH2)qOH, 3~7 yuan of naphthenic base, Aryl is selected from C by 1~31-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-OH ,-NH2Or halogen The aryl that substituent group replaces, q 0,1,2 or 3, n 0,1,2,3 or 4.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is preferred real It applies in scheme, ring A is that the nitrogenous monocycle rouge with 4 to 7 annular atoms containing 1~5 ring hetero atom selected from N, O or S is miscellaneous Ring group, the nitrogenous condensed ring alicyclic heterocyclic base with 7 to 10 annular atoms, the nitrogenous bridged ring condensed ring rouge with 7 to 10 annular atoms are miscellaneous Ring group or nitrogenous loop coil alicyclic heterocyclic base with 7 to 11 annular atoms, pass through N atom on ring and dihydro pyrido phthalazone parent nucleus It is connected；Wherein, R2It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-NH2, halogen ,-(CH2)qOH, 3~7 yuan of naphthenic base, Aryl is selected from C by 1~31-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-OH ,-NH2 Or the aryl that the substituent group of halogen replaces, q 0,1,2 or 3, n 0,1,2,3 or 4.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is more preferable In embodiment, ring A is that nitrogenous monocycle alicyclic heterocyclic base, the nitrogenous condensed ring rouge containing 1~5 ring hetero atom selected from N, O or S are miscellaneous Ring group, nitrogenous bridged ring condensed ring alicyclic heterocyclic base or nitrogenous loop coil alicyclic heterocyclic base, it is female by N atom on ring and dihydro pyrido phthalazone Nuclear phase connects, the nitrogenous monocycle alicyclic heterocyclic base, nitrogenous condensed ring alicyclic heterocyclic base, nitrogenous bridged ring condensed ring alicyclic heterocyclic base, nitrogenous loop coil rouge Heterocycle is selected from
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is more preferable In embodiment, ring A is that nitrogenous monocycle alicyclic heterocyclic base, the nitrogenous condensed ring rouge containing 1~5 ring hetero atom selected from N, O or S are miscellaneous Ring group, nitrogenous bridged ring condensed ring alicyclic heterocyclic base or nitrogenous loop coil alicyclic heterocyclic base, it is female by N atom on ring and dihydro pyrido phthalazone Nuclear phase connects, the nitrogenous monocycle alicyclic heterocyclic base, nitrogenous condensed ring alicyclic heterocyclic base, nitrogenous bridged ring condensed ring alicyclic heterocyclic base, nitrogenous loop coil rouge Heterocycle is selected from
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is more preferable In embodiment, ring A is that nitrogenous monocycle alicyclic heterocyclic base, the nitrogenous condensed ring rouge containing 1~5 ring hetero atom selected from N, O or S are miscellaneous Ring group, nitrogenous bridged ring condensed ring alicyclic heterocyclic base or nitrogenous loop coil alicyclic heterocyclic base, it is female by N atom on ring and dihydro pyrido phthalazone Nuclear phase connects, the nitrogenous monocycle alicyclic heterocyclic base, nitrogenous condensed ring alicyclic heterocyclic base, nitrogenous bridged ring condensed ring alicyclic heterocyclic base, nitrogenous loop coil rouge Heterocycle is selected from
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is more preferable In embodiment, R2It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-NH2, halogen ,-(CH2)qOH, 3~7 yuan of naphthenic base,Phenyl or by 1~ 3 are selected from C1-C6Alkyl ,-OH ,-NH2Or the phenyl that the substituent group of halogen replaces, q 0,1 or 2, n 0,1,2 or 3.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is more preferable In embodiment, R2It is each independently selected from C1-C6Alkyl, halogenated C1-C6Alkyl ,-NH2、-(CH2)qOH, 3~7 yuan of naphthenic base,Or phenyl, q 0,1 or 2, n 0,1,2 or 3。
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is more preferable In embodiment, R2It is each independently selected from C1-C4Alkyl, halogenated C1-C4Alkyl ,-NH2、-(CH2)qOH, 3~7 yuan of naphthenic base,Or phenyl, q 0,1 or 2, n 0,1,2 or 3.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is preferred real Apply in scheme, ring A be containing 1~5 selected from N, O or S ring hetero atom nitrogenous monocycle aromatic heterocyclic or nitrogenous condensed ring virtue it is miscellaneous Ring group is connected by N atom on ring with dihydro pyrido phthalazone parent nucleus；Wherein, R2It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-NH2, halogen ,-(CH2)qOH, 3~7 yuan of naphthenic base, Aryl is selected from C by 1~31-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-OH ,-NH2Or the aryl that the substituent group of halogen replaces, q 0,1,2 or 3, n 0,1, 2,3 or 4.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is preferred real It applies in scheme, ring A is that the nitrogenous monocycle virtue with 5 to 6 annular atoms containing 1~5 ring hetero atom selected from N, O or S is miscellaneous Ring group or nitrogenous condensed ring aromatic heterocyclic with 8 to 10 annular atoms, pass through N atom on ring and dihydro pyrido phthalazone parent nucleus It is connected；Wherein, R2It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-NH2, halogen ,-(CH2)qOH, 3~7 yuan of naphthenic base, Aryl is selected from C by 1~31-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-OH ,-NH2Or halogen The aryl that substituent group replaces, q 0,1,2 or 3, n 0,1,2,3 or 4.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is more preferable In embodiment, ring A is nitrogenous monocycle aromatic heterocyclic or nitrogenous condensed ring virtue containing 1~5 ring hetero atom selected from N, O or S Heterocycle is connected by N atom on ring with dihydro pyrido phthalazone parent nucleus, the nitrogenous monocycle aromatic heterocyclic, nitrogenous condensed ring Aromatic heterocyclic is selected from
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is more preferable In embodiment, ring A is nitrogenous monocycle aromatic heterocyclic or nitrogenous condensed ring virtue containing 1~5 ring hetero atom selected from N, O or S Heterocycle is connected by N atom on ring with dihydro pyrido phthalazone parent nucleus, the nitrogenous monocycle aromatic heterocyclic, nitrogenous condensed ring Aromatic heterocyclic is selected from
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is more preferable In embodiment, R2It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-(CH2)qOH、-NH2, halogen Element or phenyl, q 0,1 or 2, n 0,1,2 or 3.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is more preferable In embodiment, R2It is each independently selected from C1-C6Alkyl, halogenated C1-C6Alkyl or-NH2, n 0,1,2 or 3.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is more preferable In embodiment, R2It is each independently selected from C1-C4Alkyl, halogenated C1-C4Alkyl or-NH2, n 0,1,2 or 3.
In formula (I) of the present invention or an embodiment party of (II) compound, its pharmaceutically acceptable salt or stereoisomer In case, ring A is nitrogenous alicyclic heterocyclic base or nitrogenous aromatic heterocyclic containing 1,2,3,4 or 5 ring hetero atom selected from N, O or S, is led to N atom on ring is crossed to be connected with dihydro pyrido phthalazone parent nucleus.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is preferred real It applies in scheme, ring A is to pass through containing the nitrogenous alicyclic heterocyclic base or nitrogenous aromatic heterocyclic of 1~4 ring hetero atom selected from N, O or S N atom is connected with dihydro pyrido phthalazone parent nucleus on ring.
One in formula (I) of the present invention or (II) compound, its pharmaceutically acceptable salt or stereoisomer is preferred real It applying in scheme, ring A is the nitrogenous alicyclic heterocyclic base or nitrogenous aromatic heterocyclic that the ring hetero atom of N, O or S are selected from containing 1,2,3 or 4, It is connected by N atom on ring with dihydro pyrido phthalazone parent nucleus.
In the present invention, specific preferably logical formula (I) or (II) compound, its pharmaceutically acceptable salt or alloisomerism Body includes the following:
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4,3,2-de] Phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- Trifluoromethyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (3,5- dimethyl -1H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2- methyl-1 H-imidazole-1-group) -8,9- dihydro -2H- pyrido [4,3,2- De] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (3- trifluoromethyl -5,6- dihydro-[1,2,4] triazole [4,3-a] pyrazine -7 (8H)-yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1H- indazolyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (pyrrolidines -2,5- diketone -1- base) -8,9- dihydro -2H- pyrido [4,3,2- De] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (4,7- epoxy hexahydro iso-indoles -1,3 (2H)-diketone -2- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (4,7- epoxy -3a, 4,7,7a- tetrahydro iso-indoles -1,3 (2H)-diketone -2- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (4,7- epoxy -5- hydroxyl hexahydro iso-indoles -1,3 (2H)-diketone -2- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (iso-indoles -1,3- diketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2- De] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2- De] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- methyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- isopropyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- (2- ethoxy) -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrrole Pyridine simultaneously [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- cyclopropyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- cyclopenta -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1,5,5- trimethyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrrole Pyridine simultaneously [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- isopropyl -5,5- dimethyl -2,4- imidazolinedione -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl -5- phenyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- ((7aS)-tetrahydro-1 H-pyrrolo simultaneously [1,2-c] imidazoles -1,3 (2H)-diketone -2- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- ((S) -7a- methyl tetrahydro-1 H-pyrrolo simultaneously [1,2-c] imidazoles -1,3 (2H)-two Ketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- ((6R, 7aS) -6- hydroxy tetrahydro -1H- pyrrolo- [1,2-c] imidazoles -1,3 (2H)-diketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1,3- diaza spiro [3.4] octane -6,8- diketone -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1,3- diaza spiro [4.4] nonane -2,4- diketone -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1,3- diaza spiro [4.5] decane-2,4-diones -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2- oxygen -5,7- diaza spiro [3.4] octane -6,8- diketone -7- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2,5,7- thriazaspiros [3.4] octane -6,8- diketone -7- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2,4- thiazolidinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2- De] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- thiazolidinedione -3- base) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (oxazolidine -2,4- diketone -3- base) -8,9- dihydro -2H- pyrido [4,3,2- De] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5,5- dimethyl oxazolidine -2,4- diketone -3- base) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2H- benzo [e] [1,3] oxazines -2,4 (3H)-diketone -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (benzo [d] isothiazole -3 (2H) -one -1,1- dioxide -2- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl -3- amino -1H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrrole Pyridine simultaneously [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- isopropyl -1H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl-1 H- pyrazol-1-yl) -8,9- dihydro -2H- pyrido [4,3,2- De] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (2,4- difluorophenyl) -9- (5- methyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- methyl -2,4,5- imidazoline trione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- cyclobutyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- (azetidin -3- base) -2,4- imidazolinedione -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- (piperidin-4-yl) -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (3- methyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro -2H- pyrrole Pyridine simultaneously [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (4,4- dimethyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (8- oxo -6- thio -5,7- diaza spiro [3.4] octane -7- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (the thio tetrahydro-1 H-pyrrolo of (S) -1- oxo -3- simultaneously [1,2-c] imidazoles -2 (3H)-yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (3- cyclopropyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (7- oxo -5- thio -4,6- diaza spiro [2.4] heptane -6- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (3,4,4- trimethyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl -8- oxo -6- is thio -5,7- diaza spiro [3.4] octane -7- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (4- oxo -2- thio -1,3- diaza spiro [4.4] nonane -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (4,7- methylene -3a, 4,7,7a- tetrahydro iso-indoles -1,3 (2H)-diketone -2- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2- methyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2- butyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (6- methyl -8- oxo -5,7- diaza spiro-[3.4] octyl- 5- alkene -7- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl -7- oxo -4,6- diaza spiro-[2.4] hept- 4- alkene -6- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2,4,4- trimethyl -5- oxo -4,5- dihydro-IH- imidazoles -1- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2- methyl -5- oxo -4,5- dihydro -1H- imidazoles -1- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (1- methyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (1- methyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- imidazolinedione -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- imidazolinedione -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (5- methyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (5- methyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (5- methyl -8- oxo -6- is thio-and 5,7- diaza spiro [3.4] is pungent Alkane -7- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (5- methyl -8- oxo -6- is thio-and 5,7- diaza spiro [3.4] is pungent Alkane -7- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (2- methyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene - 3- yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (2- methyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene - 3- yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (2- butyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene - 3- yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (2- butyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene - 3- yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (6- methyl -8- oxo -5,7- diaza spiro-[3.4] octyl- 5- alkene - 7- yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (6- methyl -8- oxo -5,7- diaza spiro-[3.4] octyl- 5- alkene - 7- yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (5- methyl -7- oxo -4,6- diaza spiro-[2.4] hept- 4- alkene - 6- yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (5- methyl -7- oxo -4,6- diaza spiro-[2.4] hept- 4- alkene - 6- yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one.
The present invention also provides the method for preparing logical formula (II) compound, it the following steps are included:
Wherein, ring A, ring B, R1、R2、R3, m, n it is identical as the meaning in above-mentioned logical formula (II).
Raw material (a) obtains compound (b) through esterification；Compound (b) and tributyl (1- ethoxy ethylene base) tin exist Reaction obtains compound (c) under catalyst action；Compound (c) obtains compound (d) through reductive hydrolysis；Compound (d) and change It closes object (e) and obtains compound (f) through condensation reaction；Compound (f) obtains compound (g) through ring closure reaction；Compound (g) warp Boc protects to obtain compound (h)；Compound (h) reacts to obtain with trifluoromethanesulfonic acid t-butyldimethylsilyl ester in the presence of a base Compound (i)；Compound (i) is oxidized to obtain compound (j)；Compound (j) and hydrazine hydrate obtain compound through annulation (k)；Compound (k) deprotection obtains compound (1)；Compound (1) obtains intermediate 1 through chlorination reaction；Intermediate 1 withIt carries out substitution reaction and obtains compound (m)；Compound (m) removing Boc protecting group obtains formula (II) compound.
In the preparation method of the above-mentioned logical formula (II) compound of the present invention, compound (b) reaction obtain compound (c) be Carried out in the presence of catalyst, the catalyst include but is not limited to [1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride, Tetrakis triphenylphosphine palladium etc.；It includes iron powder that reductive hydrolysis compound (c), which obtains reducing agent used in compound (d) step,；Change The condensation reaction for closing object (d) and compound (e) is to carry out in presence of an acid, and the acid includes but is not limited to L-PROLINE, acetic acid Deng；The ring closure reaction of compound (f) is to carry out in the presence of a base, and the alkali includes but is not limited to sodium carbonate, potassium carbonate, carbonic acid Caesium, sodium ethoxide, sodium methoxide, potassium tert-butoxide etc.；Compound (h) reaction in the presence of a base obtains compound (i), wherein the alkali packet Include but be not limited to lithium hexamethyldisilazide, sodium hydrogen, lithium diisopropylamine etc.；The oxidant of oxidized compound (i) includes But it is not limited to metachloroperbenzoic acid；The deprotection reaction of compound (k) is carried out in the presence of tetrabutyl ammonium fluoride；Chemical combination Chlorination reagent used in the chlorination reaction of object (1) includes but is not limited to mesyl chloride, thionyl chloride etc.；Intermediate 1 withSubstitution reaction be to carry out in the presence of a base, the alkali includes but is not limited to potassium carbonate, sodium carbonate, bicarbonate Sodium, saleratus etc.；Above-mentioned Boc protection reaction and de- Boc protection reaction, are all to carry out under normal conditions.
The present invention also provides another method for preparing logical formula (II) compound, it the following steps are included:
Wherein, ring A, ring B, R1、R2、R3, m, n it is identical as the meaning in above-mentioned logical formula (II).
Intermediate 1 and hydrazine hydrate carry out substitution reaction and obtain compound (s)；Compound (s) obtains chemical combination through annulation Object (m)；Compound (m) takes off Boc protecting group and obtains formula (II) compound.
In the preparation method of the above-mentioned logical formula (II) compound of the present invention, compound (s) and corresponding reaction raw materials are frequent Rule method annulation obtains compound (m)；It is to carry out under normal conditions that compound (m), which takes off Boc protecting group,.
The present invention also provides another method for preparing logical formula (II) compound, it the following steps are included:
Wherein, ring A, ring B, R1、R2、R3, m, n it is identical as the meaning in above-mentioned logical formula (II).
Intermediate 1 is substituted with sodium azide to react to obtain compound (n)；Compound (n) is under the action of catalyst through hydrogen Change reduction and obtains compound (o)；Compound (o) reacts to obtain compound (p) in the presence of a base with thiophosgene；Compound (p) warp Annulation obtains compound (m)；Compound (m) takes off Boc protecting group and obtains formula (II) compound.
In the preparation method of the above-mentioned logical formula (II) compound of the present invention, urged used in catalytic hydrogen reduction compound (n) Agent includes but is not limited to palladium carbon, platinum dioxide；Compound (o) reacts to obtain compound (p) in the presence of a base with thiophosgene Alkali used in step includes but is not limited to triethylamine, diisopropylethylamine etc.；Compound (p) and corresponding reaction raw materials are frequent Rule method annulation obtains compound (m)；It is to carry out under normal conditions that compound (m), which takes off Boc protection,.
The present invention also provides 1 compound of intermediate of such as formula,
Wherein, R1For halogen, ring B is phenyl, R3For halogen, m is 1 or 2.
In the present invention, the abbreviation of agents useful for same respectively indicates:
- BOC tertbutyloxycarbonyl
- TBS t-Butyldimethylsilyl
Tris-HCl tri- (methylol) aminomethane-hydrochloric acid
DMSO dimethyl sulfoxide
In the present invention, " halogen " refers to fluorine, chlorine, bromine, iodine etc., preferably fluorine, chlorine, bromine, more preferable fluorine.
In the present invention, " C1-C6Alkyl " refers to the linear chain or branched chain hydrocarbon containing 1~6 carbon atom, including but not limited to Methyl, ethyl, propyl, isopropyl, butyl, isobutyl group, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methyl amyl, 2,2- dimethylbutyl, 2,3- dimethylbutyl；It is preferred that " C1-C4Alkyl ", including but not limited to methyl, second Base, propyl, isopropyl, butyl, isobutyl group, sec-butyl and tert-butyl；More preferable methyl, ethyl, propyl, isopropyl and butyl.
In the present invention, " C1-C6Alkoxy " refers to the alkoxy with 1 to 6 carbon atom, including but not limited to, such as Methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, amoxy, hexyloxy Deng；It is preferred that " C1-C4Alkoxy ", C1-C4Alkoxy refers to the alkoxy with 1 to 4 carbon atom, including but not limited to, methoxy Base, ethyoxyl, propoxyl group, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy, more preferable methoxyl group, second Oxygroup, propoxyl group, isopropoxy and butoxy.
In the present invention, " halogenated C1-C6Alkyl " refers to that, by one or more halogens, preferably one to five halogen atom replaces " C as defined herein1-C6Alkyl "；It is preferred that " halogenated C1-C4Alkyl ", including but not limited to trifluoromethyl, trifluoroethyl, two Chloro- 2 fluoro ethyl of methyl fluoride, 1- etc., more preferable trifluoromethyl and trifluoroethyl.
In the present invention, " alkenyl " refers to the monovalent radical that hydrocarbyl group derives, " C2-C6Alkenyl " refers to containing 2 to 6 carbon Atom and alkenyl at least containing a carbon-to-carbon double bond, including but not limited to, vinyl, acrylic, cyclobutenyl, 2- methyl -2- Butylene, 2- methyl -2- amylene and similar group.
In the present invention, " alkynyl " refers to the monovalent radical that hydrocarbyl group derives, " C2-C6Alkynyl " refers to containing 2 to 6 carbon Atom and alkynyl at least containing a carbon-carbon triple bond, including but not limited to, acetenyl, propinyl, 1- butynyl, 2- butine Base and similar group.
In the present invention, " deuterated C1-C6Alkyl " refers to " C as defined herein replaced by one or more D-atoms1- C6Alkyl ", including but not limited to-CD3、-CH2CD3、-C2D5、-C3D7、-CD(CD3)2、-CH2CH2CD3Deng preferably-CD3。
In the present invention, " hetero atom " refers to the atom in addition to carbon or hydrogen." hetero atom " mostly independently selected from N, O, S or P, but it is not limited to these atoms.There are in two or more heteroatomic embodiments, two or more hetero atoms that Some or all of this identical or two or more hetero atom are differing from each other.
In the present invention, " ring " refers to any covalence closed structure, ring (such as aryl and cycloalkanes including being full carbon atom Base) and (such as aromatic heterocyclic and alicyclic heterocyclic base) containing heteroatomic ring, or including monocycle, condensed ring, bridged ring and loop coil etc..
In the present invention, " condensed ring " refers to that wherein two rings share the ring group that the annular atom that two are connected directly is formed, it can be with Be saturation, part it is unsaturated or completely it is unsaturated, the atom for forming ring may include one or more ring hetero atoms.It is " thick Ring " includes fused ring bicyclic base and condensed ring polycyclic group.In some embodiments of the invention, condensed ring contain one or more carbonyls, Thiocarbonyl or sulfuryl, for example, containing aerobic or sulphur group." fused ring bicyclic base " citing include but is not limited to naphthalene, quinolyl, Indyl, " condensed ring polycyclic group " citing includes but is not limited to anthryl and phenanthryl.
In the present invention, " bridged ring " refers to that wherein two rings share the ring group that three or more annular atoms are formed, it can be Be saturated or part is unsaturated, and the atom for forming ring may include one or more ring hetero atoms." bridged ring " includes that bridged ring is bicyclic Base and bridged ring polycyclic group.In some embodiments of the invention, bridged ring contains one or more carbonyls, thiocarbonyl or sulfuryl, For example, containing aerobic or sulphur group." bridged ring bicyclic group " citing includes but is not limited to two rings [2.2.1] heptane base, two rings [3.2.1] octyl," bridged ring polycyclic group " illustrates But it is not limited to adamantyl.
In the present invention, " loop coil " refers to that wherein two rings share the ring group that an annular atom is formed, it can be saturation Or part is unsaturated, the atom for forming ring may include one or more ring hetero atoms.The shared annular atom of two rings is in loop coil Spiro-atom includes single loop coil, two loop coils, more loop coils etc. by the classification of spiro-atom number.In some embodiments of the invention, loop coil contains There are one or more carbonyls, thiocarbonyl or sulfuryl, for example, containing aerobic or sulphur group." single loop coil " citing includes but unlimited In 1- methylspiro [4.5] decyl, " two loop coils " citing includes but is not limited to two spiral shells [5.2.5.2] cetyl；" more loop coils " Citing includes but is not limited to three spiral shell [2.2.2.29.26.23] cetyl.
In the present invention, " annular atom " refers to form the atom of ring, including but not limited to C, N, O, P and S；" ring hetero atom " Refer to the annular atom in addition to C atom, including but not limited to N, O, P and S.In the present invention, described " N atom on ring " is finger-type The annular atom N atom of cyclization.
