WO2019174607A1 - Dihydropyridophthalazinone derivative, and preparation method therefor and application thereof - Google Patents

Dihydropyridophthalazinone derivative, and preparation method therefor and application thereof Download PDF

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WO2019174607A1
WO2019174607A1 PCT/CN2019/078089 CN2019078089W WO2019174607A1 WO 2019174607 A1 WO2019174607 A1 WO 2019174607A1 CN 2019078089 W CN2019078089 W CN 2019078089W WO 2019174607 A1 WO2019174607 A1 WO 2019174607A1
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fluoro
fluorophenyl
pyridazine
dihydro
pyrido
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PCT/CN2019/078089
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French (fr)
Chinese (zh)
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罗会兵
周华勇
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上海艾力斯医药科技有限公司
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Priority to CN201980018770.XA priority Critical patent/CN111868060B/en
Publication of WO2019174607A1 publication Critical patent/WO2019174607A1/en

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    • A—HUMAN NECESSITIES
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    • 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
    • A—HUMAN NECESSITIES
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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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Definitions

  • the present invention relates to a dihydropyridoxinone derivative capable of inhibiting poly(ADP-ribose) polymerase activity, a process for the preparation thereof, and a pharmaceutical composition comprising the same, and the derivative is prepared for use in therapy or A pharmaceutical aspect of preventing a disease that is ameliorated by inhibition of PARP activity.
  • Poly(ADP-ribose) polymerase also known as poly(ADP-ribose) synthase, poly ADP-ribosyltransferase, is commonly referred to as PARP.
  • the PARP family includes approximately 18 proteins, such as PARP-1, PARP-2, PARP-3, terminal anchorase-1, terminal anchorase-2, scorpion PARP, TiPARP, and the like.
  • PARP is involved in the signaling of DNA damage through its ability to recognize and rapidly bind to single or double stranded strands of DNA (Biochem J (1999) 342: 249-268).
  • PARP inhibitors can cause a significant increase in DNA-strand breaks and cell killing (Nature (1980) 283: 593-596; Radiat Res (1985) 101: 4 -14); Radiotherapy and many chemotherapy methods act by inducing DNA damage, making PARP inhibitors a chemical and radiosensitizer for cancer treatment (US5032617, US5215738 and US5041653); PARP inhibitors are available for antiviral therapy and cancer Treatment (WO 91/18591); the association of BRCA1 and/or BRCA2 mutations with breast cancer is well recognized in the art (Exp Clin Cancer Res (2002) 21 (suppl 3): 9-12), BRCA1 and/or BRCA2 The medium-mutated vector is also at increased risk of ovarian, prostate and pancreatic cancer, and PARP inhibitors have been shown to be useful for specific killing of BRCA1 and BRCA2-deficient tumors (Nature (2005) 434: 913-916 and 917-921; Cancer Biol Ther (2005) 4:
  • the currently disclosed small molecule PARP inhibitors include: amide substituted benzene rings fused to a 5-membered heteroaryl ring disclosed in WO 1999/59973, amide substituted oximes disclosed in WO 2001/85687, WO 2003/106430, WO 2006/110816 publication Amide substituted benzimidazole, amide substituted benzoxazole disclosed in EP0879820, amide substituted benzopyrazole disclosed in WO2008/84261, dihydropyridinopyridinone disclosed in WO2010/17055, and the like.
  • the small-molecule PARP inhibitors that have been marketed include Olaparib disclosed in WO2004/80976, Rucaparib disclosed in WO2000/42040, and Niraparib disclosed in WO2008/84261, all of which are used for the treatment of ovarian cancer, and the specific structure is as follows.
  • the present invention provides a class of dihydropyridinopyridazinone derivatives, pharmaceutically acceptable salts or stereoisomers thereof, which have good PARP inhibitory activity and can be used for the preparation of a therapeutic or prophylactically inhibiting PARP activity. And drugs that improve the disease.
  • the present invention provides a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof,
  • Ring A is a nitrogen-containing aliphatic heterocyclic group or a nitrogen-containing aromatic heterocyclic group having 1 to 5 ring hetero atoms selected from N, O or S, and is bonded to the dihydropyridinopyrazine ketone through a ring N atom. ;
  • Ring B is an aryl or an aromatic heterocyclic group
  • R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, halogenated C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl , 3 to 7-membered cycloalkyl, -CN, -OH, -NO 2 or -NR 5 R 6 ;
  • R 5 and R 6 are each independently selected from H, C 1 -C 6 alkyl or halo C 1 -C 6 alkyl;
  • R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -NH 2 , halogen, hydrazine, deuterated C 1 -C 6 alkane Base, -(CH 2 ) q OH, 3- to 7-membered cycloalkyl,
  • the aryl group is substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -OH, -NH 2 or halogen Aryl;
  • R 3 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -OH, -NH 2 or halogen;
  • q 0, 1, 2 or 3;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2 or 3.
  • the invention provides a process for the preparation of a compound of formula (I).
  • the present invention provides intermediate 1, which is useful in the preparation of compounds of the invention.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
  • the present invention provides the use of a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition thereof, for the preparation of a medicament for treating or preventing a disease which is ameliorated by inhibition of PARP activity.
  • the present invention also provides a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of vascular diseases, septic shock, ischemic injury, and further Perfusion injury, neurotoxicity, hemorrhagic shock, inflammatory disease, neurological disease, multiple sclerosis, secondary effects of diabetes, acute treatment of cytotoxicity after cardiovascular surgery, retinal damage, skin aging or UV-induced skin damage Application in medicine.
  • vascular diseases septic shock, ischemic injury, and further Perfusion injury, neurotoxicity, hemorrhagic shock, inflammatory disease, neurological disease, multiple sclerosis, secondary effects of diabetes, acute treatment of cytotoxicity after cardiovascular surgery, retinal damage, skin aging or UV-induced skin damage Application in medicine.
  • the invention also provides the use of a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment or prevention of cancer.
  • the present invention also provides the use of a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition thereof, for the preparation of a medicament for treating or preventing cancer, the medicament and ionizing radiation Administration with one or more chemotherapeutic drugs or a combination thereof.
  • the present invention also provides the use of a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition thereof, for the preparation of a medicament for treating or preventing cancer, the cancer comprising Or a plurality of cancer cells having the ability to repair DNA double-strand breaks (DSBs) using homologous recombination (HR) relative to normal cells, reduced or abolished.
  • a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition thereof for the preparation of a medicament for treating or preventing cancer, the cancer comprising Or a plurality of cancer cells having the ability to repair DNA double-strand breaks (DSBs) using homologous recombination (HR) relative to normal cells, reduced or abolished.
  • the present invention also provides the use of a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition thereof, for the preparation of a medicament for treating or preventing cancer, the cancer comprising Or a plurality of cancer cells having the ability to repair DNA DSB with HR reduced or abolished relative to normal cells, eg, the cancer cells have a BRCA1 or BRCA2 deletion phenotype.
  • the present invention further provides a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition thereof, for use in the preparation or treatment of homologous recombination (HR)-dependent DNA double-strand breaks ( DSB)
  • HR homologous recombination
  • DSB homologous recombination-dependent DNA double-strand breaks
  • the invention further provides a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, for use in the manufacture or prevention of homologous recombination (HR)-dependent DNA double-strand breaks ( DSB)
  • HR homologous recombination
  • DSB homologous recombination-dependent DNA double-strand breaks
  • the invention further provides a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, for use in the manufacture or prevention of homologous recombination (HR)-dependent DNA double-strand breaks ( DSB)
  • a medicament for repairing a cancer in which a pathway is absent the cancer comprising one or more cancer cells having the ability to repair DNA DSB using HR, such as the cancer, reduced or abolished relative to normal cells
  • the cells have a BRCA1 or BRCA2 deletion phenotype.
  • the cancer of the present invention includes, but is not limited to, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, prostate cancer, pancreatic cancer, blood cancer, stomach cancer, gallbladder cancer, liver cancer, head and neck cancer, esophageal cancer, kidney cancer, brain. Cancer, leukemia, colon cancer, intestinal tumor, glioblastoma, lymphoma or melanoma.
  • the present invention provides a method of treating or preventing a disease ameliorated by inhibition of PARP activity, which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer of the present invention.
  • the invention also provides a treatment or prevention of vascular diseases, septic shock, ischemic injury, reperfusion injury, neurotoxicity, hemorrhagic shock, inflammatory disease, neurological disease, multiple sclerosis, secondary effects of diabetes
  • vascular diseases septic shock, ischemic injury, reperfusion injury, neurotoxicity, hemorrhagic shock, inflammatory disease, neurological disease, multiple sclerosis, secondary effects of diabetes
  • a method of acute treatment of cytotoxicity after cardiovascular surgery, retinal damage, skin aging or UV-induced skin damage comprising administering to a patient in need thereof an effective amount of a compound of formula (I) of the invention, which is pharmaceutically acceptable A salt or stereoisomer or a pharmaceutical composition of a compound of formula (I).
  • the invention also provides a method of treating or preventing cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof or formula (I) a pharmaceutical composition of the compound.
  • the invention also provides a method of treating or preventing cancer, the cancer comprising one or more cancer cells having reduced or abolished ability to repair DNA DSB with HR relative to normal cells, the method This includes administering to a patient in need thereof an effective amount of a pharmaceutical composition of a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a compound of formula (I) of the present invention.
  • the present invention also provides a method of treating or preventing cancer, the cancer comprising one or more cancer cells having the ability to repair DNA DSB with HR reduced or abolished relative to normal cells, such as A cancer cell has a BRCA1 or BRCA2 deletion phenotype, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a compound of formula (I), of the present invention. combination.
  • the invention also provides a method of treating or preventing cancer by administering in combination with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof, the method comprising administering to a patient in need thereof an effective amount of a formula (I) of the invention
  • the invention also provides a method of treating or preventing a cancer in which a homologous recombination (HR)-dependent DNA double-strand break (DSB) repair pathway is deleted, the method comprising administering to a patient in need thereof an effective amount of the formula (I) a pharmaceutical composition of a compound, a pharmaceutically acceptable salt or stereoisomer thereof or a compound of formula (I).
  • HR homologous recombination
  • DAB DNA double-strand break
  • the present invention also provides a method of treating or preventing a cancer in which a homologous recombination (HR)-dependent DNA double-strand break (DSB) repair pathway is deleted, the cancer comprising one or more cancer cells having The ability to repair DNA DSB using HR, relative to normal cells, reduced or abolished, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer or formula thereof, of the invention (I) A pharmaceutical composition of a compound.
  • HR homologous recombination
  • DSB DNA double-strand break
  • the present invention also provides a method of treating or preventing a cancer in which a homologous recombination (HR)-dependent DNA double-strand break (DSB) repair pathway is deleted, the cancer comprising one or more cancer cells having The ability to repair a DNA DSB with HR relative to normal cells reduced or abolished, eg, the cancer cell has a BRCA1 or BRCA2 deletion phenotype, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I) of the invention, A pharmaceutically acceptable salt or stereoisomer or a pharmaceutical composition of a compound of formula (I).
  • HR homologous recombination
  • DSB DNA double-strand break
  • the present invention still further provides a method of treating or preventing cancer of a cancer cell having a BRCA1 or BRCA2 deletion phenotype, the method comprising administering to a patient in need thereof an effective amount of a compound of the formula (I) of the present invention, which is pharmaceutically acceptable Accepted salts or stereoisomers or pharmaceutical compositions of the compounds of formula (I).
  • the cancer cells of the present invention which are reduced or abolished by normal cells with the ability to repair DNA DSB by HR lack HR-dependent DNA DSB repair activity of one or more phenotypes selected from the group consisting of: 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) , NBS1 (NM-002485), ADPRT (PARP-1), ADPRTL2 (PARP02), CTPS, RPA, RPA1,
  • the compound is a compound of formula (II),
  • Ring A is a nitrogen-containing aliphatic heterocyclic group or a nitrogen-containing aromatic heterocyclic group having 1 to 5 ring hetero atoms selected from N, O or S, and is bonded to the dihydropyridinopyrazine ketone through a ring N atom. ;
  • Ring B is an aryl or an aromatic heterocyclic group
  • R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, halogenated C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl , 3 to 7-membered cycloalkyl, -CN, -OH, -NO 2 or -NR 5 R 6 ;
  • R 5 and R 6 are each independently selected from H, C 1 -C 6 alkyl or halo C 1 -C 6 alkyl;
  • R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -NH 2 , halogen, hydrazine, deuterated C 1 -C 6 alkane Base, -(CH 2 ) q OH, 3- to 7-membered cycloalkyl,
  • the aryl group is substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -OH, -NH 2 or halogen Aryl;
  • R 3 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -OH, -NH 2 or halogen;
  • q 0, 1, 2 or 3;
  • n 0, 1, 2, 3 or 4;
  • n 0, 1, 2 or 3.
  • R 1 is selected from hydrogen, C 1 -C 6 alkyl or halogen, more preferably It is halogen.
  • ring B is phenyl or pyridyl
  • R 3 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -OH, -NH 2 or halogen
  • m is 0, 1, 2 or 3.
  • ring B is phenyl or pyridyl
  • R 3 is halogen
  • m is 1 Or 2.
  • ring B is phenyl
  • R 3 is halogen
  • m is 1 or 2.
  • the ring A is a ring heterocyclic ring containing 1 to 5 selected from N, O or S.
  • the ring A is a ring heterocyclic ring containing 1 to 5 selected from N, O or S.
  • the pyridazinone core is linked; wherein R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -NH 2 , halogen, - (CH 2 ) q OH, 3 to 7-membered cycloalkyl,
  • the aryl group is substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl
  • the ring A is a ring heterocyclic ring containing 1 to 5 selected from N, O or S. a nitrogen-containing monocyclic heterocyclic heterocyclic group having 4 to 7 ring atoms, a nitrogen-containing fused ring heterocyclic group having 7 to 10 ring atoms, a nitrogen-containing bridged ring fused ring having 7 to 10 ring atoms An alicyclic group or a nitrogen-containing spiroaliphatic heterocyclic group having 7 to 11 ring atoms, which is bonded to the dihydropyridazinone nucleus via a ring N atom; wherein R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -NH 2 , halogen, -(CH 2 ) q OH
  • the ring A is a ring containing from 1 to 5 selected from N, O or S. a hetero atom containing a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing fused ring heterocyclic group, a nitrogen-containing bridged ring fused ring heterocyclic group or a nitrogen-containing spirocyclic heterocyclic group, through a ring of a N atom and a dihydropyridine And a pyridazinone core, wherein the nitrogen-containing monocyclic heterocyclic group, the nitrogen-containing fused ring heterocyclic group, the nitrogen-containing bridged ring fused ring heterocyclic group, and the nitrogen-containing spirocyclic heterocyclic group are selected from the group consisting of
  • the ring A is a ring containing from 1 to 5 selected from N, O or S. a hetero atom containing a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing fused ring heterocyclic group, a nitrogen-containing bridged ring fused ring heterocyclic group or a nitrogen-containing spirocyclic heterocyclic group, through a ring of a N atom and a dihydropyridine And a pyridazinone core, wherein the nitrogen-containing monocyclic heterocyclic group, the nitrogen-containing fused ring heterocyclic group, the nitrogen-containing bridged ring fused ring heterocyclic group, and the nitrogen-containing spirocyclic heterocyclic group are selected from the group consisting of
  • the ring A is a ring containing from 1 to 5 selected from N, O or S. a hetero atom containing a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing fused ring heterocyclic group, a nitrogen-containing bridged ring fused ring heterocyclic group or a nitrogen-containing spirocyclic heterocyclic group, through a ring of a N atom and a dihydropyridine And a pyridazinone core, wherein the nitrogen-containing monocyclic heterocyclic group, the nitrogen-containing fused ring heterocyclic group, the nitrogen-containing bridged ring fused ring heterocyclic group, and the nitrogen-containing spirocyclic heterocyclic group are selected from the group consisting of
  • R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -NH 2 , halogen, -(CH 2 ) q OH, 3- to 7-membered cycloalkyl, Phenyl or phenyl substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, -OH, -NH 2 or halogen, q is 0, 1 or 2, n is 0, 1, 2 or 3.
  • R 2 is each independently selected from C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, -NH 2 , -(CH 2 ) q OH, 3-7-membered cycloalkyl, Or phenyl, q is 0, 1 or 2, and n is 0, 1, 2 or 3.
  • R 2 is each independently selected from C 1 -C 4 alkyl, halo C 1 -C 4 alkyl, -NH 2 , -(CH 2 ) q OH, 3-7-membered cycloalkyl, Or phenyl, q is 0, 1 or 2, and n is 0, 1, 2 or 3.
  • the ring A is a ring heterocyclic ring containing 1 to 5 selected from N, O or S. a nitrogen-containing monocyclic aromatic heterocyclic group or a nitrogen-containing fused ring aromatic heterocyclic group bonded to a dihydropyridazinone nucleus via a ring N atom; wherein R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -NH 2 , halogen, -(CH 2 ) q OH, 3- to 7-membered cycloalkyl,
  • the aryl group is substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -OH, -NH 2 or
  • the ring A is a ring heterocyclic ring containing 1 to 5 selected from N, O or S. a nitrogen-containing monocyclic aromatic heterocyclic group having 5 to 6 ring atoms or a nitrogen-containing fused ring aromatic heterocyclic group having 8 to 10 ring atoms, through a ring atom N and a dihydropyridinopyridazinone Nuclei linked; wherein R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -NH 2 , halogen, -(CH 2 ) q OH, 3 to 7-membered cycloalkyl, The aryl group is substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen
  • the ring A is a ring containing from 1 to 5 selected from N, O or S. a nitrogen-containing monocyclic aromatic heterocyclic group or a nitrogen-containing fused aromatic heterocyclic group of a hetero atom, which is bonded to a dihydropyridazinone nucleus via a N atom on the ring, said nitrogen-containing monocyclic aromatic heterocyclic group, A nitrogen fused ring aromatic heterocyclic group is selected from
  • the ring A is a ring containing from 1 to 5 selected from N, O or S. a nitrogen-containing monocyclic aromatic heterocyclic group or a nitrogen-containing fused aromatic heterocyclic group of a hetero atom, which is bonded to a dihydropyridazinone nucleus via a N atom on the ring, said nitrogen-containing monocyclic aromatic heterocyclic group, A nitrogen fused ring aromatic heterocyclic group is selected from
  • R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -(CH 2 ) q OH, -NH 2 , halogen or phenyl, q is 0, 1 or 2, n is 0, 1, 2 or 3.
  • R 2 is each independently selected from C 1 -C 6 alkyl, halo C 1 -C 6 alkyl or -NH 2 , n is 0, 1, 2 or 3.
  • R 2 is each independently selected from C 1 -C 4 alkyl, halo C 1 -C 4 alkyl or -NH 2 , n is 0, 1, 2 or 3.
  • ring A is 1, 2, 3, 4 or 5 selected from N, O Or a nitrogen-containing aliphatic heterocyclic group or a nitrogen-containing aromatic heterocyclic group of a ring hetero atom of S, which is bonded to the dihydropyridinopyrazine ketone through a N atom on the ring.
  • the ring A is a ring heterocyclic ring containing from 1 to 4 selected from N, O or S.
  • the nitrogen-containing aliphatic heterocyclic group or the nitrogen-containing aromatic heterocyclic group of the atom is bonded to the dihydropyridinopyridinone mother nucleus via a N atom on the ring.
  • the ring A is contained in 1, 2, 3 or 4 selected from N, O or
  • the nitrogen-containing aliphatic heterocyclic group or the nitrogen-containing aromatic heterocyclic group of the ring hetero atom of S is bonded to the dihydropyridinopyridinone mother nucleus via a N atom on the ring.
  • particularly preferred compounds of the formula (I) or (II), pharmaceutically acceptable salts or stereoisomers thereof include the following:
  • the invention also provides a process for the preparation of a compound of formula (II) which comprises the steps of:
  • the ring A, the ring B, R 1 , R 2 , R 3 , m, and n have the same meanings as in the above formula (II).
  • the raw material (a) is esterified to obtain the compound (b); the compound (b) is reacted with tributyl (1-ethoxyvinyl) tin under the action of a catalyst to obtain a compound (c); and the compound (c) is subjected to reduction hydrolysis
  • the compound (d) is obtained; the compound (d) is reacted with the compound (e) to obtain a compound (f); the compound (f) is subjected to a ring closure reaction to obtain a compound (g); and the compound (g) is protected by Boc to obtain a compound (h).
  • the compound (b) is reacted to obtain the compound (c) which is carried out in the presence of a catalyst including, but not limited to, [1,1'-bis(diphenyl) a phosphinyl)ferrocene]palladium dichloride, tetrakis(triphenylphosphine)palladium or the like; a reduction hydrolyzed compound (c) to obtain a reducing agent used in the step of the compound (d), including iron powder; a compound (d) and a compound
  • the condensation reaction of (e) is carried out in the presence of an acid including, but not limited to, L-valine, acetic acid, etc.; the ring closure reaction of the compound (f) is carried out in the presence of a base including but not Limited to sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, potassium t-butoxide, etc.; compound (h)
  • the invention also provides another process for the preparation of a compound of formula (II) which comprises the steps of:
  • the ring A, the ring B, R 1 , R 2 , R 3 , m, and n have the same meanings as in the above formula (II).
  • the intermediate 1 is subjected to a substitution reaction with hydrazine hydrate to obtain a compound (s); the compound (s) is subjected to a ring-forming reaction to obtain a compound (m); and the compound (m) is decarboxylated to give a compound of the formula (II).
  • the compound (s) is reacted with a corresponding reaction raw material by a conventional method to obtain a compound (m); the compound (m) is deprotected by a Boc protecting group under normal conditions. .
  • the invention also provides another process for the preparation of a compound of formula (II) which comprises the steps of:
  • the ring A, the ring B, R 1 , R 2 , R 3 , m, and n have the same meanings as in the above formula (II).
  • the catalyst used for the catalytic hydrogenation reduction compound (n) includes, but is not limited to, palladium carbon and platinum dioxide; and the compound (o) is reacted with sulfur phosgene in the presence of a base.
  • the base used in the step of the compound (p) includes, but is not limited to, triethylamine, diisopropylethylamine and the like; the compound (p) is cyclically reacted with the corresponding reaction raw material by a usual method to obtain a compound (m);
  • the de Boc protection is carried out under normal conditions.
  • the present invention also provides an intermediate 1 compound of the formula:
  • R 1 is halogen
  • ring B is phenyl
  • R 3 is halogen
  • m is 1 or 2.
  • halogen means fluorine, chlorine, bromine, iodine or the like, preferably fluorine, chlorine or bromine, more preferably fluorine.
  • C 1 -C 6 alkyl means a straight or branched hydrocarbon having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl. , isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-di Methyl butyl; preferably "C 1 -C 4 alkyl", including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl; more preferably Methyl, ethyl, propyl, isopropyl and butyl.