In the present invention, " naphthenic base " refers to the unsaturated aliphatic carbon cyclic group of saturation or part, including monocycle, bicyclic And polycyclic naphthene base, or including monocyclic cycloalkyl, condensed ring naphthenic base, bridged ring naphthenic base and loop coil naphthenic base etc..Monocyclic cycloalkyl Citing include but is not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclopropanyl, cyclobutane base, Cyclopentenyl, cyclohexenyl group and cycloheptenyl；Bicyclic cycloalkyl is illustrated Two rings [2.2.1] heptane base, two rings [3.2.1] octyl,1- methylspiro [4.5] Decyl,Polycyclic naphthene base is illustrated Adamantyl；Condensed ring naphthenic base is illustrated Bridged ring naphthenic base citing include but is not limited to two rings [2.2.1] heptane base, two rings [3.2.1] octyl, adamantyl andLoop coil naphthenic base citing include but is not limited to 1- methylspiro [4.5] decyl, two spiral shells [5.2.5.2] cetyl, Preferably comprise " 3~7 yuan of cycloalkanes of 3 to 7 annular atoms Base ", " 3~7 yuan of naphthenic base " includes but is not limited to cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclopropylene Base, cyclobutane base, cyclopentenyl, cyclohexenyl group and cycloheptenyl.
In the present invention, " alicyclic heterocyclic base " refers to that wherein forming one or more atoms of ring is heteroatomic non-aromatic ring Base." alicyclic heterocyclic base " includes the unsaturated " monocycle of saturation or part containing one or more ring hetero atoms selected from N, S or O Alicyclic heterocyclic base " has 3 to 8 annular atoms, preferably has 4 to 7 annular atoms；Containing one or more selected from N, S or O The saturation of ring hetero atom or part are unsaturated " condensed ring alicyclic heterocyclic base ", have 5 to 18 annular atoms, preferably have 7 to 16 A annular atom more preferably has 7 to 10 annular atoms；Saturation or portion containing one or more ring hetero atoms selected from N, S or O Dividing the unsaturated condensed ring alicyclic heterocyclic base with bridged ring is " bridged ring condensed ring alicyclic heterocyclic base ", has 6 to 20 annular atoms, preferably has There are 6 to 12 annular atoms, more preferably there are 7 to 10 annular atoms；Contain one or more ring hetero atoms selected from N, S or O Saturation or part are unsaturated " loop coil alicyclic heterocyclic base ", have 5 to 21 annular atoms, preferably have 5 to 12 annular atoms, more It is preferred that having 7 to 11 annular atoms；Saturation or part containing one or more ring hetero atoms selected from N, S or O are unsaturated " bridged ring alicyclic heterocyclic base " has 5 to 12 annular atoms, preferably has 6 to 10 annular atoms；Containing one or more selected from N, The unsaturated condensed ring alicyclic heterocyclic base with loop coil of the saturation of the ring hetero atom of S or O or part is " loop coil condensed ring alicyclic heterocyclic base ", With 7 to 22 annular atoms, preferably there are 9 to 18 annular atoms, more preferably there are 9 to 14 annular atoms；With containing one or The unsaturated loop coil alicyclic heterocyclic base with bridged ring of the saturation of multiple ring hetero atoms selected from N, S or O or part is " bridged ring loop coil rouge Heterocycle " has 7 to 22 annular atoms, preferably has 8 to 16 annular atoms.In some embodiments of the invention, rouge is miscellaneous Ring group, monocycle alicyclic heterocyclic base, condensed ring alicyclic heterocyclic base, bridged ring condensed ring alicyclic heterocyclic base, loop coil alicyclic heterocyclic base, bridged ring alicyclic heterocyclic base, spiral shell Ring condensed ring alicyclic heterocyclic base or bridged ring loop coil alicyclic heterocyclic base contain one or more carbonyls, thiocarbonyl or sulfuryl, for example, containing aerobic Or the group of sulphur." monocycle alicyclic heterocyclic base " citing includes but is not limited to THP trtrahydropyranyl, dihydro pyranyl, oxetanylmethoxy, sulphur Heterocycle butyl, piperidyl, 1,3- dioxanes base, Isosorbide-5-Nitrae-dioxanes base, piperazinyl, 1,3- thioxane base, Isosorbide-5-Nitrae-oxygen sulphur Heterocycle hexadienyl, Isosorbide-5-Nitrae-thioxane base, dimaleoyl imino, thiobarbituricacidα- base, dioxo piperazinyl, dihydro Uracil base, trioxane base, hexahydro -1,3,5-triazines base, tetrahydro-thienyl, tetrahydrofuran base, dihydrofuryl, pyrrolinone Base, imidazolinyl, 1,3- dioxa cyclopentenyl, 1,3- dioxolane base, 1,3- dithiole base, is disliked at pyrazolinyl Oxazoline base, thiazolinyl, 1,3- oxathiolane base, " condensed ring alicyclic heterocyclic base " illustrates " bridged ring condensed ring alicyclic heterocyclic base " illustrates " loop coil alicyclic heterocyclic base " illustrates " bridged ring rouge Heterocycle " is illustrated" loop coil condensed ring alicyclic heterocyclic base " Citing includes but is not limited to" bridged ring loop coil alicyclic heterocyclic base " illustrates
In the present invention, " nitrogenous alicyclic heterocyclic base " refers to that at least one annular atom is above-mentioned " the alicyclic heterocyclic base " of N atom, contains There is 1~5 (i.e. containing 1,2,3,4,5, preferably comprising 1,2,3,4) to be selected from the ring hetero atom of N, O or S, it is former by N on ring Son is connected with dihydro pyrido phthalazone parent nucleus, including nitrogenous monocycle alicyclic heterocyclic base, nitrogenous condensed ring alicyclic heterocyclic base, nitrogenous bridged ring are thick Ring grease heterocycle, nitrogenous loop coil alicyclic heterocyclic base, nitrogenous bridged ring alicyclic heterocyclic base, nitrogenous loop coil condensed ring alicyclic heterocyclic base and nitrogenous bridged ring spiral shell Ring grease heterocycle.In some embodiments of the invention, nitrogenous alicyclic heterocyclic base, nitrogenous monocycle alicyclic heterocyclic base, nitrogenous condensed ring rouge are miscellaneous Ring group, nitrogenous bridged ring condensed ring alicyclic heterocyclic base, nitrogenous loop coil alicyclic heterocyclic base, nitrogenous bridged ring alicyclic heterocyclic base, nitrogenous loop coil condensed ring rouge are miscellaneous Ring group or nitrogenous bridged ring loop coil alicyclic heterocyclic base contain one or more carbonyls, thiocarbonyl or sulfuryl, for example, containing aerobic or sulphur Group." the nitrogenous monocycle alicyclic heterocyclic base " refers to that at least one annular atom is above-mentioned " the monocycle alicyclic heterocyclic base " of N atom, contains 1~5 (contain 1,2,3,4,5, preferably comprise 1,2,3) is selected from ring hetero atom of N, O or S, by N atom on ring with Dihydro pyrido phthalazone parent nucleus be connected, have 3 to 8 annular atoms, preferably have 4 to 7 annular atoms, concrete example include but Be not limited to piperidyl, imidazolinyl, " nitrogenous condensed ring alicyclic heterocyclic base " refers to that at least one annular atom is above-mentioned " the condensed ring alicyclic heterocyclic base " of N atom, (i.e. containing 1~5 Containing 1,2,3,4,5,1,2,3,4 is preferably comprised) it is selected from the ring hetero atom of N, O or S, pass through N atom on ring and dihydro pyrrole Pyridine and phthalazone parent nucleus are connected, and have 5 to 18 annular atoms, preferably have 7 to 10 annular atoms, and concrete example includes but unlimited In " nitrogenous bridged ring condensed ring alicyclic heterocyclic base " refers to that at least one annular atom is the above-mentioned " bridged ring of N atom Condensed ring alicyclic heterocyclic base " is selected from the miscellaneous original of ring of N, O or S containing 1~5 (containing 1,2,3,4,5, preferably comprise 1,2,3) Son is connected by N atom on ring with dihydro pyrido phthalazone parent nucleus, has 6 to 20 annular atoms, preferably has 7 to 10 Annular atom, concrete example include but is not limited to " nitrogenous loop coil alicyclic heterocyclic base " refers to that at least one annular atom is above-mentioned " the loop coil alicyclic heterocyclic base " of N atom, (i.e. containing 1~5 Containing 1,2,3,4,5,1,2,3 is preferably comprised) it is selected from the ring hetero atom of N, O or S, pass through N atom and dihydropyridine on ring And phthalazone parent nucleus is connected, and has 5 to 21 annular atoms, preferably has 7 to 11 annular atoms, concrete example includes but is not limited to " nitrogenous bridge Ring grease heterocycle " refers to that at least one annular atom is above-mentioned " the bridged ring alicyclic heterocyclic base " of N atom, containing 1~5 (i.e. containing 1, 2,3,4,5,1,2,3 is preferably comprised) it is selected from the ring hetero atom of N, O or S, pass through N atom on ring and dihydro pyrido phthalazines Ketone parent nucleus is connected, and has 5 to 12 annular atoms, preferably has 6 to 10 annular atoms, concrete example includes but is not limited to" nitrogenous loop coil condensed ring alicyclic heterocyclic base " refer at least one annular atom be N atom above-mentioned " loop coil is thick Ring grease heterocycle " is selected from the miscellaneous original of ring of N, O or S containing 1~5 (containing 1,2,3,4,5, preferably comprise 1,2,3,4) Son is connected by N atom on ring with dihydro pyrido phthalazone parent nucleus, has 7 to 22 annular atoms, preferably has 9 to 14 Annular atom, concrete example include but is not limited to" nitrogenous bridged ring loop coil alicyclic heterocyclic base " refers at least one ring Atom is above-mentioned " the bridged ring loop coil alicyclic heterocyclic base " of N atom, containing 1~5 (contain 1,2,3,4,5, preferably comprise 1,2, 3) it is selected from the ring hetero atom of N, O or S, it is connected by N atom on ring with dihydro pyrido phthalazone parent nucleus, there are 7 to 22 Annular atom, preferably has 8 to 16 annular atoms, and concrete example includes but is not limited to
In the present invention, " aryl " refers to aromatic ring alkyl, has one or more aromatic rings, including monocyclic aryl and thick Cyclophane base, specific " monocyclic aryl " includes phenyl, and " fused ring aryl " includes but is not limited to naphthalene, anthryl, phenanthryl, preferably ring carbon Atomicity is 6 to 14, more preferably 6 to 10 aryl, such as phenyl and naphthalene, more preferable phenyl.
In the present invention, " aromatic heterocyclic " refers to the armaticity ring containing one or more ring hetero atoms selected from N, S or O Base, including monocycle aromatic heterocyclic and monocycle aromatic heterocyclic and monocycle aromatic heterocyclic, monocycle aromatic heterocyclic and it is aryl-condensed made of Condensed ring aromatic heterocyclic, monocycle aromatic heterocyclic have 5 to 6 annular atoms, and condensed ring aromatic heterocyclic has 8 to 14 annular atoms.It is described " monocycle aromatic heterocyclic " be specifically including but not limited to furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, Tetrazole radical, thiadiazolyl group, pyridyl group, pyrimidine radicals, pyridazinyl, pyrazinyl, It is preferred that pyridyl group, pyrimidine radicals, pyrazinyl, " the condensed ring aromatic heterocyclic " is specifically including but not limited to benzofuranyl, benzothienyl, diazosulfide Base, benzothiazolyl, isoindolyl, quinolyl, isoquinolyl, quinazolyl, indole-2-ketone base, It is preferred that
In the present invention, " nitrogenous aromatic heterocyclic " refers to that at least one annular atom is above-mentioned " aromatic heterocyclic " of N atom, contains 1~5 (containing 1,2,3,4,5, preferably comprise 1,2,3,4) is selected from the ring hetero atom of N, O or S, passes through N atom on ring It is connected with dihydro pyrido phthalazone parent nucleus, including nitrogenous monocycle aromatic heterocyclic and nitrogenous condensed ring aromatic heterocyclic." the nitrogenous list Cyclophane heterocycle " refers to that at least one annular atom is above-mentioned " the monocycle aromatic heterocyclic " of N atom, containing 1~5 (i.e. containing 1, 2,3,4,5,1,2,3 is preferably comprised) it is selected from the ring hetero atom of N, O or S, pass through N atom on ring and dihydro pyrido phthalazines Ketone parent nucleus is connected, and has 5 to 6 annular atoms, and concrete example includes but is not limited toIt is preferred that" contain Nitrogen condensed ring aromatic heterocyclic " is by above-mentioned " nitrogenous monocycle aromatic heterocyclic " and above-mentioned " monocycle aromatic heterocyclic " or above-mentioned " nitrogenous monocycle Aromatic heterocyclic " is condensed with above-mentioned " aryl " and is formed, and contains 1~5 (containing 1,2,3,4,5, preferably comprise 1,2,3) choosing From the ring hetero atom of N, O or S, it is connected by N atom on ring with dihydro pyrido phthalazone parent nucleus, there are 8 to 14 annular atoms, It is preferred that having 8 to 10 annular atoms, concrete example includes but is not limited to It is preferred that
In the present invention, " monocycle " includes " monocyclic cycloalkyl ", " monocyclic aryl ", " monocycle alicyclic heterocyclic base " and " monocycle virtue Heterocycle ".
In the present invention, " ring A is nitrogenous alicyclic heterocyclic base or nitrogenous virtue containing 1~5 ring hetero atom selected from N, O or S " 1~5 " includes 1,2,3,4 or 5, preferably 1,2,3 or 4 described in heterocycle ".
In the present invention, " x to y annular atom " refers to all naturally several annular atoms between x and y, and including x and y, Wherein x and y is random natural number and x is less than y, such as " 3 to 8 annular atoms " refers to 3,4,5,6,7,8 annular atoms.
In the present invention, " dihydro pyrido phthalazone parent nucleus " is such as flowering structure,
The present invention also includes formula (I) compound pharmaceutically acceptable salt.Term " pharmaceutically acceptable salt " refers to The acid-addition salts or base addition salts of the compounds of this invention of relative nontoxic.The acid-addition salts be formula (I) compound of the present invention and The salt that suitable inorganic acid or organic acid are formed, these salt can be prepared in the last separation of compound and purification process, or Person used can be such that formula (I) compound of purifying is reacted with suitable organic acid or inorganic acid with its free alkali form to make It is standby.Representative acid-addition salts include hydrobromate, hydrochloride, sulfate, disulfate, sulphite, acetate, oxalates, Valerate, oleate, palmitate, stearate, moon silicate, borate, benzoate, lactate, phosphate, phosphoric acid hydrogen Salt, carbonate, bicarbonate, toluate, citrate, maleate, fumarate, succinate, tartrate, benzene Formates, mesylate, tosilate, gluconate, Lactobionate and lauryl sulfonate etc..The base addition salts For the salt that formula (I) compound and suitable inorganic base or organic base are formed, including for example with alkali metal, alkaline-earth metal, quaternary ammonium The salt, such as sodium salt, lithium salts, sylvite, calcium salt, magnesium salts, tetramethyl based quaternary ammonium salt, tetrem based quaternary ammonium salt etc. that cation is formed；Amine salt, Including the salt formed with ammonia (NH3), primary amine, secondary amine or tertiary amine, such as methylamine salt, dimethylamine salt, front three amine salt, triethylamine salt, second Amine salt etc..
In some embodiments, compound described in the invention exists as stereoisomer, wherein in the presence of not right Title or chiral centre.Stereoisomer is named as (R) or (S) according to the substituent group configuration around asymmetric carbon atom.It retouches herein The embodiment stated particularly including various stereoisomers and its mixture.Stereoisomer include raceme, enantiomter, The mixture of diastereoisomer and enantiomer or diastereomer.In some embodiments, compound is each Stereoisomer is synthetically prepared from the commercial materials containing asymmetric or chiral centre, or by preparing racemic mixture, so After split and prepare.Method for splitting is for example: (1) by the mixture of enantiomter with chiral auxiliary in conjunction with, by recrystallization or The non-enantiomer mixture that chromatographic isolation obtains discharges optically pure product from auxiliary agent；Or (2) on chiral chromatographic column It is directly separated the mixture of optical enantiomorphs.
Formula (I) compound, its pharmaceutically acceptable salt or stereoisomer of the present invention can easily be given by any Medicine approach is administered to treatment object, can be whole body/periphery or applies in desired site of action, including but not limited to, warp Oral (such as ingesting), part (including for example transdermal, intranasal, eye, oral cavity and sublingual), lung (such as are passed through using aerosol Mouthful or nose sucking or be blown into treatment), rectum, vagina, parenterally (such as inject, including it is subcutaneous, intradermal, intramuscular, intravenous, Intra-arterial, intracardiac, intrathecal, vertebra is interior, under intracapsular, capsule, in eye socket, in peritonaeum, under intratracheal, epidermis, under intra-articular, arachnoid In breastbone), and implantation reservoir agent (such as being subcutaneously or intramuscularly implanted into).
Treatment object can be eucaryote, animal, vertebrate, mammal, rodent (such as cavy, hamster, Rat, mouse), murine (such as mouse), canid (such as dog), primate, anthropoid (such as monkey or anury Ape), monkey (such as marmoset, baboon), ape without tail (such as gorilla, chimpanzee, orangutan, gibbon) or the mankind.
Pharmaceutical composition of the present invention includes formula (I) compound of the present invention, its pharmaceutically acceptable salt or solid Isomers and pharmaceutically acceptable carrier, excipient or diluent etc..Formula (I) compound of the present invention, it can pharmaceutically connect The salt or stereoisomer received can mix system with pharmaceutical carrier, excipient, diluent etc. according to the pharmaceutical operation of standard Standby to obtain corresponding pharmaceutical composition, being administered to mammal includes the mankind.
Carrier, excipient and diluent of the present invention are referred to not causing apparent irritation to organism and not interfered Non-active ingredient in the pharmaceutical composition of the property of the bioactivity of given compound is specifically including but not limited to water, cream Sugar, glucose, fructose, sucrose, D-sorbite, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gel, alginates, silicon Sour calcium, calcium phosphate, cellulose, aqueous syrup, methylcellulose, polyvinylpyrrolidone, para hydroxybenzene and sorb dialkylaminobenzoic acid The various oil such as ester, talcum, magnesium stearate, stearic acid, glycerol, sesame oil, olive oil, soybean oil and its mixture.
Formula (I) compound, its pharmaceutically acceptable salt, stereoisomer or its pharmaceutical composition of the present invention can be made into system It includes the mankind that agent, which is administered to mammal,.Said preparation can be easily provided with unit dosage forms, and preferably ripe by pharmaceutical field The method known prepares said preparation.Such methods include joining the carrier of the compounds of this invention and the one or more auxiliary elements of composition The step of conjunction.In general, formula (I) compound of the present invention and the solid carrier or two kinds of carriers of liquid-carrier or fine segmentation is close Joint, to prepare preparation, then makes product shaping as needed.Preparation can be liquid, solution, suspension, emulsion, the wine made of broomcorn millet Agent, syrup, tablet, pastille, granule, pulvis, capsule, cachet, pill, ampulla, suppository, vaginal suppository, ointment, Gelling agent, paste, creme, spray, smoke agent, foaming agent, lotion, finish, bolus, electuary or aerosol form.
The preparation for being suitable for taking orally (such as ingesting) includes tablet, capsule, cachet, pulvis, granule, solution, hangs Supernatant liquid, emulsion, bolus, electuary or paste etc..
Tablet suitable for oral administration can be prepared by a conventional method, such as optionally with one or more auxiliary elements Compacting or molding.Compressed tablets can by suitable machine compress free-flowing form formula (I) compound of the present invention, its Pharmaceutically acceptable salt or stereoisomer (such as powder or particle) and prepare, formula (I) compound of the present invention, its pharmaceutically Acceptable salt or stereoisomer optionally with filler or diluent (such as starch, lactose, sucrose, microcrystalline cellulose, phosphorus Sour hydrogen calcium)；One or more adhesives (such as polyvinyl pyrrolidone, hydroxymethyl cellulose, starch, gelatin, gum arabic, D-sorbite, tragacanth, hydroxypropyl methyl cellulose, sucrose)；Disintegrating agent (such as sodium starch glycolate, crosslinked polyethylene pyrroles Ketone, croscarmellose sodium, agar, calcium carbonate, potato starch or tapioca, alginic acid)；Lubricant (such as it is stearic Or mixtures thereof sour magnesium, talcum, calcium stearate, solid polyethylene glycol, lauryl sodium sulfate etc.)；Surface-active or dispersion or Wetting agent (such as NaLS, cetanol, glycerin monostearate)；And preservative (such as methyl p-hydroxybenzoate, Propylparaben, sorbic acid) mixing.Molded tablet can be by will be wet with inert liquid diluent in suitable machine Profit containing formula (I) compound of the present invention, its pharmaceutically acceptable salt or stereoisomer mixture of powders plastotype and make It is standby.Can optionally tablet be coated or be delineated, and can be by preparing and formula (I) chemical combination of the present invention used by offer wherein The sustained release or controlled release of object, such as required release characteristic is provided using the hydroxypropyl methyl cellulose of different proportion.It can be optional Ground provides the tablet with casing, in the part enteral release in addition to stomach.
Liquid dosage form suitable for oral administration can be prepared by a conventional method, including but not limited to as the sheet of active constituent Invention formula (I) compound, its pharmaceutically acceptable salt or stereoisomer, the inert diluent routinely used in this field, Such as water and other solvents, solubilizer and emulsifier, for example, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3- Butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame Oil etc. or the mixture of these substances etc..Other than these inert diluents, fluid present invention dosage form also may include conven-tional adjuvants, Such as wetting agent, emulsifier and suspending agent, sweetener, corrigent and fragrance.
Preparation suitable for local administration (such as transdermal, intranasal, eye, oral cavity and sublingual) includes ointment, suppository, creme, outstanding Liquid, lotion, pulvis, solution, gelling agent etc..Formula (I) compound of the present invention, its pharmaceutically acceptable salt as active constituent Or stereoisomer or when necessary may be used aseptically with physiologically acceptable carrier and optional preservative, buffer The propellant that can be needed is mixed together.
Preparation suitable for local administration in mouth includes pastille (lozenge), including formula (I) compound of the present invention or its pharmacy Upper acceptable salt or stereoisomer, the matrix (such as sucrose, Arabic gum) by flavoring；Pastille (pastille), packet Include formula (I) compound or its pharmaceutically acceptable salt of the present invention, inert base (such as gelatin and glycerol)；And collutory, Including formula (I) compound of the present invention or its pharmaceutically acceptable salt or stereoisomer and suitable liquid-carrier.