  • C 1 -C 6 alkoxy means an alkoxy group having 1 to 6 carbon atoms, including but not limited to, for example, methoxy, ethoxy, propoxy, isopropoxy Base, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.; preferably "C 1 -C 4 alkoxy", C 1 -C 4 alkoxy By alkoxy having 1 to 4 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and Tert-butoxy group, more preferably methoxy, ethoxy, propoxy, isopropoxy and butoxy.
  • halogenated C 1 -C 6 alkyl means a "C 1 -C 6 alkyl group" as defined herein substituted by one or more halogens, preferably one to five halogen atoms; preferably "halogen” C 1 -C 4 alkyl", including but not limited to trifluoromethyl, trifluoroethyl, difluoromethyl, 1-chloro-2fluoroethyl, etc., more preferably trifluoromethyl and trifluoroethyl .
  • alkenyl means a monovalent group derived from a hydrocarbon group
  • C 2 -C 6 alkenyl means an alkenyl group having 2 to 6 carbon atoms and having at least one carbon-carbon double bond. These include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-butene, 2-methyl-2-pentene, and the like.
  • alkynyl means a monovalent group derived from a hydrocarbon group
  • C 2 -C 6 alkynyl means an alkynyl group having 2 to 6 carbon atoms and having at least one carbon-carbon triple bond. These include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, and the like.
  • deuterated C 1 -C 6 alkyl refers to a "C 1 -C 6 alkyl group" as defined herein substituted by one or more deuterium atoms, including but not limited to -CD 3 ,- CH 2 CD 3 , -C 2 D 5 , -C 3 D 7 , -CD(CD 3 ) 2 , -CH 2 CH 2 CD 3 or the like, preferably -CD 3 .
  • hetero atom means an atom other than carbon or hydrogen.
  • Hetero atoms are generally independently selected from N, O, S or P, but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, two or more heteroatoms are identical to each other, or some or all of the two or more heteroatoms are different from each other.
  • ring means any covalently closed structure, including a ring of all carbon atoms (such as an aryl group and a cycloalkyl group) and a ring containing a hetero atom (such as an aromatic heterocyclic group and an aliphatic heterocyclic group). ), or include single rings, fused rings, bridge rings, and spiral rings.
  • fused ring means a ring group in which two rings share two directly connected ring atoms, which may be saturated, partially unsaturated or fully unsaturated, and the ring-forming atoms may include one or Multiple ring heteroatoms.
  • fused rings include fused ring bicyclic groups and fused ring polycyclic groups. In some embodiments of the invention, the fused ring contains one or more carbonyl, thiocarbonyl or sulfone groups, for example, oxygen or sulfur containing groups.
  • fused ring bicyclic groups include, but are not limited to, naphthyl, quinolyl, fluorenyl
  • fused ring polycyclic groups include, but are not limited to, anthracenyl and phenanthryl.
  • bridged ring means a ring group in which two rings share three or more ring atoms, which may be saturated or partially unsaturated, and the ring-forming atoms may include one or more ring hetero atoms.
  • “Bridge loops” include bridged bicyclic groups and bridged ring polycyclic groups.
  • the bridged ring contains one or more carbonyl, thiocarbonyl or sulfone groups, for example, oxygen or sulfur containing groups.
  • bridged bicyclic groups include, but are not limited to, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl,
  • bridged polycyclic groups include, but are not limited to, adamantyl.
  • spirocyclic means a cyclic group in which two rings share a ring atom, which may be saturated or partially unsaturated, and the ring-forming atom may include one or more ring heteroatoms.
  • the ring atom shared by the two rings in the spiro ring is a spiro atom, and is classified into a single spiro ring, a two spiro ring, a multi-spiral ring, and the like according to the number of spiro atoms.
  • the spiro ring contains one or more carbonyl, thiocarbonyl or sulfone groups, for example, oxygen or sulfur containing groups.
  • single spiro examples include, but are not limited to, 1-methylspiro[4.5]decyl
  • two spiro rings include, but are not limited to, snail [5.2.5.2] hexadecyl
  • multi-spiro examples include, but are not limited to, triple snail [2.2.2.2 9 .2 6 .2 3 ] hexadecyl .
  • ring atom means an atom forming a ring, including but not limited to C, N, O, P and S;
  • ring hetero atom means a ring atom other than C atom, including but not limited to N, O, P and S.
  • the "N atom on the ring” means a ring atom N atom forming a ring.
  • cycloalkyl means a saturated or partially unsaturated aliphatic carbocyclic group, including monocyclic, bicyclic and polycyclic cycloalkyl groups, or includes monocyclic cycloalkyl groups, fused ring cycloalkyl groups , bridged cycloalkyl and spirocycloalkyl, and the like.
  • Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexene And cycloheptenyl; bicyclic cycloalkyl examples include, but are not limited to, Bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, 1-methylspiro[4.5]decyl, Polycyclic cycloalkyl groups include, but are not limited to, adamantyl; fused ring cycloalkyl groups include, but are not limited to, Examples of bridged cycloalkyl groups include, but are not limited to, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, a
  • aliphatic heterocyclic group means a non-aromatic cyclic group in which one or more atoms forming a ring are hetero atoms.
  • “Aroheterocyclyl” includes saturated or partially unsaturated “monocyclic heteroheterocyclyl” containing one or more ring heteroatoms selected from N, S or O, having from 3 to 8 ring atoms, preferably having 4 to 7 ring atoms; a saturated or partially unsaturated "fused ring heterocyclic group” containing one or more ring heteroatoms selected from N, S or O, having 5 to 18 ring atoms, preferably having 7 to 16 ring atoms, more preferably 7 to 10 ring atoms; a saturated or partially unsaturated bridged ring fused ring heterocyclic group containing one or more ring heteroatoms selected from N, S or O Namely, "bridged fused ring aliphatic heterocyclic group” having 6 to 20 ring atoms,
  • an aliphatic heterocyclic group a monocyclic aliphatic heterocyclic group, a fused ring heterocyclic group, a bridged fused ring heterocyclic group, a spiroaliphatic heterocyclic group, a bridged aliphatic heterocyclic group
  • the spiro fused ring alicyclic or bridged ring spiroaliphatic heterocyclic group contains one or more carbonyl, thiocarbonyl or sulfone groups, for example, oxygen or sulfur containing groups.
  • Examples of “monocyclic heterocyclic heterocyclic groups” include, but are not limited to, tetrahydropyranyl, dihydropyranyl, oxetanyl, thioheterobutyl, piperidinyl, 1,3-dioxyl, 1,4-dioxanyl, piperazinyl, 1,3-oxathiolanyl, 1,4-oxethiohexadienyl, 1,4-oxathiane, Maleimide, thiobarbituric acid, dioxopiperazinyl, dihydrouracil, trioxo, hexahydro-1,3,5-triazinyl, tetrahydrothiophenyl , tetrahydrofuranyl, dihydrofuranyl, pyrrolinone, pyrazolinyl, imidazolinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-d
  • the "nitrogen-containing heterocyclic group” means at least one of the above-mentioned “aliphatic heterocyclic groups” having a ring atom of N atoms, and contains 1 to 5 (i.e., contains 1, 2, 3, 4, 5,
  • the ring hetero atom selected from 1, 2, 3, 4) selected from N, O or S is bonded to the dihydropyridazinone nucleus via a N atom on the ring, including a nitrogen-containing monocyclic heterocyclic group, Nitrogen-containing fused ring heterocyclic group, nitrogen-containing bridged ring fused ring heterocyclic group, nitrogen-containing spirocyclic heterocyclic group, nitrogen-containing bridged ring heterocyclic group, nitrogen-containing spiro ring fused ring heterocyclic group and A nitrogen bridged ring spirocyclic heterocyclic group.
  • the "nitrogen-containing monocyclic heterocyclic group” means the above-mentioned “monocyclic heterocyclic group” having at least one ring atom of N atom, and contains 1 to 5 (i.e., contains 1, 2, 3, 4, 5) , preferably containing 1, 2, 3) ring heteroatoms selected from N, O or S, attached to the dihydropyridazinone nucleus via a ring N atom, having 3 to 8 ring atoms, preferably having 4 Up to 7 ring atoms, specific examples include, but are not limited to, piperidinyl, imidazolinyl,
  • the "nitrogen-containing fused ring heterocyclic group” means the above-mentioned "fused ring heterocyclic group” in which at least one ring atom is an N atom, and contains 1 to 5 (i.e., contains 1, 2, 3, 4, 5, preferably a ring hetero atom containing 1, 2, 3 or 4) selected from N, O or S, bonded to the di
  • the "nitrogen-containing bridged ring heterocyclic group” means at least one of the above-mentioned “bridged aliphatic heterocyclic groups” having a ring atom of N atoms, and contains 1 to 5 (i.e., contains 1, 2, 3, 4, 5, preferably a ring hetero atom containing 1, 2, 3) selected from N, O or S, bonded to the dihydropyridazinone nucleus via a N atom on the ring, having 5 to 12 ring atoms, preferably having 6 to 10 Ring atoms, specific examples include but are not limited to
  • the "nitrogen-containing spirocyclic fused ring heterocyclic group” means at least one of the above-mentioned "spirocyclic fused ring heterocyclic group” having a ring atom of N atom, and contains 1 to 5 (ie, contains 1, 2, 3, 4, 5, preferably containing 1, 2, 3, 4) ring heteroatoms selected from N, O or S, attached to the dihydropyr
  • aryl means an aromatic cyclic hydrocarbon group having one or more aromatic rings including a monocyclic aryl group and a fused ring aryl group
  • a specific "monocyclic aryl group” includes a phenyl group, "fused ring”
  • the aryl group includes, but is not limited to, a naphthyl group, an anthracenyl group, a phenanthryl group, preferably an aryl group having 6 to 14 ring carbon atoms, more preferably 6 to 10 carbon atoms such as a phenyl group and a naphthyl group, and more preferably a phenyl group.
  • aromatic heterocyclic group means an aromatic cyclic group containing one or more ring hetero atoms selected from N, S or O, and includes a monocyclic aromatic heterocyclic group and a monocyclic aromatic heterocyclic group.
  • a fused ring aromatic heterocyclic group in which a monocyclic aromatic heterocyclic group, a monocyclic aromatic heterocyclic group and an aryl group are fused, a monocyclic aromatic heterocyclic group having 5 to 6 ring atoms, and a fused ring aromatic heterocyclic group having 8 Up to 14 ring atoms.
  • the "monocyclic aromatic heterocyclic group” specifically includes, but is not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrimidine Base, pyridazinyl, pyrazinyl, Preferred is pyridyl, pyrimidinyl, pyrazinyl,
  • the "fused ring aromatic heterocyclic group” specifically includes but is not limited to a benzofuranyl group, a benzothienyl group, a benzothiadiazolyl group, a benzothiazolyl group, an isodecyl group, a quinolyl group, an isoquinolyl group. , quinazolinyl, porphyrin-2-one, Optimal
  • the "nitrogen-containing heterocyclic group” means the above-mentioned “aromatic heterocyclic group” in which at least one ring atom is an N atom, and contains 1 to 5 (i.e., contains 1, 2, 3, 4, 5, preferably Containing 1, 2, 3, 4) ring heteroatoms selected from N, O or S, attached to the dihydropyridazinone nucleus via a ring N atom, including a nitrogen-containing monocyclic aromatic heterocyclic group and A nitrogen fused ring aromatic heterocyclic group.
  • the "nitrogen-containing monocyclic aromatic heterocyclic group” means the above-mentioned “monocyclic aromatic heterocyclic group” having at least one ring atom of N atoms, and contains 1 to 5 (i.e., contains 1, 2, 3, 4, 5) , preferably containing 1, 2, 3) ring heteroatoms selected from N, O or S, linked to the dihydropyridinopyridinone core by a ring of N atoms, having 5 to 6 ring atoms, specific examples include But not limited to Optimal
  • the "nitrogen-containing fused ring aromatic heterocyclic group” is the above "nitrogen-containing monocyclic aromatic heterocyclic group” and the above “monocyclic aromatic heterocyclic group” or the above "nitrogen-containing monocyclic aromatic heterocyclic group” and the above “aryl group””Condensed, containing 1 to 5 (ie containing 1, 2, 3, 4, 5, preferably containing 1, 2, 3) ring heteroatoms selected from N, O or S, through the ring
  • “monocyclic” includes “monocyclic cycloalkyl”, “monocyclic aryl”, “monocyclic heterocyclic group” and “monocyclic aromatic heterocyclic group”.
  • “1 to 5" as described in “Ring A is a nitrogen-containing aliphatic heterocyclic group or a nitrogen-containing aromatic heterocyclic group having 1 to 5 ring heteroatoms selected from N, O or S" It comprises 1, 2, 3, 4 or 5, preferably 1, 2, 3 or 4.
  • x to y ring atoms means all natural ring atoms between x and y, and includes x and y, wherein x and y are arbitrary natural numbers and x is smaller than y, for example, "3 to 8" "A ring atom” means 3, 4, 5, 6, 7, 8 ring atoms.
  • the "dihydropyridazinone nucleus” has the following structure.
  • the invention further comprises a pharmaceutically acceptable salt of a compound of formula (I).
  • pharmaceutically acceptable salt refers to an acid addition or base addition salt of a relatively non-toxic compound of the invention.
  • the acid addition salt is a salt of the compound of the formula (I) of the present invention and a suitable inorganic or organic acid, which can be prepared during the final isolation and purification of the compound, or can be used to purify the formula (I).
  • the compounds are prepared in their free base form by reaction with a suitable organic or inorganic acid.
  • Representative acid addition salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearic acid Salt, silicate, borate, benzoate, lactate, phosphate, hydrogen phosphate, carbonate, bicarbonate, toluate, citrate, maleate, rich Formate, succinate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, gluconate, lactobate and lauryl sulfonate.
  • the base addition salt is a salt of a compound of formula (I) with a suitable inorganic or organic base, including, for example, a salt with an alkali metal, an alkaline earth metal, a quaternary ammonium cation, such as a sodium salt, a lithium salt, a potassium salt, a calcium salt, a magnesium salt, a tetramethyl quaternary ammonium salt, a tetraethyl quaternary ammonium salt, etc.; an amine salt, including a salt formed with ammonia (NH 3 ), a primary amine, a secondary amine or a tertiary amine, such as methylamine salt, Methylamine salt, trimethylamine salt, triethylamine salt, ethylamine salt and the like.
  • a salt with an alkali metal, an alkaline earth metal a quaternary ammonium cation, such as a sodium salt, a lithium salt, a potassium salt
  • the compounds described herein exist as stereoisomers in which asymmetric or chiral centers are present.
  • Stereoisomers are named (R) or (S) depending on the substituent configuration around the chiral carbon atom.
  • Embodiments described herein specifically include various stereoisomers and mixtures thereof.
  • Stereoisomers include racemates, enantiomers, diastereomers, and mixtures of enantiomers or diastereomers.
  • each stereoisomer of a compound is prepared synthetically from a commercial starting material containing an asymmetric or chiral center, or by preparing a racemic mixture, followed by resolution.
  • the method of resolution is, for example: (1) combining a mixture of enantiomers with a chiral auxiliary, and releasing a mixture of diastereomers by recrystallization or chromatography to release an optically pure product from the auxiliary; or (2) Direct separation of the mixture of optical enantiomers on a chiral column.
  • the compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof of the present invention can be administered to a subject by any convenient administration route, and can be administered systemically/peripherally or at a desired site of action, including but not Limited to oral (eg, feeding), topical (including, for example, transdermal, intranasal, ocular, buccal, and sublingual), lung (eg, inhalation or insufflation by aerosol or nasal), rectal, vaginal , parenteral (eg injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraocular, intraperitoneal, intratracheal, subepidermal, joint) Internal, subarachnoid, and sternal), as well as implanted depots (eg, subcutaneous or intramuscular).
  • oral eg, feeding
  • topical including, for example, transdermal, in
  • the subject may be a eukaryote, an animal, a vertebrate, a mammal, a rodent (eg, guinea pig, hamster, rat, mouse), a murine (eg, a mouse), a canine (eg, a dog), a primate , apes (such as monkeys or apes), monkeys (such as apes, baboons), apes (such as gorillas, chimpanzees, orangutans, gibbons) or humans.
  • a rodent eg, guinea pig, hamster, rat, mouse
  • a murine eg, a mouse
  • a canine eg, a dog
  • a primate apes (such as monkeys or apes), monkeys (such as apes, baboons), apes (such as gorillas, chimpanzees, orangutans
  • the pharmaceutical composition of the present invention comprises a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or diluent, and the like.
  • the compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof of the present invention can be prepared by mixing with a pharmaceutically acceptable carrier, excipient, diluent, etc. according to standard pharmaceutical practice, to obtain a corresponding pharmaceutical composition.
  • Administration to mammals includes humans.
  • the carriers, excipients and diluents of the present invention refer to inactive ingredients in pharmaceutical compositions which do not cause significant irritation to the organism and which do not interfere with the biological activity of the administered compound, including but not limited to water. , lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gel, alginate, calcium silicate, calcium phosphate, cellulose, aqueous syrup, methyl fiber
  • Various oils such as polyvinylpyrrolidone, alkyl p-hydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil, and the like, and mixtures thereof.
  • the compound of the formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a pharmaceutical composition thereof of the present invention can be formulated into a mammal, including a human.
  • the formulation may conveniently be presented in unit dosage form and, preferably, may be prepared by methods well known in the art of pharmacy. Such methods include the step of bringing into association a compound of the invention with a carrier which comprises one or more accessory ingredients.
  • the compound of the formula (I) of the present invention is intimately combined with a liquid carrier or a finely divided solid carrier or both carriers to prepare a formulation, which is then shaped as needed.
  • the preparation may be a liquid, a solution, a suspension, an emulsion, an elixir, a syrup, a tablet, a lozenge, a granule, a powder, a capsule, a cachet, a pill, an ampoule, a suppository, a vaginal suppository, an ointment, or a gel.
  • a dose a paste, a cream, a spray, an aerosol, a foam, a lotion, an oil, a boluse, a medicinal or an aerosol.
  • Formulations suitable for oral administration include tablets, capsules, cachets, powders, granules, solutions, suspensions, emulsions, granules, syrups or pastes and the like.
  • Tablets suitable for oral administration can be prepared by conventional methods, for example, by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing a free-flowing form of a compound of formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof (e.g., a powder or granule) of the present invention in a suitable machine, a compound of formula (I) of the present invention.
  • a pharmaceutically acceptable salt or stereoisomer thereof optionally with a filler or diluent (eg, starch, lactose, sucrose, microcrystalline cellulose, calcium hydrogen phosphate); one or more binders (eg, Polyvinylpyrrolidone, hydroxymethylcellulose, starch, gelatin, gum arabic, sorbitol, tragacanth, hydroxypropylmethylcellulose, sucrose); disintegrants (eg sodium starch glycolate, crosslinked polyethylene) Pyrrolidone, croscarmellose sodium, agar, calcium carbonate, potato starch or tapioca starch, alginic acid); lubricants (such as magnesium stearate, talc, calcium stearate, solid polyethylene glycol, ten Sodium dialkyl sulfates and the like or mixtures thereof; surface active or dispersing or wetting agents (for example, sodium lauryl sulfate, cetyl alcohol, glyceryl monostearate);
  • Molded tablets may be made by molding in a suitable machine a powder mixture containing a compound of formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated to provide sustained or controlled release of a compound of formula (I) of the invention employed therein, for example, using different proportions of hydroxypropyl methylcellulose. The desired release characteristics.
  • a tablet having a casing may optionally be provided for release in a portion of the intestine other than the stomach.
  • Liquid dosage forms suitable for oral administration can be prepared by conventional methods including, but not limited to, the compounds of formula (I), pharmaceutically acceptable salts or stereoisomers thereof of the present invention as active ingredients, inert in the art conventionally employed Thinners such as water and other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, especially It is cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, etc. or a mixture of these substances.
  • the liquid dosage forms of the present invention may also contain conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and flavoring agents.
  • Formulations suitable for topical administration include ointments, suppositories, creams, suspensions, lotions, powders, solutions, gels, and the like.
  • the propellants needed are mixed together.
  • Formulations suitable for intra-oral administration include lozenges, including a compound of formula (I) of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, a flavored substrate (eg, sucrose, acacia); Pastille, comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, an inert matrix (such as gelatin and glycerin), and a mouthwash, including a compound of formula (I) of the present invention or a pharmaceutically acceptable compound thereof Accepted salts or stereoisomers, and suitable liquid carriers.
  • lozenges including a compound of formula (I) of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, a flavored substrate (eg, sucrose, acacia); Pastille, comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, an inert matrix (such as gelatin and glycerin), and a mouthwash, including a compound of formula (I) of the present invention or a pharmaceutical
  • Formulations suitable for topical administration via the skin include ointments, creams and lotions.
  • suitable matrices e.g., paraffinic, water-mixable ointment bases), skin penetration enhancers (e.g., Dimethyl sulfoxide);
  • suitable matrices e.g., oil-in-water cream bases;
  • suitable matrices eg, oil-in-water cream bases
  • suitable matrices eg, emulsifiers, emulsifiers and fats, emulsifiers and oils, emulsifiers, and fats
  • suitable matrices eg, emulsifiers, emulsifiers and fats, emulsifiers and oils, emulsifiers, and fats
  • Formulations suitable for topical administration to the eye include eye drops comprising a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, dissolved or suspended in a suitable carrier.
  • Formulations suitable for nasal administration include a solid powder which is a solid, which is administered by nasal inhalation; the carrier is a liquid aqueous or oily solution, such as a nasal spray, nasal drops or aerosolized by a nebulizer Medicine, etc.
  • Formulations suitable for rectal administration include suppositories, including a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, a suitable matrix (e.g., cocoa butter, salicylate).
  • a suitable matrix e.g., cocoa butter, salicylate.
  • Formulations suitable for vaginal administration include pessaries, sprays, creams or gels, and the like, including a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, and suitable in the art a.
  • Formulations suitable for parenteral include aqueous or non-aqueous, physiologically acceptable sterile injectable solutions, dispersions, suspensions or emulsions. And a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • a suitable daily dose for the compound of the formula (I) of the present invention is 0.1 to 500 mg, preferably 0.1 to 250 mg, more preferably 0.1 to 150 mg, 0.3 to 120 mg, 0.3 to 100 mg, 0.3 to 80 mg, 0.3 to 50 mg, or 0.5 to 0.5%. 50 mg, 0.5 to 30 mg or 0.5 to 10 mg, and the like.
  • the compound of the formula (I) of the present invention is a salt, an ester, a prodrug or the like, the application amount is calculated on the basis of the parent compound.
  • the compound of the formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof of the present invention can be administered for treatment or prevention of cancer in combination with ionizing radiation, one or more chemotherapeutic drugs or a combination thereof.
  • the compound of the formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof of the present invention can potentiate the therapeutic effects of a large number of cancer chemotherapy.
  • the chemotherapeutic drugs include HDAC inhibitors for treating cancer (such as suberoylanilide hydroxamic acid (SAHA)), estrogen receptor modulators (such as tamoxifen, raloxifene, and iindoxifen).
  • cytotoxicity/cytostatic agents eg cyclophosphamide, carmustine (BCNU), temozolomide, cisplatin, carboplatin
  • microtubule inhibitors / microtubule stabilizers eg paclitaxel, vindesine sulfate, vincristine
  • topoisomerase Inhibitors such as irinotecan, topotecan and rubitecan
  • proteasome inhibitors such as bortezomib
  • anti-proliferative agents such as capecitabine, Carbopolamine
  • HMG-CoA reductase inhibitors lovastatin, simvastatin
  • HIV protease inhibitors angiogenesis inhibitors
  • the compound of the formula (I), a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition thereof of the present invention can also be used in combination with a non-anticancer drug.
  • a combination with a PPAR-gamma (PPAR-gamma) agonist and a PPAR-delta agonist can be used to treat certain cancers; in combination with an antiviral drug such as the nucleoside analog ganciclovir.
  • a combination of a body antagonist or a 5HT3 receptor antagonist such as ondansetron, granisetron for the treatment of nausea or vomiting, including acute, delayed, late, and cerebral, may be caused by the use of a compound of the invention alone or in combination with radiation therapy. Early onset vomiting and so on.
  • the test proves that the compound of the general formula (I) of the present invention has a cancer cell proliferation inhibitory effect and can be used for treating cancer and preparing a medicament for treating cancer.
  • the pharmacological effect of the compound of the present invention for inhibiting the proliferation of cancer cells can be determined by a conventional method.
  • a preferred evaluation method is Sulforhodam Ine B (SRB) protein staining method, and the light absorption produced by the action of the drug on cancer cells is determined. The change in value is used to calculate the rate of inhibition of cancer cell proliferation by the drug.
  • SRB Sulforhodam Ine B
  • Inhibition rate (%) [(blank control OD-dosing OD) / blank control OD] ⁇ 100%
  • Blank control OD refers to the OD value of the wells of cells that do not have normal drug growth.
  • Dosing OD refers to the OD value of the wells of the cells to which the compound to be screened is added.
  • the half-inhibitor concentration (IC 50 ) value was calculated using the GraphPad PrIsm software version 5.0, four-parameter fitting method. Each experiment was repeated 3 times, and the average IC 50 value of the 3 experiments was determined as the final index of inhibition ability.
  • the compound of the formula (I) of the present invention has significant inhibitory activity against PARP-1 and PARP-2 enzymes at the molecular level.
  • the inhibitory activity of the compounds of the present invention on the PARP-1 and PARP-2 enzymes at the molecular level can be determined by a conventional method.
  • a preferred method is that the histone is encapsulated in a 96-well plate and incubated overnight at 4 ° C with 200 ⁇ L of PBST ( After washing the plate 3 times with a phosphate buffer solution, it was blocked with a blocking solution, incubated at room temperature for 30 minutes, and then washed 3 times with a PBST solution.
  • the test compound was treated to be added to the well plate, after which 20 ⁇ L of diluted PARP-1 (1 nM) or 20 ⁇ L of PARP-2 (3 nM) solution was added to the reaction system for 1 or 2 hours.
  • a mixture of 50 ⁇ L streptavidin-HRP (horseradish peroxidase) (1:50) was added to the well plate and incubated for 30 minutes at room temperature, and washed three times with PBST buffer. 100 ⁇ L of HRP chemiluminescent substrate mixture was added to the well plates. Immediately read on a microplate reader (Envision, PerkinElmer). The IC50 value of the compound for PARP-1 and PARP-2 enzyme inhibitory activity was obtained by calculation.
  • the compound of the formula (I) of the present invention has good pharmacokinetic properties, and the test method is: healthy SD rats, and the compound of the present invention is administered by a certain dose. Fasting for 12 hours before the test, free to drink water. Uniformly eaten 2 hours after administration. After 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after intragastric administration, venous blood was taken from the posterior venous plexus of rats, and plasma was separated and determined by liquid chromatography-tandem mass spectrometry. Concentration; in healthy SD rats, the compounds of the invention are administered intravenously at a dose. Fasting for 12 hours before the test, free to drink water. Uniformly eaten 2 hours after administration.
  • venous blood was taken from the posterior venous plexus of rats, and plasma was separated and plasma was determined by liquid chromatography-tandem mass spectrometry. The concentration of the compound in the medium.
  • the pharmacological effect of the compound of the general formula (I) of the present invention for inhibiting the growth of transplanted tumor of an animal can be determined by a conventional method, and a preferred evaluation method is the growth inhibitory effect on the subcutaneous transplantation tumor of human triple negative breast cancer cell MDA-MB-436 nude mice.
  • Experimental method Human triple negative breast cancer cell MDA-MB-436 cell line (5 ⁇ 10 6 cells/only) was inoculated subcutaneously into the right side of BALB/cA nude mice. When the tumors were grown to 100-200 mm 3 , they were randomly grouped according to tumor size and mouse body weight.
  • the test compound was administered by a certain dose, and the solvent control group was intragastrically administered with an equal amount of solvent, once a day for 20 days.
  • the body weight and tumor size of the mice were measured twice a week during the entire experiment to see if a toxic reaction occurred.
  • Figure 1 is a graph showing the tumor volume change of human 56-negative breast cancer cell MDA-MB-436 nude mouse subcutaneous xenografts of Compound 56 and LT-00628 at a dose of 1 mg/kg.
  • Figure 2 is a graph showing body weight changes of human 56-negative breast cancer cells MDA-MB-436 nude mice at a dose of 1 mg/kg of Compound 56 and LT-00628.
  • Step 2 2-(1-Ethoxyvinyl)-5-fluoro-3-nitrobenzoic acid tert-butyl ester
  • tert-Butyl 2-bromo-5-fluoro-3-nitrobenzoate (72.4 g, 0.227 mol), tributyl(1-ethoxyvinyl)tin (98 g, 0.27 mol), [1,1' Bis(diphenylphosphino)ferrocene]palladium dichloride (6 g, 8.56 mmol) was dissolved in dioxane (500 mL). The reaction was heated to 80 ° C under argon for 5 hours and cooled to room temperature. A solution of potassium fluoride dihydrate (21 g) dissolved in 250 mL of water was added to the reaction solution, and the mixture was stirred for 1 hour.
  • Step 4 (E)-2-Acetyl-5-fluoro-3-((4-fluorobenzylidene)amino)benzoic acid tert-butyl ester
  • Step 5 7-Fluoro-2-(4-fluorophenyl)-2,3-dihydroquinolin-4(1H)-one-5-carboxylic acid tert-butyl ester
  • Step 6 N-tert-Butoxycarbonyl-7-fluoro-2-(4-fluorophenyl)-2,3-dihydroquinolin-4-one-5-carboxylic acid tert-butyl ester
  • Step 7 7-Fluoro-2-(4-fluorophenyl)-4-(tert-butyldimethylsilyloxy)-1,2-dihydroquinoline-1,5-dicarboxylic acid tert-butyl ester
  • N-tert-Butoxycarbonyl-7-fluoro-2-(4-fluorophenyl)-2,3-dihydroquinolin-4-one-5-carboxylic acid tert-butyl ester (9 g, 19.61 mmol) dissolved in tetrahydrofuran (100 mL), cooled to -70 °C.
  • a 1 mol/L solution of hexamethyldisilazide lithium tetrahydrofuran (59 mL, 58.82 mmol) was added dropwise, and the temperature was controlled to not exceed -60 °C. Stirring was continued for 1 hour after the completion of the dropping.
  • Step 8 7-Fluoro-2-(4-fluorophenyl)-3-tert-butyldimethylsilyl-2,3-dihydroquinolin-4(1H)-one-1,5-di Tert-butyl carboxylate
  • Step 9 5-Fluoro-8-(4-fluorophenyl)-9-tert-butyldimethylsilyloxy-8,9-dihydro-2H-pyrido[4,3,2-de]fluorene Pyrazin-3-one-7-carboxylic acid tert-butyl ester
  • Step 10 5-Fluoro-8-(4-fluorophenyl)-9-hydroxy-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazin-3-one-7- Tert-butyl carboxylate
  • Step 11 5-Fluoro-9-chloro-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazin-3-one-7- Tert-butyl carboxylate (intermediate 1a)
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(5-trifluoromethyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(5-trifluoromethyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 3,5-dimethyl-1H-1,2,4-triazole with intermediate 1a. The yield was 53%. MS (ESI): 495.2 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-1H-imidazol-1-yl)-8,9-dihydro-2H-pyrido[4,3, 2-de]pyridazine-3(7H)-keto-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-1H-imidazol-1-yl)-8,9-dihydro-2H-pyrido[4,3, 2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(3-trifluoromethyl-5,6-dihydro-[1,2,4]triazole [4,3-a] Pyrazin-7(8H)-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(3-trifluoromethyl-5,6-dihydro-[1,2,4]triazole [4,3-a] Pyrazin-7(8H)-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1H-carbazolyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine- 3(7H)-keto-7-carboxylic acid tert-butyl ester
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(pyrrolidine-2,5-dione-1-yl)-8,9-dihydro-2H-pyrido[4,3 ,2-de]pyridazine-3(7H)-keto-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(pyrrolidine-2,5-dione-1-yl)-8,9-dihydro-2H-pyrido[4,3 ,2-de]pyridazine-3(7H)-one
  • Example 8 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxyhexahydroisoindol-1,3(2H)-dione-2-yl)-8, 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 8)
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxyhexahydroisoindol-1,3(2H)-dione-2-yl)-8,9 -Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 4,7-epoxyhexahydroisoindol-1,3(2H)-dione with intermediate 1a. MS (ESI): 565.1 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxyhexahydroisoindol-1,3(2H)-dione-2-yl)-8,9 -dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxy-3a,4,7,7a-tetrahydroisoindole-1,3(2H)-dione 2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 4,7-epoxy-3a,4,7,7a-tetrahydroisoindole-1,3(2H)-dione with intermediate 1a.
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxy-3a,4,7,7a-tetrahydroisoindol-1,3(2H)-dione -2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxy-5hydroxyhexahydroisoindole-1,3(2H)-dione-2-yl)- 8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 4,7-epoxy-5hydroxyhexahydroisoindol-1,3(2H)-dione with Intermediate 1a. MS (ESI): 581.1 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxy-5-hydroxyhexahydroisoindol-1,3(2H)-dione-2-yl) -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(isoindole-1,3-dione-2-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(isoindole-1,3-dione-2-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4,3, 2-de]pyridazine-3(7H)-keto-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(2,4-imidazolidin-2-one-3-yl)-8,9-dihydro-2H-pyrido[4,3, 2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1-isopropyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 1-isopropyl-2,4-imidazolidinone with Intermediate 1a. MS (ESI): 540.2 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(1-isopropyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1-(2-hydroxyethyl)-2,4-imidazolinedion-3-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(1-(2-hydroxyethyl)-2,4-imidazolinedion-3-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1-cyclopropyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 1-cyclopropyl-2,4-imidazolidinone with Intermediate 1a. MS (ESI): 538.1 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(1-cyclopropyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1-cyclopentyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 1-cyclopentyl-2,4-imidazolidinone with Intermediate 1a. MS (ESI): 566.2 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(1-cyclopentyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 5,5-dimethyl-2,4-imidazolidinone with Intermediate 1a. The yield was 35%. MS (ESI): 526.1 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1,5,5-trimethyl-2,4-imidazolidin-2-one)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 1,5,5-trimethyl-2,4-imidazolidinone with Intermediate 1a. The yield was 74%. MS (ESI): 540.2 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(1,5,5-trimethyl-2,4-imidazolidin-2-one)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1-isopropyl-5,5-dimethyl-2,4-imidazolidindione-3-yl)-8, 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(1-isopropyl-5,5-dimethyl-2,4-imidazolidindione-3-yl)-8, 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-5-phenyl-2,4-imidazolidin-2-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 5-methyl-5-phenyl-2,4-imidazolidinone with Intermediate 1a. MS (ESI): 588.2 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-5-phenyl-2,4-imidazolidin-2-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-((7aS)-tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione- 2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting (7aS)-tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione with Intermediate 1a. MS (ESI): 538.2 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-((7aS)-tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione- 2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-((S)-7a-methyltetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H) -dione-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting (S)-7a-methyltetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione with Intermediate 1a. The yield was 68%. MS (ESI): 552.2 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-((S)-7a-methyltetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H) -dione-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-((6R,7aS)-6-hydroxytetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3 (2H )-Dione-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-((6R,7aS)-6-hydroxytetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3 (2H )-dione-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[3.4]octane-6,8-dione-3-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 1,3-diazaspiro[3.4]octane-6,8-dione with intermediate 1a. The yield was 52%. MS (ESI): 536.2 [MH] - .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[3.4]octane-6,8-dione-3-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[4.4]nonane-2,4-dione-3-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 1,3-diazaspiro[4.4]nonane-2,4-dione with intermediate 1a.
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[4.4]nonane-2,4-dione-3-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[4.5]decane-2,4-dione-3-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 1,3-diazaspiro[4.5]nonane-2,4-dione with intermediate 1a. MS (ESI): 566.2 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[4.5]decane-2,4-dione-3-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(2-oxo-5,7-diazaspiro[3.4]octane-6,8-dione-7-yl)- 8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(2-oxo-5,7-diazaspiro[3.4]octane-6,8-dione-7-yl)- 8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(2-tert-butoxycarbonyl-2,5,7-triazaspiro[3.4]octane-6,8-dione -7-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. Prepared by the reaction of 2-tert-butoxycarbonyl-2,5,7-triazaspiro[3.4]octane-6,8-dione and intermediate 1a.
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(2,5,7-triazaspiro[3.4]octane-6,8-dione-7-yl)-8, 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(2,4-thiazolidinedione-3-yl)-8,9-dihydro-2H-pyrido[4,3, 2-de]pyridazine-3(7H)-keto-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(2,4-thiazolidinedione-3-yl)-8,9-dihydro-2H-pyrido[4,3, 2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-thiazolidinedione-3-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 5,5-dimethyl-2,4-thiazolidinedione with intermediate 1a.
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-thiazolidinedione-3-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(oxazolidine-2,4-dione-3-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(oxazolidine-2,4-dione-3-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyloxazolidine-2,4-dione-3-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 5,5-dimethyl-2,4-oxazolidinedione with intermediate 1a.
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyloxazolidine-2,4-dione-3-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(2H-benzo[e][1,3]oxazine-2,4(3H)-dione-3-yl)- 8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(2H-benzo[e][1,3]oxazine-2,4(3H)-dione-3-yl)- 8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(benzo[d]isothiazole-3(2H)-one-1,1-dioxide-2-yl)-8, 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting sodium o-benzoylsulfonamide with intermediate 1a. The yield was 40%.
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(benzo[d]isothiazole-3(2H)-one-1,1-dioxide-2-yl)-8, 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-9-mercapto-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)- Keto-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-3-tert-butoxycarbonylamino-1H-1,2,4-triazol-1-yl)- 8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 3 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-3-amino-1H-1,2,4-triazol-1-yl)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(5-isopropyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • reaction solution was cooled to room temperature, and 20 mL of ethyl acetate was added. It was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified (jjjjjjj MS (ESI): 509.2 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(5-isopropyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-pyrazol-1-yl)-8,9-dihydro-2H-pyrido[4,3 ,2-de]pyridazine-3(7H)-keto-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-pyrazol-1-yl)-8,9-dihydro-2H-pyrido[4,3 ,2-de]pyridazine-3(7H)-one
  • Acetamide (1.18 g, 20 mmol) and N,N-dimethylformamide dimethyl acetal (3 mL, 22.6 mmol) were dissolved in 20 mL of dioxane and heated to 90 ° C for 3 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and a small amount of petroleum ether was added to precipitate a solid, which was filtered to give N-(dimethylamino)methyleneacetamide.
  • step 3 of intermediate 1a Yellow solid with a yield of 70%.
  • Step 4 (E)-2-Acetyl-5-fluoro-3-((2,4-difluorobenzylidene)amino)benzoic acid methyl ester
  • Step 5 Methyl 7-fluoro-2-(2,4-difluorophenyl)-2,3-dihydroquinolin-4(1H)-one-5-carboxylate
  • Methyl (E)-2-acetyl-5-fluoro-3-((2,4-difluorobenzylidene)amino)benzoate (6.8 g, 20.3 mmol) was dissolved in dichloromethane (100 mL) Bismuth methanesulfonate (3.5 g, 7.1 mmol). The reaction was carried out at room temperature for 1.5 hours. The reaction mixture was washed with water and aq.
  • Step 6 Methyl N-tert-butoxycarbonyl-7-fluoro-2-(2,4-difluorophenyl)-2,3-dihydroquinolin-4-one-5-carboxylate
  • Step 7 N-tert-Butoxycarbonyl-7-fluoro-2-(2,4-difluorophenyl)-4-(tert-butyldimethylsilyloxy)-1,2-dihydroquinoline -5-methyl formate
  • Step 8 N-tert-Butoxycarbonyl-3-bromo-7-fluoro-2-(2,4-difluorophenyl)-4-oxo-3,4-dihydroquinoline-1,5 ( 2H)-5-carboxylic acid methyl ester
  • Step 9 5-Fluoro-9-mercapto-8-(2,4-difluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3 ( 7H)-keto-7-carboxylic acid tert-butyl ester
  • Step 10 5-Fluoro-8-(2,4-difluorophenyl)-9-(5-methyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4,5-imidazolin-3-one-3-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4,5-imidazolin-3-one-3-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1-cyclobutyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 1-cyclobutyl-2,4-imidazolidinone with Intermediate 1a. MS (ESI): 552.1 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(1-cyclobutyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1-(1-tert-butoxycarbonylazetidin-3-yl)-2,4-imidazolidin-2-one-3- ,8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(1-(azetidin-3-yl)-2,4-imidazolidindione-3-yl)-8,9 -dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(1-(1-tert-butoxycarbonylpiperidin-4-yl)-2,4-imidazolinedion-3-yl) -8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(1-(piperidin-4-yl)-2,4-imidazolidin-2-one)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-9-azido-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3 (7H) -keto-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-9-amino-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one -7-carboxylic acid tert-butyl ester
  • Step 3 5-Fluoro-9-isothiocyanato-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3 (7H )-keto-7-carboxylic acid tert-butyl ester
  • Step 4 5-Fluoro-8-(4-fluorophenyl)-9-(3-methyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 5 5-Fluoro-8-(4-fluorophenyl)-9-(3-methyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H-pyrido[4 ,3,2-de]pyridazine-3(7H)-keto-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H-pyrido[4 ,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(4,4-dimethyl-5-oxo-2-thioimidazolin-1-yl)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(4,4-dimethyl-5-oxo-2-thioimidazolin-1-yl)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(8-oxo-6-thio-5,7-diazaspiro[3.4]octane-7-yl)-8 , 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(8-oxo-6-thio-5,7-diazaspiro[3.4]octane-7-yl)-8 ,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-((S)-1-oxo-3-thiotetrahydro-1H-pyrrolo[1,2-c]imidazole-2 (3H)-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-((S)-1-oxo-3-thiotetrahydro-1H-pyrrolo[1,2-c]imidazole-2 (3H)-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(3-cyclopropyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(3-cyclopropyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(7-oxo-5-thio-4,6-diazaspiro[2.4]heptane-6-yl)-8 , 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(7-oxo-5-thio-4,6-diazaspiro[2.4]heptane-6-yl)-8 ,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(3,4,4-trimethyl-5-oxo-2-thioimidazolin-1-yl)-8,9 -Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(3,4,4-trimethyl-5-oxo-2-thioimidazolin-1-yl)-8,9 -dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-8-oxo-6-thio-5,7-diazaspiro[3.4]octane-7 -yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-8-oxo-6-thio-5,7-diazaspiro[3.4]octane-7 -yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(4-oxo-2-thio-1,3-diazaspiro[4.4]decane-3-yl)-8 , 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(4-oxo-2-thio-1,3-diazaspiro[4.4]decane-3-yl)-8 ,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Example 55 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-methylene-3a,4,7,7a-tetrahydroisoindole-1,3(2H)- Diketo-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 55)
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-methylene-3a,4,7,7a-tetrahydroisoindol-1,3(2H)-di Keto-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 4,7-methylene-3a,4,7,7a-tetrahydroisoindol-1,3(2H)-dione with intermediate 1a.
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-methylene-3a,4,7,7a-tetrahydroisoindol-1,3(2H)-di Keto-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene-3- ,8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene-3- -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(2-butyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene-3- ,8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(2-butyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene-3- -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(6-methyl-8-oxo-5,7-diazaspiro-[3.4]oct-5-ene-7- ,8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 6-methyl-5,7-diazaspiro-[3.4]oct-5-en-8-one with intermediate 1a. MS (ESI): 536.2 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(6-methyl-8-oxo-5,7-diazaspiro-[3.4]oct-5-ene-7- -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-7-oxo-4,6-diazaspiro-[2.4]hept-4-ene-6- ,8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • step 1 of the embodiment 1. It is prepared by reacting 5-methyl-4,6-diazaspiro-[2.4]hept-4-en-7-one with Intermediate 1a. MS (ESI): 522.2 [M+H] + .
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-7-oxo-4,6-diazaspiro-[2.4]hept-4-ene-6- -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(2,4,4-trimethyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl) -8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(2,4,4-trimethyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl) -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Step 1 5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
  • Step 2 5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
  • Test Example 1 Study on cell proliferation inhibitory activity
  • Tumor cells in the logarithmic growth phase were seeded in 96-well culture plates (180 ⁇ L/well), and cultured at 37 ° C, 5% CO 2 for 24 hours to adhere the cells.
  • Each compound was previously dissolved in DMSO to prepare a 10 mM stock solution.
  • the medium was further diluted to another 10-fold concentration of the target in another 96-well plate, and then 20 ⁇ L/well of the diluted compound was added to the 96-well plate inoculated with the cells to reach the target concentration.
  • Three replicate wells were set for each concentration and a blank control was set. Continue to incubate for 120 hours at 37 ° C, 5% CO 2 .
  • the culture was terminated, 50 ⁇ L of pre-cooled (4 ° C) 50% trichloroacetic acid, ie TCA (final concentration 10%), was added to each well, placed at 4 ° C for 1 hour, washed with purified water at least 5 times, naturally dried in the air or 60 °C oven drying.
  • SRB sulforhodamine B
  • LT-00628 (preparation method reference CN102171214B Example 94), Talazoparib (preparation method reference CN102171214B Example 155) and Olaparib (preparation method reference CN1788000B Example 9 compound 168) are reported PARP inhibitors.
  • LT-00628 is the racemate of Talazoparib.
  • test results show that the compound of the present invention has obvious effects on human triple negative breast cancer cell line MDA-MB-436 and estrogen receptor negative (ER - ) and progesterone receptor negative (PR - ) inflammatory breast cancer cell line SUM149PT. Proliferation inhibitory activity.