It include ointment, creme and emulsion suitable for the preparation via dermal topical application.For ointment, including but it is unlimited In formula (I) compound of the present invention or its pharmaceutically acceptable salt or stereoisomer, suitable matrix (such as paraffin class, water Combination ointment bases), skin penetration enhancer (such as dimethyl sulfoxide)；For creme, formula (I) including but not limited to of the present invention Compound or its pharmaceutically acceptable salt or stereoisomer, suitable matrix (such as oil-in-water type cream base)；For Emulsion, formula (I) compound including but not limited to of the present invention or its pharmaceutically acceptable salt or stereoisomer, suitable matrix (such as emulsifier, emulsifier and fat, emulsifier and oil, emulsifier and fat and oil).
It include eye drops suitable for the preparation to topical ocular administration, including formula (I) compound of the present invention, it can pharmaceutically connect The salt or stereoisomer received are dissolved or are suspended in suitable carrier.
Preparation suitable for nasal administration includes the coarse powder that carrier is solid, and the mode of snuffing is taken to be administered；Carrier is liquid Aqueous solution or oil solution, for example, nasal spray, nasal drop or by atomizer with aerosol drug delivery etc..
Preparation suitable for rectally includes suppository, including formula (I) compound of the present invention or its pharmaceutically acceptable salt Or stereoisomer, suitable matrix (such as cocoa butter, salicylate).
Preparation suitable for vagina administration includes vaginal plug, spray, creme or gelling agent etc., including formula (I) of the present invention Close object or its pharmaceutically acceptable salt or stereoisomer and carrier appropriate known in the art.
Preparation suitable for parenteral (such as injecting, including epidermis, subcutaneous, intramuscular, intravenous and intradermal) administration includes Aqueous or non-aqueous physiologically acceptable aseptic injectable solution, dispersion liquid, suspension or lotion, and for re-dissolving At the aseptic powdery of sterile Injectable solution or dispersion liquid.Suitable carrier, diluent, solvent or excipient includes water, second Alcohol, polyalcohol and its suitable mixture.
In general, the adult suitable unit dose of formula (I) compound of the present invention be 0.1~500mg, preferably 0.1~ 250mg, further preferred 0.1~150mg, 0.3~120mg, 0.3~100mg, 0.3~80mg, 0.3~50mg, 0.5~ 50mg, 0.5~30mg or 0.5~10mg etc..When formula (I) compound of the present invention is salt, ester, prodrug etc., with parent compound Based on calculate amount of application.
Formula (I) compound, its pharmaceutically acceptable salt or stereoisomer of the present invention or its pharmaceutical composition can be with electricity It is administered in combination from radiation, one or more chemotherapeutics or combinations thereof for treating or preventing cancer.Particularly, formula (I) compound, its pharmaceutically acceptable salt or stereoisomer or its pharmaceutical composition can strengthen a large amount of cancer chemotherapies Therapeutic effect.The chemotherapeutics includes hdac inhibitor (such as Vorinostat for treating cancer (SAHA)), estrogenic agents (such as tamoxifen, Raloxifene, Idoxifene), androgen receptor modifier is (such as non- That male amine, abiraterone acetate), Retinoid receptor modulators (such as bexarotene), cytotoxicity/cytostatic agent { such as alkylating reagent (such as cyclophosphamide, Carmustine (BCNU), Temozolomide, cis-platinum, carboplatin), microtubule inhibitors/micro-pipe Stabilizer (such as taxol, vindesine sulfate, vincristine), topoisomerase enzyme inhibitor (such as Irinotecan, topotecan With rubitecan (rubitecan)), proteasome inhibitor (such as bortezomib) and ubiquitinbond enzyme inhibitor) }, anti-increasing Raw agent (such as capecitabine, Galocitabine), HMG-CoA reductase inhibitor (Lovastatin, Simvastatin), hiv protease suppression Preparation, angiogenesis inhibitors (such as tyrosine kinase inhibitor), hyperplasia and the (inhibition of such as EGFR of survival signaling inhibitor Agent such as Gefitinib and Tarceva, the inhibitor of ERB-2 such as Herceptin, the inhibitor of IGFR such as WO03/ Disclosed in 059951 those, the inhibitor of cytokine receptor, the inhibitor of PI3K such as LY294002, the suppression of Raf kinases Preparation such as BAY-43-9006, the inhibitor of MEK such as PD-098059) etc..The compounds of this invention is common with radiotherapy It is especially effective when application.
Formula (I) compound, its pharmaceutically acceptable salt or stereoisomer of the present invention or its pharmaceutical composition equally may be used To be combined with non-anticancer drug.Such as with PPAR- γ (PPAR-gamma) agonist and PPAR- δ (PPAR-delta) agonist Combination medicine can be used for treating certain cancers；Combine with antiviral agent (such as nucleoside analog Ganciclovir) for treating cancer Disease；Combine with gene therapy for treating cancer；MDR related with the high level expression of transport protein inhibitor (such as LY335979, Verapamil) it is administered in combination；(such as antagonists of neurokinine-1 receptor or 5HT3 receptor antagonist are such as with antiemetic Ondansetron, Granisetron) it is used in combination, treatment may cause because being used alone or being used together the compounds of this invention with radiotherapy Nausea or vomiting, including acute, Delayed onset, later period and anticipatory emesis etc..
Testing proves that the logical formula (I) compound of the present invention has cancer cell increment inhibiting effect, can be used for treating cancer and system It is ready for use on the drug for the treatment of cancer.The compounds of this invention inhibits the drug effect of cancer cell multiplication that can be measured with conventional method, Yi Zhongyou The evaluation method of choosing be Sulforhodamine B (SulforhodamIne B, SRB) protein staining method, by measurement drug effect in The variation of generated absorbance value is after cancer cell to calculate drug to the inhibiting rate of cancer cell multiplication.
Inhibiting rate (%)=[(blank control OD- dosing OD)/blank control OD] × 100%
Blank control OD: refer to the OD value in the hole of the cell of no drug effect normal growth.
Dosing OD: refer to the OD value that the hole of cell of compound effects to be screened is added.
Half inhibitor concentration (IC50) value use 5.0 version of GraphPad company PrIsm software, four parameter fitness methods It calculates.Each experiment is repeated 3 times, and finds out the average IC of 3 experiments50Value is the final index of rejection ability.
The present invention, which leads to formula (I) compound, has apparent inhibitory activity to PARP-1 and PARP-2 enzyme in molecular level.This Invention compound can measure by conventional method in inhibitory activity of the molecular level to PARP-1 and PARP-2 enzyme, a kind of preferred Method are as follows: histone is enclosed in 96 orifice plates and 4 DEG C of overnight incubations, washs this with 200 μ L PBST (phosphate buffer) solution After plate 3 times, it is closed with confining liquid, after incubation at room temperature 30 minutes, is washed 3 times with PBST solution.At tested compound Reason is added in orifice plate, will be added to reactant in PARP-2 (3nM) solution of the diluted PARP-1 of 20 μ L (1nM) or 20 μ L later It is incubated for 1 or 2 hour in system.The mixed liquor of 50 μ L Streptavidin-HRP (horseradish peroxidase) (1: 50) is added in orifice plate And after being incubated at room temperature 30 minutes, PBST buffer is washed three times.Orifice plate is added in 100 μ L HRP chemiluminescent substrate mixtures.It is vertical It arrives on microplate reader (Envision, PerkinElmer) and reads.Compound is obtained to PARP-1 and PARP-2 enzyme by calculating again The IC50 value of inhibitory activity.
The present invention, which leads to formula (I) compound, has good pharmacokinetic property, test method are as follows: healthy SD rat, it will The compounds of this invention presses doses gastric infusion.Fasting 12h, free water before testing.2h is unified after administration feeds.Stomach-filling is given 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and for 24 hours after medicine, through rat eye rear vein beard extracting vein blood, separation prepares blood plasma, with The concentration of compound in liquid chromatography-tandem mass spectrometry blood plasma；The compounds of this invention is pressed doses by healthy SD rat Intravenously administrable.Fasting 12h, free water before testing.2h is unified after administration feeds.0.08h, 0.25h after intravenously administrable, 0.5h, 1h, 2h, 4h, 6h, 8h and for 24 hours, through rat eye rear vein beard extracting vein blood, separation prepares blood plasma, with liquid chromatography-tandem matter Spectrometry measures the concentration of compound in blood plasma.
The present invention leads to formula (I) compound and inhibits the drug effect of animal-transplanted tumor growth that can be measured with conventional method, a kind of preferred Evaluation method be to the growth inhibition effect of people's triple negative breast cancer cell MDA-MB-436 nude mouse subcutaneous transplantation tumor.Experiment Method: people triple negative breast cancer cell MDA-MB-436 cell strain (5 × 106A/only) it is inoculated in back on the right side of BALB/cA nude mouse Portion is subcutaneous.To tumour growth to 100-200mm3When be grouped at random according to tumor size and mouse weight.It tests compound and presses one Determine dosage gastric infusion, solvent control group stomach-filling is given equivalent solvent, is administered once a day, and successive administration 20 days.Entire experiment In the process, the size for measuring the weight and tumour of mouse twice weekly, sees whether toxic reaction occur.Gross tumor volume (tumor Volume calculation formula) are as follows: TV=1/2 × a × b2, wherein a, b respectively indicate tumour length and width.
Detailed description of the invention
Attached drawing 1 is the people's triple negative breast cancer cell MDA- of compound 56 and LT-00628 under 1mg/kg dosage The tumor volume change curve of MB-436 nude mouse subcutaneous transplantation tumor.
Attached drawing 2 is the people's triple negative breast cancer cell MDA- of compound 56 and LT-00628 under 1mg/kg dosage The changes of weight curve of MB-436 nude mouse.
Present invention will be further explained below with reference to specific examples.It should be understood that these embodiments are only used for illustrating this It invents rather than limits the scope of the invention.In the following examples, the experimental methods for specific conditions are not specified, usually according to normal Rule condition, or according to the normal condition proposed by manufacturer.Unless otherwise stated, otherwise parts and percentages be respectively parts by weight and Weight percent.
Specific embodiment
I. the compounds of this invention prepares embodiment
The chloro- 8- of the fluoro- 9- of intermediate 1a:5- (4- fluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3- Ketone -7- carboxylic acid tert-butyl ester (intermediate 1a)
The fluoro- 3- nitrobenzoyl tert-butyl acrylate of the bromo- 5- of step 1:2-
The fluoro- 3- nitrobenzoic acid (274g, 1.038mol) of the bromo- 5- of 2- and the tert-butyl alcohol (660mL, 7mol) are dissolved in methylene chloride (2L) adds anhydrous magnesium sulfate (600g, 5mol) and the concentrated sulfuric acid (55mL, 1.038mol).It is stirred to react at room temperature 2 days.Instead Liquid is answered to be filtered with diatomite, methylene chloride washing.Dichloromethane layer is successively washed with water, saturated sodium bicarbonate solution, anhydrous sulphur Sour magnesium dries, filters.Residue is purified through silica gel column chromatography (petrol ether/ethyl acetate=20/1, v/v) after filtrate concentration, is obtained To product 132g (yield 39.9%).1H NMR (400MHz, DMSO-d6) δ 8.25 (dd, J=7.8,3.0Hz, 1H), 7.93 (dd, J=8.2,3.0Hz, 1H), 1.57 (s, 9H).
The fluoro- 3- nitrobenzoyl tert-butyl acrylate of step 2:2- (1- ethoxy ethylene base) -5-
The fluoro- 3- nitrobenzoyl tert-butyl acrylate (72.4g, 0.227mol) of the bromo- 5- of 2-, tributyl (1- ethoxy ethylene base) tin (98g, 0.27mol), [1,1 '-bis- (diphenylphosphino) ferrocene] palladium chloride (6g, 8.56mmol) are dissolved in dioxane (500mL).80 DEG C are warming up under argon gas protection to react 5 hours, are cooled to room temperature.Dihydrate of potassium fluoride (21g) is dissolved in 250mL water Solution be added reaction solution in, stir 1 hour.Reaction solution is filtered with diatomite, ethyl acetate washing.The organic layer water separated Washing 2 times, anhydrous magnesium sulfate dries, filters.It is concentrated under reduced pressure, residue is through silica gel column chromatography (petrol ether/ethyl acetate=50/ 1, v/v) it purifies, obtains 70.6g product (yield 100%).1H NMR (400MHz, CDCl3) δ 7.58 (m, 2H), 4.38 (d, J= 3.1Hz, 1H), 4.23 (d, J=3.1Hz, 1H), 3.90 (q, J=7.0Hz, 2H), 1.56 (s, 9H), 1.33 (t, J=7.0Hz, 3H)。
The step 3:2- acetyl group -3- amino-5-fluorobenzoic acid tert-butyl ester
The fluoro- 3- nitrobenzoyl tert-butyl acrylate (36.5g, 0.117mol) of 2- (1- ethoxy ethylene base) -5-, reduced iron powder (26.3g, 0.47mol) and ammonium chloride (12.5g, 0.235mol) are added to ethyl alcohol (200mL)-water (50mL) in the mixed solvent.It rises Temperature is stayed overnight to 85 DEG C of reactions.Reaction solution is filtered with diatomite, ethanol washing, is concentrated under reduced pressure.It is added ethyl acetate (750mL), according to It is secondary to be washed with saturated sodium bicarbonate solution, saturated sodium chloride solution.Organic layer is dry with anhydrous magnesium sulfate, filters.It is concentrated under reduced pressure Gained residue is purified through silica gel column chromatography (petrol ether/ethyl acetate=9/1, v/v), obtains 27.5g product (yield 92.9%) 。1H NMR (400MHz, CDCl3) δ 6.84 (dd, J=8.8,2.4Hz, 1H), 6.50 (dd, J=10.1,2.4Hz, 1H), 4.74 (s, 2H), 1.55 (s, 9H).
Step 4:(E) the fluoro- 3- of -2- acetyl group -5- ((4- fluorine benzal) amino) t-butyl perbenzoate
2- acetyl group -3- amino-5-fluorobenzoic acid the tert-butyl ester (25.6g, 101.2mmol), 4-Fluorobenzaldehyde (12.55g, 101.2mmol) and L-PROLINE (3.5g, 30.36mmol) is dissolved in methanol (100mL).It is stirred overnight at room temperature.It filters, collects analysis Solid out, solid are washed with methanol, obtain white solid.After part methanol is evaporated off in filtrate decompression, one day is stood, and have solid analysis Out.Filtering, washs to obtain white solid with methanol.Merge the resulting white solid of filtering and obtains 27.4g product (yield 75.4%).1H NMR (400MHz, CDCl3) δ 8.36 (s, 1H), 7.88-7.83 (m, 2H), 7.48 (dd, J=8.9,2.4Hz, 1H), 7.15 (t, J=8.6Hz, 2H), 6.97 (dd, J=9.0,2.4Hz, 1H), 2.63 (s, 3H), 1.58 (s, 9H).
The fluoro- 2- of step 5:7- (4- fluorophenyl) -2,3- dihydroquinoline -4 (1H) -one -5- t-butyl formate
(E) the fluoro- 3- of -2- acetyl group -5- ((4- fluorine benzal) amino) t-butyl perbenzoate (27.4g, 76.3mmol), carbonic acid Caesium (7.4g, 22.9mmol) is heated to 60 DEG C in acetonitrile (250mL) and reacts 5 hours.Filtering, filtrate decompression concentration, residue By silica gel chromatography column (petrol ether/ethyl acetate=4/1, v/v) purifying, obtains 22.4g product (yield 81.8%).MS (ESI): 358.1[M-H]-。1H NMR (400MHz, DMSO-d6) δ 7.62 (s, 1H), 7.54 (dd, J=8.6,5.5Hz, 2H), 7.24 (t, J=8.9Hz, 2H), 6.67 (dd, J=9.0,2.4Hz, 1H), 6.38 (dd, J=8.5,2.4Hz, 1H), 4.85 (dd, J= 12.1,4.2Hz, 1H), 2.88 (dd, J=16.0,12.2Hz, 1H), 2.67 (dd, J=16.0,3.8Hz, 1H), 1.52 (s, 9H)。
The fluoro- 2- of step 6:N- tert-butoxycarbonyl -7- (4- fluorophenyl) -2,3- dihydroquinoline -4- ketone -5- t-butyl formate
The fluoro- 2- of 7- (4- fluorophenyl) -2,3- dihydroquinoline -4 (1H) -one -5- t-butyl formate (21.4g, 59.61mmol), n,N-diisopropylethylamine (8.51g, 65.97mmol), 4-dimethylaminopyridine (700mg, 5.74mmol) and Di-tert-butyl dicarbonate (14.3g, 65.6mmol) is dissolved in methylene chloride (250mL).It is stirred overnight at room temperature.It is concentrated under reduced pressure, it is remaining Object by silica gel chromatography column (petrol ether/ethyl acetate=10/1, v/v) purifies to obtain 16g product (yield 58.5%).1H NMR (400MHz, DMSO-d6) δ 7.71 (dd, J=11.6,2.4Hz, 1H), 7.27 (dd, J=8.4,5.4Hz, 2H), 7.18-7.08 (m, 2H), 6.99 (dd, J=8.0,2.5Hz, 1H), 6.03 (d, J=5.2Hz, 1H), 3.51 (dd, J=17.8,5.9Hz, 1H), 3.29 (dd, J=17.8,2.1Hz, 1H), 1.54 (s, 9H), 1.49 (s, 9H).
The fluoro- 2- of step 7:7- (4- fluorophenyl) -4- (tertiary butyl dimethyl Si base) -1,2- dihydroquinoline -1,5- dicarboxyl Tert-butyl acrylate
The fluoro- 2- of N- tert-butoxycarbonyl -7- (4- fluorophenyl) -2,3- dihydroquinoline -4- ketone -5- t-butyl formate (9g, It 19.61mmol) is dissolved in tetrahydrofuran (100mL), is cooled to -70 DEG C.The lithium hexamethyldisilazide tetrahydro of 1mol/L is added dropwise Tetrahydrofuran solution (59mL, 58.82mmol), control temperature are no more than -60 DEG C.Continue stirring 1 hour after dripping off.Fluoroform is added dropwise again Tetrahydrofuran (50mL) solution of sulfonic acid t-butyldimethylsilyl ester (9.2g, 34.88mmol), control dropping temperature be no more than- 60 DEG C, continue stirring 30 minutes.It is added saturated ammonium chloride (100mL), is warming up to room temperature naturally.It is added ethyl acetate (500mL), Separate organic layer.Organic layer is washed 2 times with saturated sodium chloride solution, and anhydrous magnesium sulfate dries, filters, and is concentrated under reduced pressure, residue 9.3g product (yield 82.8%) is purified to obtain through silica gel column chromatography (petrol ether/ethyl acetate=50/1, v/v).1H NMR (400MHz, CDCl3) δ 7.39-7.32 (m, 2H), 7.24-7.17 (m, 1H), 6.97-6.92 (m, 1H), 6.92-6.85 (m, 2H), 6.20 (d, J=7.3Hz, 1H), 5.55 (d, J=7.5Hz, 1H), 1.60 (s, 9H), 1.57 (s, 9H), 0.87 (s, 9H), 0.21 (s, 3H), 0.12 (s, 3H).
- 4 (1H) -one -1 of the fluoro- 2- of step 8:7- (4- fluorophenyl) -3- tertiary butyl dimethyl Si base -2,3- dihydroquinoline, 5- dicarboxyl tert-butyl acrylate
The fluoro- 2- of 7- (4- fluorophenyl) -4- (tertiary butyl dimethyl Si base)-tertiary fourth of 1,2- dihydroquinoline -1,5- dicarboxylic acids Ester (9g, 15.71mmol) is dissolved in methylene chloride (70mL), adds metachloroperbenzoic acid (5.4g, 31.41mmol), room It is stirred to react under temperature 5.5 hours.Reaction solution becomes muddy from clarifying, and filtering, methylene chloride washs solid.Filtrate successively uses 10% Solution of sodium bisulfite washs 1 time, saturated sodium chloride solution washing 2 times, and anhydrous magnesium sulfate dries, filters, and is concentrated under reduced pressure to obtain production Object is directly used in and reacts in next step.MS (ESI): 590.2 [M+H]+。1H NMR (400MHz, CDCl3) δ 7.69 (dd, J= 11.4,2.4Hz, 1H), 7.12 (dd, J=8.5,5.2Hz, 2H), 6.99-6.92 (m, 2H), 6.78 (dd, J=7.6,2.4Hz, 1H), 5.88 (d, J=3.2Hz, 1H), 4.43 (d, J=3.5Hz, 1H), 1.58 (s, 9H), 1.56 (s, 9H), 0.90 (s, 9H), 0.20 (s, 3H), 0.12 (s, 3H).
The fluoro- 8- of step 9:5- (4- fluorophenyl) -9- tertiary butyl dimethyl Si base -8,9- dihydro -2H- pyrido [4,3, 2-de] phthalazines -3- ketone -7- carboxylic acid tert-butyl ester
The fluoro- 2- of 7- (4- fluorophenyl) -3- tertiary butyl dimethyl Si base -2,3- dihydroquinoline -4 prepared by previous step It is dissolved in methanol (200mL), is added 80% hydrazine hydrate (10mL, 206mmol), at room temperature in (1H) -one -1,5- dicarboxyl tert-butyl acrylate Reaction is overnight.It is concentrated under reduced pressure, residue purifies to obtain 5.1g product through silica gel column chromatography (petrol ether/ethyl acetate=5/1, v/v) (61.4%, two step yields).MS (ESI): 530.2 [M+H]+。1H NMR (400MHz, CDCl3) δ 11.52 (s, 1H), 8.15 (d, J=9.3Hz, 1H), 7.75 (dd, J=7.9,2.4Hz, 1H), 7.05 (dd, J=8.5,5.2Hz, 2H), 6.93-6.85 (m, 2H), 6.07 (s, 1H), 5.14 (d, J=3.0Hz, 1H), 1.62 (s, 9H), 0.88 (d, J=2.7Hz, 9H), 0.28 (s, 3H), 0.01 (s, 3H).
The fluoro- 8- of step 10:5- (4- fluorophenyl) -9- hydroxyl -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3- Ketone -7- carboxylic acid tert-butyl ester
The fluoro- 8- of 5- (4- fluorophenyl) -9- tertiary butyl dimethyl Si base -8,9- dihydro -2H- pyrido [4,3,2-de] phthalein Piperazine -3- ketone -7- carboxylic acid tert-butyl ester (2.8g, 5.29mmol) is dissolved in tetrahydrofuran (20mL), addition tetrabutyl ammonium fluoride (2.07g, 7.94mmol), reaction 4.5 hours is stirred at room temperature.It is concentrated under reduced pressure, residue by silica gel chromatography column (petrol ether/ethyl acetate =1/2, v/v) purifying obtain 2.1g product (yield 95.7%).MS (ESI): 416.1 [M+H]+。1H NMR (400MHz, DMSO- D6) δ 12.75 (s, 1H), 8.19 (dd, J=12.0,2.2Hz, 1H), 7.60 (dd, J=8.2,2.5Hz, 1H), 7.24-7.14 (m, 2H), 7.13-6.99 (m, 2H), 6.25 (d, J=3.9Hz, 1H), 6.00-5.94 (m, 1H), 5.07-4.99 (m, 1H), 1.53 (s, 9H).