  • LT-00628 is a racemate of Talazoparib.
  • Example 94 of CN102171214B For the preparation method, refer to Example 94 of CN102171214B.
  • the test results indicate that the compound of the present invention has significant inhibitory activity against PARP-1 and PARP-2 enzymes at the molecular level.
  • Test Example 3 Study on pharmacokinetic properties
  • test results show that the compound of the invention has low clearance rate, high plasma exposure, high oral bioavailability and good pharmacokinetic properties.
  • Test Example 4 Growth inhibition of human triple negative breast cancer cell MDA-MB-436 subcutaneous xenograft in nude mice
  • MDA-MB-436 was cultured in a modified Eagle medium-Lybowitz medium mixture (1/1, v/v) supplemented with 10% fetal bovine serum and placed at 37 ° C containing 5% CO 2 culture incubator. Cells in the exponential growth phase are collected and counted for inoculation.
  • Test animals BALB/cA nude mice, 15 females, 5 weeks old, 18 ⁇ 2 g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • test groups were set up: 10% dimethylacetamide/5% polyethylene glycol-15 hydroxystearate/85% phosphate buffered saline solvent control group, compound 56 1 mg/kg group and LT -00628 of the 1 mg/kg group.
  • Test protocol Human triple-negative breast cancer cell line MDA-MB-436 (5 ⁇ 10 6 cells/only) was inoculated subcutaneously into the right side of BALB/cA nude mice. The inoculation amount of each mouse was 2 mL, and the tumor was observed regularly. The growth was randomized according to tumor size and mouse body weight when the tumor grew to 100-200 mm 3 .
  • Compound 56 and the control compound LT-00628 (LT-00628 is a racemate of Talazoparib) were each administered intragastrically at 1 mg/kg, and the solvent control group was intragastrically administered with an equal amount of solvent once a day for 20 consecutive days. The body weight and tumor size of the mice were measured twice a week during the entire experiment to see if a toxic reaction occurred.
  • the tumor volume change curve and the mouse body weight change curve of the three test groups are shown in Fig. 1 and Fig. 2.
  • the results showed that the compound of the present invention has a good inhibitory effect on the growth of subcutaneous xenografts of MDA-MB-436 nude mice, and has little effect on the body weight of nude mice, showing good safety.

Abstract

The present invention relates to a dihydropyridophthalazinone derivative as represented by formula (I), and a preparation method therefor and an application thereof. the R1, R2, R3, m, n, ring A, and ring B in the formula are as defined in the description. The dihydropyridophthalazinone derivative in the present invention has good PARP inhibitory activity, and can be used for treating or preventing diseases by inhibiting the PARP activity.

Description

二氢吡啶并酞嗪酮衍生物、其制备方法及应用Dihydropyridinopyridazinone derivative, preparation method and application thereof 技术领域Technical field
本发明涉及一种能够抑制聚(ADP-核糖)聚合酶活性的二氢吡啶并酞嗪酮衍生物、其制备方法以及包含所述衍生物的药物组合物和该衍生物在制备用于治疗或预防因抑制PARP活性而改善的疾病的药物方面的应用。The present invention relates to a dihydropyridoxinone derivative capable of inhibiting poly(ADP-ribose) polymerase activity, a process for the preparation thereof, and a pharmaceutical composition comprising the same, and the derivative is prepared for use in therapy or A pharmaceutical aspect of preventing a disease that is ameliorated by inhibition of PARP activity.
背景技术Background technique
聚(ADP-核糖)聚合酶，也称聚(ADP-核糖)合成酶、聚ADP-核糖基转移酶，普遍被称为PARP。PARP家族包括大约18种蛋白，如PARP-1、PARP-2、PARP-3、端锚酶-1、端锚酶-2、穹状PARP、TiPARP等。PARP通过其识别并迅速结合到DNA单链或双链断链的能力而参与DNA损伤的信号传导(Biochem J(1999)342：249-268)。其参与多种DNA相关的功能，包括基因扩增、细胞分裂、分化、细胞程序死亡、DNA碱基切除修复、以及影响端粒长度和染色体稳定性(Nature Gen(1999)23：76-80)，这使PARP抑制剂成为用于多种疾病的目标。Poly(ADP-ribose) polymerase, also known as poly(ADP-ribose) synthase, poly ADP-ribosyltransferase, is commonly referred to as PARP. The PARP family includes approximately 18 proteins, such as PARP-1, PARP-2, PARP-3, terminal anchorase-1, terminal anchorase-2, scorpion PARP, TiPARP, and the like. PARP is involved in the signaling of DNA damage through its ability to recognize and rapidly bind to single or double stranded strands of DNA (Biochem J (1999) 342: 249-268). It is involved in a variety of DNA-related functions, including gene amplification, cell division, differentiation, apoptosis, DNA base excision repair, and effects on telomere length and chromosome stability (Nature Gen (1999) 23:76-80) This makes PARP inhibitors a target for a variety of diseases.
例如，在经烷基化剂处理的细胞中，PARP抑制剂作用下可引起DNA-链断裂和细胞杀死的显著增加(Nature(1980)283：593-596；Radiat Res(1985)101：4-14)；放疗和很多化疗方法是通过诱发DNA损伤起作用，使得PARP抑制剂可作为癌症治疗的化学和辐射敏化剂(US5032617，US5215738和US5041653)；PARP抑制剂可用于抗病毒治疗和癌症治疗(WO91/18591)；BRCA1和/或BRCA2突变与乳腺癌的关联在本领域中已被充分认识(Exp Clin Cancer Res(2002)21(suppl 3)：9-12)，BRCA1和/或BRCA2中突变的载体也处于卵巢、前列腺和胰腺癌症的升高风险中，PARP抑制剂已被证实可用于BRCA1和BRCA2缺陷肿瘤的特异性杀伤(Nature(2005)434：913-916和917-921；Cancer Biol Ther(2005)4：934-936)；PARP抑制剂可用于治疗神经性病症，例如中风、创伤和帕金森病；PARP抑制剂还显示出用于治疗急性和慢性心肌病(Pharmacol Res(2005)52：34-43)；PARP抑制剂可用于治疗某些血管病，脓毒性休克，缺血性损伤和神经毒性(Biochim Biophys Acta(1989)1014：1-7；J Clin Invest(1997)100： 723-735)；PARP抑制剂可用于治疗炎性疾病(Pharmacol Res(2005)52：72-82和83-92)，例如关节炎，痛风，炎性肠病等；PARP抑制剂能用来治疗或预防自身免疫病，例如I型糖尿病和糖尿病并发症(Pharmacol Res(2005)52：60-71)；PARP抑制剂能用来治疗或预防逆转录病毒感染(US5652260)、视网膜损伤(Curr Eye Res(2004)29：403)、皮肤衰老和UV诱发的皮肤损伤(US5589483和Biochem Pharmacol(2002)63：921)等。For example, in cells treated with alkylating agents, PARP inhibitors can cause a significant increase in DNA-strand breaks and cell killing (Nature (1980) 283: 593-596; Radiat Res (1985) 101: 4 -14); Radiotherapy and many chemotherapy methods act by inducing DNA damage, making PARP inhibitors a chemical and radiosensitizer for cancer treatment (US5032617, US5215738 and US5041653); PARP inhibitors are available for antiviral therapy and cancer Treatment (WO 91/18591); the association of BRCA1 and/or BRCA2 mutations with breast cancer is well recognized in the art (Exp Clin Cancer Res (2002) 21 (suppl 3): 9-12), BRCA1 and/or BRCA2 The medium-mutated vector is also at increased risk of ovarian, prostate and pancreatic cancer, and PARP inhibitors have been shown to be useful for specific killing of BRCA1 and BRCA2-deficient tumors (Nature (2005) 434: 913-916 and 917-921; Cancer Biol Ther (2005) 4: 934-936); PARP inhibitors are useful in the treatment of neurological disorders such as stroke, trauma and Parkinson's disease; PARP inhibitors have also been shown to treat acute and chronic cardiomyopathy (Pharmacol Res ( 2005) 52:34-43); PARP inhibitors are available Treatment of certain vascular diseases, septic shock, ischemic injury and neurotoxicity (Biochim Biophys Acta (1989) 1014:1-7; J Clin Invest (1997) 100: 723-735); PARP inhibitors can be used to treat inflammation Sexual diseases (Pharmacol Res (2005) 52: 72-82 and 83-92), such as arthritis, gout, inflammatory bowel disease, etc.; PARP inhibitors can be used to treat or prevent autoimmune diseases such as type 1 diabetes and diabetes Complications (Pharmacol Res (2005) 52: 60-71); PARP inhibitors can be used to treat or prevent retroviral infection (US5652260), retinal damage (Curr Eye Res (2004) 29: 403), skin aging and UV Induced skin damage (US5589483 and Biochem Pharmacol (2002) 63:921) and the like.
目前已公开的小分子PARP抑制剂包括：WO1999/59973公开的与5元杂芳环稠合的酰胺取代的苯环、WO2001/85687公开的酰胺取代的吲哚、WO2003/106430、WO2006/110816公开的酰胺取代的苯并咪唑、EP0879820公开的酰胺取代的苯并噁唑、WO2008/84261公开的酰胺取代的苯并吡唑、WO2010/17055公开的二氢吡啶并酞嗪酮等等。The currently disclosed small molecule PARP inhibitors include: amide substituted benzene rings fused to a 5-membered heteroaryl ring disclosed in WO 1999/59973, amide substituted oximes disclosed in WO 2001/85687, WO 2003/106430, WO 2006/110816 publication Amide substituted benzimidazole, amide substituted benzoxazole disclosed in EP0879820, amide substituted benzopyrazole disclosed in WO2008/84261, dihydropyridinopyridinone disclosed in WO2010/17055, and the like.
已经上市的小分子PARP抑制剂包括WO2004/80976公开的Olaparib、WO2000/42040公开的Rucaparib、以及WO2008/84261公开的Niraparib，三者都用于治疗卵巢癌，具体结构如下，The small-molecule PARP inhibitors that have been marketed include Olaparib disclosed in WO2004/80976, Rucaparib disclosed in WO2000/42040, and Niraparib disclosed in WO2008/84261, all of which are used for the treatment of ovarian cancer, and the specific structure is as follows.
Figure PCTCN2019078089-appb-000001
Figure PCTCN2019078089-appb-000001
开发新的小分子PARP抑制剂，更有效的用于治疗通过抑制PARP而改善的疾病，是人类所需。The development of new small-molecule PARP inhibitors, which are more effective for the treatment of diseases that are ameliorated by inhibition of PARP, is desirable for humans.
发明内容Summary of the invention
本发明提供了一类二氢吡啶并酞嗪酮衍生物、其药学上可接受的盐或立体异构体，这类化合物具有良好的PARP抑制活性，能够用于制备治疗或预防因抑制PARP活性而改善的疾病的药物。The present invention provides a class of dihydropyridinopyridazinone derivatives, pharmaceutically acceptable salts or stereoisomers thereof, which have good PARP inhibitory activity and can be used for the preparation of a therapeutic or prophylactically inhibiting PARP activity. And drugs that improve the disease.
本发明提供了如下式(I)化合物、其药学上可接受的盐或立体异构体，The present invention provides a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof,
Figure PCTCN2019078089-appb-000002
Figure PCTCN2019078089-appb-000002
式中：In the formula:
环A为含有1～5个选自N、O或S的环杂原子的含氮脂杂环基或含氮芳杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连；Ring A is a nitrogen-containing aliphatic heterocyclic group or a nitrogen-containing aromatic heterocyclic group having 1 to 5 ring hetero atoms selected from N, O or S, and is bonded to the dihydropyridinopyrazine ketone through a ring N atom. ;
环B为芳基或芳杂环基；Ring B is an aryl or an aromatic heterocyclic group;
R 1选自氢、C 1-C 6烷基、C 1-C 6烷氧基、卤素、卤代C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、3～7元环烷基、-CN、-OH、-NO 2或-NR 5R 6； R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, halogenated C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl , 3 to 7-membered cycloalkyl, -CN, -OH, -NO 2 or -NR 5 R 6 ;
R 5、R 6各自独立地选自H、C 1-C 6烷基或卤代C 1-C 6烷基； R 5 and R 6 are each independently selected from H, C 1 -C 6 alkyl or halo C 1 -C 6 alkyl;
R 2各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-NH 2、卤素、氘、氘代C 1-C 6烷基、-(CH 2) qOH、3～7元环烷基、
Figure PCTCN2019078089-appb-000003
Figure PCTCN2019078089-appb-000004
芳基或被1～3个选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-OH、-NH 2或卤素的取代基取代的芳基； R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -NH 2 , halogen, hydrazine, deuterated C 1 -C 6 alkane Base, -(CH 2 ) q OH, 3- to 7-membered cycloalkyl,
Figure PCTCN2019078089-appb-000003
Figure PCTCN2019078089-appb-000004
The aryl group is substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -OH, -NH 2 or halogen Aryl;
R 3各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-OH、-NH 2或卤素； R 3 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -OH, -NH 2 or halogen;
q为0、1、2或3；q is 0, 1, 2 or 3;
n为0、1、2、3或4；n is 0, 1, 2, 3 or 4;
m为0、1、2或3。m is 0, 1, 2 or 3.
本发明提供了式(I)化合物的制备方法。The invention provides a process for the preparation of a compound of formula (I).
本发明提供了中间体1，用于制备本发明化合物。The present invention provides intermediate 1, which is useful in the preparation of compounds of the invention.
本发明提供了药物组合物，包括本发明式(I)化合物、其药学上可接受的盐或立体异构体，以及药学上可接受的载体、赋形剂或稀释剂。The invention provides a pharmaceutical composition comprising a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
本发明提供本发明式(I)化合物、其药学上可接受的盐或立体异构体或其药物组合物在制备治疗或预防因抑制PARP活性而改善的疾 病的药物中的应用。The present invention provides the use of a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition thereof, for the preparation of a medicament for treating or preventing a disease which is ameliorated by inhibition of PARP activity.
本发明还提供了本发明式(I)化合物、其药学上可接受的盐或立体异构体或其药物组合物在制备用于治疗或预防血管疾病、脓毒性休克、缺血性损伤、再灌注损伤、神经毒性、失血性休克、炎性疾病、神经性疾病、多发性硬化症、糖尿病继发效应、心血管手术后细胞毒性的急性治疗、视网膜损伤、皮肤衰老或UV诱发的皮肤损伤的药物中的应用。The present invention also provides a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition thereof, for use in the treatment or prevention of vascular diseases, septic shock, ischemic injury, and further Perfusion injury, neurotoxicity, hemorrhagic shock, inflammatory disease, neurological disease, multiple sclerosis, secondary effects of diabetes, acute treatment of cytotoxicity after cardiovascular surgery, retinal damage, skin aging or UV-induced skin damage Application in medicine.
本发明还提供了本发明式(I)化合物、其药学上可接受的盐或立体异构体或其药物组合物在制备用于治疗或预防癌症的药物中的应用。The invention also provides the use of a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, for the manufacture of a medicament for the treatment or prevention of cancer.
本发明还提供了本发明式(I)化合物、其药学上可接受的盐或立体异构体或其药物组合物在制备用于治疗或预防癌症的药物中的应用，所述药物与电离辐射、一种或多种化疗药物或其组合组合施用。The present invention also provides the use of a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition thereof, for the preparation of a medicament for treating or preventing cancer, the medicament and ionizing radiation Administration with one or more chemotherapeutic drugs or a combination thereof.
本发明还提供了本发明式(I)化合物、其药学上可接受的盐或立体异构体或其药物组合物在制备用于治疗或预防癌症的药物中的应用，所述癌症包含一种或多种癌细胞，所述癌细胞具有相对于正常细胞降低或废除的利用同源重组(HR)修复DNA双链断裂(DSB)的能力。The present invention also provides the use of a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition thereof, for the preparation of a medicament for treating or preventing cancer, the cancer comprising Or a plurality of cancer cells having the ability to repair DNA double-strand breaks (DSBs) using homologous recombination (HR) relative to normal cells, reduced or abolished.
本发明还提供了本发明式(I)化合物、其药学上可接受的盐或立体异构体或其药物组合物在制备用于治疗或预防癌症的药物中的应用，所述癌症包含一种或多种癌细胞，所述癌细胞具有相对于正常细胞降低或废除的利用HR修复DNA DSB的能力，例如所述癌细胞具有BRCA1或BRCA2缺失表型。The present invention also provides the use of a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition thereof, for the preparation of a medicament for treating or preventing cancer, the cancer comprising Or a plurality of cancer cells having the ability to repair DNA DSB with HR reduced or abolished relative to normal cells, eg, the cancer cells have a BRCA1 or BRCA2 deletion phenotype.
本发明还提供了本发明式(I)化合物、其药学上可接受的盐或立体异构体或其药物组合物在制备用于治疗或预防同源重组(HR)依赖性DNA双链断裂(DSB)修复途径缺失的癌症的药物中的应用。The present invention further provides a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, or a pharmaceutical composition thereof, for use in the preparation or treatment of homologous recombination (HR)-dependent DNA double-strand breaks ( DSB) The use of drugs to repair cancers with missing pathways.
本发明进一步提供了本发明式(I)化合物、其药学上可接受的盐或立体异构体或其药物组合物在制备用于治疗或预防同源重组(HR)依赖性DNA双链断裂(DSB)修复途径缺失的癌症的药物中的应用，所述癌症包含一种或多种癌细胞，所述癌细胞具有相对于正常细胞降低或废除的利用HR修复DNA DSB的能力。The invention further provides a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, for use in the manufacture or prevention of homologous recombination (HR)-dependent DNA double-strand breaks ( DSB) The use of a drug for repairing a cancer with a missing pathway, the cancer comprising one or more cancer cells having the ability to repair DNA DSB with HR reduced or abolished relative to normal cells.
本发明进一步提供了本发明式(I)化合物、其药学上可接受的盐或立体异构体或其药物组合物在制备用于治疗或预防同源重组(HR)依赖性DNA双链断裂(DSB)修复途径缺失的癌症的药物中的应用，所述 癌症包含一种或多种癌细胞，所述癌细胞具有相对于正常细胞降低或废除的利用HR修复DNA DSB的能力，例如所述癌细胞具有BRCA1或BRCA2缺失表型。The invention further provides a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof, for use in the manufacture or prevention of homologous recombination (HR)-dependent DNA double-strand breaks ( DSB) The use of a medicament for repairing a cancer in which a pathway is absent, the cancer comprising one or more cancer cells having the ability to repair DNA DSB using HR, such as the cancer, reduced or abolished relative to normal cells The cells have a BRCA1 or BRCA2 deletion phenotype.
本发明所述癌症包括但不限于乳腺癌、卵巢癌、子宫内膜癌、宫颈癌、肺癌、前列腺癌、胰腺癌、血癌、胃癌、胆囊癌、肝癌、头颈癌、食管癌、肾癌、脑癌、白血病、结肠癌、肠肿瘤、胶质母细胞瘤、淋巴瘤或黑色素瘤。The cancer of the present invention includes, but is not limited to, breast cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, prostate cancer, pancreatic cancer, blood cancer, stomach cancer, gallbladder cancer, liver cancer, head and neck cancer, esophageal cancer, kidney cancer, brain. Cancer, leukemia, colon cancer, intestinal tumor, glioblastoma, lymphoma or melanoma.
本发明提供了一种治疗或预防因抑制PARP活性而改善的疾病的方法，所述方法包括对需要的患者施用有效量的本发明式(I)化合物、其药学上可接受的盐或立体异构体或式(I)化合物的药物组合物。The present invention provides a method of treating or preventing a disease ameliorated by inhibition of PARP activity, which comprises administering to a patient in need thereof an effective amount of a compound of the formula (I), a pharmaceutically acceptable salt thereof or a stereoisomer of the present invention. A pharmaceutical composition of a construct or a compound of formula (I).
本发明还提供了一种治疗或预防血管疾病、脓毒性休克、缺血性损伤、再灌注损伤、神经毒性、失血性休克、炎性疾病、神经性疾病、多发性硬化症、糖尿病继发效应、心血管手术后细胞毒性的急性治疗、视网膜损伤、皮肤衰老或UV诱发的皮肤损伤的方法，所述方法包括对需要的患者施用有效量的本发明式(I)化合物、其药学上可接受的盐或立体异构体或式(I)化合物的药物组合物。The invention also provides a treatment or prevention of vascular diseases, septic shock, ischemic injury, reperfusion injury, neurotoxicity, hemorrhagic shock, inflammatory disease, neurological disease, multiple sclerosis, secondary effects of diabetes A method of acute treatment of cytotoxicity after cardiovascular surgery, retinal damage, skin aging or UV-induced skin damage, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I) of the invention, which is pharmaceutically acceptable A salt or stereoisomer or a pharmaceutical composition of a compound of formula (I).
本发明还提供了一种治疗或预防癌症的方法，所述方法包括对需要的患者施用有效量的本发明式(I)化合物、其药学上可接受的盐或立体异构体或式(I)化合物的药物组合物。The invention also provides a method of treating or preventing cancer, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof or formula (I) a pharmaceutical composition of the compound.
本发明还提供了一种治疗或预防癌症的方法，所述癌症包含一种或多种癌细胞，所述癌细胞具有相对于正常细胞降低或废除的利用HR修复DNA DSB的能力，所述方法包括对需要的患者施用有效量的本发明式(I)化合物、其药学上可接受的盐或立体异构体或式(I)化合物的药物组合物。The invention also provides a method of treating or preventing cancer, the cancer comprising one or more cancer cells having reduced or abolished ability to repair DNA DSB with HR relative to normal cells, the method This includes administering to a patient in need thereof an effective amount of a pharmaceutical composition of a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a compound of formula (I) of the present invention.
本发明还提供了一种治疗或预防癌症的方法，所述癌症包含一种或多种癌细胞，所述癌细胞具有相对于正常细胞降低或废除的利用HR修复DNA DSB的能力，例如所述癌细胞具有BRCA1或BRCA2缺失表型，所述方法包括对需要的患者施用有效量的本发明式(I)化合物、其药学上可接受的盐或立体异构体或式(I)化合物的药物组合物。The present invention also provides a method of treating or preventing cancer, the cancer comprising one or more cancer cells having the ability to repair DNA DSB with HR reduced or abolished relative to normal cells, such as A cancer cell has a BRCA1 or BRCA2 deletion phenotype, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a compound of formula (I), of the present invention. combination.
本发明还提供了一种通过与电离辐射、一种或多种化疗药物或其组合组合施用来治疗或预防癌症的方法，所述方法包括对需要的患者施用有效量的本发明式(I)化合物、其药学上可接受的盐或立体异构 体或式(I)化合物的药物组合物。The invention also provides a method of treating or preventing cancer by administering in combination with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof, the method comprising administering to a patient in need thereof an effective amount of a formula (I) of the invention A pharmaceutical composition of a compound, a pharmaceutically acceptable salt or stereoisomer thereof or a compound of formula (I).
本发明还提供了一种治疗或预防同源重组(HR)依赖性DNA双链断裂(DSB)修复途径缺失的癌症的方法，所述方法包括对需要的患者施用有效量的本发明式(I)化合物、其药学上可接受的盐或立体异构体或式(I)化合物的药物组合物。The invention also provides a method of treating or preventing a cancer in which a homologous recombination (HR)-dependent DNA double-strand break (DSB) repair pathway is deleted, the method comprising administering to a patient in need thereof an effective amount of the formula (I) a pharmaceutical composition of a compound, a pharmaceutically acceptable salt or stereoisomer thereof or a compound of formula (I).
本发明还提供了一种治疗或预防同源重组(HR)依赖性DNA双链断裂(DSB)修复途径缺失的癌症的方法，所述癌症包含一种或多种癌细胞，所述癌细胞具有相对于正常细胞降低或废除的利用HR修复DNA DSB的能力，所述方法包括对需要的患者施用有效量的本发明式(I)化合物、其药学上可接受的盐或立体异构体或式(I)化合物的药物组合物。The present invention also provides a method of treating or preventing a cancer in which a homologous recombination (HR)-dependent DNA double-strand break (DSB) repair pathway is deleted, the cancer comprising one or more cancer cells having The ability to repair DNA DSB using HR, relative to normal cells, reduced or abolished, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer or formula thereof, of the invention (I) A pharmaceutical composition of a compound.
本发明还提供了一种治疗或预防同源重组(HR)依赖性DNA双链断裂(DSB)修复途径缺失的癌症的方法，所述癌症包含一种或多种癌细胞，所述癌细胞具有相对于正常细胞降低或废除的利用HR修复DNA DSB的能力，例如所述癌细胞具有BRCA1或BRCA2缺失表型，所述方法包括对需要的患者施用有效量的本发明式(I)化合物、其药学上可接受的盐或立体异构体或式(I)化合物的药物组合物。The present invention also provides a method of treating or preventing a cancer in which a homologous recombination (HR)-dependent DNA double-strand break (DSB) repair pathway is deleted, the cancer comprising one or more cancer cells having The ability to repair a DNA DSB with HR relative to normal cells reduced or abolished, eg, the cancer cell has a BRCA1 or BRCA2 deletion phenotype, the method comprising administering to a patient in need thereof an effective amount of a compound of formula (I) of the invention, A pharmaceutically acceptable salt or stereoisomer or a pharmaceutical composition of a compound of formula (I).
本发明更进一步提供了一种治疗或预防具有BRCA1或BRCA2缺失表型的癌细胞的癌症的方法，所述方法包括对需要的患者施用有效量的本发明式(I)化合物、其药学上可接受的盐或立体异构体或式(I)化合物的药物组合物。The present invention still further provides a method of treating or preventing cancer of a cancer cell having a BRCA1 or BRCA2 deletion phenotype, the method comprising administering to a patient in need thereof an effective amount of a compound of the formula (I) of the present invention, which is pharmaceutically acceptable Accepted salts or stereoisomers or pharmaceutical compositions of the compounds of formula (I).
本发明所述的相对于正常细胞降低或废除的利用HR修复DNA DSB的能力的癌细胞，缺乏一种或多种表型的HR依赖性DNA DSB修复活性，所述表型选自：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和RAD9。The cancer cells of the present invention which are reduced or abolished by normal cells with the ability to repair DNA DSB by HR lack HR-dependent DNA DSB repair activity of one or more phenotypes selected from the group consisting of: 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) , NBS1 (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.
在本发明式(I)化合物、其药学上可接受的盐或立体异构体的一个优选实施方案中，所述化合物为式(II)化合物，In a preferred embodiment of the compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, the compound is a compound of formula (II),
Figure PCTCN2019078089-appb-000005
Figure PCTCN2019078089-appb-000005
式中：In the formula:
环A为含有1～5个选自N、O或S的环杂原子的含氮脂杂环基或含氮芳杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连；Ring A is a nitrogen-containing aliphatic heterocyclic group or a nitrogen-containing aromatic heterocyclic group having 1 to 5 ring hetero atoms selected from N, O or S, and is bonded to the dihydropyridinopyrazine ketone through a ring N atom. ;
环B为芳基或芳杂环基；Ring B is an aryl or an aromatic heterocyclic group;
R 1选自氢、C 1-C 6烷基、C 1-C 6烷氧基、卤素、卤代C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、3～7元环烷基、-CN、-OH、-NO 2或-NR 5R 6； R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, halogenated C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl , 3 to 7-membered cycloalkyl, -CN, -OH, -NO 2 or -NR 5 R 6 ;
R 5、R 6各自独立地选自H、C 1-C 6烷基或卤代C 1-C 6烷基； R 5 and R 6 are each independently selected from H, C 1 -C 6 alkyl or halo C 1 -C 6 alkyl;
R 2各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-NH 2、卤素、氘、氘代C 1-C 6烷基、-(CH 2) qOH、3～7元环烷基、
Figure PCTCN2019078089-appb-000006
Figure PCTCN2019078089-appb-000007
芳基或被1～3个选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-OH、-NH 2或卤素的取代基取代的芳基； R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -NH 2 , halogen, hydrazine, deuterated C 1 -C 6 alkane Base, -(CH 2 ) q OH, 3- to 7-membered cycloalkyl,
Figure PCTCN2019078089-appb-000006
Figure PCTCN2019078089-appb-000007
The aryl group is substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -OH, -NH 2 or halogen Aryl;
R 3各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-OH、-NH 2或卤素； R 3 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -OH, -NH 2 or halogen;
q为0、1、2或3；q is 0, 1, 2 or 3;
n为0、1、2、3或4；n is 0, 1, 2, 3 or 4;
m为0、1、2或3。m is 0, 1, 2 or 3.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异 构体的一个优选实施方案中，R 1选自氢、C 1-C 6烷基或卤素，更优选为卤素。 In a preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, R 1 is selected from hydrogen, C 1 -C 6 alkyl or halogen, more preferably It is halogen.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个优选实施方案中，环B为苯基或吡啶基，R 3各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-OH、-NH 2或卤素，m为0、1、2或3。 In a preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, ring B is phenyl or pyridyl, and R 3 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -OH, -NH 2 or halogen, m is 0, 1, 2 or 3.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个更优选实施方案中，环B为苯基或吡啶基，R 3为卤素，m为1或2。 In a more preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, ring B is phenyl or pyridyl, R 3 is halogen, m is 1 Or 2.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个更优选实施方案中，环B为苯基，R 3为卤素，m为1或2。 In a more preferred embodiment of the compound of formula (I) or (II), a pharmaceutically acceptable salt or stereoisomer thereof, ring B is phenyl, R 3 is halogen, and m is 1 or 2.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个优选实施方案中，环A为含有1～5个选自N、O或S的环杂原子的含氮单环脂杂环基、含氮稠环脂杂环基、含氮桥环稠环脂杂环基、含氮螺环脂杂环基、含氮桥环脂杂环基、含氮螺环稠环脂杂环基或含氮桥环螺环脂杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连；其中，R 2各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-NH 2、卤素、-(CH 2) qOH、3～7元环烷基、
Figure PCTCN2019078089-appb-000008
Figure PCTCN2019078089-appb-000009
芳基或被1～3个选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-OH、-NH 2或卤素的取代基取代的芳基，q为0、1、2或3，n为0、1、2、3或4。 In a preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, the ring A is a ring heterocyclic ring containing 1 to 5 selected from N, O or S. Atomous nitrogen-containing monocyclic aliphatic heterocyclic group, nitrogen-containing fused ring heterocyclic group, nitrogen-containing bridged ring fused ring heterocyclic group, nitrogen-containing spirocyclic heterocyclic group, nitrogen-containing bridged ring heterocyclic group, a nitrogen spiro fused ring alicyclic heterocyclic group or a nitrogen-containing bridged ring spiroaliphatic heterocyclic group, which is bonded to the dihydropyridinopyridinone nucleus via a ring N atom; wherein R 2 is each independently selected from C 1 - C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -NH 2 , halogen, -(CH 2 ) q OH, 3- to 7-membered cycloalkyl,
Figure PCTCN2019078089-appb-000008
Figure PCTCN2019078089-appb-000009
The aryl group is substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -OH, -NH 2 or halogen An aryl group, q is 0, 1, 2 or 3, and n is 0, 1, 2, 3 or 4.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个优选实施方案中，环A为含有1～5个选自N、O或S的环杂原子的含氮单环脂杂环基、含氮稠环脂杂环基、含氮桥环稠环脂杂环基或含氮螺环脂杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连；其中，R 2各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6 烷基、-NH 2、卤素、-(CH 2) qOH、3～7元环烷基、
Figure PCTCN2019078089-appb-000010
Figure PCTCN2019078089-appb-000011
芳基或被1～3个选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-OH、-NH 2或卤素的取代基取代的芳基，q为0、1、2或3，n为0、1、2、3或4。 In a preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, the ring A is a ring heterocyclic ring containing 1 to 5 selected from N, O or S. A nitrogen-containing monocyclic heterocyclic heterocyclic group, a nitrogen-containing fused ring heterocyclic group, a nitrogen-containing bridged ring fused ring heterocyclic group or a nitrogen-containing spirocyclic heterocyclic group through a ring of N atoms and dihydropyridine The pyridazinone core is linked; wherein R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -NH 2 , halogen, - (CH 2 ) q OH, 3 to 7-membered cycloalkyl,
Figure PCTCN2019078089-appb-000010
Figure PCTCN2019078089-appb-000011
The aryl group is substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -OH, -NH 2 or halogen An aryl group, q is 0, 1, 2 or 3, and n is 0, 1, 2, 3 or 4.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个优选实施方案中，环A为含有1～5个选自N、O或S的环杂原子的具有4至7个环原子的含氮单环脂杂环基、具有7至10个环原子的含氮稠环脂杂环基、具有7至10个环原子的含氮桥环稠环脂杂环基或具有7至11个环原子的含氮螺环脂杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连；其中，R 2各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-NH 2、卤素、-(CH 2) qOH、3～7元环烷基、
Figure PCTCN2019078089-appb-000012
芳基或被1～3个选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-OH、-NH 2或卤素的取代基取代的芳基，q为0、1、2或3，n为0、1、2、3或4。 In a preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, the ring A is a ring heterocyclic ring containing 1 to 5 selected from N, O or S. a nitrogen-containing monocyclic heterocyclic heterocyclic group having 4 to 7 ring atoms, a nitrogen-containing fused ring heterocyclic group having 7 to 10 ring atoms, a nitrogen-containing bridged ring fused ring having 7 to 10 ring atoms An alicyclic group or a nitrogen-containing spiroaliphatic heterocyclic group having 7 to 11 ring atoms, which is bonded to the dihydropyridazinone nucleus via a ring N atom; wherein R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -NH 2 , halogen, -(CH 2 ) q OH, 3- to 7-membered cycloalkyl,
Figure PCTCN2019078089-appb-000012
The aryl group is substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -OH, -NH 2 or halogen An aryl group, q is 0, 1, 2 or 3, and n is 0, 1, 2, 3 or 4.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个更优选实施方案中，环A为含有1～5个选自N、O或S的环杂原子的含氮单环脂杂环基、含氮稠环脂杂环基、含氮桥环稠环脂杂环基或含氮螺环脂杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连，所述含氮单环脂杂环基、含氮稠环脂杂环基、含氮桥环稠环脂杂环基、含氮螺环脂杂环基选自
Figure PCTCN2019078089-appb-000013
Figure PCTCN2019078089-appb-000014
Figure PCTCN2019078089-appb-000015
In a more preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, the ring A is a ring containing from 1 to 5 selected from N, O or S. a hetero atom containing a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing fused ring heterocyclic group, a nitrogen-containing bridged ring fused ring heterocyclic group or a nitrogen-containing spirocyclic heterocyclic group, through a ring of a N atom and a dihydropyridine And a pyridazinone core, wherein the nitrogen-containing monocyclic heterocyclic group, the nitrogen-containing fused ring heterocyclic group, the nitrogen-containing bridged ring fused ring heterocyclic group, and the nitrogen-containing spirocyclic heterocyclic group are selected from the group consisting of
Figure PCTCN2019078089-appb-000013
Figure PCTCN2019078089-appb-000014
Figure PCTCN2019078089-appb-000015
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个更优选实施方案中，环A为含有1～5个选自N、O或S的 环杂原子的含氮单环脂杂环基、含氮稠环脂杂环基、含氮桥环稠环脂杂环基或含氮螺环脂杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连，所述含氮单环脂杂环基、含氮稠环脂杂环基、含氮桥环稠环脂杂环基、含氮螺环脂杂环基选自
Figure PCTCN2019078089-appb-000016
Figure PCTCN2019078089-appb-000017
In a more preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, the ring A is a ring containing from 1 to 5 selected from N, O or S. a hetero atom containing a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing fused ring heterocyclic group, a nitrogen-containing bridged ring fused ring heterocyclic group or a nitrogen-containing spirocyclic heterocyclic group, through a ring of a N atom and a dihydropyridine And a pyridazinone core, wherein the nitrogen-containing monocyclic heterocyclic group, the nitrogen-containing fused ring heterocyclic group, the nitrogen-containing bridged ring fused ring heterocyclic group, and the nitrogen-containing spirocyclic heterocyclic group are selected from the group consisting of
Figure PCTCN2019078089-appb-000016
Figure PCTCN2019078089-appb-000017
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个更优选实施方案中，环A为含有1～5个选自N、O或S的环杂原子的含氮单环脂杂环基、含氮稠环脂杂环基、含氮桥环稠环脂 杂环基或含氮螺环脂杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连，所述含氮单环脂杂环基、含氮稠环脂杂环基、含氮桥环稠环脂杂环基、含氮螺环脂杂环基选自
Figure PCTCN2019078089-appb-000018
Figure PCTCN2019078089-appb-000019
In a more preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, the ring A is a ring containing from 1 to 5 selected from N, O or S. a hetero atom containing a nitrogen-containing monocyclic heterocyclic group, a nitrogen-containing fused ring heterocyclic group, a nitrogen-containing bridged ring fused ring heterocyclic group or a nitrogen-containing spirocyclic heterocyclic group, through a ring of a N atom and a dihydropyridine And a pyridazinone core, wherein the nitrogen-containing monocyclic heterocyclic group, the nitrogen-containing fused ring heterocyclic group, the nitrogen-containing bridged ring fused ring heterocyclic group, and the nitrogen-containing spirocyclic heterocyclic group are selected from the group consisting of
Figure PCTCN2019078089-appb-000018
Figure PCTCN2019078089-appb-000019
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个更优选实施方案中，R 2各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-NH 2、卤素、-(CH 2) qOH、3～7元环烷基、
Figure PCTCN2019078089-appb-000020
苯基或被1～3个选自C 1-C 6烷基、-OH、-NH 2或卤素的取代基取代的苯基，q为0、1或2，n为0、1、2或3。 In a more preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -NH 2 , halogen, -(CH 2 ) q OH, 3- to 7-membered cycloalkyl,
Figure PCTCN2019078089-appb-000020
Phenyl or phenyl substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, -OH, -NH 2 or halogen, q is 0, 1 or 2, n is 0, 1, 2 or 3.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个更优选实施方案中，R 2各自独立地选自C 1-C 6烷基、卤代C 1-C 6烷基、-NH 2、-(CH 2) qOH、3～7元环烷基、
Figure PCTCN2019078089-appb-000021
Figure PCTCN2019078089-appb-000022
或苯基，q为0、1或2，n为0、1、2或3。 In a more preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, R 2 is each independently selected from C 1 -C 6 alkyl, halo C 1 -C 6 alkyl, -NH 2 , -(CH 2 ) q OH, 3-7-membered cycloalkyl,
Figure PCTCN2019078089-appb-000021
Figure PCTCN2019078089-appb-000022
Or phenyl, q is 0, 1 or 2, and n is 0, 1, 2 or 3.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个更优选实施方案中，R 2各自独立地选自C 1-C 4烷基、卤代C 1-C 4烷基、-NH 2、-(CH 2) qOH、3～7元环烷基、
Figure PCTCN2019078089-appb-000023
Figure PCTCN2019078089-appb-000024
或苯基，q为0、1或2，n为0、1、2或3。 In a more preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, R 2 is each independently selected from C 1 -C 4 alkyl, halo C 1 -C 4 alkyl, -NH 2 , -(CH 2 ) q OH, 3-7-membered cycloalkyl,
Figure PCTCN2019078089-appb-000023
Figure PCTCN2019078089-appb-000024
Or phenyl, q is 0, 1 or 2, and n is 0, 1, 2 or 3.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个优选实施方案中，环A为含有1～5个选自N、O或S的环杂原子的含氮单环芳杂环基或含氮稠环芳杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连；其中，R 2各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-NH 2、卤素、-(CH 2) qOH、3～7元环烷基、
Figure PCTCN2019078089-appb-000025
芳基或被1～3个选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-OH、-NH 2或卤素的取代基取代的芳基，q为0、1、2或3，n为0、1、2、3或4。 In a preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, the ring A is a ring heterocyclic ring containing 1 to 5 selected from N, O or S. a nitrogen-containing monocyclic aromatic heterocyclic group or a nitrogen-containing fused ring aromatic heterocyclic group bonded to a dihydropyridazinone nucleus via a ring N atom; wherein R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -NH 2 , halogen, -(CH 2 ) q OH, 3- to 7-membered cycloalkyl,
Figure PCTCN2019078089-appb-000025
The aryl group is substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -OH, -NH 2 or halogen An aryl group, q is 0, 1, 2 or 3, and n is 0, 1, 2, 3 or 4.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个优选实施方案中，环A为含有1～5个选自N、O或S的环 杂原子的具有5至6个环原子的含氮单环芳杂环基或具有8至10个环原子的含氮稠环芳杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连；其中，R 2各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-NH 2、卤素、-(CH 2) qOH、3～7元环烷基、
Figure PCTCN2019078089-appb-000026
Figure PCTCN2019078089-appb-000027
芳基或被1～3个选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-OH、-NH 2或卤素的取代基取代的芳基，q为0、1、2或3，n为0、1、2、3或4。 In a preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, the ring A is a ring heterocyclic ring containing 1 to 5 selected from N, O or S. a nitrogen-containing monocyclic aromatic heterocyclic group having 5 to 6 ring atoms or a nitrogen-containing fused ring aromatic heterocyclic group having 8 to 10 ring atoms, through a ring atom N and a dihydropyridinopyridazinone Nuclei linked; wherein R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -NH 2 , halogen, -(CH 2 ) q OH, 3 to 7-membered cycloalkyl,
Figure PCTCN2019078089-appb-000026
Figure PCTCN2019078089-appb-000027
The aryl group is substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -OH, -NH 2 or halogen An aryl group, q is 0, 1, 2 or 3, and n is 0, 1, 2, 3 or 4.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个更优选实施方案中，环A为含有1～5个选自N、O或S的环杂原子的含氮单环芳杂环基或含氮稠环芳杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连，所述含氮单环芳杂环基、含氮稠环芳杂环基选自
Figure PCTCN2019078089-appb-000028
Figure PCTCN2019078089-appb-000029
In a more preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, the ring A is a ring containing from 1 to 5 selected from N, O or S. a nitrogen-containing monocyclic aromatic heterocyclic group or a nitrogen-containing fused aromatic heterocyclic group of a hetero atom, which is bonded to a dihydropyridazinone nucleus via a N atom on the ring, said nitrogen-containing monocyclic aromatic heterocyclic group, A nitrogen fused ring aromatic heterocyclic group is selected from
Figure PCTCN2019078089-appb-000028
Figure PCTCN2019078089-appb-000029
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个更优选实施方案中，环A为含有1～5个选自N、O或S的环杂原子的含氮单环芳杂环基或含氮稠环芳杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连，所述含氮单环芳杂环基、含氮稠环芳杂环基选自
Figure PCTCN2019078089-appb-000030
In a more preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, the ring A is a ring containing from 1 to 5 selected from N, O or S. a nitrogen-containing monocyclic aromatic heterocyclic group or a nitrogen-containing fused aromatic heterocyclic group of a hetero atom, which is bonded to a dihydropyridazinone nucleus via a N atom on the ring, said nitrogen-containing monocyclic aromatic heterocyclic group, A nitrogen fused ring aromatic heterocyclic group is selected from
Figure PCTCN2019078089-appb-000030
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个更优选实施方案中，R 2各自独立地选自C 1-C 6烷基、C 1-C 6 烷氧基、卤代C 1-C 6烷基、-(CH 2) qOH、-NH 2、卤素或苯基，q为0、1或2，n为0、1、2或3。 In a more preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -(CH 2 ) q OH, -NH 2 , halogen or phenyl, q is 0, 1 or 2, n is 0, 1, 2 or 3.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个更优选实施方案中，R 2各自独立地选自C 1-C 6烷基、卤代C 1-C 6烷基或-NH 2，n为0、1、2或3。 In a more preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, R 2 is each independently selected from C 1 -C 6 alkyl, halo C 1 -C 6 alkyl or -NH 2 , n is 0, 1, 2 or 3.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个更优选实施方案中，R 2各自独立地选自C 1-C 4烷基、卤代C 1-C 4烷基或-NH 2，n为0、1、2或3。 In a more preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, R 2 is each independently selected from C 1 -C 4 alkyl, halo C 1 -C 4 alkyl or -NH 2 , n is 0, 1, 2 or 3.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个实施方案中，环A为含有1、2、3、4或5个选自N、O或S的环杂原子的含氮脂杂环基或含氮芳杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连。In one embodiment of the compound of formula (I) or (II), a pharmaceutically acceptable salt or stereoisomer thereof, ring A is 1, 2, 3, 4 or 5 selected from N, O Or a nitrogen-containing aliphatic heterocyclic group or a nitrogen-containing aromatic heterocyclic group of a ring hetero atom of S, which is bonded to the dihydropyridinopyrazine ketone through a N atom on the ring.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个优选实施方案中，环A为含有1～4个选自N、O或S的环杂原子的含氮脂杂环基或含氮芳杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连。In a preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, the ring A is a ring heterocyclic ring containing from 1 to 4 selected from N, O or S. The nitrogen-containing aliphatic heterocyclic group or the nitrogen-containing aromatic heterocyclic group of the atom is bonded to the dihydropyridinopyridinone mother nucleus via a N atom on the ring.
在本发明式(I)或(II)化合物、其药学上可接受的盐或立体异构体的一个优选实施方案中，环A为含有1、2、3或4个选自N、O或S的环杂原子的含氮脂杂环基或含氮芳杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连。In a preferred embodiment of the compound of the formula (I) or (II), a pharmaceutically acceptable salt or a stereoisomer thereof, the ring A is contained in 1, 2, 3 or 4 selected from N, O or The nitrogen-containing aliphatic heterocyclic group or the nitrogen-containing aromatic heterocyclic group of the ring hetero atom of S is bonded to the dihydropyridinopyridinone mother nucleus via a N atom on the ring.