The chloro- 8- of the fluoro- 9- of step 11:5- (4- fluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3- ketone - 7- carboxylic acid tert-butyl ester (intermediate 1a)
The fluoro- 8- of 5- (4- fluorophenyl) -9- hydroxyl -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3- ketone -7- carboxylic acid The tert-butyl ester (3.Sg, 9.157mmol), triethylamine (3.8mL, 27.47mmol) are dissolved in tetrahydrofuran (30mL).It is cooled to 0 DEG C of left side The right side is added mesyl chloride (0.8mL, 10.34mmol), then reacts 1.5 hours at room temperature.It is added ethyl acetate (120mL), Successively with 10% citric acid solution, saturated common salt water washing, anhydrous magnesium sulfate is dried, filtered, and is concentrated under reduced pressure, and is added in residue Ethyl acetate, mashing handle to obtain 2.6g white solid (yield 57.6%).MS (ESI): 434.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.96 (s, 1H), 8.22 (dd, J=11.7,2.4Hz, 1H), 7.65 (dd, J=8.2,2.5Hz, 1H), 7.33 (dd, J=8.4,5.4Hz, 2H), 7.09 (dd, J=12.3,5.4Hz, 2H), 6.23 (s, 1H), 6.08 (d, J=2.8Hz, 1H), 1.55 (s, 9H).
The fluoro- 8- of embodiment 1:5- (4- fluorophenyl) -9- (1H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 1)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
The chloro- 8- of the fluoro- 9- of 5- (4- fluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3- ketone -7- carboxylic acid uncle Butyl ester (intermediate 1a, 50mg, 0.115mmol), 1,2,4- triazoles (21mg, 0.303mmol) and potassium carbonate (41mg, N,N dimethylformamide (0.5mL) is added in 0.3mmol), is stirred to react at room temperature overnight.Ethyl acetate is added, successively uses Water, saturated common salt water washing, anhydrous magnesium sulfate dry, filter, and are concentrated under reduced pressure, and residue is prepared thin layer chromatography (petroleum Ether/ethyl acetate=1/2, v/v), obtain product 39mg (yield 72%).MS (ESI): 467.1 [M+H]+。1H NMR (400MHz, CDCl3) δ 8.82 (s, 1H), 8.10 (dd, J=11.5,2.5Hz, 1H), 7.96 (s, 1H), 7.64 (dd, J= 8.3,2.5Hz, 1H), 7.40 (dd, J=8.3,5.4Hz, 2H), 7.13 (dd, J=12.2,5.4Hz, 2H), 6.51 (d, J= 2.3Hz, 1H), 6.29 (s, 1H), 1.36 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4,3,2-de] Phthalazines -3- ketone -7- carboxylic acid tert-butyl ester (36mg, 0.077mmol) is dissolved in methylene chloride (1mL), is added trifluoroacetic acid (0.5mL), It is stirred to react at room temperature 2 hours.Evaporating solvent under reduced pressure, residue are dissolved in ethyl acetate (20mL), successively use saturated sodium bicarbonate Solution, water washing, anhydrous sodium sulfate dry, filter concentration, residue prepared thin layer chromatography (methylene chloride/methanol= 20/1, v/v) product 25mg (yield 88%), is obtained.MS (ESI): 367.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.51 (s, 1H), 8.48 (s, 1H), 7.96 (s, 1H), 7.84 (s, 1H), 7.43 (dd, J=8.2,5.6Hz, 2H), 7.18 (t, J=8.7Hz, 2H), 7.12 (dd, J=8.9,2.0Hz, 1H), 6.96 (dd, J=11.0,2.0Hz, 1H), 6.08 (d, J= 10.1Hz, 1H), 5.15 (d, J=10.1Hz, 1H).
The fluoro- 8- of embodiment 2:5- (4- fluorophenyl) -9- (5- Trifluoromethyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 2)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (5- Trifluoromethyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 5- Trifluoromethyl-1 H-1,2,4- triazoles and intermediate 1a reaction preparation.MS (ESI): 535.1 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (5- Trifluoromethyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 435.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.51 (s, 1H), 8.42 (s, 1H), 7.92 (s, 1H), 7.47 (dd, J=8.5,5.5Hz, 2H), 7.20 (t, J=8.8Hz, 2H), 7.14 (dd, J=8.9,2.3Hz, 1H), 6.98 (dd, J=11.1,2.4Hz, 1H), 6.15 (d, J=10.7Hz, 1H), 5.26 (d, J =10.7Hz, 1H).
The fluoro- 8- of embodiment 3:5- (4- fluorophenyl) -9- (3,5- dimethyl -1H-1,2,4- triazol-1-yls) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 3)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (3,5- dimethyl -1H-1,2,4- triazol-1-yls) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 3,5- dimethyl -1H-1,2,4- triazoles and intermediate 1a reaction preparation.Yield is 53%.MS (ESI): 495.2 [M+H]+。1H NMR (400MHz, CDCl3) δ 11.08 (s, 1H), 7.99 (d, J=9.5Hz, 1H), 7.78 (dd, J=8.0,2.4Hz, 1H), 7.16 (dd, J=8.7,5.1Hz, 2H), 6.98 (t, J=8.5Hz, 2H), 6.25 (s, 1H), 5.74 (d, J=1.8Hz, 1H), 2.66 (s, 3H), 2.19 (s, 3H), 1.51 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (3,5- dimethyl -1H-1,2,4- triazol-1-yls) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.Yield is 80%.MS (ESI): 395.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.45 (s, 1H), 7.77 (s, 1H), 7.46 (dd, J=8.5,5.6Hz, 2H), 7.20 (t, J=8.8Hz, 2H), 7.12 (dd, J=8.9,2.3Hz, 1H), 6.95 (dd, J=11.1,2.4Hz, 1H), 5.93 (d, J=11.0Hz, 1H), 5.05 (d, J= 11.0Hz, 1H), 2.14 (s, 3H), 2.04 (s, 3H).
The fluoro- 8- of embodiment 4:5- (4- fluorophenyl) -9- (2- methyl-1 H-imidazole-1-group) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 4)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (2- methyl-1 H-imidazole-1-group) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 2- methyl-1 H- imidazoles and intermediate 1a reaction preparation.MS (ESI): 480.2 [M+ H]+。1H NMR (400MHz, DMSO-d6) δ 13.04 (s, 1H), 8.13 (dd, J=11.3,2.5Hz, 1H), 7.68 (dd, J= 8.3,2.5Hz, 1H), 7.42 (dd, J=8.4,5.3Hz, 2H), 7.13 (t, J=8.8Hz, 2H), 6.71 (s, 1H), 6.41 (s, 1H), 6.20 (s, 1H), 6.10 (s, 1H), 2.67 (s, 3H), 1.34 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (2- methyl-1 H-imidazole-1-group) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 380.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.48 (s, 1H), 7.86 (s, 1H), 7.44 (dd, J=8.5,5.5Hz, 2H), 7.25 (s, 1H), 7.19 (t, J=8.8Hz, 2H), 7.12 (dd, J=8.9,2.4Hz, 1H), 6.97 (dd, J=11.1,2.4Hz, 1H), 6.78 (s, 1H), 5.74 (d, J=11.1Hz, 1H), 5.03 (d, J=11.1Hz, 1H), 1.96 (s, 3H).
The fluoro- 8- of embodiment 5:5- (4- fluorophenyl) -9- (3- trifluoromethyl -5,6- dihydro-[1,2,4] triazole [4,3-a] pyrrole Piperazine -7 (8H)-yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 5)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (3- trifluoromethyl -5,6- dihydro-[1,2,4] triazole [4,3-a] pyrrole Piperazine -7 (8H)-yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 3- (trifluoromethyl) -5,6,7,8- tetrahydros-[1,2,4] triazol [4,3-a] pyrazine Hydrochloride and intermediate 1a reaction preparation.MS (ESI): 590.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.85 (s, 1H), 8.12 (dd, J=11.6,2.4Hz, 1H), 7.60 (dd, J=8.3,2.5Hz, 1H), 7.26 (dd, J=8.6,5.4Hz, 2H), 7.06 (dd, J=12.3,5.4Hz, 2H), 6.36 (s, 1H), 4.41 (d, J=2.5Hz, 1H), 4.24 (d, J= 15.6Hz, 1H), 4.15-4.04 (m, 2H), 4.04-3.96 (m, 1H), 3.27 (dt, J=18.6,5.7Hz, 1H), 3.18- 3.09 (m, 1H), 1.45 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (3- trifluoromethyl -5,6- dihydro-[1,2,4] triazole [4,3-a] pyrrole Piperazine -7 (8H)-yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 490.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.53 (s, 1H), 7.81 (d, J=2.1Hz, 1H), 7.38 (dd, J=8.7,5.5Hz, 2H), 7.15 (t, J=8.8Hz, 2H), 7.01 (dd, J=9.0,2.4Hz, 1H), 6.93 (dd, J=11.2,2.4Hz, 1H), 5.09 (dd, J=4.8,2.1Hz, 1H), 4.33 (d, J =15.7Hz, 1H), 4.21 (d, J=5.2Hz, 1H), 4.16 (d, J=15.7Hz, 1H), 4.03 (dd, J=8.8,3.5Hz, 2H), 3.40-3.31 (m, 1H), 3.13-3.02 (m, 1H).
The fluoro- 8- of embodiment 6:5- (4- fluorophenyl) -9- (1H- indazolyl) -8,9- dihydro -2H- pyrido [4,3,2-de] Phthalazines -3 (7H) -one (compound 6)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1H- indazolyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalein Piperazine -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By indazole and intermediate 1a reaction preparation.Yield is 46%.MS (ESI): 516.2 [M+ H]+。1H NMR (400MHz, CDCl3) δ 11.16 (s, 1H), 8.12 (d, J=9.2Hz, 1H), 7.82 (dd, J=7.9,2.4Hz, 1H), 7.71 (d, J=8.7Hz, 1H), 7.59 (s, 1H), 7.54 (d, J=8.5Hz, 1H), 7.33-7.29 (m, 1H), 7.23 (dd, J=8.5,5.1Hz, 2H), 7.06 (dd, J=8.0,7.0Hz, 1H), 6.98 (t, J=8.6Hz, 2H), 6.73 (s, 1H), 6.31 (d, J=2.3Hz, 1H), 1.22 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1H- indazolyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalein Piperazine -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 416.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.45 (s, 1H), 8.33 (s, 1H), 7.87 (s, 1H), 7.64 (d, J=8.4Hz, 1H), 7.60-7.54 (d, J=8.8Hz, 1H), 7.47 (dd, J=8.6,5.5Hz, 2H), 7.24-7.17 (m, 1H), 7.16-7.09 (m, 3H), 7.03-6.96 (m, 2H), 6.24 (d, J =9.4Hz, 1H), 5.43 (d, J=9.5Hz, 1H).
The fluoro- 8- of embodiment 7:5- (4- fluorophenyl) -9- (pyrrolidines -2,5- diketone -1- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 7)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (pyrrolidines -2,5- diketone -1- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By succinimide and intermediate 1a reaction preparation.MS (ESI): 497.1 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (pyrrolidines -2,5- diketone -1- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 397.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.46 (s, 1H), 7.66 (s, 1H), 7.48 (dd, J=8.6,5.5Hz, 2H), 7.25 (t, J=8.8Hz, 2H), 7.12 (dd, J=8.9, 2.4Hz, 1H), 6.92 (dd, J=11.1,2.4Hz, 1H), 5.35 (d, J=11.5Hz, 1H), 5.11 (d, J=11.5Hz, 1H), 2.77-2.54 (m, 4H).
The fluoro- 8- of embodiment 8:5- (4- fluorophenyl) -9- (4,7- epoxy hexahydro iso-indoles -1,3 (2H)-diketone -2- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 8)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (4,7- epoxy hexahydro iso-indoles -1,3 (2H)-diketone -2- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 4,7- epoxy hexahydro iso-indoles -1,3 (2H)-diketone and intermediate 1a reaction preparation. MS (ESI): 565.1 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (4,7- epoxy hexahydro iso-indoles -1,3 (2H)-diketone -2- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 465.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.44 (s, 1H), 7.62 (s, 1H), 7.43 (dd, J=8.5,5.6Hz, 2H), 7.18 (t, J=8.8Hz, 2H), 7.10 (dd, J=8.9, 2.3Hz, 1H), 6.90 (dd, J=11.1,2.3Hz, 1H), 5.29 (d, J=11.4Hz, 1H), 5.03 (d, J=11.5Hz, 1H), 4.65 (s, 1H), 4.37 (s, 1H), 3.07 (d, J=7.2Hz, 1H), 2.99 (d, J=7.2Hz, 1H), 1.65-1.48 (m, 4H).
The fluoro- 8- of embodiment 9:5- (4- fluorophenyl) -9- (4,7- epoxy -3a, 4,7,7a- tetrahydro iso-indoles -1,3 (2H)-two Ketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 9)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (4,7- epoxy -3a, 4,7,7a- tetrahydro iso-indoles -1,3 (2H)-two Ketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 4,7- epoxy -3a, 4,7,7a- tetrahydro iso-indoles -1,3 (2H)-diketone and intermediate 1a reaction preparation.MS (ESI): 563.1 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (4,7- epoxy -3a, 4,7,7a- tetrahydro iso-indoles -1,3 (2H)-two Ketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 463.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.45 (s, 1H), 7.64 (s, 1H), 7.43 (dd, J=8.7,5.5Hz, 2H), 7.17 (t, J=8.8Hz, 2H), 7.11 (dd, J=8.9, 2.4Hz, 1H), 6.91 (dd, J=11.1,2.4Hz, 1H), 6.50 (qd, J=5.7,1.5Hz, 2H), 5.33 (d, J= 11.3Hz, 1H), 5.10 (s, 1H), 5.04 (d, J=11.4Hz, 1H), 4.84 (s, 1H), 2.99 (d, J=6.6Hz, 1H), 2.89 (d, J=6.6Hz, 1H).
The fluoro- 8- of embodiment 10:5- (4- fluorophenyl) -9- (4,7- epoxy -5- hydroxyl hexahydro iso-indoles -1,3 (2H)-diketone - 2- yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 10)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (- 5 hydroxyl hexahydro iso-indoles -1,3 (2H) of 4,7- epoxy-diketone -2- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.It is anti-by -5 hydroxyl hexahydro iso-indoles -1,3 (2H) of 4,7- epoxy-diketone and intermediate 1a It should prepare.MS (ESI): 581.1 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (4,7- epoxy -5- hydroxyl hexahydro iso-indoles -1,3 (2H)-diketone -2- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 481.1 [M+H]+。1H NMR (400MHz, DMSO) δ 12.46 (s, 1H), 7.63 (s, 1H), 7.44 (dd, J=8.6,5.5Hz, 2H), 7.19 (t, J=8.8Hz, 2H), 7.10 (dd, J=8.9,2.4Hz, 1H), 6.91 (dd, J=11.1,2.4Hz, 1H), 5.31 (d, J=11.5Hz, 1H), 5.03 (m, 2H), 3.90 (m, 1H), 3.31 (m, 1H), 2.95 (m, 2H), 1.93 (m, 1H), 1.38 (m, 1H).
The fluoro- 8- of embodiment 11:5- (4- fluorophenyl) -9- (iso-indoles -1,3- diketone -2- base) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one (compound 11)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (iso-indoles -1,3- diketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By potassium phthalimide and intermediate 1a reaction preparation.Yield is 33%.MS (ESI): 545.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.99 (s, 1H), 8.08 (s, 1H), 8.00-7.61 (m, 5H), 7.32 (m, 2H), 7.14 (m, 2H), 6.21 (m, 1H), 5.78 (m, 1H), 1.20 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (iso-indoles -1,3- diketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.Yield is 59%.MS (ESI): 445.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.39 (s, 1H), 7.88 (m, 4H), 7.74 (s, 1H), 7.53 (dd, J=8.3,5.5Hz, 2H), 7.20 (t, J=8.7Hz, 2H), 7.12 (dd, J=8.9,2.1Hz, 1H), 6.94 (dd, J=11.1,2.1Hz, 1H), 5.60 (d, J=11.8Hz, 1H), 5.23 (d, J=11.8Hz, 1H).
The fluoro- 8- of embodiment 12:5- (4- fluorophenyl) -9- (2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 12)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 2,4- imidazolinedione and intermediate 1a reaction preparation.MS (ESI): 498.2 [M+ H]+。1H NMR (400MHz, DMSO-d6) δ 12.95 (s, 1H), 8.43 (s, 1H), 8.06 (dd, J=11.3,2.5Hz, 1H), 7.63 (dd, J=8.3,2.5Hz, 1H), 7.26 (dd, J=8.5,5.4Hz, 2H), 7.15-7.08 (m, 2H), 6.13 (s, 1H), 5.46 (d, J=1.8Hz, 1H), 4.03 (d, J=18.1Hz, 1H), 3.90 (d, J=18.1Hz, 1H), 1.47 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 398.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.50 (s, 1H), 8.20 (s, 1H), 7.66 (s, 1H), 7.51 (dd, J=8.5,5.5Hz, 2H), 7.27 (t, J=8.8Hz, 2H), 7.11 (dd, J=8.9,2.3Hz, 1H), 6.92 (dd, J=11.1,2.4Hz, 1H), 5.27 (d, J=11.7Hz, 1H), 5.17 (d, J =11.7Hz, 1H), 3.95 (d, J=18.3Hz, 1H), 3.88 (d, J=18.4Hz, 1H).
The fluoro- 8- of embodiment 13:5- (4- fluorophenyl) -9- (1- methyl -2,4- imidazolinedione -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 13)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1- methyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrrole Pyridine simultaneously [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 1- methyl -2,4- imidazolinedione and intermediate 1a reaction preparation.Yield is 45%.MS (ESI): 512.2 [M+H]+。1H NMR (400MHz, CDCl3) δ 10.90 (s, 1H), 7.92 (dd, J=10.9, 2.5Hz, 1H), 7.76 (dd, J=8.1,2.5Hz, 1H), 7.19 (dd, J=8.4,5.2Hz, 2H), 6.97-6.90 (m, 2H), 6.28 (s, 1H), 5.64 (d, J=1.7Hz, 1H), 3.93 (d, J=17.5Hz, 1H), 3.86 (d, J=17.5Hz, 1H), 2.98 (s, 3H), 1.55 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1- methyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrrole Pyridine simultaneously [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 412.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.46 (s, 1H), 7.61 (s, 1H), 7.50 (dd, J=8.6,5.5Hz, 2H), 7.26 (t, J=8.8Hz, 2H), 7.11 (dd, J=8.9, 2.4Hz, 1H), 6.92 (dd, J=11.1,2.4Hz, 1H), 5.30 (d, J=11.6Hz, 1H), 5.16 (d, J=11.6Hz, 1H), 4.04 ((d, J=18.4Hz, 1H), 3.96 (d, J=18.4Hz, 1H), 2.81 (s, 3H).
Chiral resolving compound 13 obtains (8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (1- methyl -2,4- imidazoline two Ketone -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 13a) and (8S, 9S) -5- it is fluoro- 8- (4- fluorophenyl) -9- (1- methyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines - 3 (7H) -one (compound 13b)
By the fluoro- 8- of 5- (4- fluorophenyl) -9- (1- methyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 13) is dissolved in ethanol/methylene in the mixed solvent, using supercritical fluid Chromatography (SFC) carries out chiral resolution and obtains a pair of of enantiomter.Chiral column isCellulose-2, eluant, eluent are dioxy Change carbon (55%) and methanol (45%, contain 0.1% ammonium hydroxide).
The fluoro- 8- of embodiment 14:5- (4- fluorophenyl) -9- (1- isopropyl -2,4- imidazolinedione -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 14)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1- isopropyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 1- isopropyl -2,4- imidazolinedione and intermediate 1a reaction preparation.MS (ESI): 540.2[M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1- isopropyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 440.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.46 (s, 1H), 7.66 (s, 1H), 7.48 (dd, J=8.5,5.5Hz, 2H), 7.25 (t, J=8.8Hz, 2H), 7.11 (dd, J=8.9, 2.3Hz, 1H), 6.92 (dd, J=11.1,2.3Hz, 1H), 5.25 (d, J=11.6Hz, 1H), 5.12 (d, J=11.6Hz, 1H), 4.06-4.01 (m, 1H), 4.00-3.85 (m, 2H), 1.07 (d, J=6.7Hz, 3H), 1.01 (d, J=6.7Hz, 3H).
The fluoro- 8- of embodiment 15:5- (4- fluorophenyl) -9- (1- (2- ethoxy) -2,4- imidazolinedione -3- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 15)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1- (2- ethoxy) -2,4- imidazolinedione -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 1- (2- ethoxy) -2,4- imidazolinedione and intermediate 1a reaction preparation.MS (ESI): 542.1 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1- (2- ethoxy) -2,4- imidazolinedione -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 442.1 [M+H]+。1H NMR (400MHz, DMSO) δ 12.48 (s, 1H), 7.65 (s, 1H), 7.49 (dd, J=8.4,5.6Hz, 2H), 7.25 (t, J=8.8Hz, 2H), 7.11 (dd, J=8.9,2.3Hz, 1H), 7.00-6.85 (m, 1H), 5.27 (d, J=11.5Hz, 1H), 5.14 (d, J=11.5Hz, 1H), 4.82 (t, J= 5.0Hz, 1H), 4.13-3.92 (m, 2H), 3.52-3.42 (m, 2H), 3.32-3.15 (m, 2H).
The fluoro- 8- of embodiment 16:5- (4- fluorophenyl) -9- (1- cyclopropyl -2,4- imidazolinedione -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 16)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1- cyclopropyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 1- cyclopropyl -2,4- imidazolinedione and intermediate 1a reaction preparation.MS (ESI): 538.1[M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1- cyclopropyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 438.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.47 (s, 1H), 7.64 (s, 1H), 7.48 (dd, J=8.7,5.5Hz, 2H), 7.26 (t, J=8.8Hz, 2H), 7.11 (dd, J=8.9, 2.4Hz, 1H), 6.92 (dd, J=11.1,2.4Hz, 1H), 5.26 (d, J=11.5Hz, 1H), 5.12 (d, J=11.5Hz, 1H), 4.05-3.90 (m, 2H), 2.65-2.55 (m, 1H), 0.72-0.52 (m, 4H).