在本发明中，具体优选的通式(I)或(II)化合物、其药学上可接受的盐或立体异构体，包括如下：In the present invention, particularly preferred compounds of the formula (I) or (II), pharmaceutically acceptable salts or stereoisomers thereof, include the following:
5-氟-8-(4-氟苯基)-9-(1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyrido[4,3,2 -de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(5-三氟甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-trifluoromethyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(3，5-二甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(2-甲基-1H-咪唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2-methyl-1H-imidazol-1-yl)-8,9-dihydro-2H-pyrido[4,3,2-de Pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(3-三氟甲基-5，6-二氢-[1，2，4]三唑[4，3-a]吡嗪-7(8H)-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(3-trifluoromethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine- 7(8H)-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(1H-吲唑基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1H-carbazolyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3 (7H )-ketone;
5-氟-8-(4-氟苯基)-9-(吡咯烷-2，5-二酮-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(pyrrolidine-2,5-dione-1-yl)-8,9-dihydro-2H-pyrido[4,3,2- De]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(4，7-环氧六氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(4,7-epoxyhexahydroisoindol-1,3(2H)-dione-2-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(4，7-环氧-3a，4，7，7a-四氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(4,7-epoxy-3a,4,7,7a-tetrahydroisoindole-1,3(2H)-dione-2- ,8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(4，7-环氧-5-羟基六氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(4,7-epoxy-5-hydroxyhexahydroisoindole-1,3(2H)-dione-2-yl)-8, 9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(异吲哚-1，3-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(isoindole-1,3-dione-2-yl)-8,9-dihydro-2H-pyrido[4,3,2 -de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de Pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(1-甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(1-异丙基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-isopropyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4 , 3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(1-(2-羟乙基)-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-(2-hydroxyethyl)-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(1-环丙基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-cyclopropyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4 , 3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(1-环戊基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-cyclopentyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4 , 3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(1，5，5-三甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1,5,5-trimethyl-2,4-imidazolidin-2-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(1-异丙基-5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-isopropyl-5,5-dimethyl-2,4-imidazolidin-2-yl)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(5-甲基-5-苯基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-5-phenyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-((7aS)-四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-((7aS)-tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione-2-yl -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-((S)-7a-甲基四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-((S)-7a-methyltetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione -2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-((6R，7aS)-6-羟基四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-((6R,7aS)-6-hydroxytetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-di Keto-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(1，3-二氮杂螺[3.4]辛烷-6，8-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[3.4]octane-6,8-dione-3-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(1，3-二氮杂螺[4.4]壬烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[4.4]nonane-2,4-dione-3-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(1，3-二氮杂螺[4.5]癸烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[4.5]decane-2,4-dione-3-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(2-氧-5，7-二氮杂螺[3.4]辛烷-6，8-二酮-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2-oxo-5,7-diazaspiro[3.4]octane-6,8-dione-7-yl)-8,9 - dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(2，5，7-三氮杂螺[3.4]辛烷-6，8-二酮-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2,5,7-triazaspiro[3.4]octane-6,8-dione-7-yl)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(2，4-噻唑烷二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2,4-thiazolidinedione-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de Pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-噻唑烷二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-thiazolidinedione-3-yl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(噁唑烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(oxazolidine-2,4-dione-3-yl)-8,9-dihydro-2H-pyrido[4,3,2 -de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(5，5-二甲基噁唑烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyloxazolidine-2,4-dione-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(2H-苯并[e][1，3]噁嗪-2，4(3H)-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2H-benzo[e][1,3]oxazine-2,4(3H)-dione-3-yl)-8,9 - dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(苯并[d]异噻唑-3(2H)-酮-1，1-二氧化物-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(benzo[d]isothiazole-3(2H)-one-1,1-dioxide-2-yl)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(5-甲基-3-氨基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-3-amino-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(5-异丙基-1H-1，2，4-三唑-1-基)-8，9-二氢 -2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-isopropyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(5-甲基-1H-吡唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-pyrazol-1-yl)-8,9-dihydro-2H-pyrido[4,3,2- De]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(5-甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyrido[ 4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(2，4-二氟苯基)-9-(5-甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(2,4-difluorophenyl)-9-(5-methyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(1-甲基-2，4，5-咪唑啉三酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4,5-imidazolin-3-one-3-yl)-8,9-dihydro-2H-pyrido[ 4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(1-环丁基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-cyclobutyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4 , 3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(1-(氮杂环丁-3-基)-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-(azetidin-3-yl)-2,4-imidazolinedion-3-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(1-(哌啶-4-基)-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-(piperidin-4-yl)-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(3-甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(3-methyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H-pyrido[4,3, 2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(4，4-二甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(4,4-dimethyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(8-氧代-6-硫代-5，7-二氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(8-oxo-6-thio-5,7-diazaspiro[3.4]octane-7-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-((S)-1-氧代-3-硫代四氢-1H-吡咯并[1，2-c]咪唑-2(3H)-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-((S)-1-oxo-3-thiotetrahydro-1H-pyrrolo[1,2-c]imidazole-2(3H) -yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(3-环丙基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(3-cyclopropyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(7-氧代-5-硫代-4，6-二氮杂螺[2.4]庚烷-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(7-oxo-5-thio-4,6-diazaspiro[2.4]heptane-6-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(3，4，4-三甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(3,4,4-trimethyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(5-甲基-8-氧代-6-硫代-5，7-二氮杂螺[3.4] 辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-8-oxo-6-thio-5,7-diazaspiro[3.4]octane-7-yl) -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(4-氧代-2-硫代-1，3-二氮杂螺[4.4]壬烷-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(4-oxo-2-thio-1,3-diazaspiro[4.4]decane-3-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(4，7-亚甲基-3a，4，7，7a-四氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(4,7-methylene-3a,4,7,7a-tetrahydroisoindole-1,3(2H)-dione-2 -yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(2-甲基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2-methyl-4-oxo-1,3-diazaspiro-[4.4]non-1-en-3-yl)- 8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(2-丁基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2-butyl-4-oxo-1,3-diazaspiro-[4.4]non-1-en-3-yl)- 8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(6-甲基-8-氧代-5，7-二氮杂螺-[3.4]辛-5-烯-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(6-methyl-8-oxo-5,7-diazaspiro-[3.4]oct-5-ene-7-yl)- 8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(5-甲基-7-氧代-4，6-二氮杂螺-[2.4]庚-4-烯-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-7-oxo-4,6-diazaspiro-[2.4]hept-4-ene-6-yl)- 8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(2，4，4-三甲基-5-氧代-4，5-二氢-1H-咪唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2,4,4-trimethyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-8, 9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
5-氟-8-(4-氟苯基)-9-(2-甲基-5-氧代-4，5-二氢-1H-咪唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8R，9R)-5-氟-8-(4-氟苯基)-9-(1-甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8S，9S)-5-氟-8-(4-氟苯基)-9-(1-甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8R，9R)-5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-imidazolidin-2-one)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8S，9S)-5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-imidazolidin-2-one)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8R，9R)-5-氟-8-(4-氟苯基)-9-(5-甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8S，9S)-5-氟-8-(4-氟苯基)-9-(5-甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8R，9R)-5-氟-8-(4-氟苯基)-9-(5-甲基-8-氧代-6-硫代-5，7-二氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-8-oxo-6-thio-5,7-diazaspiro[3.4]xin Alkan-7-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8S，9S)-5-氟-8-(4-氟苯基)-9-(5-甲基-8-氧代-6-硫代-5，7-二 氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-8-oxo-6-thio-5,7-diazaspiro[3.4]xin Alkan-7-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8R，9R)-5-氟-8-(4-氟苯基)-9-(2-甲基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(2-methyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene 3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8S，9S)-5-氟-8-(4-氟苯基)-9-(2-甲基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(2-methyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene 3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8R，9R)-5-氟-8-(4-氟苯基)-9-(2-丁基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(2-butyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene 3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8S，9S)-5-氟-8-(4-氟苯基)-9-(2-丁基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(2-butyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene 3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8R，9R)-5-氟-8-(4-氟苯基)-9-(6-甲基-8-氧代-5，7-二氮杂螺-[3.4]辛-5-烯-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(6-methyl-8-oxo-5,7-diazaspiro-[3.4]oct-5-ene -7-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8S，9S)-5-氟-8-(4-氟苯基)-9-(6-甲基-8-氧代-5，7-二氮杂螺-[3.4]辛-5-烯-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(6-methyl-8-oxo-5,7-diazaspiro-[3.4]oct-5-ene -7-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8R，9R)-5-氟-8-(4-氟苯基)-9-(5-甲基-7-氧代-4，6-二氮杂螺-[2.4]庚-4-烯-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-7-oxo-4,6-diazaspiro-[2.4]hept-4-ene -6-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
(8S，9S)-5-氟-8-(4-氟苯基)-9-(5-甲基-7-氧代-4，6-二氮杂螺-[2.4]庚-4-烯-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮。(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-7-oxo-4,6-diazaspiro-[2.4]hept-4-ene -6-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one.
本发明还提供制备通式(II)化合物的方法，它包括以下步骤：The invention also provides a process for the preparation of a compound of formula (II) which comprises the steps of:
Figure PCTCN2019078089-appb-000031
Figure PCTCN2019078089-appb-000031
其中，环A、环B、R 1、R 2、R 3、m、n与上述通式(II)中的含义相同。 Here, the ring A, the ring B, R 1 , R 2 , R 3 , m, and n have the same meanings as in the above formula (II).
原料(a)经酯化反应得到化合物(b)；化合物(b)与三丁基(1-乙氧基乙烯基)锡在催化剂作用下反应得到化合物(c)；化合物(c)经还原水解得到化合物(d)；化合物(d)与化合物(e)经缩合反应得到化合物(f)；化合物(f)经关环反应得到化合物(g)；化合物(g)经Boc保护得到化合物(h)；在碱存在下化合物(h)与三氟甲磺酸叔丁基二甲硅烷酯反应得到化合物(i)；化合物(i)被氧化得到化合物(j)；化合物(j)与水合肼经成环反应得到化合物(k)；化合物(k)脱保护得到化合物(l)；化合物(l)经氯化反应得到中间体1；中间体1与
Figure PCTCN2019078089-appb-000032
进行取代反应得到化合物(m)；化合物(m)脱除Boc保护基得到式(II)化合物。 The raw material (a) is esterified to obtain the compound (b); the compound (b) is reacted with tributyl (1-ethoxyvinyl) tin under the action of a catalyst to obtain a compound (c); and the compound (c) is subjected to reduction hydrolysis The compound (d) is obtained; the compound (d) is reacted with the compound (e) to obtain a compound (f); the compound (f) is subjected to a ring closure reaction to obtain a compound (g); and the compound (g) is protected by Boc to obtain a compound (h). Compound (h) is reacted with tert-butyldimethylsilane trifluoromethanesulfonate in the presence of a base to obtain compound (i); compound (i) is oxidized to give compound (j); compound (j) is hydrated with hydrazine The ring reaction gives the compound (k); the compound (k) is deprotected to obtain the compound (1); the compound (1) is chlorinated to obtain the intermediate 1; the intermediate 1 and
Figure PCTCN2019078089-appb-000032
Substitution reaction is carried out to give compound (m); compound (m) is removed from the Boc protecting group to give a compound of formula (II).
在本发明上述通式(II)化合物的制备方法中，化合物(b)反应 得到化合物(c)是在催化剂的存在下进行，所述催化剂包括但不限于[1，1′-双(二苯基膦基)二茂铁]二氯化钯、四(三苯基膦)钯等；还原水解化合物(c)得到化合物(d)步骤中使用的还原剂包括铁粉；化合物(d)与化合物(e)的缩合反应是在酸存在下进行，所述酸包括但不限于L-脯氨酸、乙酸等；化合物(f)的关环反应是在碱存在下进行，所述碱包括但不限于碳酸钠、碳酸钾、碳酸铯、乙醇钠、甲醇钠、叔丁醇钾等；在碱存在下化合物(h)反应得到化合物(i)，其中所述碱包括但不限于六甲基二硅基氨基锂、钠氢、二异丙基氨基锂等；氧化化合物(i)的氧化剂包括但不限于间氯过氧苯甲酸；化合物(k)的脱保护反应是在四丁基氟化铵的存在下进行；化合物(l)的氯化反应中所用的氯化试剂包括但不限于甲磺酰氯、氯化亚砜等；中间体1与
Figure PCTCN2019078089-appb-000033
的取代反应是在碱存在下进行，所述碱包括但不限于碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾等；上述Boc保护反应和脱Boc保护反应，都是在常规条件下进行。 In the process for producing the compound of the above formula (II) of the present invention, the compound (b) is reacted to obtain the compound (c) which is carried out in the presence of a catalyst including, but not limited to, [1,1'-bis(diphenyl) a phosphinyl)ferrocene]palladium dichloride, tetrakis(triphenylphosphine)palladium or the like; a reduction hydrolyzed compound (c) to obtain a reducing agent used in the step of the compound (d), including iron powder; a compound (d) and a compound The condensation reaction of (e) is carried out in the presence of an acid including, but not limited to, L-valine, acetic acid, etc.; the ring closure reaction of the compound (f) is carried out in the presence of a base including but not Limited to sodium carbonate, potassium carbonate, cesium carbonate, sodium ethoxide, sodium methoxide, potassium t-butoxide, etc.; compound (h) is reacted in the presence of a base to give compound (i), including but not limited to hexamethyldisiloxane Lithium amide, sodium hydrogen, lithium diisopropylamide, etc.; the oxidizing agent for oxidizing compound (i) includes, but is not limited to, m-chloroperoxybenzoic acid; the deprotection reaction of compound (k) is in tetrabutylammonium fluoride In the presence of; the chlorinating reagent used in the chlorination of the compound (1) includes, but is not limited to, methanesulfonyl chloride, chlorination Sulfone; and Intermediate 1
Figure PCTCN2019078089-appb-000033
The substitution reaction is carried out in the presence of a base including, but not limited to, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, and the like; the above Boc protection reaction and de Boc protection reaction are carried out under ordinary conditions.
本发明还提供另一种制备通式(II)化合物的方法，它包括以下步骤：The invention also provides another process for the preparation of a compound of formula (II) which comprises the steps of:
Figure PCTCN2019078089-appb-000034
Figure PCTCN2019078089-appb-000034
其中，环A、环B、R 1、R 2、R 3、m、n与上述通式(II)中的含义相同。 Here, the ring A, the ring B, R 1 , R 2 , R 3 , m, and n have the same meanings as in the above formula (II).
中间体1与水合肼进行取代反应得到化合物(s)；化合物(s)经 成环反应得到化合物(m)；化合物(m)脱Boc保护基得到式(II)化合物。The intermediate 1 is subjected to a substitution reaction with hydrazine hydrate to obtain a compound (s); the compound (s) is subjected to a ring-forming reaction to obtain a compound (m); and the compound (m) is decarboxylated to give a compound of the formula (II).
在本发明上述通式(II)化合物的制备方法中，化合物(s)与相应的反应原料经常规方法成环反应得到化合物(m)；化合物(m)脱Boc保护基是在常规条件下进行。In the preparation method of the above compound of the above formula (II), the compound (s) is reacted with a corresponding reaction raw material by a conventional method to obtain a compound (m); the compound (m) is deprotected by a Boc protecting group under normal conditions. .
本发明还提供另一种制备通式(II)化合物的方法，它包括以下步骤：The invention also provides another process for the preparation of a compound of formula (II) which comprises the steps of:
Figure PCTCN2019078089-appb-000035
Figure PCTCN2019078089-appb-000035
其中，环A、环B、R 1、R 2、R 3、m、n与上述通式(II)中的含义相同。 Here, the ring A, the ring B, R 1 , R 2 , R 3 , m, and n have the same meanings as in the above formula (II).
中间体1与叠氮化钠经取代反应得到化合物(n)；化合物(n)在催化剂作用下经氢化还原得到化合物(o)；化合物(o)在碱存在下与硫光气反应得到化合物(p)；化合物(p)经成环反应得到化合物(m)；化合物(m)脱Boc保护基得到式(II)化合物。Intermediate 1 is substituted with sodium azide to obtain compound (n); compound (n) is hydrogenated under the action of a catalyst to obtain compound (o); compound (o) is reacted with thiophosgene in the presence of a base to obtain a compound ( p); compound (p) is subjected to ring formation to give compound (m); compound (m) is decarboxylated to give compound of formula (II).
在本发明上述通式(II)化合物的制备方法中，催化氢化还原化合物(n)所用的催化剂包括但不限于钯碳、二氧化铂；化合物(o)在碱存在下与硫光气反应得到化合物(p)的步骤中所用的碱包括但不限于三乙胺、二异丙基乙胺等；化合物(p)与相应的反应原料经常规方法成环反应得到化合物(m)；化合物(m)脱Boc保护是在常规条件下进行。In the preparation method of the above compound of the general formula (II) of the present invention, the catalyst used for the catalytic hydrogenation reduction compound (n) includes, but is not limited to, palladium carbon and platinum dioxide; and the compound (o) is reacted with sulfur phosgene in the presence of a base. The base used in the step of the compound (p) includes, but is not limited to, triethylamine, diisopropylethylamine and the like; the compound (p) is cyclically reacted with the corresponding reaction raw material by a usual method to obtain a compound (m); The de Boc protection is carried out under normal conditions.
本发明还提供了如下式结构的中间体1化合物，The present invention also provides an intermediate 1 compound of the formula:
Figure PCTCN2019078089-appb-000036
Figure PCTCN2019078089-appb-000036
其中，R 1为卤素，环B为苯基，R 3为卤素，m为1或2。 Wherein R 1 is halogen, ring B is phenyl, R 3 is halogen, and m is 1 or 2.
在本发明中，所用试剂的缩写分别表示：In the present invention, the abbreviations of the reagents used are respectively indicated:
-BOC                叔丁氧羰基-BOC tert-butoxycarbonyl
-TBS                叔丁基二甲基硅基-TBS tert-butyldimethylsilyl
Tris-HCl            三(羟甲基)氨基甲烷-盐酸Tris-HCl Tris(hydroxymethyl)aminomethane-hydrochloric acid
DMSO                二甲基亚砜DMSO dimethyl sulfoxide
在本发明中，“卤素”是指氟、氯、溴、碘等，优选氟、氯、溴，更优选氟。In the present invention, "halogen" means fluorine, chlorine, bromine, iodine or the like, preferably fluorine, chlorine or bromine, more preferably fluorine.
在本发明中，“C 1-C 6烷基”是指含有1～6个碳原子的直链或支链烃，包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、3-甲基戊基、2，2-二甲基丁基、2，3-二甲基丁基；优选“C 1-C 4烷基”，包括但不限于甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基和叔丁基；更优选甲基、乙基、丙基、异丙基和丁基。 In the present invention, "C 1 -C 6 alkyl" means a straight or branched hydrocarbon having 1 to 6 carbon atoms, including but not limited to methyl, ethyl, propyl, isopropyl, butyl. , isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylpentyl, 2,2-dimethylbutyl, 2,3-di Methyl butyl; preferably "C 1 -C 4 alkyl", including but not limited to methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl; more preferably Methyl, ethyl, propyl, isopropyl and butyl.
在本发明中，“C 1-C 6烷氧基”是指具有1至6个碳原子的烷氧基，包括但不限于，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基、叔丁氧基、戊氧基、己氧基等；优选“C 1-C 4烷氧基”，C 1-C 4烷氧基是指具有1至4个碳原子的烷氧基，包括但不限于，甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、仲丁氧基和叔丁氧基，更优选甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基。 In the present invention, "C 1 -C 6 alkoxy" means an alkoxy group having 1 to 6 carbon atoms, including but not limited to, for example, methoxy, ethoxy, propoxy, isopropoxy Base, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, etc.; preferably "C 1 -C 4 alkoxy", C 1 -C 4 alkoxy By alkoxy having 1 to 4 carbon atoms, including, but not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and Tert-butoxy group, more preferably methoxy, ethoxy, propoxy, isopropoxy and butoxy.
在本发明中，“卤代C 1-C 6烷基”是指被一个或多个卤素，优选一至五个卤原子取代的如本文定义的“C 1-C 6烷基”；优选“卤代C 1-C 4烷基”，包括但不限于三氟甲基、三氟乙基、二氟甲基、1-氯-2氟乙基等，更优选三氟甲基和三氟乙基。 In the present invention, "halogenated C 1 -C 6 alkyl" means a "C 1 -C 6 alkyl group" as defined herein substituted by one or more halogens, preferably one to five halogen atoms; preferably "halogen" C 1 -C 4 alkyl", including but not limited to trifluoromethyl, trifluoroethyl, difluoromethyl, 1-chloro-2fluoroethyl, etc., more preferably trifluoromethyl and trifluoroethyl .
在本发明中，“烯基”是指烃基团衍生出的单价基，“C 2-C 6烯基” 是指含有2至6个碳原子且至少含有一个碳-碳双键的烯基，包括但不限于，乙烯基、丙烯基、丁烯基、2-甲基-2-丁烯、2-甲基-2-戊烯及类似基团。 In the present invention, "alkenyl" means a monovalent group derived from a hydrocarbon group, and "C 2 -C 6 alkenyl" means an alkenyl group having 2 to 6 carbon atoms and having at least one carbon-carbon double bond. These include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-butene, 2-methyl-2-pentene, and the like.
在本发明中，“炔基”是指烃基团衍生出的单价基，“C 2-C 6炔基”是指含有2至6个碳原子且至少含有一个碳-碳三键的炔基，包括但不限于，乙炔基、丙炔基、1-丁炔基、2-丁炔基及类似基团。 In the present invention, "alkynyl" means a monovalent group derived from a hydrocarbon group, and "C 2 -C 6 alkynyl" means an alkynyl group having 2 to 6 carbon atoms and having at least one carbon-carbon triple bond. These include, but are not limited to, ethynyl, propynyl, 1-butynyl, 2-butynyl, and the like.
在本发明中，“氘代C 1-C 6烷基”是指被一个或多个氘原子取代的如本文定义的“C 1-C 6烷基”，包括但不限于-CD 3、-CH 2CD 3、-C 2D 5、-C 3D 7、-CD(CD 3) 2、-CH 2CH 2CD 3等，优选-CD 3。 In the present invention, "deuterated C 1 -C 6 alkyl" refers to a "C 1 -C 6 alkyl group" as defined herein substituted by one or more deuterium atoms, including but not limited to -CD 3 ,- CH 2 CD 3 , -C 2 D 5 , -C 3 D 7 , -CD(CD 3 ) 2 , -CH 2 CH 2 CD 3 or the like, preferably -CD 3 .