The fluoro- 8- of embodiment 17:5- (4- fluorophenyl) -9- (1- cyclopenta -2,4- imidazolinedione -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 17)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1- cyclopenta -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 1- cyclopenta -2,4- imidazolinedione and intermediate 1a reaction preparation.MS (ESI): 566.2[M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1- cyclopenta -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 466.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.46 (s, 1H), 7.66 (s, 1H), 7.47 (dd, J=8.4,5.6Hz, 2H), 7.25 (t, J=8.8Hz, 2H), 7.11 (dd, J=8.9, 2.3Hz, 1H), 6.92 (dd, J=11.1,2.3Hz, 1H), 5.25 (d, J=11.6Hz, 1H), 5.13 (d, J=11.6Hz, 1H), 4.17 (p, J=7.1,6.7Hz, 1H), 4.07-3.89 (m, 2H), 1.82-1.36 (m, 8H).
The fluoro- 8- of embodiment 18:5- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- imidazolinedione -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 18)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- imidazolinedione -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 5,5- dimethyl -2,4- imidazolinedione and intermediate 1a reaction preparation.Yield is 35%.MS (ESI): 526.1 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- imidazolinedione -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.Yield is 35%.MS (ESI): 426.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.48 (s, 1H), 8.34 (s, 1H), 7.66 (s, 1H), 7.49 (dd, J=8.4,5.6Hz, 2H), 7.28 (t, J=8.8Hz, 2H), 7.11 (dd, J=8.9,2.3Hz, 1H), 6.92 (dd, J=11.1,2.3Hz, 1H), 5.19 (d, J=11.8Hz, 1H), 5.15 (d, J=11.8Hz, 1H), 1.19 (s, 3H), 1.08 (s, 3H).
Chiral resolving compound 18 obtains (8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- imidazoles Quinoline diketone -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 18a) and (8S, 9S) -5- Fluoro- 8- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2- De] phthalazines -3 (7H) -one (compound 18b)
By the fluoro- 8- of 5- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrrole Simultaneously [4,3,2-de] phthalazines -3 (7H) -one (compound 18) is dissolved in methanol/dimethyl sulfoxide in the mixed solvent for pyridine, and use is overcritical Fluid Chromatography (SFC) carries out chiral resolution and obtains a pair of of enantiomter.Chiral column isCellulose-2, eluant, eluent are Carbon dioxide (60%) and methanol (40%, contain 0.1% ammonium hydroxide).
The fluoro- 8- of embodiment 19:5- (4- fluorophenyl) -9- (1,5,5- trimethyl -2,4- imidazolinedione -3- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 19)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1,5,5- trimethyl -2,4- imidazolinedione -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 1,5,5- trimethyl -2,4- imidazolinedione and intermediate 1a reaction preparation.Yield It is 74%.MS (ESI): 540.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1,5,5- trimethyl -2,4- imidazolinedione -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 440.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.46 (s, 1H), 7.67 (s, 1H), 7.49 (dd, J=8.6,5.5Hz, 2H), 7.27 (t, J=8.8Hz, 2H), 7.11 (dd, J=8.9, 2.4Hz, 1H), 6.92 (dd, J=11.1,2.4Hz, 1H), 5.25 (d, J=11.7Hz, 1H), 5.15 (d, J=11.8Hz, 1H), 2.74 (s, 3H), 1.21 (s, 3H), 1.09 (s, 3H).
The fluoro- 8- of embodiment 20:5- (4- fluorophenyl) -9- (1- isopropyl -5,5- dimethyl -2,4- imidazolinedione -3- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 20)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1- isopropyl -5,5- dimethyl -2,4- imidazolinedione -3- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl esters
With the step 1 of embodiment 1.By 1- isopropyl -5,5- dimethyl -2,4- imidazolinedione and intermediate 1a reaction system It is standby.Yield is 41%.MS (ESI): 568.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1- isopropyl -5,5- dimethyl -2,4- imidazolinedione -3- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 468.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.47 (s, 1H), 7.68 (s, 1H), 7.47 (dd, J=8.6,5.5Hz, 2H), 7.28 (t, J=8.8Hz, 2H), 7.12 (dd, J=8.9, 2.4Hz, 1H), 6.92 (dd, J=11.1,2.4Hz, 1H), 5.21 (d, J=11.7Hz, 1H), 5.12 (d, J=11.7Hz, 1H), 3.52 (dt, J=13.5,6.7Hz, 1H), 1.29 (d, J=6.7Hz, 3H), 1.20 (s, 3H), 1.16 (d, J=6.7Hz, 3H), 1.06 (s, 3H).
The fluoro- 8- of embodiment 21:5- (4- fluorophenyl) -9- (5- methyl -5- phenyl -2,4- imidazolinedione -3- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 21)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (5- methyl -5- phenyl -2,4- imidazolinedione -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 5- methyl -5- phenyl -2,4- imidazolinedione and intermediate 1a reaction preparation.MS (ESI): 588.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (5- methyl -5- phenyl -2,4- imidazolinedione -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 488.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.54 (s, 1H), 8.89 (s, 1H), 7.67 (s, 1H), 7.49 (dd, J=8.4,5.6Hz, 2H), 7.39-7.20 (m, 7H), 7.11 (dd, J =8.9,2.4Hz, 1H), 6.91 (dd, J=11.1,2.4Hz, 1H), 5.27 (d, J=11.8Hz, 1H), 5.20 (d, J= 11.8Hz, 1H), 1.60 (s, 3H).
The fluoro- 8- of embodiment 22:5- (4- fluorophenyl) -9- ((7aS)-tetrahydro-1 H-pyrrolo simultaneously [1,2-c] imidazoles -1,3 (2H)-diketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 22)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- ((7aS)-tetrahydro-1 H-pyrrolo simultaneously [1,2-c] imidazoles -1,3 (2H)-two Ketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By (7aS)-tetrahydro-1 H-pyrrolo simultaneously [1,2-c] imidazoles -1,3 (2H)-diketone and centre Body 1a reaction preparation.MS (ESI): 538.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- ((7aS)-tetrahydro-1 H-pyrrolo simultaneously [1,2-c] imidazoles -1,3 (2H)-two Ketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 438.1 [M+H]+。
The fluoro- 8- of embodiment 23:5- (4- fluorophenyl) -9- ((S) -7a- methyl tetrahydro-1 H-pyrrolo simultaneously [1,2-c] imidazoles -1, 3 (2H)-diketone -2- bases) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 23)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- ((S) -7a- methyl tetrahydro-1 H-pyrrolo simultaneously [1,2-c] imidazoles -1,3 (2H)-diketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By (S) -7a- methyl tetrahydro-1 H-pyrrolo simultaneously [1,2-c] imidazoles -1,3 (2H)-diketone It reacts and prepares with intermediate 1a.Yield is 68%.MS (ESI): 552.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- ((S) -7a- methyl tetrahydro-1 H-pyrrolo simultaneously [1,2-c] imidazoles -1,3 (2H)-diketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.Yield is 33%.MS (ESI): 452.2 [M+H]+。
The fluoro- 8- of embodiment 24:5- (4- fluorophenyl) -9- ((6R, 7aS) -6- hydroxy tetrahydro -1H- pyrrolo- [1,2-c] miaow Azoles -1,3 (2H)-diketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 24)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- ((6R, 7aS) -6- hydroxy tetrahydro -1H- pyrrolo- [1,2-c] imidazoles - 1,3 (2H)-diketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By (6R, 7aS) -6- hydroxy tetrahydro -1H- pyrrolo- [1,2-c] imidazoles -1,3 (2H) - Diketone and intermediate 1a reaction preparation.MS (ESI): 554.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- ((6R, 7aS) -6- hydroxy tetrahydro -1H- pyrrolo- [1,2-c] imidazoles - 1,3 (2H)-diketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 454.1 [M+H]+。
The fluoro- 8- of embodiment 25:5- (4- fluorophenyl) -9- (1,3- diaza spiro [3.4] octane -6,8- diketone -3- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 25)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1,3- diaza spiro [3.4] octane -6,8- diketone -3- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 1,3- diaza spiro [3.4] octane -6,8- diketone and intermediate 1a reaction preparation. Yield is 52%.MS (ESI): 536.2 [M-H]-。1H NMR (400MHz, CDCl3) δ 11.07 (s, 1H), 7.98 (dd, J= 10.9,2.3Hz, 1H), 7.75 (dd, J=8.0,2.4Hz, 1H), 7.18 (dd, J=8.4,5.2Hz, 2H), 6.93 (t, J= 8.6Hz, 2H), 6.43 (s, 1H), 6.27 (s, 1H), 5.60 (d, J=1.6Hz, 1H), 2.56 (dd, J=10.5,6.6Hz, 2H), 2.36 (dd, J=11.7,6.6Hz, 2H), 2.14-1.98 (m, 1H), 1.88-1.75 (m, 1H), 1.55 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1,3- diaza spiro [3.4] octane -6,8- diketone -3- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 438.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.46 (s, 1H), 8.69 (s, 1H), 7.66 (s, 1H), 7.47 (dd, J=8.7,5.5Hz, 2H), 7.26 (t, J=8.8Hz, 2H), 7.11 (dd, J=8.9,2.4Hz, 1H), 6.92 (dd, J=11.1,2.4Hz, 1H), 5.20 (d, J=11.7Hz, 1H), 5.11 (d, J =11.7Hz, 1H), 2.35-2.15 (m, 3H), 2.01 (dd, J=14.1,6.8Hz, 1H), 1.85 (dd, J=19.0,9.8Hz, 1H), 1.76-1.65 (m, 1H).
The fluoro- 8- of embodiment 26:5- (4- fluorophenyl) -9- (1,3- diaza spiro [4.4] nonane -2,4- diketone -3- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 26)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1,3- diaza spiro [4.4] nonane -2,4- diketone -3- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 1,3- diaza spiro [4.4] nonane -2,4- diketone and intermediate 1a reaction preparation. MS (ESI): 550.3 [M-H]-。1H NMR (400MHz, CDCl3) δ 11.38 (s, 1H), 7.97 (dd, J=11.0,2.4Hz, 1H), 7.74 (dd, J=8.0,2.5Hz, 1H), 7.18 (dd, J=8.5,5.2Hz, 2H), 6.96-6.90 (m, 2H), 6.80 (s, 1H), 6.28 (s, 1H), 5.62 (d, J=1.8Hz, 1H), 2.11 (dd, J=13.5,6.4Hz, 2H), 1.92-1.63 (m, 6H), 1.55 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1,3- diaza spiro [4.4] nonane -2,4- diketone -3- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 452.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.49 (s, 1H), 8.54 (s, 1H), 7.67 (s, 1H), 7.48 (dd, J=8.5,5.5Hz, 2H), 7.28 (t, J=8.8Hz, 2H), 7.11 (dd, J=8.9,2.3Hz, 1H), 6.92 (dd, J=11.1,2.3Hz, 1H), 5.21 (d, J=11.7Hz, 1H), 5.13 (d, J =11.7Hz, 1H), 1.91-1.84 (m, 1H), 1.68 (br s, 4H), 1.59-1.50 (m, 3H).
The fluoro- 8- of embodiment 27:5- (4- fluorophenyl) -9- (1,3- diaza spiro [4.5] decane-2,4-diones -3- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 27)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1,3- diaza spiro [4.5] decane-2,4-diones -3- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 1,3- diaza spiro [4.5] decane-2,4-diones and intermediate 1a reaction preparation. MS (ESI): 566.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1,3- diaza spiro [4.5] decane-2,4-diones -3- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.Yield is 38%.MS (ESI): 466.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.45 (s, 1H), 8.74 (s, 1H), 7.64 (s, 1H), 7.47 (dd, J=8.6,5.5Hz, 2H), 7.27 (t, J=8.8Hz, 2H), 7.10 (dd, J=8.9,2.4Hz, 1H), 6.91 (dd, J=11.1,2.4Hz, 1H), 5.18 (d, J=11.8Hz, 1H), 5.14 (d, J=11.8Hz, 1H), 1.68-1.20 (m, 10H).
The fluoro- 8- of embodiment 28:5- (4- fluorophenyl) -9- (2- oxygen -5,7- diaza spiro [3.4] octane -6,8- diketone -7- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 28)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (2- oxygen -5,7- diaza spiro [3.4] octane -6,8- diketone -7- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl esters
With the step 1 of embodiment 1.It is reacted by 2- oxygen -5,7- diaza spiro [3.4] octane -6,8- diketone and intermediate 1a Preparation.Yield is 32%.MS (ESI): 538.1 [M-H]-。1H NMR (400MHz, CDCl3) δ 11.57 (s, 1H), 7.93 (dd, J =10.8,2.3Hz, 1H), 7.76 (dd, J=7.9,2.4Hz, 1H), 7.47 (s, 1H), 7.16 (dd, J=8.5,5.1Hz, 2H), 6.93 (t, J=8.6Hz, 2H), 6.27 (s, 1H), 5.63 (d, J=1.7Hz, 1H), 4.96 (d, J=7.0Hz, 2H), 4.73 (t, J=7.1Hz, 2H), 1.54 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (2- oxygen -5,7- diaza spiro [3.4] octane -6,8- diketone -7- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.Yield is 70%.MS (ESI): 440.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.45 (s, 1H), 9.27 (s, 1H), 7.69 (s, 1H), 7.47 (dd, J=8.6,5.5Hz, 2H), 7.25 (t, J=8.8Hz, 2H), 7.12 (dd, J=8.9,2.4Hz, 1H), 6.93 (dd, J=11.1,2.4Hz, 1H), 5.24 (d, J=11.6Hz, 1H), 5.09 (d, J=11.6Hz, 1H), 4.72 (d, J=6.7Hz, 1H), 4.62 (dd, J=6.5,4.6Hz, 2H), 4.44 (d, J= 5.3Hz, 1H).
The fluoro- 8- of embodiment 29:5- (4- fluorophenyl) -9- (2,5,7- thriazaspiros [3.4] octane -6,8- diketone -7- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 29)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (2- tert-butoxycarbonyl -2,5,7- thriazaspiro [3.4] octane -6, 8- diketone -7- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 2- tert-butoxycarbonyl -2,5,7- thriazaspiro [3.4] octane -6,8- diketone and Intermediate 1a reaction preparation.1H NMR (400MHz, DMSO-d6) δ 12.95 (s, 1H), 9.20 (s, 1H), 8.05 (dd, J= 11.3,2.5Hz, 1H), 7.62 (dd, J=8.3,2.5Hz, 1H), 7.23 (dd, J=8.5,5.4Hz, 2H), 7.12 (t, J= 8.8Hz, 2H), 6.12 (s, 1H), 5.45 (d, J=1.9Hz, 1H), 4.05-3.87 (m, 4H), 1.47 (s, 9H), 1.37 (s, 9H)。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (2,5,7- thriazaspiros [3.4] octane -6,8- diketone -7- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 439.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.48 (s, 1H), 9.22 (s, 2H), 7.71 (s, 1H), 7.48 (dd, J=8.6,5.5Hz, 2H), 7.26 (t, J=8.8Hz, 2H), 7.11 (dd, J=8.9,2.4Hz, 1H), 6.93 (dd, J=11.1,2.4Hz, 1H), 5.27 (d, J=11.3Hz, 1H), 5.03 (d, J =11.3Hz, 1H), 4.23 (d, J=11.5Hz, 1H), 4.17 (d, J=12.5Hz, 2H), 3.80 (d, J=11.3Hz, 1H).
The fluoro- 8- of embodiment 30:5- (4- fluorophenyl) -9- (2,4- thiazolidinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 30)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (2,4- thiazolidinedione -3- base) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 2,4- thiazolidinedione and intermediate 1a reaction preparation.MS (ESI): 515.1 [M+ H]+。1H NMR (400MHz, CDCl3) δ 12.10 (s, 1H), 7.91 (dd, J=10.7,2.4Hz, 1H), 7.77 (dd, J=8.0, 2.5Hz, 1H), 7.19 (dd, J=8.5,5.1Hz, 2H), 6.97-6.88 (m, 2H), 6.25 (s, 1H), 5.76 (d, J= 1.6Hz, 1H), 4.03 (d, J=17.6Hz, 1H), 3.95 (d, J=17.6Hz, 1H), 1.55 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (2,4- thiazolidinedione -3- base) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 415.0 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.51 (s, 1H), 7.68 (s, 1H), 7.52 (dd, J=8.6,5.5Hz, 2H), 7.28 (t, J=8.8Hz, 2H), 7.12 (dd, J=8.9, 2.3Hz, 1H), 6.92 (dd, J=11.1,2.4Hz, 1H), 5.54 (d, J=11.5Hz, 1H), 5.14 (d, J=11.5Hz, 1H), 4.35 (d, J=18.3Hz, 1H), 4.23 (d, J=18.3Hz, 1H).
The fluoro- 8- of embodiment 31:5- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- thiazolidinedione -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 31)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- thiazolidinedione -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 5,5- dimethyl -2,4- thiazolidinedione and intermediate 1a reaction preparation.MS (ESI): 543.2 [M+H]+。1H NMR (400MHz, CDCl3) δ 11.07 (s, 1H), 7.91 (dd, J=10.8,2.4Hz, 1H), 7.78 (dd, J=8.0,2.5Hz, 1H), 7.19 (dd, J=8.4,5.1Hz, 2H), 6.98-6.89 (m, 2H), 6.28 (s, 1H), 5.72 (d, J=1.6Hz, 1H), 1.74 (s, 6H), 1.56 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- thiazolidinedione -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.Yield is 74%.MS (ESI): 443.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.51 (s, 1H), 7.72 (s, 1H), 7.57-7.45 (m, 2H), 7.30 (t, J=8.5Hz, 2H), 7.13 (d, J=7.5Hz, 1H), 6.92 (d, J=10.9Hz, 1H), 5.52 (d, J=11.6Hz, 1H), 5.13 (d, J=11.6Hz, 1H), 1.57 (s, 3H), 1.36 (s, 3H).
The fluoro- 8- of embodiment 32:5- (4- fluorophenyl) -9- (oxazolidine -2,4- diketone -3- base) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one (compound 32)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (oxazolidine -2,4- diketone -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 2,4- oxazolidinedione and intermediate 1a reaction preparation.MS (ESI): 499.1 [M+ H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (oxazolidine -2,4- diketone -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 399.1 [M+H]+。1H NMR (400MHz, DMSO) δ 12.57 (s, 1H), 7.73 (s, 1H), 7.56 (dd, J=8.7,5.5Hz, 2H), 7.29 (t, J=8.8Hz, 2H), 7.13 (dd, J=8.9,2.4Hz, 1H), 6.93 (dd, J=11.1,2.4Hz, 1H), 5.45 (d, J=11.5Hz, 1H), 5.10 (d, J=11.6Hz, 1H), 5.05 (q, J=16.8Hz, 2H).
The fluoro- 8- of embodiment 33:5- (4- fluorophenyl) -9- (5,5- dimethyl oxazolidine -2,4- diketone -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 33)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (5,5- dimethyl oxazolidine -2,4- diketone -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 5,5- dimethyl -2,4- oxazolidinedione and intermediate 1a reaction preparation.MS (ESI): 527.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 11.53 (s, 1H), 7.88 (dd, J=10.8,2.4Hz, 1H), 7.77 (dd, J=8.0,2.5Hz, 1H), 7.15 (dd, J=8.5,5.1Hz, 2H), 6.99-6.83 (m, 2H), 6.32 (s, 1H), 5.58 (d, J=1.8Hz, 1H), 1.59 (s, 3H), 1.58 (s, 3H), 1.55 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (5,5- dimethyl oxazolidine -2,4- diketone -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 427.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.56 (s, 1H), 7.76 (s, 1H), 7.56 (dd, J=8.6,5.5Hz, 2H), 7.32 (t, J=8.8Hz, 2H), 7.14 (dd, J=8.9, 2.4Hz, 1H), 6.93 (dd, J=11.1,2.4Hz, 1H), 5.37 (d, J=11.7Hz, 1H), 5.09 (d, J=11.8Hz, 1H), 1.44 (s, 3H), 1.30 (s, 3H).
The fluoro- 8- of embodiment 34:5- (4- fluorophenyl) -9- (2H- benzo [e] [1,3] oxazines -2,4 (3H)-diketone -3- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 34)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (2H- benzo [e] [1,3] oxazines -2,4 (3H)-diketone -3- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 2H- benzo [e] [1,3] oxazines -2,4 (3H)-diketone and intermediate 1a reaction system It is standby.MS (ESI): 561.2 [M+H]+。1H NMR (400MHz, CDCl3) δ 11.67 (s, 1H), 8.10-7.90 (m, 2H), 7.85- 7.70 (m, 2H), 7.41-7.28 (m, 4H), 6.99-6.93 (m, 2H), 6.46-6.44 (s, 1H), 6.33 (s, 1H), 1.44 (s, 9H)。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (2H- benzo [e] [1,3] oxazines -2,4 (3H)-diketone -3- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 461.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.42 (s, 1H), 8.05-7.82 (m, 2H), 7.72 (s, 1H), 7.63-7.42 (m, 4H), 7.22 (t, J=8.7Hz, 2H), 7.14 (dd, J =8.9,2.4Hz, 1H), 6.95 (dd, J=11.1,2.4Hz, 1H), 6.35 (d, J=10.9Hz, 1H), 5.34 (d, J= 10.9Hz, 1H).
The fluoro- 8- of embodiment 35:5- (4- fluorophenyl) -9- (benzo [d] isothiazole -3 (2H) -one -1,1- dioxide -2- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 35)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (benzo [d] isothiazole -3 (2H) -one -1,1- dioxide -2- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl esters
With the step 1 of embodiment 1.By o-benzoyl sulfonamide sodium and intermediate 1a reaction preparation.Yield is 40%.1H NMR (400MHz, CDCl3) δ 10.63 (s, 1H), 8.18 (d, J=9.7Hz, 1H), 8.10-8.05 (m, 1H), 7.95-7.84 (m, 3H), 7.78 (dd, J=7.9,2.5Hz, 1H), 7.22 (dd, J=8.5,5.1Hz, 2H), 7.02-6.93 (m, 2H), 6.55 (s, 1H), 5.88 (d, J=1.8Hz, 1H), 1.43 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (benzo [d] isothiazole -3 (2H) -one -1,1- dioxide -2- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 481.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.49 (s, 1H), 8.23 (d, J=7.3Hz, 1H), 8.12 (d, J=7.6Hz, 1H), 8.03 (dtd, J=21.4,7.5,1.1Hz, 2H), 7.78 (s, 1H), 7.59 (dd, J=8.6,5.5Hz, 2H), 7.22 (t, J=8.9Hz, 2H), 7.12 (dd, J=8.9,2.4Hz, 1H), 6.95 (dd, J=11.1,2.4Hz, 1H), 5.58 (d, J=11.1Hz, 1H), 5.28 (d, J=11.1Hz, 1H).
The fluoro- 8- of embodiment 36:5- (4- fluorophenyl) -9- (5- methyl -3- amino -1H-1,2,4- triazol-1-yls) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 36)
The fluoro- 9- diazanyl -8- of step 1:5- (4- fluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
The chloro- 8- of the fluoro- 9- of 5- (4- fluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic Tert-butyl acrylate (intermediate 1a, 1.0g, 2.31mmol) is dissolved in 10mL ethyl alcohol, is added hydrazine hydrate (2mL), is heated to 60 DEG C of reactions 2 Hour.Evaporating solvent under reduced pressure, residue are dissolved in ethyl acetate, wash 2 times.Organic phase is dried, filtered with anhydrous magnesium sulfate.Filtrate Evaporated under reduced pressure, through silica gel column chromatography, (methylene chloride/methanol=20: 1, v/v), obtaining 800mg product, (yield is residue 81%).MS (ESI): 430.1 [M+H]+。1H NMR (400MHz, CDCl3) δ 11.80 (s, 1H), 8.08 (d, J=10.9Hz, 1H), 7.68 (dd, J=7.9,2.2Hz, 1H), 7.10 (dd, J=8.6,5.2Hz, 2H), 6.92-6.82 (m, 2H), 6.35 (s, 1H), 4.28 (s, 1H), 3.82 (br s, 3H), 1.59 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (5- methyl -3- tertbutyloxycarbonylamino -1H-1,2,4- triazole -1- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
The fluoro- 9- diazanyl -8- of 5- (4- fluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3- ketone -7- carboxylic acid The tert-butyl ester (100mg, 0.233mmol) and acetylamino (methyl mercapto) methene amido t-butyl formate (46mg, 0.85mmol) It is dissolved in n,N-Dimethylformamide (0.5mL), is added diisopropylethylamine (52 μ L, 1.28mmol), room temperature reaction is overnight.It is added 10mL ethyl acetate, washing is twice.Organic phase is dried, filtered with anhydrous magnesium sulfate, and filtrate decompression concentration, residue prepares thin Layer chromatography isolates and purifies (methylene chloride/methanol=20/1, v/v), obtains 60mg product (yield 43%).MS (ESI): 596.2 [M+H]+。1H NMR (400MHz, MeOD) δ 8.08 (dd, J=11.2,2.4Hz, 1H), 7.67 (dd, J=8.3,2.5Hz, 1H), 7.38 (dd, J=8.5,5.2Hz, 2H), 7.07-6.99 (m, 2H), 6.35 (s, 1H), 6.18 (d, J=2.2Hz, 1H), 2.70 (s, 3H), 1.49 (s, 9H), 1.40 (d, J=9.1Hz, 9H).
The fluoro- 8- of step 3:5- (4- fluorophenyl) -9- (5- methyl -3- amino -1H-1,2,4- triazol-1-yls) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl -3- tertbutyloxycarbonylamino -1H-1,2,4- triazol-1-yls) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester (60mg, 0.101mmol) is dissolved in 2mL bis- Chloromethanes and 1mL trifluoroacetic acid react at room temperature 3 hours.Evaporating solvent under reduced pressure is added 10mL ethyl acetate, successively uses saturated carbon Sour hydrogen sodium water solution, water washing, anhydrous magnesium sulfate dry, filter.Filtrate decompression is evaporated off, and a small amount of ethyl acetate is added, and is precipitated white Color solid.Filtering, solid are dried to obtain 20mg product (yield 50%).MS (ESI): 396.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.46 (s, 1H), 7.70 (s, 1H), 7.48 (dd, J=8.5,5.6Hz, 2H), 7.22 (t, J=8.8Hz, 2H), 7.10 (dd, J=8.9,2.3Hz, 1H), 6.93 (dd, J=11.1,2.4Hz, 1H), 5.74 (d, J=10.9Hz, 1H), 5.12 (s, 2H), 4.98 (d, J=10.9Hz, 1H), 1.92 (s, 3H).
The fluoro- 8- of embodiment 37:5- (4- fluorophenyl) -9- (5- isopropyl -1H-1,2,4- triazol-1-yls) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 37)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (5- isopropyl -1H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
Isobutyramide (61mg, 0.701mmol) and n,N-Dimethylformamide dimethylacetal (100 μ L, 0.754mmol) It is dissolved in n,N-dimethylacetamide (0.3mL), reactant is heated to 80 DEG C and reacts 2 hours.The fluoro- 9- of 5- is added into reaction solution again Diazanyl -8- (4- fluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester (100mg, 0.233mmol) and 2mL acetic acid, the reaction was continued 2 hours.Reaction solution is cooled to room temperature, 20mL ethyl acetate is added. It is washed with water and washs, anhydrous magnesium sulfate dries, filters.Filtrate decompression concentration, residue purify (petroleum with preparing TLC separation Ether/ethyl acetate=1/1, v/v), obtain 80mg product (yield 68%).MS (ESI): 509.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (5- isopropyl -1H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 409.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.43 (s, 1H), 7.86 (s, 1H), 7.79 (s, 1H), 7.44 (dd, J=8.4,5.6Hz, 2H), 7.19 (t, J=8.8Hz, 2H), 7.12 (dd, J=8.9,2.2Hz, 1H), 6.96 (dd, J=11.1,2.3Hz, 1H), 6.06 (d, J=11.1Hz, 1H), 5.12 (d, J =11.1Hz, 1H), 2.94 (hept, J=6.7Hz, 1H), 1.12 (d, J=6.7Hz, 3H), 0.71 (d, J=6.7Hz, 3H).
The fluoro- 8- of embodiment 38:5- (4- fluorophenyl) -9- (5- methyl-1 H- pyrazol-1-yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 38)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (5- methyl-1 H- pyrazol-1-yl) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 37.By 4,4- dimethoxy-2-butanone and the fluoro- 9- diazanyl -8- of 5- (4- fluorophenyl) -8, The reaction preparation of 9- dihydro -2H- pyrido [4,3,2-de] phthalazines-(7H) -one -7- carboxylic acid tert-butyl ester.MS (ESI): 480.2 [M+ H]+。1H NMR (400MHz, CDCl3) δ 11.06 (s, 1H), 8.13 (d, J=11.1Hz, 1H), 7.77 (dt, J=11.4, 5.7Hz, 1H), 7.18 (dd, J=8.5,5.2Hz, 2H), 6.94 (t, J=8.6Hz, 2H), 6.90 (d, J=2.1Hz, 1H), 6.54 (s, 1H), 6.01 (d, J=2.2Hz, 1H), 5.92d, J=2.3Hz, 1H), 2.31 (s, 3H), 1.46 (s, 9H).
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (5- methyl-1 H- pyrazol-1-yl) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 380.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.48 (s, 1H), 7.76 (s, 1H), 7.46 (s, 1H), 7.39 (s, 2H), 7.17 (d, J=7.7Hz, 2H), 7.09 (d, J=7.8Hz, 1H), 6.94 (d, J=10.3Hz, 1H), 5.91 (s, 1H), 5.72 (d, J=9.2Hz, 1H), 5.14 (d, J=9.1Hz, 1H), 2.10 (s, 3H).
The fluoro- 8- of embodiment 39:5- (4- fluorophenyl) -9- (5- methyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 39)
Acetamide (1.18g, 20mmol) and n,N-Dimethylformamide dimethylacetal (3mL, 22.6mmol) are dissolved in 20mL dioxane is heated to 90 DEG C and reacts 3 hours.It is cooled to room temperature, evaporating solvent under reduced pressure, a small amount of petroleum ether is added, be precipitated N- (dimethylamino) methylene yl acetamide is obtained by filtration in solid.
The fluoro- 9- diazanyl-8- of 5- (4- fluorophenyl)-8,9- dihydro-2H- pyrido [4,3,2-de] (7H) -one of phthalazines-3-7- Carboxylic acid tert-butyl ester (100mg, 0.233mmol) and N- (dimethylamino) methylene yl acetamide (50mg, 0.439mmol) are dissolved in 1mL Acetic acid reacts 6 hours in 95 DEG C.It is cooled to room temperature, adds 1mL trifluoroacetic acid, react 2 hours at room temperature.Reaction solution decompression Concentration, residue are dissolved in 20mL ethyl acetate, successively use saturated sodium bicarbonate solution, water washing, anhydrous magnesium sulfate is dry, mistake Filter, concentration, prepares thin layer chromatography (methylene chloride/methanol=20/1, v/v), obtains 20mg product (yield 23%).MS (ESI): 381.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.47 (s, 1H), 7.86 (s, 1H), 7.83 (s, 1H), 7.46 (dd, J=8.6,5.6Hz, 2H), 7.19 (t, J=8.8Hz, 2H), 7.12 (dd, J=8.9,2.4Hz, 2H), 6.98 (dd, J=11.1,2.4Hz, 1H), 6.05 (d, J=10.9Hz, 1H), 5.09 (d, J=10.9Hz, 1H), 2.12 (s, 3H).
Chiral resolving compound 39 obtain (8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (5- methyl-1 H-1,2,4- tri- Azoles -1- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 39a) and (8S, 9S) -5- it is fluoro- 8- (4- fluorophenyl) -9- (5- methyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 39b)
By the fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 39) is dissolved in ethanol/methylene in the mixed solvent, using supercritical fluid Chromatography (SFC) carries out chiral resolution and obtains a pair of of enantiomter.Chiral column is ChiralCel OD, and eluant, eluent is carbon dioxide (55%) and methanol (45%, contain 0.1% ammonium hydroxide).
The fluoro- 8- of embodiment 40:5- (2,4- difluorophenyl) -9- (5- methyl-1 H-1,2,4- triazol-1-yls) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 40)
The fluoro- 3- nitrobenzene methyl of the bromo- 5- of step 1:2-
The fluoro- 3- nitrobenzoic acid (315g, 1.19mol) of the bromo- 5- of 2- is dissolved in 1L methanol, and the 50mL concentrated sulfuric acid is added, and 80 DEG C anti- It should stay overnight.Ice-water bath is cooling, and yellow solid is precipitated.Filtering, filter cake are washed to obtain the fluoro- 3- nitrobenzene of the bromo- 5- of 2- with 200mL methanol Methyl formate (70g, yield 21%).1H NMR (400MHz, CDCl3) δ 7.63 (dd, J=7.8,3.0Hz, 1H), 7.54 (dd, J =6.9,3.0Hz, 1H), 3.99 (s, 3H).
The fluoro- 3- nitrobenzene methyl of step 2:2- (1- ethoxy ethylene base) -5-
The fluoro- 3- nitrobenzene methyl (100g, 0.36mol) of the bromo- 5- of 2-, tributyl (1- ethoxy ethylene base) tin (134mL, 0.397mol), two (triphenylphosphine) palladium chlorides (8g, 0.011mol) are dissolved in dioxane (500mL).Argon gas protection Under in 95 DEG C react 3 hours, be cooled to room temperature.The solution that 100g dihydrate of potassium fluoride is dissolved in 300mL water is added into reaction solution, stirs It mixes 2 hours.Filtering, filtrate decompression concentration.Residue is dissolved in 400mL ethyl acetate, successively uses water and saturated common salt water washing.Have Machine is mutually dried, filtered with anhydrous magnesium sulfate.Filtrate is concentrated to get the fluoro- 3- nitrobenzoic acid first of 2- (1- ethoxy ethylene base) -5- Ester.1H NMR (400MHz, CDCl3) δ 7.62 (dd, J=8.0,2.7Hz, 1H), 7.60 (dd, J=7.4,2.7Hz, 1H), 4.35 (d, J=3.2Hz, 1H), 4.19 (d, J=3.2Hz, 1H), 3.93-3.84 (m, 5H), 1.32 (t, J=7.0Hz, 3H).
Step 3:2- acetyl group -3- amino-5-fluorobenzoic acid methyl esters
With the step 3 of intermediate 1a.Yellow solid, yield 70%.
Step 4:(E) the fluoro- 3- of -2- acetyl group -5- ((2,4- difluoro benzal) amino) methyl benzoate
Upper step products and 2,4- difluorobenzaldehyde react, with the step 4 of intermediate 1a.White solid, yield 63% 。1H NMR (400MHz, CDCl3) δ 8.80 (s, 1H), 8.05 (dd, J=15.4,8.4Hz, 1H), 7.70 (dd, J=9.8, 2.2Hz, 1H), 7.58 (dd, J=8.8,2.3Hz, 1H), 7.52-7.42 (m, 1H), 7.33-7.24 (m, 1H), 3.84 (s, 3H), 2.51 (s, 3H).
The fluoro- 2- of step 5:7- (2,4- difluorophenyl) -2,3- dihydroquinoline -4 (1H) -one -5- methyl formate
(E) the fluoro- 3- of -2- acetyl group -5- ((2,4- difluoro benzal) amino) methyl benzoate (6.8g, 20.3mmol) is dissolved in 100mL methylene chloride adds trifluoromethane sulfonic acid scandium (3.5g, 7.1mmol).Room temperature reaction 1.5 hours.Reaction solution successively with Water, saturated common salt water washing, organic phase are concentrated under reduced pressure, and residue silica gel column chromatography obtains 6.07g white solid, and (yield is 89%).1H NMR (400MHz, DMSO-d6) δ 7.73 (s, 1H), 7.58 (td, J=8.6,6.8Hz, 1H), 7.31 (ddd, J= 11.5,9.3,2.5Hz, 1H), 7.15 (td, J=8.5,2.1Hz, 1H), 6.72 (dd, J=11.0,2.4Hz, 1H), 6.49 (dd, J=8.5,2.4Hz, 1H), 5.07 (dd, J=11.2,4.7Hz, 1H), 3.75 (s, 3H), 2.88 (dd, J=16.1, 11.3Hz, 1H), 2.75 (dd, J=16.1,4.5Hz, 1H).
The fluoro- 2- of step 6:N- tert-butoxycarbonyl -7- (2,4- difluorophenyl) -2,3- dihydroquinoline -4- ketone -5- formic acid first Ester
With the step 6 of intermediate 1a.Yield is 50%.1H NMR (400MHz, DMSO-d6) δ 7.81 (dd, J=11.7, 2.5Hz, 1H), 7.33-7.24 (m, 1H), 7.15 (dd, J=8.0,2.5Hz, 1H), 7.00 (dd, J=10.7,3.8Hz, 1H), 6.19 (d, J=5.8Hz, 1H), 3.82 (dd, J=7.5,6.0Hz, 1H), 3.77 (s, 3H), 3.61 (dd, J=17.6, 6.5Hz, 1H), 3.01 (dd, J=17.6,1.6Hz, 1H), 1.49 (s, 9H).
Step 7:N- tert-butoxycarbonyl -7- fluoro- 2- (2,4- difluorophenyl) -4- (tertiary butyl dimethyl Si base) -1, 2- dihydroquinoline -5- methyl formate
With the step 7 of intermediate 1a.Faint yellow solid.Yield is 83%.1H NMR (400MHz, DMSO-d6) δ 7.43 (d, J=8.4Hz, 1H), 7.29-7.17 (m, 1H), 7.11 (br s, 2H), 6.93 (t, J=6.9Hz, 1H), 6.40 (d, J= 6.6Hz, 1H), 5.60 (d, J=6.8Hz, 1H), 3.80 (s, 3H), 1.46 (s, 9H), 0.82 (s, 9H), 0.18 (s, 3H), 0.16 (s, 3H).
The step bromo- 7- of 8:N- tert-butoxycarbonyl -3- fluoro- 2- (2,4- difluorophenyl) -4- oxo -3,4- dihydroquinoline - 1,5 (2H) -5- methyl formate
By N- tert-butoxycarbonyl -7- fluoro- 2- (2,4- difluorophenyl) -4- (tertiary butyl dimethyl Si base) -1,2- bis- Hydrogen quinoline -5- methyl formate (200mg, 0.36mmol) is dissolved in 5mL tetrahydrofuran, and reaction solution is cooled to -30 DEG C, and N- bromo is added Succimide (65mg, 0.36mmol) reacts 40 minutes.40mL ethyl acetate is added into reaction solution, successively with water, saturation Brine It.Organic phase is dried, filtered with anhydrous magnesium sulfate, and filtrate decompression concentration, product is directly used in next without further purification Step reaction.MS (ESI): 514,516 [M+H]+。
The fluoro- 9- diazanyl -8- of step 9:5- (2,4- difluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
Previous step reaction product is dissolved in methanol (5mL), is added hydrazine hydrate (45 μ L, 1.44mmol), and it is small to react 2 at room temperature When.20mL ethyl acetate is added into reaction solution, successively uses water and saturated common salt water washing.Organic phase is dry with anhydrous magnesium sulfate Dry, filtering, filtrate decompression is concentrated, and residue is obtained with thin layer chromatography (methylene chloride/methanol=20/1, v/v) is prepared 95mg white solid (two step yields 58%).MS (ESI): 448.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.79 (s, 1H), 8.20 (dd, J=12.1,2.2Hz, 1H), 7.61 (dd, J=8.2,2.5Hz, 1H), 7.35-7.20 (m, 1H), 6.83 (t, J=8.4Hz, 1H), 6.70 (dd, J=15.1,8.6Hz, 1H), 6.50 (s, 1H), 4.11 (s, 3H), 3.89 (s, 1H), 1.49 (s, 9H).
The fluoro- 8- of step 10:5- (2,4- difluorophenyl) -9- (5- methyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
The fluoro- 9- diazanyl -8- of 5- (2,4- difluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) - Ketone -7- carboxylic acid tert-butyl ester (93mg, 0.21mmol) and N- (dimethylaminomethylene) acetamide (29mg, 0.25mmol) are dissolved in ice Acetic acid (3mL) then reacts 2 hours in 90 DEG C.3mL trifluoroacetic acid is added into reaction solution, 40 DEG C are stirred 2 hours.Decompression is steamed Except solvent, residue is dissolved in 50mL ethyl acetate, is successively washed with saturated sodium bicarbonate and saturated sodium chloride solution, prepares thin layer Chromatogram purification (methylene chloride/methanol=30/1, v/v) obtains 40mg faint yellow solid (yield 48%).MS (ESI): 399.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.49 (s, 1H), 7.81 (d, J=13.8Hz, 2H), 7.32-7.06 (m, 3H), 6.94 (dd, J=11.0,2.4Hz, 1H), 6.18 (d, J=10.6Hz, 1H), 5.38 (d, J=10.6Hz, 1H), 2.25 (s, 3H).
The fluoro- 8- of embodiment 41:5- (4- fluorophenyl) -9- (1- methyl -2,4,5- imidazoline trione -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 41)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1- methyl -2,4,5- imidazoline trione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 1- methyl -2,4,5- imidazoline trione and intermediate 1a reaction preparation.MS (ESI): 526.1[M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1- methyl -2,4,5- imidazoline trione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 426.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.52 (s, 1H), 7.72 (s, 1H), 7.55 (dd, J=8.5,5.5Hz, 2H), 7.26 (t, J=8.8Hz, 2H), 7.11 (dd, J=8.9, 2.3Hz, 1H), 6.93 (dd, J=11.1,2.3Hz, 1H), 5.61 (d, J=10.8Hz, 1H), 5.09 (d, J=10.8Hz, 1H), 3.30 (s, 3H).
The fluoro- 8- of embodiment 42:5- (4- fluorophenyl) -9- (1- cyclobutyl -2,4- imidazolinedione -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 42)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1- cyclobutyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 1- cyclobutyl -2,4- imidazolinedione and intermediate 1a reaction preparation.MS (ESI): 552.1[M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1- cyclobutyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 452.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.46 (s, 1H), 7.63 (s, 1H), 7.48 (dd, J=8.6,5.5Hz, 2H), 7.25 (t, J=8.8Hz, 2H), 7.11 (dd, J=8.9, 2.4Hz, 1H), 6.92 (dd, J=11.1,2.4Hz, 1H), 5.28 (d, J=11.5Hz, 1H), 5.13 (d, J=11.6Hz, 1H), 4.43-4.30 (m, 1H), 4.19-4.01 (m, 2H), 2.15 (q, J=9.8Hz, 2H), 2.09-1.91 (m, 2H), 1.66- 1.51 (m, 2H).
The fluoro- 8- of embodiment 43:5- (4- fluorophenyl) -9- (1- (azetidin -3- base) -2,4- imidazolinedione -3- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 43)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1- (1- tertbutyloxycarbonyl azetidin -3- base) -2,4- imidazoline two Ketone -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 1- (1- tertbutyloxycarbonyl azetidin -3- base) -2,4- imidazolinedione and centre Body 1a reaction preparation.MS (ESI): 653.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1- (azetidin -3- base) -2,4- imidazolinedione -3- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 453.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.48 (s, 1H), 9.00 (s, 1H), 7.67 (s, 1H), 7.49 (dd, J=8.5,5.5Hz, 2H), 7.25 (t, J=8.8Hz, 2H), 7.11 (dd, J=8.9,2.3Hz, 1H), 6.93 (dd, J=11.1,2.3Hz, 1H), 5.32 (d, J=11.3Hz, 1H), 5.10 (d, J =11.3Hz, 1H), 4.99-4.82 (m, 1H), 4.33 (q, J=18.0Hz, 2H), 4.25-4.19 (m, 2H), 4.17-4.04 (m, 2H).
The fluoro- 8- of embodiment 44:5- (4- fluorophenyl) -9- (1- (piperidin-4-yl) -2,4- imidazolinedione -3- base) -8,9- Dihydro -2H- pyrrole
Pyridine simultaneously [4,3,2-de] phthalazines -3 (7H) -one (compound 44)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (1- (1- t-butoxycarbonylpiperidin -4- base) -2,4- imidazolinedione - 3- yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 1- (1- t-butoxycarbonylpiperidin -4- base) -2,4- imidazolinedione and intermediate 1a Reaction preparation.MS (ESI): 681.3 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (1- (piperidin-4-yl) -2,4- imidazolinedione -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 481.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.47 (s, 1H), 8.55 (s, 1H), 7.68 (s, 1H), 7.49 (dd, J=8.5,5.6Hz, 2H), 7.25 (t, J=8.8Hz, 2H), 7.12 (dd, J=8.9,2.3Hz, 1H), 6.93 (dd, J=11.1,2.3Hz, 1H), 5.27 (d, J=11.5Hz, 1H), 5.12 (d, J =11.5Hz, 1H), 4.16-3.90 (m, 3H), 3.35-3.30 (m, 2H), 3.05-2.95 (m, 2H), 1.86-1.59 (m, 4H).