在本发明中，“杂原子”指除碳或氢之外的原子。“杂原子”通常独立地选自N、O、S或P，但不限于这些原子。在存在两个或更多个杂原子的实施方案中，两个或更多个杂原子彼此相同，或两个或更多个杂原子中的一些或全部彼此不相同。In the present invention, "hetero atom" means an atom other than carbon or hydrogen. "Hetero atoms" are generally independently selected from N, O, S or P, but are not limited to these atoms. In embodiments in which two or more heteroatoms are present, two or more heteroatoms are identical to each other, or some or all of the two or more heteroatoms are different from each other.
在本发明中，“环”是指任何共价闭合的结构，包括全是碳原子的环(如芳基和环烷基)和含杂原子的环(如芳杂环基和脂杂环基)，或包括单环、稠环、桥环和螺环等。In the present invention, "ring" means any covalently closed structure, including a ring of all carbon atoms (such as an aryl group and a cycloalkyl group) and a ring containing a hetero atom (such as an aromatic heterocyclic group and an aliphatic heterocyclic group). ), or include single rings, fused rings, bridge rings, and spiral rings.
在本发明中，“稠环”是指其中两环共用两直接相连的环原子形成的环基，它可以是饱和的、部分不饱和的或完全不饱和的，形成环的原子可包括一个或多个环杂原子。“稠环”包括稠环双环基和稠环多环基。在本发明一些实施方案中，稠环含有一个或多个羰基、硫代羰基或砜基，例如，含有氧或硫的基团。“稠环双环基”举例包括但不限于萘基、喹啉基、吲哚基、
Figure PCTCN2019078089-appb-000037
Figure PCTCN2019078089-appb-000038
Figure PCTCN2019078089-appb-000039
“稠环多环基”举例包括但不限于蒽基和菲基。 In the present invention, "fused ring" means a ring group in which two rings share two directly connected ring atoms, which may be saturated, partially unsaturated or fully unsaturated, and the ring-forming atoms may include one or Multiple ring heteroatoms. "Fused rings" include fused ring bicyclic groups and fused ring polycyclic groups. In some embodiments of the invention, the fused ring contains one or more carbonyl, thiocarbonyl or sulfone groups, for example, oxygen or sulfur containing groups. Examples of "fused ring bicyclic groups" include, but are not limited to, naphthyl, quinolyl, fluorenyl,
Figure PCTCN2019078089-appb-000037
Figure PCTCN2019078089-appb-000038
Figure PCTCN2019078089-appb-000039
Examples of "fused ring polycyclic groups" include, but are not limited to, anthracenyl and phenanthryl.
在本发明中，“桥环”是指其中两环共用三个或以上环原子形成的环基，它可以是饱和的或部分不饱和的，形成环的原子可包括一个或多个环杂原子。“桥环”包括桥环双环基和桥环多环基。在本发明一些实施方案中，桥环含有一个或多个羰基、硫代羰基或砜基，例如，含有氧或硫的基团。“桥环双环基”举例包括但不限于二环[2.2.1]庚烷基、二环[3.2.1]辛烷基、
Figure PCTCN2019078089-appb-000040
“桥环多环基”举例包括但不限于金刚烷基。 In the present invention, "bridged ring" means a ring group in which two rings share three or more ring atoms, which may be saturated or partially unsaturated, and the ring-forming atoms may include one or more ring hetero atoms. . "Bridge loops" include bridged bicyclic groups and bridged ring polycyclic groups. In some embodiments of the invention, the bridged ring contains one or more carbonyl, thiocarbonyl or sulfone groups, for example, oxygen or sulfur containing groups. Examples of "bridged bicyclic groups" include, but are not limited to, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl,
Figure PCTCN2019078089-appb-000040
Examples of "bridged polycyclic groups" include, but are not limited to, adamantyl.
在本发明中，“螺环”是指其中两环共用一个环原子形成的环基，它可以是饱和的或部分不饱和的，形成环的原子可包括一个或多个环杂原子。螺环中两环共用的环原子为螺原子，按螺原子数分类包括单螺环、二螺环、多螺环等。在本发明一些实施方案中，螺环含有一个或多个羰基、硫代羰基或砜基，例如，含有氧或硫的基团。“单螺环”举例包括但不限于1-甲基螺[4.5]癸烷基、
Figure PCTCN2019078089-appb-000041
Figure PCTCN2019078089-appb-000042
Figure PCTCN2019078089-appb-000043
Figure PCTCN2019078089-appb-000044
“二螺环”举例包括但不限于二螺[5.2.5.2]十六烷基；“多螺环”举例包括但不限于三螺[2.2.2.2 9.2 6.2 3]十六烷基。 In the present invention, "spirocyclic" means a cyclic group in which two rings share a ring atom, which may be saturated or partially unsaturated, and the ring-forming atom may include one or more ring heteroatoms. The ring atom shared by the two rings in the spiro ring is a spiro atom, and is classified into a single spiro ring, a two spiro ring, a multi-spiral ring, and the like according to the number of spiro atoms. In some embodiments of the invention, the spiro ring contains one or more carbonyl, thiocarbonyl or sulfone groups, for example, oxygen or sulfur containing groups. Examples of "single spiro" include, but are not limited to, 1-methylspiro[4.5]decyl,
Figure PCTCN2019078089-appb-000041
Figure PCTCN2019078089-appb-000042
Figure PCTCN2019078089-appb-000043
Figure PCTCN2019078089-appb-000044
Examples of "two spiro rings" include, but are not limited to, snail [5.2.5.2] hexadecyl; examples of "multi-spiro" include, but are not limited to, triple snail [2.2.2.2 9 .2 6 .2 3 ] hexadecyl .
在本发明中，“环原子”是指形成环的原子，包括但不限于C、N、O、P和S；“环杂原子”是指除C原子之外的环原子，包括但不限于N、O、P和S。在本发明中，所述“环上N原子”是指形成环的环原子N原子。In the present invention, "ring atom" means an atom forming a ring, including but not limited to C, N, O, P and S; "ring hetero atom" means a ring atom other than C atom, including but not limited to N, O, P and S. In the present invention, the "N atom on the ring" means a ring atom N atom forming a ring.
在本发明中，“环烷基”是指饱和或部分不饱和的脂肪族碳环基团，包括单环、双环和多环环烷基，或包括单环环烷基、稠环环烷基、桥环环烷基和螺环环烷基等。单环环烷基举例包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环丙烯基、环丁烯基、环戊烯基、环己烯基和环庚烯基；双环环烷基举例包括但不限于
Figure PCTCN2019078089-appb-000045
Figure PCTCN2019078089-appb-000046
二环[2.2.1]庚烷基、二环[3.2.1]辛烷基、
Figure PCTCN2019078089-appb-000047
1-甲基螺[4.5]癸烷基、
Figure PCTCN2019078089-appb-000048
Figure PCTCN2019078089-appb-000049
多环环烷基举例包括但不限于金刚烷基；稠环环烷基举例包括 但不限于
Figure PCTCN2019078089-appb-000050
桥环环烷基举例包括但不限于二环[2.2.1]庚烷基、二环[3.2.1]辛烷基、金刚烷基和
Figure PCTCN2019078089-appb-000051
螺环环烷基举例包括但不限于1-甲基螺[4.5]癸烷基、二螺[5.2.5.2]十六烷基、
Figure PCTCN2019078089-appb-000052
优选含有3至7个环原子的“3～7元环烷基”，所述“3～7元环烷基”包括但不限于环丙基、环丁基、环戊基、环己基、环庚基、环丙烯基、环丁烯基、环戊烯基、环己烯基和环庚烯基。 In the present invention, "cycloalkyl" means a saturated or partially unsaturated aliphatic carbocyclic group, including monocyclic, bicyclic and polycyclic cycloalkyl groups, or includes monocyclic cycloalkyl groups, fused ring cycloalkyl groups , bridged cycloalkyl and spirocycloalkyl, and the like. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexene And cycloheptenyl; bicyclic cycloalkyl examples include, but are not limited to,
Figure PCTCN2019078089-appb-000045
Figure PCTCN2019078089-appb-000046
Bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl,
Figure PCTCN2019078089-appb-000047
1-methylspiro[4.5]decyl,
Figure PCTCN2019078089-appb-000048
Figure PCTCN2019078089-appb-000049
Polycyclic cycloalkyl groups include, but are not limited to, adamantyl; fused ring cycloalkyl groups include, but are not limited to,
Figure PCTCN2019078089-appb-000050
Examples of bridged cycloalkyl groups include, but are not limited to, bicyclo [2.2.1] heptyl, bicyclo [3.2.1] octyl, adamantyl, and
Figure PCTCN2019078089-appb-000051
Examples of spirocyclic cycloalkyl groups include, but are not limited to, 1-methylspiro[4.5]decylalkyl, dispiro[5.2.5.2]hexadecyl,
Figure PCTCN2019078089-appb-000052
A "3- to 7-membered cycloalkyl group" having 3 to 7 ring atoms is preferred, and the "3- to 7-membered cycloalkyl group" includes, but is not limited to, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a ring. Heptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl.
在本发明中，“脂杂环基”是指其中形成环的一个或多个原子是杂原子的非芳香环基。“脂杂环基”包括含有一个或多个选自N、S或O的环杂原子的饱和或部分不饱和的“单环脂杂环基”，其具有3至8个环原子，优选具有4至7个环原子；含有一个或多个选自N、S或O的环杂原子的饱和或部分不饱和的“稠环脂杂环基”，其具有5至18个环原子，优选具有7至16个环原子，更优选具有7至10个环原子；含有一个或多个选自N、S或O的环杂原子的饱和或部分不饱和的带桥环的稠环脂杂环基即“桥环稠环脂杂环基”，其具有6至20个环原子，优选具有6至12个环原子，更优选具有7至10个环原子；含有一个或多个选自N、S或O的环杂原子的饱和或部分不饱和的“螺环脂杂环基”，其具有5至21个环原子，优选具有5至12个环原子，更优选具有7至11个环原子；含有一个或多个选自N、S或O的环杂原子的饱和或部分不饱和的“桥环脂杂环基”，其具有5至12个环原子，优选具有6至10个环原子；含有一个或多个选自N、S或O的环杂原子的饱和或部分不饱和的带螺环的稠环脂杂环基即“螺环稠环脂杂环基”，其具有7至22个环原子，优选具有9至18个环原子，更优选具有9至14个环原子；和含有一个或多个选自N、S或O的环杂原子的饱和或部分不饱和的带桥环的螺环脂杂环基即“桥环螺环脂杂 环基”，其具有7至22个环原子，优选具有8至16个环原子。在本发明一些实施方案中，脂杂环基、单环脂杂环基、稠环脂杂环基、桥环稠环脂杂环基、螺环脂杂环基、桥环脂杂环基、螺环稠环脂杂环基或桥环螺环脂杂环基含有一个或多个羰基、硫代羰基或砜基，例如，含有氧或硫的基团。“单环脂杂环基”举例包括但不限于四氢吡喃基、二氢吡喃基、氧杂环丁基、硫杂环丁基、哌啶基、1，3-二噁烷基、1，4-二噁烷基、哌嗪基、1，3-氧硫杂环己烷基、1，4-氧硫杂环己二烯基、1，4-氧硫杂环己烷基、马来酰亚胺基、硫代巴比妥酸基、二氧代哌嗪基、二氢尿嘧啶基、三噁烷基、六氢-1，3，5-三嗪基、四氢噻吩基、四氢呋喃基、二氢呋喃基、吡咯啉酮基、吡唑啉基、咪唑啉基、1，3-二氧杂环戊烯基、1，3-二氧戊烷基、1，3-二硫杂环戊烯基、噁唑啉基、噻唑啉基、1，3-氧硫杂环戊烷基、
Figure PCTCN2019078089-appb-000053
Figure PCTCN2019078089-appb-000054
Figure PCTCN2019078089-appb-000055
“稠环脂杂环基”举例包括但不限于
Figure PCTCN2019078089-appb-000056
Figure PCTCN2019078089-appb-000057
Figure PCTCN2019078089-appb-000058
“桥 环稠环脂杂环基”举例包括但不限于
Figure PCTCN2019078089-appb-000059
Figure PCTCN2019078089-appb-000060
“螺环脂杂环基”举例包括但不限于
Figure PCTCN2019078089-appb-000061
Figure PCTCN2019078089-appb-000062
Figure PCTCN2019078089-appb-000063
“桥环脂杂环基”举例包括但不限于
Figure PCTCN2019078089-appb-000064
Figure PCTCN2019078089-appb-000065
“螺环稠环脂杂环基”举例包括但不限于
Figure PCTCN2019078089-appb-000066
“桥环螺环脂杂环基”举例包括但不限于
Figure PCTCN2019078089-appb-000067
In the present invention, "aliphatic heterocyclic group" means a non-aromatic cyclic group in which one or more atoms forming a ring are hetero atoms. "Aroheterocyclyl" includes saturated or partially unsaturated "monocyclic heteroheterocyclyl" containing one or more ring heteroatoms selected from N, S or O, having from 3 to 8 ring atoms, preferably having 4 to 7 ring atoms; a saturated or partially unsaturated "fused ring heterocyclic group" containing one or more ring heteroatoms selected from N, S or O, having 5 to 18 ring atoms, preferably having 7 to 16 ring atoms, more preferably 7 to 10 ring atoms; a saturated or partially unsaturated bridged ring fused ring heterocyclic group containing one or more ring heteroatoms selected from N, S or O Namely, "bridged fused ring aliphatic heterocyclic group" having 6 to 20 ring atoms, preferably having 6 to 12 ring atoms, more preferably having 7 to 10 ring atoms; containing one or more selected from N, S Or a saturated or partially unsaturated "spirocyclic heteroheterocyclyl" of a ring hetero atom of O having from 5 to 21 ring atoms, preferably from 5 to 12 ring atoms, more preferably from 7 to 11 ring atoms; a saturated or partially unsaturated "bridged heteroalicyclic" group containing one or more ring heteroatoms selected from N, S or O having from 5 to 12 ring atoms, preferably 6 to 10 ring atoms; a saturated or partially unsaturated fused ring heteroalicyclic group containing one or more ring heteroatoms selected from N, S or O, ie, a "spirocyclic fused ring heterocyclic ring" a group having 7 to 22 ring atoms, preferably having 9 to 18 ring atoms, more preferably having 9 to 14 ring atoms; and saturation of one or more ring hetero atoms selected from N, S or O Or a partially unsaturated, spirocyclic heterocyclic group having a bridged ring, that is, a "bridged ring spiroaliphatic heterocyclic group" having 7 to 22 ring atoms, preferably having 8 to 16 ring atoms. In some embodiments of the invention, an aliphatic heterocyclic group, a monocyclic aliphatic heterocyclic group, a fused ring heterocyclic group, a bridged fused ring heterocyclic group, a spiroaliphatic heterocyclic group, a bridged aliphatic heterocyclic group, The spiro fused ring alicyclic or bridged ring spiroaliphatic heterocyclic group contains one or more carbonyl, thiocarbonyl or sulfone groups, for example, oxygen or sulfur containing groups. Examples of "monocyclic heterocyclic heterocyclic groups" include, but are not limited to, tetrahydropyranyl, dihydropyranyl, oxetanyl, thioheterobutyl, piperidinyl, 1,3-dioxyl, 1,4-dioxanyl, piperazinyl, 1,3-oxathiolanyl, 1,4-oxethiohexadienyl, 1,4-oxathiane, Maleimide, thiobarbituric acid, dioxopiperazinyl, dihydrouracil, trioxo, hexahydro-1,3,5-triazinyl, tetrahydrothiophenyl , tetrahydrofuranyl, dihydrofuranyl, pyrrolinone, pyrazolinyl, imidazolinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-di Thiolopenyl, oxazolinyl, thiazolinyl, 1,3-oxathiolanyl,
Figure PCTCN2019078089-appb-000053
Figure PCTCN2019078089-appb-000054
Figure PCTCN2019078089-appb-000055
Examples of "fused ring heterocyclic heterocyclic groups" include but are not limited to
Figure PCTCN2019078089-appb-000056
Figure PCTCN2019078089-appb-000057
Figure PCTCN2019078089-appb-000058
Examples of "bridged ring fused ring heterocyclic groups" include, but are not limited to,
Figure PCTCN2019078089-appb-000059
Figure PCTCN2019078089-appb-000060
Examples of "spirocyclic heterocyclic groups" include, but are not limited to,
Figure PCTCN2019078089-appb-000061
Figure PCTCN2019078089-appb-000062
Figure PCTCN2019078089-appb-000063
Examples of "bridged aliphatic heterocyclic groups" include, but are not limited to,
Figure PCTCN2019078089-appb-000064
Figure PCTCN2019078089-appb-000065
Examples of "spirocyclic fused ring heterocyclic groups" include, but are not limited to,
Figure PCTCN2019078089-appb-000066
Examples of "bridged ring spiroaliphatic heterocyclic groups" include but are not limited to
Figure PCTCN2019078089-appb-000067
在本发明中，“含氮脂杂环基”是指至少一个环原子为N原子的上述“脂杂环基”，含有1～5个(即含有1、2、3、4、5个，优选含有1、2、3、4个)选自N、O或S的环杂原子，通过环上N原子与二氢吡啶并酞嗪酮母核相连，包括含氮单环脂杂环基、含氮稠环脂杂环基、含氮桥环稠环脂杂环基、含氮螺环脂杂环基、含氮桥环脂杂环基、含氮螺环稠环脂杂环基和含氮桥环螺环脂杂环基。在本发明一些实施方案中，含氮脂杂环基、含氮单环脂杂环基、含氮稠环脂杂环基、含氮桥环稠环脂杂环基、含氮螺环脂杂环基、含氮桥环脂杂环基、含氮螺环稠环脂杂环基或含氮桥环螺环脂杂环基含有一个或多个羰基、硫代羰基或砜基，例如，含有氧或硫的基团。所述“含氮单环脂杂环基”是指至少一个环原子为N原子的上述“单环脂杂环基”，含有1～5个(即含有1、2、3、4、5个，优选含有1、2、3个)选自N、O或S的环杂原子，通过环上N原子与二氢吡啶并酞嗪酮母核相连，具有3至8个环原子，优选具有4至7个环原子，具体举例包括但不限于哌啶基、咪唑啉基、
Figure PCTCN2019078089-appb-000068
Figure PCTCN2019078089-appb-000069
Figure PCTCN2019078089-appb-000070
“含氮稠环脂杂环基”是指至少一个环原子为N原子的上述“稠环脂杂环基”，含有1～5个(即含有1、2、3、4、5个，优选含有1、2、3、4个)选自N、O或S的环杂原子，通过环上N原子与二氢吡啶并酞嗪酮母核相连，具有5至18个环原子，优选具有7至10个环原子，具体举例包括但不限于
Figure PCTCN2019078089-appb-000071
Figure PCTCN2019078089-appb-000072
Figure PCTCN2019078089-appb-000073
“含氮桥环稠环脂杂环基”是指至少一个环原子为N原子的上述“桥环稠环脂杂环基”，含有1～5个(即含有1、2、3、4、5个，优选含有1、2、3个)选自N、O或S的环杂原子，通过环上N原子与二氢吡啶并酞嗪酮母核相连，具有6至20个环原子，优选具有7至10个环原子，具体举例包括但不限于
Figure PCTCN2019078089-appb-000074
Figure PCTCN2019078089-appb-000075
“含氮螺环脂杂环基”是指至少一个环原子为N原子的上述“螺环脂杂环基”，含有1～5个(即含有1、2、3、4、5个，优选含有1、2、3个)选自N、O或S的环杂原子，通过环上N原子与二氢吡啶并酞嗪酮母核相连，具有5至21个环原子，优选具有7至11个环原子，具体举例包括但不限于 In the present invention, the "nitrogen-containing heterocyclic group" means at least one of the above-mentioned "aliphatic heterocyclic groups" having a ring atom of N atoms, and contains 1 to 5 (i.e., contains 1, 2, 3, 4, 5, Preferably, the ring hetero atom selected from 1, 2, 3, 4) selected from N, O or S is bonded to the dihydropyridazinone nucleus via a N atom on the ring, including a nitrogen-containing monocyclic heterocyclic group, Nitrogen-containing fused ring heterocyclic group, nitrogen-containing bridged ring fused ring heterocyclic group, nitrogen-containing spirocyclic heterocyclic group, nitrogen-containing bridged ring heterocyclic group, nitrogen-containing spiro ring fused ring heterocyclic group and A nitrogen bridged ring spirocyclic heterocyclic group. In some embodiments of the invention, the nitrogen-containing aliphatic heterocyclic group, the nitrogen-containing monocyclic aliphatic heterocyclic group, the nitrogen-containing fused ring heterocyclic group, the nitrogen-containing bridged ring fused ring heterocyclic group, the nitrogen-containing spiroaliphatic group a cyclic group, a nitrogen-containing bridged ring heterocyclic group, a nitrogen-containing spirocyclic fused ring heterocyclic group or a nitrogen-containing bridged ring heterocyclic heterocyclic group containing one or more carbonyl, thiocarbonyl or sulfone groups, for example, containing Oxygen or sulfur group. The "nitrogen-containing monocyclic heterocyclic group" means the above-mentioned "monocyclic heterocyclic group" having at least one ring atom of N atom, and contains 1 to 5 (i.e., contains 1, 2, 3, 4, 5) , preferably containing 1, 2, 3) ring heteroatoms selected from N, O or S, attached to the dihydropyridazinone nucleus via a ring N atom, having 3 to 8 ring atoms, preferably having 4 Up to 7 ring atoms, specific examples include, but are not limited to, piperidinyl, imidazolinyl,
Figure PCTCN2019078089-appb-000068
Figure PCTCN2019078089-appb-000069
Figure PCTCN2019078089-appb-000070
The "nitrogen-containing fused ring heterocyclic group" means the above-mentioned "fused ring heterocyclic group" in which at least one ring atom is an N atom, and contains 1 to 5 (i.e., contains 1, 2, 3, 4, 5, preferably a ring hetero atom containing 1, 2, 3 or 4) selected from N, O or S, bonded to the dihydropyridazinone nucleus via a ring N atom, having 5 to 18 ring atoms, preferably having 7 Up to 10 ring atoms, specific examples include but are not limited to
Figure PCTCN2019078089-appb-000071
Figure PCTCN2019078089-appb-000072
Figure PCTCN2019078089-appb-000073
The "nitrogen-containing bridged ring fused ring heterocyclic group" means the above-mentioned "bridged ring fused ring heterocyclic group" having at least one ring atom of N atom, and contains 1 to 5 (ie, contains 1, 2, 3, 4, 5, preferably containing 1, 2, 3) ring heteroatoms selected from N, O or S, attached to the dihydropyridazinone nucleus via a ring N atom, having 6 to 20 ring atoms, preferably There are 7 to 10 ring atoms, and specific examples include, but are not limited to,
Figure PCTCN2019078089-appb-000074
Figure PCTCN2019078089-appb-000075
The "nitrogen-containing spiroalicyclic heterocyclic group" means at least one of the above-mentioned "spirocyclic heterocyclic group" having a ring atom of N atom, and contains 1 to 5 (i.e., contains 1, 2, 3, 4, 5, preferably a ring hetero atom containing 1, 2, 3) selected from N, O or S, bonded to the dihydropyridazinone nucleus via a N atom on the ring, having 5 to 21 ring atoms, preferably having 7 to 11 Ring atoms, specific examples include but are not limited to
Figure PCTCN2019078089-appb-000076
Figure PCTCN2019078089-appb-000077
Figure PCTCN2019078089-appb-000078
“含氮桥环脂杂环基”是指至少一个环原子为N原子的上述“桥环脂杂环基”，含有1～5个(即含有1、2、3、4、5个，优选含有1、2、3个)选自N、O或S的环杂原子，通过环上N原子与二氢吡啶并酞嗪酮母核相连，具有5至12个环原子，优选具有6至10个环原子，具体举例包括但不限于
Figure PCTCN2019078089-appb-000079
“含氮螺环稠环脂杂环基”是指至少一个环原子为N原子的上述“螺环稠环脂杂环基”，含有1～5个(即含有1、2、3、4、5个，优选含有1、2、3、4个)选自N、O或S的环杂原子，通过环上N原子与二氢吡啶并酞嗪酮母核相连，具有7至22个环原子，优选具有9至14个环原子，具体举例包括但不限于
Figure PCTCN2019078089-appb-000080
“含氮桥环螺环脂杂环基”是指至少一个环原子为N原子的上述“桥环螺环脂杂环基”，含有1～5个(即含有1、2、3、4、5个，优选含有1、2、3个)选自N、O或S的环杂原子，通过环上N原子与二氢吡啶并酞嗪酮母核相连，具有7至22个环原子，优选具有8至16个环原子，具体举例包括但不限于
Figure PCTCN2019078089-appb-000081
Figure PCTCN2019078089-appb-000076
Figure PCTCN2019078089-appb-000077
Figure PCTCN2019078089-appb-000078
The "nitrogen-containing bridged ring heterocyclic group" means at least one of the above-mentioned "bridged aliphatic heterocyclic groups" having a ring atom of N atoms, and contains 1 to 5 (i.e., contains 1, 2, 3, 4, 5, preferably a ring hetero atom containing 1, 2, 3) selected from N, O or S, bonded to the dihydropyridazinone nucleus via a N atom on the ring, having 5 to 12 ring atoms, preferably having 6 to 10 Ring atoms, specific examples include but are not limited to
Figure PCTCN2019078089-appb-000079
The "nitrogen-containing spirocyclic fused ring heterocyclic group" means at least one of the above-mentioned "spirocyclic fused ring heterocyclic group" having a ring atom of N atom, and contains 1 to 5 (ie, contains 1, 2, 3, 4, 5, preferably containing 1, 2, 3, 4) ring heteroatoms selected from N, O or S, attached to the dihydropyridazinone nucleus via a ring N atom, having 7 to 22 ring atoms , preferably having 9 to 14 ring atoms, specific examples include but are not limited to
Figure PCTCN2019078089-appb-000080
"Nitrogen-containing bridged-ring spiroaliphatic heterocyclic group" means at least one of the above-mentioned "bridged-ring spiroaliphatic heterocyclic groups" having a ring atom of N atoms, and contains 1 to 5 (ie, contains 1, 2, 3, 4, 5, preferably containing 1, 2, 3) ring heteroatoms selected from N, O or S, bonded to the dihydropyridazinone nucleus via a ring N atom, having 7 to 22 ring atoms, preferably There are 8 to 16 ring atoms, and specific examples include, but are not limited to,
Figure PCTCN2019078089-appb-000081
在本发明中，“芳基”是指芳香族环烃基，具有一或多个芳香环，包括单环芳基和稠环芳基，具体的“单环芳基”包括苯基，“稠环芳基”包括但不限于萘基、蒽基、菲基，优选环碳原子数为6至14个，更优选为6至10个的芳基，如苯基和萘基，更优选苯基。In the present invention, "aryl" means an aromatic cyclic hydrocarbon group having one or more aromatic rings including a monocyclic aryl group and a fused ring aryl group, and a specific "monocyclic aryl group" includes a phenyl group, "fused ring" The aryl group includes, but is not limited to, a naphthyl group, an anthracenyl group, a phenanthryl group, preferably an aryl group having 6 to 14 ring carbon atoms, more preferably 6 to 10 carbon atoms such as a phenyl group and a naphthyl group, and more preferably a phenyl group.