The fluoro- 8- of embodiment 45:5- (4- fluorophenyl) -9- (3- methyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 45)
The fluoro- 9- azido -8- of step 1:5- (4- fluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
The chloro- 8- of the fluoro- 9- of 5- (4- fluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic Tert-butyl acrylate (intermediate 1a, 3.0g, 6.91mmol) is dissolved in n,N-Dimethylformamide (40mL), addition sodium azide (0.9g, 13.82mmol), 50 DEG C are heated to react 3 hours.100mL water and 100mL ethyl acetate is added in reaction solution, separates organic phase, has Machine is mutually washed with water twice, and anhydrous magnesium sulfate dries, filters.Filtrate decompression is concentrated to get 3.06g faint yellow solid (yield 100%).MS (ESI): 441.1 [M+H]+。
The fluoro- 9- amino -8- of step 2:5- (4- fluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
The fluoro- 9- azido -8- of 5- (4- fluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one - 7- carboxylic acid tert-butyl ester (3.06g, 6.91mmol) is dissolved in methanol (40mL), is added 10% palladium carbon (0.6g), is used hydrogen balloon at room temperature Hydrogenation 2 days.Reaction solution passes through suction filtered through kieselguhr, filtrate decompression concentration, residue petroleum ether-ethyl acetate (5/1, v/ V) mashing is handled, and obtains product 1.86g (yield 65%).MS (ESI): 415.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.65 (s, 1H), 8.19 (m, 1H), 7.58 (m, 1H), 7.16 (m, 2H), 7.06 (m, 2H), 5.89 (brs, 1H), 4.41 (d, J =2.6Hz, 1H), 2.41 (brs, 2H), 1.54 (s, 9H).
The fluoro- 9- isothiocyano -8- of step 3:5- (4- fluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
The fluoro- 9- amino-8- of 5- (4- fluorophenyl)-8,9- dihydro-2H- pyrido [4,3,2-de] (7H) -one of phthalazines-3-7- Carboxylic acid tert-butyl ester (250mg, 0.6mmol) and triethylamine (0.21mL, 1.5mmol) are dissolved in methylene chloride (10mL), and reactant is cold But it to 0 DEG C, is added thiophosgene (64 μ L, 0.84mmol), continues at 0 DEG C and react 2 hours.Reactant is concentrated under reduced pressure, and residue is not Purified be directly used in is reacted in next step.MS (ESI): 457.1 [M+H]+。
The fluoro- 8- of step 4:5- (4- fluorophenyl) -9- (3- methyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
Previous step reaction product is dissolved in ethyl alcohol (10mL), is added sarcosine (122mg, 1.38mmol), is heated back Stream reaction 2 hours.Reactant decompression boils off solvent, and 15mL water is added, and is extracted with 24mL ethyl acetate, organic phase anhydrous slufuric acid Magnesium dries, filters, and filtrate decompression concentration, gained residue silica gel column chromatography (petrol ether/ethyl acetate=2/1, v/v) obtains 81mg yellow solid.MS (ESI): 528.1 [M+H]+。
The fluoro- 8- of step 5:5- (4- fluorophenyl) -9- (3- methyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
The fluoro- 8- of 5- (4- fluorophenyl) -9- (3- methyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro -2H- pyrrole Simultaneously [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester (70mg, 0.13mmol) is dissolved in methylene chloride (2mL) for pyridine, then plus Enter trifluoroacetic acid (1mL), is stirred to react at room temperature 1 hour.Reaction solution evaporated under reduced pressure, residue are dissolved in ethyl acetate (20mL), Saturated sodium bicarbonate solution, water washing are successively used, anhydrous sodium sulfate dries, filters, and filtrate concentration, residue is prepared thin layer color Spectrum purifying (methylene chloride/methanol=30/1, v/v), obtains product 28mg (yield 50%).MS (ESI): 428.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.46 (s, 1H), 7.67 (s, 1H), 7.58-7.45 (m, 2H), 7.30-7.20 (m, 2H), 7.17-7.07 (m, 1H), 6.98-6.91 (m, 1H), 6.06-6.01 (m, 1H), 5.26-5.20 (m, 1H), 4.34 (s, 2H), 3.15 (s, 3H).
The fluoro- 8- of embodiment 46:5- (4- fluorophenyl) -9- (5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 46)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 4 of embodiment 45.By glycine ethyl ester hydrochloride and the fluoro- 9- isothiocyano -8- of 5- (4- fluorophenyl) -8, The reaction preparation of 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester.MS (ESI): 514.1 [M+ H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one
With the step 5 of embodiment 45.MS (ESI): 414.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.47 (s, 1H), 10.32 (s, 1H), 7.67 (s, 1H), 7.50 (m, 2H), 7.24 (m, 2H), 7.12 (m, 1H), 6.94 (m, 1H), 6.02 (d, J=11.0Hz, 1H), 5.25 (d, J=11.0Hz, 1H), 4.17 (s, 2H).
The fluoro- 8- of embodiment 47:5- (4- fluorophenyl) -9- (4,4- dimethyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 47)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (4,4- dimethyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 4 of embodiment 45.By 2- aminoisobutyric acid methyl ester hydrochloride and fluoro- 9- isothiocyano -8- (the 4- fluorobenzene of 5- Base) the reaction preparation of -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester.MS (ESI): 542.2[M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (4,4- dimethyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 5 of embodiment 45.MS (ESI): 441.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.47 (s, 1H), 10.49 (s, 1H), 7.71 (s, 1H), 7.46 (m, 2H), 7.26 (m, 2H), 7.13 (m, 1H), 6.94 (m, 1H), 5.99 (d, J=11.2Hz, 1H), 5.24 (d, J=11.2Hz, 1H), 1.30 (s, 3H), 1.15 (s, 3H).
The fluoro- 8- of embodiment 48:5- (4- fluorophenyl) -9- (8- oxo -6- is thio -5,7- diaza spiro [3.4] octane -7- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 48)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (8- oxo -6- thio -5,7- diaza spiro [3.4] octane -7- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl esters
With the step 4 of embodiment 45.By 1- Aminocyclobutyl methyl formate hydrochloride and the fluoro- 9- isothiocyano -8- (4- of 5- Fluorophenyl) the reaction preparation of -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester.MS (ESI): 554.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (8- oxo -6- thio -5,7- diaza spiro [3.4] octane -7- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 5 of embodiment 45.MS (ESI): 454.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.44 (s, 1H), 10.75 (s, 1H), 7.70 (s, 1H), 7.46 (m, 2H), 7.23 (m, 2H), 7.12 (m, 1H), 6.94 (m, 1H), 5.95 (d, J=11.3Hz, 1H), 5.25 (d, J=11.5Hz, 1H), 2.31 (m, 4H), 1.88 (m, 2H).
(the thio tetrahydro-1 H-pyrrolo of (S) -1- oxo -3- is simultaneously [1,2-c] by the fluoro- 8- of embodiment 49:5- (4- fluorophenyl) -9- Imidazoles -2 (3H)-yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 49)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (the thio tetrahydro-1 H-pyrrolo of (S) -1- oxo -3- simultaneously [1,2-c] miaow Azoles -2 (3H)-yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 4 of embodiment 45.By L-PROLINE methyl ester hydrochloride and the fluoro- 9- isothiocyano -8- of 5- (4- fluorophenyl) - The reaction preparation of 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl esters.MS (ESI): 554.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (the thio tetrahydro-1 H-pyrrolo of (S) -1- oxo -3- simultaneously [1,2-c] miaow Azoles -2 (3H)-yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 5 of embodiment 45.MS (ESI): 454.1 [M+H]+。
The fluoro- 8- of embodiment 50:5- (4- fluorophenyl) -9- (3- cyclopropyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 50)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (3- cyclopropyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 4 of embodiment 45.By N- cyclopropylglycine ethyl ester and the fluoro- 9- isothiocyano -8- of 5- (4- fluorophenyl) - The reaction preparation of 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl esters.MS (ESI): 554.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (3- cyclopropyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 5 of embodiment 45.MS (ESI): 454.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.46 (s, 1H), 7.68 (s, 1H), 7.48 (m, 2H), 7.24 (m, 2H), 7.12 (m, 1H), 6.94 (d, J=10.7Hz, 1H), 6.06 (d, J =10.3Hz, 1H), 5.18 (d, J=10.4Hz, 1H), 4.26 (s, 2H), 3.12 (m, 1H), 0.83-0.70 (m, 4H).
The fluoro- 8- of embodiment 51:5- (4- fluorophenyl) -9- (7- oxo -5- is thio -4,6- diaza spiro [2.4] heptane -6- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 51)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (7- oxo -5- thio -4,6- diaza spiro [2.4] heptane -6- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl esters
With the step 4 of embodiment 45.By 1- amino cyclopropyl -1- carboxylate hydrochloride and the fluoro- 9- isothiocyano -8- of 5- The reaction preparation of (4- fluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester.MS (ESI): 540.1 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (7- oxo -5- thio -4,6- diaza spiro [2.4] heptane -6- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 5 of embodiment 45.MS (ESI): 440.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.55 (s, 1H), 8.03 (d, J=7.8Hz, 1H), 7.79 (s, 1H), 7.39 (m, 2H), 7.19 (m, 2H), 7.05 (dd, J=8.9, 2.0Hz, 1H), 6.95 (dd, J=11.2,2.0Hz, 1H), 5.09 (t, J=7.3Hz, 1H), 4.83 (d, J=6.5Hz, 1H), 1.56-1.42 (m, 4H).
The fluoro- 8- of embodiment 52:5- (4- fluorophenyl) -9- (3,4,4- trimethyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 52)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (3,4,4- trimethyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 4 of embodiment 45.By 2- methyl -2- methylaminopropionic acid ethyl ester and fluoro- 9- isothiocyano -8- (the 4- fluorine of 5- Phenyl) the reaction preparation of -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester.MS (ESI): 556.2[M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (3,4,4- trimethyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 5 of embodiment 45.MS (ESI): 456.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.45 (s, 1H), 7.73 (s, 1H), 7.47 (m, 2H), 7.25 (t, J=8.7Hz, 2H), 7.13 (dd, J=8.9,2.2Hz, 1H), 6.94 (d, J=9.2Hz, 1H), 6.08 (d, J=11.6Hz, 1H), 5.25 (d, J=11.6Hz, 1H), 3.09 (s, 3H), 1.36 (s, 3H), 1.21 (s, 3H).
The fluoro- 8- of embodiment 53:5- (4- fluorophenyl) -9- (5- methyl -8- oxo -6- is thio -5,7- diaza spiro [3.4] Octane -7- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 53)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (5- methyl -8- oxo -6- is thio-and 5,7- diaza spiro [3.4] is pungent Alkane -7- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 4 of embodiment 45.By 1- methylamino cyclobutyl -1- carboxylic acid, ethyl ester and the fluoro- 9- isothiocyano -8- (4- of 5- Fluorophenyl) the reaction preparation of -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester.MS (ESI): 568.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (5- methyl -8- oxo -6- is thio-and 5,7- diaza spiro [3.4] is pungent Alkane -7- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 5 of embodiment 45.MS (ESI): 468.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.43 (s, 1H), 7.71 (s, 1H), 7.48 (m, 2H), 7.23 (m, 2H), 7.13 (m, 1H), 6.94 (d, J=9.7Hz, 1H), 6.04 (d, J =11.5Hz, 1H), 5.28 (d, J=11.3Hz, 1H), 3.24 (s, 3H), 2.64 (m, 2H), 2.23 (m, 2H), 1.92 (m, 2H)。
Chiral resolving compound 53 obtains (8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (5- methyl -8- oxo -6- sulphur Generation -5,7- diaza spiro [3.4] octane -7- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (chemical combination Object 53a) and (8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (5- methyl -8- oxo -6- is thio-and 5,7- diaza spiro [3.4] is pungent Alkane -7- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 53b)
By the fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl -8- oxo -6- is thio -5,7- diaza spiro [3.4] octane -7- Base) to be dissolved in ethanol/methylene mixed for -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 53) In bonding solvent, chiral resolution is carried out using supercritical fluid chromatography (SFC) and obtains a pair of of enantiomter.Chiral column is ChiralCel OD, eluant, eluent is carbon dioxide (55%) and methanol (45%, contain 0.1% ammonium hydroxide).
The fluoro- 8- of embodiment 54:5- (4- fluorophenyl) -9- (4- oxo -2- is thio -1,3- diaza spiro [4.4] nonane -3- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 54)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (4- oxo -2- thio -1,3- diaza spiro [4.4] nonane -3- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl esters
With the step 4 of embodiment 45.By 1- amino cyclopentyl -1- carboxylate hydrochloride and the fluoro- 9- isothiocyano -8- of 5- The reaction preparation of (4- fluorophenyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester.MS (ESI): 568.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (4- oxo -2- thio -1,3- diaza spiro [4.4] nonane -3- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 5 of embodiment 45.MS (ESI): 468.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.47 (s, 1H), 10.64 (s, 1H), 7.71 (s, 1H), 7.46 (m, 2H), 7.25 (m, 2H), 7.13 (d, J=6.9Hz, 1H), 6.94 (d, J =10.0Hz, 1H), 6.00 (d, J=11.6Hz, 1H), 5.23 (d, J=11.6Hz, 1H), 1.97-1.49 (m, 8H).
The fluoro- 8- of embodiment 55:5- (4- fluorophenyl) -9- (4,7- methylene -3a, 4,7,7a- tetrahydro iso-indoles -1,3 (2H)-diketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 55)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (4,7- methylene -3a, 4,7,7a- tetrahydro iso-indoles -1,3 (2H)-two Ketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 4,7- methylene -3a, 4,7,7a- tetrahydro iso-indoles -1,3 (2H)-diketone and centre Body 1a reaction preparation.MS (ESI): 561.1 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (4,7- methylene -3a, 4,7,7a- tetrahydro iso-indoles -1,3 (2H)-two Ketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 461.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.47 (s, 1H), 7.48 (m, 3H), 7.28 (t, J=8.8Hz, 2H), 7.09 (dd, J=8.9,2.4Hz, 1H), 6.86 (dd, J=11.1, 2.4Hz, 1H), 5.67 (s, 1H), 5.39 (d, J=11.7Hz, 1H), 5.08 (s, 1H), 5.02 (d, J=11.8Hz, 1H), 3.38 (dd, J=7.8,4.5Hz, 1H), 3.27 (dd, J=7.8,4.5Hz, 1H), 3.15 (s, 1H), 3.10 (s, 1H), 1.45 (q, J=8.5Hz, 2H).
The fluoro- 8- of embodiment 56:5- (4- fluorophenyl) -9- (2- methyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- Alkene -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 56)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (2- methyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 2- methyl-1,3- diaza spiro-[4.4] nonyl- 1- alkene -4- ketone and intermediate 1a are anti- It should prepare.MS (ESI): 550.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (2- methyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 450.2 [M+H]+。
Chiral resolving compound 56 obtains (8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (2- methyl -4- oxo -1,3- bis- Azaspiro-[4.4] nonyl- 1- alkene -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 56a) and the fluoro- 8- of (8S, 9S) -5- (4- fluorophenyl) -9- (2- methyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 56b)
By the fluoro- 8- of 5- (4- fluorophenyl) -9- (2- methyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- base) - It is molten that 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 56) are dissolved in ethanol/methylene mixing In agent, chiral resolution is carried out using supercritical fluid chromatography (SFC) and obtains a pair of of enantiomter.Chiral column is ChiralCel OD, eluant, eluent is carbon dioxide (55%) and methanol (45%, contain 0.1% ammonium hydroxide).
The fluoro- 8- of embodiment 57:5- (4- fluorophenyl) -9- (2- butyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- Alkene -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 57)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (2- butyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By 2- butyl -1,3- diaza spiro-[4.4] nonyl- 1- alkene -4- keto hydrochloride and centre Body 1a reaction preparation.MS (ESI): 592.3 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (2- butyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 492.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.48 (s, 1H), 7.72 (s, 1H), 7.51 (dd, J=8.1,5.6Hz, 2H), 7.28 (t, J=8.7Hz, 2H), 7.11 (dd, J=8.9, 2.1Hz, 1H), 6.93 (dd, J=11.0,2.1Hz, 1H), 5.27 (m, 2H), 2.00-1.65 (m, 6H), 1.55-1.04 (m, 8H), 0.77 (t, J=7.2Hz, 3H).
Chiral resolving compound 57 obtains (8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (2- butyl -4- oxo -1,3- bis- Azaspiro-[4.4] nonyl- 1- alkene -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 57a) and the fluoro- 8- of (8S, 9S) -5- (4- fluorophenyl) -9- (2- butyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 57b)
By the fluoro- 8- of 5- (4- fluorophenyl) -9- (2- butyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- base) - It is molten that 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 57) are dissolved in ethanol/methylene mixing In agent, chiral resolution is carried out using supercritical fluid chromatography (SFC) and obtains a pair of of enantiomter.Chiral column is ChiralCel OD, eluant, eluent is carbon dioxide (55%) and methanol (45%, contain 0.1% ammonium hydroxide).
The fluoro- 8- of embodiment 58:5- (4- fluorophenyl) -9- (6- methyl -8- oxo -5,7- diaza spiro-[3.4] octyl- 5- Alkene -7- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 58)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (6- methyl -8- oxo -5,7- diaza spiro-[3.4] octyl- 5- alkene -7- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.It is anti-by 6- methyl -5,7- diaza spiro-[3.4] octyl- 5- alkene -8- ketone and intermediate 1a It should prepare.MS (ESI): 536.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (6- methyl -8- oxo -5,7- diaza spiro-[3.4] octyl- 5- alkene -7- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 436.2 [M+H]+。
Chiral resolving compound 58 obtains (8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (6- methyl -8- oxo -5,7- bis- Azaspiro-[3.4] octyl- 5- alkene -7- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 58a) and the fluoro- 8- of (8S, 9S) -5- (4- fluorophenyl) -9- (6- methyl -8- oxo -5,7- diaza spiro-[3.4] octyl- 5- alkene -7- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 58b)
By the fluoro- 8- of 5- (4- fluorophenyl) -9- (6- methyl -8- oxo -5,7- diaza spiro-[3.4] octyl- 5- alkene -7- base) - It is molten that 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 58) are dissolved in ethanol/methylene mixing In agent, chiral resolution is carried out using supercritical fluid chromatography (SFC) and obtains a pair of of enantiomter.Chiral column is ChiralCel OD, eluant, eluent is carbon dioxide (55%) and methanol (45%, contain 0.1% ammonium hydroxide).
The fluoro- 8- of embodiment 59:5- (4- fluorophenyl) -9- (5- methyl -7- oxo -4,6- diaza spiro-[2.4] hept- 4- Alkene -6- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 59)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (5- methyl -7- oxo -4,6- diaza spiro-[2.4] hept- 4- alkene -6- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.It is anti-by 5- methyl -4,6- diaza spiro-[2.4] hept- 4- alkene -7- ketone and intermediate 1a It should prepare.MS (ESI): 522.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (5- methyl -7- oxo -4,6- diaza spiro-[2.4] hept- 4- alkene -6- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H-) -one
With the step 2 of embodiment 1.MS (ESI): 421.1 [M+H]+。
Chiral resolving compound 59 obtains 8R, 9R) the fluoro- 8- of -5- (4- fluorophenyl) -9- (5- methyl -7- oxo -4,6- bis- Azaspiro-[2.4] hept- 4- alkene -6- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 59a) and the fluoro- 8- of (8S, 9S) -5- (4- fluorophenyl) -9- (5- methyl -7- oxo -4,6- diaza spiro-[2.4] hept- 4- alkene -6- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 59b)
By the fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl -7- oxo -4,6- diaza spiro-[2.4] hept- 4- alkene -6- base) - It is molten that 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 59) are dissolved in ethanol/methylene mixing In agent, chiral resolution is carried out using supercritical fluid chromatography (SFC) and obtains a pair of of enantiomter.Chiral column is ChiralCel OD, eluant, eluent is carbon dioxide (55%) and methanol (45%, contain 0.1% ammonium hydroxide).
The fluoro- 8- of embodiment 60:5- (4- fluorophenyl) -9- (2,4,4- trimethyl -5- oxo -4,5- dihydro -1H- imidazoles -1- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 60)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (2,4,4- trimethyl -5- oxo -4,5- dihydro -1H- imidazoles -1- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By -5 (4H) -one of 2,4,4- trimethyl -1H- imidazoles and intermediate 1a reaction preparation.MS (ESI): 524.2 [M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (2,4,4- trimethyl -5- oxo -4,5- dihydro -1H- imidazoles -1- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 424.2 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.49 (s, 1H), 7.65 (s, 1H), 7.53 (dd, J=8.6,5.5Hz, 2H), 7.28 (t, J=8.8Hz, 2H), 7.08 (dd, J=9.0, 2.3Hz, 1H), 6.88 (dd, J=11.1,2.3Hz, 1H), 5.28 (d, J=11.6Hz, 1H), 5.11 (d, J=10.8Hz, 1H), 1.87 (s, 3H), 1.04 (s, 3H), 0.98 (s, 3H).
The fluoro- 8- of embodiment 61:5- (4- fluorophenyl) -9- (2- methyl -5- oxo -4,5- dihydro -1H- imidazoles -1- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one (compound 61)
The fluoro- 8- of step 1:5- (4- fluorophenyl) -9- (2- methyl -5- oxo -4,5- dihydro -1H- imidazoles -1- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one -7- carboxylic acid tert-butyl ester
With the step 1 of embodiment 1.By -5 (4H) -one of 2- methyl-1 H- imidazoles and intermediate 1a reaction preparation.MS (ESI): 496.2[M+H]+。
The fluoro- 8- of step 2:5- (4- fluorophenyl) -9- (2- methyl -5- oxo -4,5- dihydro -1H- imidazoles -1- base) -8,9- Dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one
With the step 2 of embodiment 1.MS (ESI): 396.1 [M+H]+。1H NMR (400MHz, DMSO-d6) δ 12.58 (s, 1H), 7.75 (m, 3H), 7.32 (t, J=8.8Hz, 2H), 7.12 (dd, J=8.9,2.4Hz, 1H), 6.90 (dd, J=11.1, 2.4Hz, 1H), 5.68 (d, J=11.4Hz, 1H), 4.83 (d, J=11.4Hz, 1H), 3.97 (q, J=19.3Hz, 2H), 1.96 (s, 3H).
II. the compounds of this invention active testing embodiment
Testing example 1: cell inhibitory effect activity research
Following pharmacological evaluation is for measuring the compound of the present invention in vitro to people's triple negative breast cancer cell strain MDA-MB- 436 (BRCA1 mutation) and estrogen receptor negative (ER-), progesterone receptor feminine gender (PR-) inflammatory breast cancer cell line The proliferation inhibition activity of SUM149PT (BRCA1 mutation).
Experimentation (Sulforhodamine B decoration method): the tumor cell inoculation in logarithmic growth phase is taken to cultivate in 96 holes Plate (180 hole μ L/), 37 DEG C, 5%CO2Culture keeps cell adherent in 24 hours.Each compound is dissolved in DMSO in advance to be configured to The storing liquid of 10mM.When detection Shi Zaiyong complete medium is diluted to 10 times of purpose concentration in another 96 orifice plate, then exist 20 hole μ L/ of diluted compounds is added in 96 orifice plates of inoculating cell, i.e. arrival purpose concentration.Each concentration sets 3 multiple holes, and sets Blank control.Continue in 37 DEG C, 5%CO2In continue culture 120 hours.Culture is terminated, 50 μ L pre-cooling (4 DEG C) is added in every hole 50% trichloroacetic acid, that is, TCA (final concentration 10%) is placed on 4 DEG C and fixes 1 hour, with purifying water washing at least 5 times, in air certainly So dry or 60 DEG C of oven dryings.The Sulforhodamine that 100 μ L use the purified water containing 1% glacial acetic acid to prepare 4mg/mL is added in every hole B (SRB) solution, room temperature dye 1 hour, abandon dyeing liquor, wash at least 5 times with 1% glacial acetic acid, dried for standby.Every hole is added 150 The Tris-HCl solution of the 10mM of μ L dissolves, and OD value is surveyed at 510nm wavelength, then obtain compound on tumor cell by calculating The IC of Proliferation Ability50Value.Experimental result is shown in Table one.
Table one
Note: LT-00628 (preparation method refers to CN102171214B embodiment 94), Talazoparib (preparation method ginseng Examine CN102171214B embodiment 155) and Olaparib (compound 168 that preparation method refers to CN1788000B embodiment 9) For PARP inhibitor reported in the literature.LT-00628 is the racemic modification of Talazoparib.
Test result shows: the compounds of this invention is to people triple negative breast cancer cell strain MDA-MB-436 and estrogen receptor Feminine gender (ER-), progesterone receptor feminine gender (PR-) inflammatory breast cancer cell line SUM149PT have apparent proliferation inhibition activity. The research of testing example 2:PARP-1 and PARP-2 enzyme inhibition activity
Following pharmacological evaluation is for measuring inhibition of the compound of the present invention in molecular level to PARP-1 and PARP-2 enzyme Activity.
Experimentation: histone is enclosed in 96 orifice plates and 4 DEG C of overnight incubations.With 200 μ L PBST (phosphate buffer) After solution washs the plate 3 times, it is closed with confining liquid, after incubation at room temperature 30 minutes, is washed 3 times with PBST solution.It will be tested It tries compound processing to be added in orifice plate, will add in PARP-2 (3nM) solution of the diluted PARP-1 of 20 μ L (1nM) or 20 μ L later Enter into reaction system and is incubated for 1 or 2 hour.The mixed liquor of 50 μ L Streptavidin-HRP (horseradish peroxidase) (1: 50) adds After entering into orifice plate and being incubated at room temperature 30 minutes, PBST buffer is washed three times.100 μ LHRP chemiluminescent substrate mixtures add Enter orifice plate.It arrives on microplate reader (Envision, PerkinElmer) and reads immediately.Compound is obtained to PARP-1 by calculating again With the IC of PARP-2 enzyme inhibition activity50Value.Experimental result is shown in Table two.
Table two
Note: LT-00628 is the racemic modification of Talazoparib, and preparation method refers to CN102171214B embodiment 94.
Test result shows: the compounds of this invention there is apparent inhibition to live PARP-1 and PARP-2 enzyme in molecular level Property.
Testing example 3: pharmacokinetic property research
It is dynamic to evaluate its medicine for studying the compounds of this invention in the intracorporal pharmacokinetics behavior of rat for following experimental program Learn feature.
Experimental program: healthy SD rat 3, the compound of 10mg/kg is given in male, weight 180-200g, stomach-filling, is administered Volume is 10mL/kg, with -15 hydroxy stearic acid ester of 5%DMSO/15% polyethylene glycol/80% hydroxypropyl-β-cyclodextrin (hydroxypropyl Group-beta-cyclodextrin is 20% aqueous solution, w/v) it prepares.Fasting 12h, free water before testing.2h is unified after administration feeds.
Healthy SD rat 3, male, weight 180-200g is injected intravenously the compound for giving 5mg/kg, and administered volume is - 15 hydroxy stearic acid ester of 5mL/kg, 5%DMSO/15% polyethylene glycol/80% hydroxypropyl-β-cyclodextrin (hydroxy propyl-Beta-ring paste Essence is 20% aqueous solution, w/v) it prepares.Fasting 12h, free water before testing.2h is unified after administration feeds.
After gastric infusion 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 0.08h for 24 hours and after intravenously administrable, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, for 24 hours through rat eye rear vein beard extracting vein blood 0.1mL, set in heparinised tubes, 11000rpm is centrifuged 5min, separated plasma, with the concentration of compound in liquid chromatography-tandem mass spectrometry blood plasma.Experiment knot Fruit is shown in Table three.
Table three
Test result shows: the compounds of this invention clearance rate is low, and plasma exposure amount is high, and oral administration biaavailability is high, has Good pharmacokinetic property.
Testing example 4: to the growth inhibition of people's triple negative breast cancer cell MDA-MB-436 nude mouse subcutaneous transplantation tumor Effect
Following testing program is for studying the compounds of this invention and LT-00628 to people's triple negative breast cancer cell MDA-MB- The inhibiting effect and safety conditions of 436 nude mouse subcutaneous transplantation tumors.
Cell culture: MDA-MB-436 culture is in the improvement Eagle culture medium added with 10% fetal calf serum-Leibovitz training It supports in base mixed liquor (1/1, v/v), is placed on 37 DEG C and contains 5%CO2Constant incubator in cultivate.Collect the thin of exponential phase of growth Born of the same parents simultaneously count, for inoculation.
Experimental animal: BALB/cA nude mouse, 15, female, 5 week old, 18 ± 2g are dynamic purchased from the experiment of Beijing dimension tonneau China Object Technology Co., Ltd..
If 3 test groups, it is respectively as follows: 10% dimethyl acetamide/- 15 hydroxy stearic acid ester of 5% polyethylene glycol/85% phosphorus Acid buffering salting liquid solvent control group, the 1mg/kg group of compound 56 and the 1mg/kg group of LT-00628.
Testing program: people triple negative breast cancer cell MDA-MB-436 cell strain (5 × 106A/only) it is inoculated in BALB/cA Dorsal sc on the right side of nude mouse, every mouse inoculation amount is 2mL, routine observation tumour growth situation, to tumour growth to 100- 200mm3When be grouped at random according to tumor size and mouse weight.Compound 56 and control compound LT-00628 (LT-00628 For the racemic modification of Talazoparib) 1mg/kg gastric infusion is respectively pressed, equivalent solvent is given in solvent control group stomach-filling, daily It is administered once, continuous 20 days.In whole experiment process, the size of the weight and tumour of mouse twice is measured weekly, is seen whether There is toxic reaction.
The calculation formula of gross tumor volume (tumor volume) are as follows: TV=1/2 × a × b2, wherein a, b respectively indicate tumour Length and width.
Three test group tumor volume change curves and mouse weight change curve are shown in attached drawing 1 and attached drawing 2.The result shows that this Invention compound has good inhibiting effect to the growth of MDA-MB-436 nude mouse subcutaneous transplantation tumor, and to nude mice Ghost image sound is smaller, shows preferable safety.
Referenced herein all documents pass through reference and are incorporated into the application.Additionally it is noted that, readding After having read the above disclosure of the application, those skilled in the art be may not need away from the spirit and scope of the present invention, right The present invention makes various modifications, change or modification, but these versions equally should all fall within the application the appended claims Documented range.

Claims (24)

1. such as following formula (I) compound, its pharmaceutically acceptable salt or stereoisomer,
In formula:
Ring A is to pass through N on ring containing the nitrogenous alicyclic heterocyclic base or nitrogenous aromatic heterocyclic of 1~5 ring hetero atom selected from N, O or S Atom is connected with dihydro pyrido phthalazone parent nucleus；
Ring B is aryl or aromatic heterocyclic；
R1Selected from hydrogen, C1-C6Alkyl, C1-C6Alkoxy, halogen, halogenated C1-C6Alkyl, C2-C6Alkenyl, C2-C6Alkynyl, 3~7 yuan Naphthenic base ,-CN ,-OH ,-NO2Or-NR5R6；
R5、R6It is each independently selected from H, C1-C6Alkyl or halogenated C1-C6Alkyl；
R2It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-NH2, halogen, deuterium, deuterated C1-C6Alkane Base ,-(CH2)qOH, 3~7 yuan of naphthenic base, Aryl is selected from C by 1~31-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-OH ,-NH2 Or the aryl that the substituent group of halogen replaces；
R3It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-OH ,-NH2Or halogen；
Q is 0,1,2 or 3；
N is 0,1,2,3 or 4；
M is 0,1,2 or 3.
2. compound as described in claim 1, its pharmaceutically acceptable salt or stereoisomer, it is characterised in that describedization Conjunction object be formula (II) compound, wherein each substituent group define it is identical as the meaning in claim 1,
3. compound as claimed in claim 1 or 2, its pharmaceutically acceptable salt or stereoisomer, it is characterised in that R1Choosing From hydrogen, C1-C6Alkyl or halogen.
4. compound as claimed in claim 1 or 2, its pharmaceutically acceptable salt or stereoisomer, it is characterised in that ring B For phenyl or pyridyl group, R3 is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-OH ,-NH2Or halogen Element, m 0,1,2 or 3.
5. compound as claimed in claim 4, its pharmaceutically acceptable salt or stereoisomer, it is characterised in that the R3 For halogen, m is 1 or 2.
6. compound as claimed in claim 1 or 2, its pharmaceutically acceptable salt or stereoisomer, it is characterised in that ring A For nitrogenous monocycle alicyclic heterocyclic base, nitrogenous condensed ring alicyclic heterocyclic base, nitrogenous bridged ring containing 1~5 ring hetero atom selected from N, O or S Condensed ring alicyclic heterocyclic base or nitrogenous loop coil alicyclic heterocyclic base are connected by N atom on ring with dihydro pyrido phthalazone parent nucleus；Wherein, R2It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-NH2, halogen ,-(CH2)qOH, 3~7 member rings Alkyl,Aryl or C is selected from by 1~31-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-OH ,-NH2Or the virtue that the substituent group of halogen replaces Base, q 0,1,2 or 3, n 0,1,2,3 or 4.
7. compound as claimed in claim 6, its pharmaceutically acceptable salt or stereoisomer, it is characterised in that described to contain Nitrogen monocycle alicyclic heterocyclic base, nitrogenous condensed ring alicyclic heterocyclic base, nitrogenous bridged ring condensed ring alicyclic heterocyclic base, nitrogenous loop coil alicyclic heterocyclic base are selected from
8. compound as claimed in claim 7, its pharmaceutically acceptable salt or stereoisomer, it is characterised in that described to contain Nitrogen monocycle alicyclic heterocyclic base, nitrogenous condensed ring alicyclic heterocyclic base, nitrogenous bridged ring condensed ring alicyclic heterocyclic base, nitrogenous loop coil alicyclic heterocyclic base are selected from
9. compound as claimed in claim 6, its pharmaceutically acceptable salt or stereoisomer, it is characterised in that the R2 It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-NH2, halogen ,-(CH2)qOH, 3~7 yuan of cycloalkanes Base,Phenyl is selected from C by 1~31-C6Alkane Base ,-OH ,-NH2Or the phenyl that the substituent group of halogen replaces, q 0,1 or 2, n 0,1,2 or 3.
10. compound as claimed in claim 1 or 2, its pharmaceutically acceptable salt or stereoisomer, it is characterised in that ring A is to pass through ring containing the nitrogenous monocycle aromatic heterocyclic or nitrogenous condensed ring aromatic heterocyclic of 1~5 ring hetero atom selected from N, O or S Upper N atom is connected with dihydro pyrido phthalazone parent nucleus；Wherein, R2 is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, Halogenated C1-C6Alkyl ,-NH2, halogen ,-(CH2)qOH, 3~7 yuan of naphthenic base, Aryl is selected from C by 1~31-C6Alkyl, C1-C6Alcoxyl Base, halogenated C1-C6Alkyl ,-OH ,-NH2Or the aryl that the substituent group of halogen replaces, q 0,1,2 or 3, n 0,1,2,3 or 4.
11. compound as claimed in claim 10, its pharmaceutically acceptable salt or stereoisomer, it is characterised in that described Nitrogenous monocycle aromatic heterocyclic, nitrogenous condensed ring aromatic heterocyclic are selected from
12. compound as claimed in claim 11, its pharmaceutically acceptable salt or stereoisomer, it is characterised in that described Nitrogenous monocycle aromatic heterocyclic, nitrogenous condensed ring aromatic heterocyclic are selected from
13. compound as claimed in claim 10, its pharmaceutically acceptable salt or stereoisomer, it is characterised in that described R2It is each independently selected from C1-C6Alkyl, C1-C6Alkoxy, halogenated C1-C6Alkyl ,-(CH2)qOH、-NH2, halogen or phenyl, q It is 0,1 or 2, n 0,1,2 or 3.
14. compound as claimed in claim 1 or 2, its pharmaceutically acceptable salt or stereoisomer, it is selected from:
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalein Piperazine -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- Trifluoromethyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (3,5- dimethyl -1H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2- methyl-1 H-imidazole-1-group) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalein Piperazine -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (3- trifluoromethyl -5,6- dihydro-[1,2,4] triazole [4,3-a] pyrazine -7 (8H) - Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1H- indazolyl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) - Ketone；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (pyrrolidines -2,5- diketone -1- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalein Piperazine -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (4,7- epoxy hexahydro iso-indoles -1,3 (2H)-diketone -2- base) -8,9- dihydro -2H- pyrrole Pyridine simultaneously [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (4,7- epoxy -3a, 4,7,7a- tetrahydro iso-indoles -1,3 (2H)-diketone -2- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (4,7- epoxy -5- hydroxyl hexahydro iso-indoles -1,3 (2H)-diketone -2- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (iso-indoles -1,3- diketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalein Piperazine -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalein Piperazine -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- methyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4,3, 2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- isopropyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- (2- ethoxy) -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- cyclopropyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- cyclopenta -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1,5,5- trimethyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- isopropyl -5,5- dimethyl -2,4- imidazolinedione -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl -5- phenyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- ((7aS)-tetrahydro-1 H-pyrrolo simultaneously [1,2-c] imidazoles -1,3 (2H)-diketone -2- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- ((S) -7a- methyl tetrahydro-1 H-pyrrolo simultaneously [1,2-c] imidazoles -1,3 (2H)-diketone -2- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- ((6R, 7aS) -6- hydroxy tetrahydro -1H- pyrrolo- [1,2-c] imidazoles -1,3 (2H)-two Ketone -2- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1,3- diaza spiro [3.4] octane -6,8- diketone -3- base) -8,9- dihydro -2H- pyrrole Pyridine simultaneously [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1,3- diaza spiro [4.4] nonane -2,4- diketone -3- base) -8,9- dihydro -2H- pyrrole Pyridine simultaneously [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1,3- diaza spiro [4.5] decane-2,4-diones -3- base) -8,9- dihydro -2H- pyrrole Pyridine simultaneously [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2- oxygen -5,7- diaza spiro [3.4] octane -6,8- diketone -7- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2,5,7- thriazaspiros [3.4] octane -6,8- diketone -7- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2,4- thiazolidinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalein Piperazine -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- thiazolidinedione -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (oxazolidine -2,4- diketone -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalein Piperazine -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5,5- dimethyl oxazolidine -2,4- diketone -3- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2H- benzo [e] [1,3] oxazines -2,4 (3H)-diketone -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (benzo [d] isothiazole -3 (2H) -one -1,1- dioxide -2- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl -3- amino -1H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- isopropyl -1H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4,3, 2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl-1 H- pyrazol-1-yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalein Piperazine -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4,3,2- De] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (2,4- difluorophenyl) -9- (5- methyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- methyl -2,4,5- imidazoline trione -3- base) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- cyclobutyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyrido [4, 3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- (azetidin -3- base) -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (1- (piperidin-4-yl) -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (3- methyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro -2H- pyrido [4,3,2- De] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (4,4- dimethyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro -2H- pyrrole Pyridine simultaneously [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (8- oxo -6- thio -5,7- diaza spiro [3.4] octane -7- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (the thio tetrahydro-1 H-pyrrolo of (S) -1- oxo -3- simultaneously [1,2-c] imidazoles -2 (3H) - Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (3- cyclopropyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (7- oxo -5- thio -4,6- diaza spiro [2.4] heptane -6- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (3,4,4- trimethyl -5- oxo -2- thiocarbamoyl imidazole quinoline -1- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl -8- oxo -6- thio -5,7- diaza spiro [3.4] octane -7- base) -8, 9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (4- oxo -2- thio -1,3- diaza spiro [4.4] nonane -3- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (4,7- methylene -3a, 4,7,7a- tetrahydro iso-indoles -1,3 (2H)-diketone -2- base) - 8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2- methyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2- butyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (6- methyl -8- oxo -5,7- diaza spiro-[3.4] octyl- 5- alkene -7- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (5- methyl -7- oxo -4,6- diaza spiro-[2.4] hept- 4- alkene -6- base) -8,9- bis- Hydrogen -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2,4,4- trimethyl -5- oxo -4,5- dihydro -1H- imidazoles -1- base) -8,9- dihydro - 2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
The fluoro- 8- of 5- (4- fluorophenyl) -9- (2- methyl -5- oxo -4,5- dihydro -1H- imidazoles -1- base) -8,9- dihydro -2H- pyrrole Pyridine simultaneously [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (1- methyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (1- methyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (5,5- dimethyl -2,4- imidazolinedione -3- base) -8,9- dihydro -2H- Pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (5- methyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (5- methyl-1 H-1,2,4- triazol-1-yls) -8,9- dihydro -2H- pyridine And [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (5- methyl -8- oxo -6- is thio -5,7- diaza spiro [3.4] octane - 7- yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (5- methyl -8- oxo -6- is thio -5,7- diaza spiro [3.4] octane - 7- yl) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (2- methyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (2- methyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (2- butyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (2- butyl -4- oxo -1,3- diaza spiro-[4.4] nonyl- 1- alkene -3- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (6- methyl -8- oxo -5,7- diaza spiro-[3.4] octyl- 5- alkene -7- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (6- methyl -8- oxo -5,7- diaza spiro-[3.4] octyl- 5- alkene -7- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8R, 9R) -5- fluoro- 8- (4- fluorophenyl) -9- (5- methyl -7- oxo -4,6- diaza spiro-[2.4] hept- 4- alkene -6- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one；
(8S, 9S) -5- fluoro- 8- (4- fluorophenyl) -9- (5- methyl -7- oxo -4,6- diaza spiro-[2.4] hept- 4- alkene -6- Base) -8,9- dihydro -2H- pyrido [4,3,2-de] phthalazines -3 (7H) -one.
15. the preparation method of formula (II) compound as claimed in claim 2 comprising following steps,
Wherein, ring A, ring B, R1、R2、R3, m, n it is identical as the meaning in claim 2；
Raw material (a) obtains compound (b) through esterification；Compound (b) is being catalyzed with tributyl (1- ethoxy ethylene base) tin The lower reaction of agent effect obtains compound (c)；Compound (c) obtains compound (d) through reductive hydrolysis；Compound (d) and compound (e) compound (f) is obtained through condensation reaction；Compound (f) obtains compound (g) through ring closure reaction；Compound (g) is protected through Boc Shield obtains compound (h)；Compound (h) reacts to obtain compound with trifluoromethanesulfonic acid t-butyldimethylsilyl ester in the presence of a base (i)；Compound (i) is oxidized to obtain compound (j)；Compound (j) and hydrazine hydrate obtain compound (k) through annulation；Change It closes object (k) deprotection and obtains compound (l)；Compound (1) obtains intermediate 1 through chlorination reaction；Intermediate 1 withIt carries out substitution reaction and obtains compound (m)；Compound (m) removing Boc protecting group obtains formula (II) compound.
16. such as 1 compound of intermediate of formula,
Wherein, R1For halogen, ring B is phenyl, R3For halogen, m is 1 or 2.
17. a kind of pharmaceutical composition, including claim 1~14 described in any item compounds, its is pharmaceutically acceptable Salt or stereoisomer and pharmaceutically acceptable carrier, excipient or diluent.
18. described in any item compounds of claim 1~14, its pharmaceutically acceptable salt or stereoisomer, or power Benefit require 17 described in pharmaceutical composition in the drug that preparation treats or prevents the disease improved because inhibiting PARP active Using.
19. described in any item compounds of claim 1~14, its pharmaceutically acceptable salt or stereoisomer, or power Benefit require 17 described in pharmaceutical composition preparing the application in drug for treating or preventing cancer.
20. application as claimed in claim 19, the drug and ionising radiation, one or more chemotherapeutics or combinations thereof group Close application.
21. described in any item compounds of claim 1~14, its pharmaceutically acceptable salt or stereoisomer, or power Benefit require 17 described in pharmaceutical composition preparation for treating or preventing homologous recombination (HR) dependent DNA double-strand break (DSB) application in the drug of the cancer of approach missing is repaired.
22. the application as described in claim 19 or 21, the cancer includes one or more cancer cells, and the cancer cell has The ability using HR DNA plerosis DSB for reducing or abolishing relative to normal cell.
23. there is BRCA1 or BRCA2 to lack phenotype for application as claimed in claim 22, the cancer cell.
24. the application as described in claim 19 or 21, the cancer includes breast cancer, oophoroma, carcinoma of endometrium, uterine neck Cancer, lung cancer, prostate cancer, cancer of pancreas, leukemia, gastric cancer, gallbladder cancer, liver cancer, head and neck cancer, the cancer of the esophagus, kidney, the cancer of the brain, leukaemia, Colon cancer, intestinal tumor, glioblastoma, lymthoma or melanoma.
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* Cited by examiner, † Cited by third party
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WO2013028495A1 (en) * 2011-08-19 2013-02-28 Biomarin Pharmaceutical Inc. Dihydropyridophthalazinone inhibitors of poly (adp-ribose) polymerase (parp) for the treatment of multiple myeloma
US20130053365A1 (en) * 2011-08-30 2013-02-28 Biomarin Pharmaceutical, Inc. Dihydropyridophthalazinone inhibitors of poly(adp-ribose)polymerase (parp)

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