在本发明中，“芳杂环基”是指含有一个或多个选自N、S或O 的环杂原子的芳香性环基，包括单环芳杂环基和单环芳杂环基与单环芳杂环基、单环芳杂环基与芳基稠合而成的稠环芳杂环基，单环芳杂环基具有5至6个环原子，稠环芳杂环基具有8至14个环原子。所述“单环芳杂环基”具体包括但不限于呋喃基、噻吩基、噻唑基、异噻唑基、噁唑基、异噁唑基、四唑基、噻二唑基、吡啶基、嘧啶基、哒嗪基、吡嗪基、
Figure PCTCN2019078089-appb-000082
优选吡啶基、嘧啶基、吡嗪基、
Figure PCTCN2019078089-appb-000083
Figure PCTCN2019078089-appb-000084
所述“稠环芳杂环基”具体包括但不限于苯并呋喃基、苯并噻吩基、苯并噻二唑基、苯并噻唑基、异吲哚基、喹啉基、异喹啉基、喹唑啉基、吲哚啉-2-酮基、
Figure PCTCN2019078089-appb-000085
Figure PCTCN2019078089-appb-000086
优选
Figure PCTCN2019078089-appb-000087
In the present invention, "aromatic heterocyclic group" means an aromatic cyclic group containing one or more ring hetero atoms selected from N, S or O, and includes a monocyclic aromatic heterocyclic group and a monocyclic aromatic heterocyclic group. A fused ring aromatic heterocyclic group in which a monocyclic aromatic heterocyclic group, a monocyclic aromatic heterocyclic group and an aryl group are fused, a monocyclic aromatic heterocyclic group having 5 to 6 ring atoms, and a fused ring aromatic heterocyclic group having 8 Up to 14 ring atoms. The "monocyclic aromatic heterocyclic group" specifically includes, but is not limited to, furyl, thienyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyrimidine Base, pyridazinyl, pyrazinyl,
Figure PCTCN2019078089-appb-000082
Preferred is pyridyl, pyrimidinyl, pyrazinyl,
Figure PCTCN2019078089-appb-000083
Figure PCTCN2019078089-appb-000084
The "fused ring aromatic heterocyclic group" specifically includes but is not limited to a benzofuranyl group, a benzothienyl group, a benzothiadiazolyl group, a benzothiazolyl group, an isodecyl group, a quinolyl group, an isoquinolyl group. , quinazolinyl, porphyrin-2-one,
Figure PCTCN2019078089-appb-000085
Figure PCTCN2019078089-appb-000086
Optimal
Figure PCTCN2019078089-appb-000087
本发明中，“含氮芳杂环基”是指至少一个环原子为N原子的上述“芳杂环基”，含有1～5个(即含有1、2、3、4、5个，优选含有1、2、3、4个)选自N、O或S的环杂原子，通过环上N原子与二氢吡啶并酞嗪酮母核相连，包括含氮单环芳杂环基和含氮稠环芳杂环基。所述“含氮单环芳杂环基”是指至少一个环原子为N原子的上述“单环芳杂环基”，含有1～5个(即含有1、2、3、4、5个，优选含有1、2、3个)选自N、O或S的环杂原子，通过环上N原子与二氢吡啶并酞嗪酮母核相连，具有5至6个环原子，具体举例包括但不限于
Figure PCTCN2019078089-appb-000088
Figure PCTCN2019078089-appb-000089
优选
Figure PCTCN2019078089-appb-000090
“含氮稠环芳杂环基”是由上述“含氮单环芳杂环基”与上述“单环芳杂环基”或上述“含氮单环芳杂环基”与上述“芳基”稠合而成，含有1～5个(即含有1、2、3、4、5个，优选含有1、2、3个)选自N、O或S的环杂原子，通过环上N原子与二氢吡啶并酞嗪酮母核相连，具有8至14个环原子，优选具有8至10个环原子，具体举例包括但不限于
Figure PCTCN2019078089-appb-000091
优选
Figure PCTCN2019078089-appb-000092
In the present invention, the "nitrogen-containing heterocyclic group" means the above-mentioned "aromatic heterocyclic group" in which at least one ring atom is an N atom, and contains 1 to 5 (i.e., contains 1, 2, 3, 4, 5, preferably Containing 1, 2, 3, 4) ring heteroatoms selected from N, O or S, attached to the dihydropyridazinone nucleus via a ring N atom, including a nitrogen-containing monocyclic aromatic heterocyclic group and A nitrogen fused ring aromatic heterocyclic group. The "nitrogen-containing monocyclic aromatic heterocyclic group" means the above-mentioned "monocyclic aromatic heterocyclic group" having at least one ring atom of N atoms, and contains 1 to 5 (i.e., contains 1, 2, 3, 4, 5) , preferably containing 1, 2, 3) ring heteroatoms selected from N, O or S, linked to the dihydropyridinopyridinone core by a ring of N atoms, having 5 to 6 ring atoms, specific examples include But not limited to
Figure PCTCN2019078089-appb-000088
Figure PCTCN2019078089-appb-000089
Optimal
Figure PCTCN2019078089-appb-000090
The "nitrogen-containing fused ring aromatic heterocyclic group" is the above "nitrogen-containing monocyclic aromatic heterocyclic group" and the above "monocyclic aromatic heterocyclic group" or the above "nitrogen-containing monocyclic aromatic heterocyclic group" and the above "aryl group""Condensed, containing 1 to 5 (ie containing 1, 2, 3, 4, 5, preferably containing 1, 2, 3) ring heteroatoms selected from N, O or S, through the ring N The atom is bonded to the dihydropyridoxinone nucleus and has 8 to 14 ring atoms, preferably 8 to 10 ring atoms, and specific examples include, but are not limited to,
Figure PCTCN2019078089-appb-000091
Optimal
Figure PCTCN2019078089-appb-000092
在本发明中，“单环”包括“单环环烷基”、“单环芳基”、“单环脂杂环基”和“单环芳杂环基”。In the present invention, "monocyclic" includes "monocyclic cycloalkyl", "monocyclic aryl", "monocyclic heterocyclic group" and "monocyclic aromatic heterocyclic group".
在本发明中，“环A为含有1～5个选自N、O或S的环杂原子的含氮脂杂环基或含氮芳杂环基”中所述的“1～5个”包括1、2、3、4或5个，优选1、2、3或4个。In the present invention, "1 to 5" as described in "Ring A is a nitrogen-containing aliphatic heterocyclic group or a nitrogen-containing aromatic heterocyclic group having 1 to 5 ring heteroatoms selected from N, O or S" It comprises 1, 2, 3, 4 or 5, preferably 1, 2, 3 or 4.
在本发明中，“x至y个环原子”是指x和y之间的所有自然数个环原子，且包括x和y，其中x和y是任意自然数且x小于y，例如“3至8个环原子”是指3、4、5、6、7、8个环原子。In the present invention, "x to y ring atoms" means all natural ring atoms between x and y, and includes x and y, wherein x and y are arbitrary natural numbers and x is smaller than y, for example, "3 to 8" "A ring atom" means 3, 4, 5, 6, 7, 8 ring atoms.
在本发明中，“二氢吡啶并酞嗪酮母核”为如下结构，In the present invention, the "dihydropyridazinone nucleus" has the following structure.
Figure PCTCN2019078089-appb-000093
Figure PCTCN2019078089-appb-000093
本发明还包含式(I)化合物在药学上可接受的盐。术语“药学上可接受的盐”是指相对无毒的本发明化合物的酸加成盐或碱加成盐。所述酸加成盐为本发明式(I)化合物与合适的无机酸或者有机酸形成的盐，这些盐可在化合物最后的分离和提纯过程中制备，或者可用过使纯化的式(I)化合物以其游离碱形式与适宜的有机酸或无机酸进行反应来制备。代表性酸加成盐包括氢溴酸盐、盐酸盐、硫酸盐、硫酸氢盐、亚硫酸盐、乙酸盐、草酸盐、戊酸盐、油酸盐、棕榈酸盐、硬脂酸盐、 月硅酸盐、硼酸盐、苯甲酸盐、乳酸盐、磷酸盐、磷酸氢盐、碳酸盐、碳酸氢盐、甲苯甲酸盐、柠檬酸盐、马来酸盐、富马酸盐、琥珀酸盐、酒石酸盐、苯甲酸盐、甲磺酸盐、对甲苯磺酸盐、葡萄糖酸盐、乳糖酸盐和月桂基磺酸盐等。所述碱加成盐为式(I)化合物与合适的无机碱或者有机碱形成的盐，包括例如与碱金属、碱土金属、季铵阳离子形成的盐，例如钠盐、锂盐、钾盐、钙盐、镁盐、四甲基季铵盐、四乙基季铵盐等；胺盐，包括与氨(NH 3)、伯胺、仲胺或叔胺形成的盐，如甲胺盐、二甲胺盐、三甲胺盐、三乙胺盐、乙胺盐等。 The invention further comprises a pharmaceutically acceptable salt of a compound of formula (I). The term "pharmaceutically acceptable salt" refers to an acid addition or base addition salt of a relatively non-toxic compound of the invention. The acid addition salt is a salt of the compound of the formula (I) of the present invention and a suitable inorganic or organic acid, which can be prepared during the final isolation and purification of the compound, or can be used to purify the formula (I). The compounds are prepared in their free base form by reaction with a suitable organic or inorganic acid. Representative acid addition salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, sulfite, acetate, oxalate, valerate, oleate, palmitate, stearic acid Salt, silicate, borate, benzoate, lactate, phosphate, hydrogen phosphate, carbonate, bicarbonate, toluate, citrate, maleate, rich Formate, succinate, tartrate, benzoate, methanesulfonate, p-toluenesulfonate, gluconate, lactobate and lauryl sulfonate. The base addition salt is a salt of a compound of formula (I) with a suitable inorganic or organic base, including, for example, a salt with an alkali metal, an alkaline earth metal, a quaternary ammonium cation, such as a sodium salt, a lithium salt, a potassium salt, a calcium salt, a magnesium salt, a tetramethyl quaternary ammonium salt, a tetraethyl quaternary ammonium salt, etc.; an amine salt, including a salt formed with ammonia (NH 3 ), a primary amine, a secondary amine or a tertiary amine, such as methylamine salt, Methylamine salt, trimethylamine salt, triethylamine salt, ethylamine salt and the like.
在一些实施方案中，本发明所描述的化合物作为立体异构体存在，其中存在不对称或手性中心。立体异构体根据手性碳原子周围的取代基构型被命名为(R)或(S)。本文描述的实施方案特别包括各种立体异构体和其混合物。立体异构体包括消旋体、对映异构体、非对映异构体以及对映异构体或非对映异构体的混合物。在一些实施方案中，化合物的各立体异构体从含有不对称或手性中心的商业原料合成制备，或通过制备外消旋混合物，然后拆分而制备。拆分方法例如：(1)将对映异构体的混合物与手性助剂结合，通过重结晶或色谱分离得到的非对映异构体混合物，从助剂中释放光学纯的产品；或(2)在手性色谱柱上直接分离光学对映异构体的混合物。In some embodiments, the compounds described herein exist as stereoisomers in which asymmetric or chiral centers are present. Stereoisomers are named (R) or (S) depending on the substituent configuration around the chiral carbon atom. Embodiments described herein specifically include various stereoisomers and mixtures thereof. Stereoisomers include racemates, enantiomers, diastereomers, and mixtures of enantiomers or diastereomers. In some embodiments, each stereoisomer of a compound is prepared synthetically from a commercial starting material containing an asymmetric or chiral center, or by preparing a racemic mixture, followed by resolution. The method of resolution is, for example: (1) combining a mixture of enantiomers with a chiral auxiliary, and releasing a mixture of diastereomers by recrystallization or chromatography to release an optically pure product from the auxiliary; or (2) Direct separation of the mixture of optical enantiomers on a chiral column.
本发明式(I)化合物、其药学上可接受的盐或立体异构体可以通过任何方便的给药途径施用给治疗对象，可以是全身/外周或在所希望的作用部位施用，包括但不限于，经口服(例如摄食)、局部(包括例如透皮、鼻内、眼部、口腔和舌下)、肺部(例如利用气溶胶经口或鼻的吸入或吹入治疗)、直肠、阴道、肠道外(例如注射，包括皮下、皮内、肌内、静脉内、动脉内、心内、鞘内、脊椎内、囊内、囊下、眼眶内、腹膜内、气管内、表皮下、关节内、蛛网膜下和胸骨内)，以及植入贮库剂(例如皮下或肌内植入)。The compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof of the present invention can be administered to a subject by any convenient administration route, and can be administered systemically/peripherally or at a desired site of action, including but not Limited to oral (eg, feeding), topical (including, for example, transdermal, intranasal, ocular, buccal, and sublingual), lung (eg, inhalation or insufflation by aerosol or nasal), rectal, vaginal , parenteral (eg injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraocular, intraperitoneal, intratracheal, subepidermal, joint) Internal, subarachnoid, and sternal), as well as implanted depots (eg, subcutaneous or intramuscular).
治疗对象可以是真核生物、动物、脊椎动物、哺乳动物、啮齿动物(例如豚鼠、仓鼠、大鼠、小鼠)、鼠科动物(例如小鼠)、犬科动物(例如狗)、灵长目动物、类人猿(如猴或无尾猿)、猴(如狨猴、狒狒)、无尾猿(例如大猩猩、黑猩猩、猩猩、长臂猿)或人类。The subject may be a eukaryote, an animal, a vertebrate, a mammal, a rodent (eg, guinea pig, hamster, rat, mouse), a murine (eg, a mouse), a canine (eg, a dog), a primate , apes (such as monkeys or apes), monkeys (such as apes, baboons), apes (such as gorillas, chimpanzees, orangutans, gibbons) or humans.
本发明所述的药物组合物，包含本发明式(I)化合物、其药学上可接受的盐或立体异构体，以及药学上可接受的载体、赋形剂或稀释 剂等。本发明式(I)化合物、其药学上可接受的盐或立体异构体可以按照标准的药学操作，与可药用的载体、赋形剂、稀释剂等混合制备得到相应的药物组合物，施用给哺乳动物包括人类。The pharmaceutical composition of the present invention comprises a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or diluent, and the like. The compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof of the present invention can be prepared by mixing with a pharmaceutically acceptable carrier, excipient, diluent, etc. according to standard pharmaceutical practice, to obtain a corresponding pharmaceutical composition. Administration to mammals includes humans.
本发明所述载体、赋形剂和稀释剂指的是对有机体不引起明显的刺激性和不干扰所给予化合物的生物活性的性质的药物组合物中的非活性成分，具体包括但不限于水、乳糖、葡萄糖、果糖、蔗糖、山梨糖醇、甘露醇、聚乙二醇、丙二醇、淀粉、橡胶、凝胶、藻酸盐、硅酸钙、磷酸钙、纤维素、水性糖浆、甲基纤维素、聚乙烯基吡咯烷酮、对羟基苯并山梨酸烷基酯、滑石、硬脂酸镁、硬脂酸、甘油、芝麻油、橄榄油、大豆油等各种油以及其混合物。The carriers, excipients and diluents of the present invention refer to inactive ingredients in pharmaceutical compositions which do not cause significant irritation to the organism and which do not interfere with the biological activity of the administered compound, including but not limited to water. , lactose, glucose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, rubber, gel, alginate, calcium silicate, calcium phosphate, cellulose, aqueous syrup, methyl fiber Various oils such as polyvinylpyrrolidone, alkyl p-hydroxybenzoate, talc, magnesium stearate, stearic acid, glycerin, sesame oil, olive oil, soybean oil, and the like, and mixtures thereof.
本发明式(I)化合物、其药学上可接受的盐、立体异构体或其药物组合物可制成制剂施用给哺乳动物包括人类。可以以单位剂型方便地提供该制剂，并优选通过制药领域熟知的方法制备该制剂。这类方法包括将本发明化合物与组成一种或多种辅助成分的载体联合的步骤。通常，将本发明式(I)化合物与液体载体或精细分割的固体载体或两种载体密切联合，从而制备制剂，然后根据需要使产品成形。制剂可以是液体、溶液、悬浮液、乳剂、酏剂、糖浆、片剂、锭剂、颗粒剂、粉剂、胶囊剂、扁囊剂、丸剂、安瓿剂、栓剂、阴道栓剂、软膏剂、凝胶剂、糊剂、霜剂、喷雾剂、烟雾剂、泡沫剂、洗剂、油剂、大丸剂、药糖剂或气雾剂形式。The compound of the formula (I), a pharmaceutically acceptable salt thereof, a stereoisomer thereof or a pharmaceutical composition thereof of the present invention can be formulated into a mammal, including a human. The formulation may conveniently be presented in unit dosage form and, preferably, may be prepared by methods well known in the art of pharmacy. Such methods include the step of bringing into association a compound of the invention with a carrier which comprises one or more accessory ingredients. In general, the compound of the formula (I) of the present invention is intimately combined with a liquid carrier or a finely divided solid carrier or both carriers to prepare a formulation, which is then shaped as needed. The preparation may be a liquid, a solution, a suspension, an emulsion, an elixir, a syrup, a tablet, a lozenge, a granule, a powder, a capsule, a cachet, a pill, an ampoule, a suppository, a vaginal suppository, an ointment, or a gel. In the form of a dose, a paste, a cream, a spray, an aerosol, a foam, a lotion, an oil, a boluse, a medicinal or an aerosol.
适合于口服(例如摄食)的制剂包括片剂、胶囊剂、扁囊剂、粉剂、颗粒剂、溶液、悬浮液、乳剂、大丸剂、药糖剂或糊剂等。Formulations suitable for oral administration (e.g., ingestion) include tablets, capsules, cachets, powders, granules, solutions, suspensions, emulsions, granules, syrups or pastes and the like.
适于口服给药的片剂可以通过常规方法制备，例如任选地以一种或多种辅助成分压制或模制。压制片可以通过在合适的机器中压缩自由流动形式的本发明式(I)化合物、其药学上可接受的盐或立体异构体(例如粉末或颗粒)而制备，本发明式(I)化合物、其药学上可接受的盐或立体异构体任选地与填充剂或稀释剂(例如淀粉、乳糖、蔗糖、微晶纤维素、磷酸氢钙)；一种或多种粘合剂(例如聚乙烯吡咯酮、羟甲基纤维素、淀粉、明胶、阿拉伯树胶、山梨糖醇、黄芪胶、羟丙基甲基纤维素、蔗糖)；崩解剂(例如羟乙酸淀粉钠、交联聚乙烯吡咯酮、交联羧甲基纤维素钠、琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸)；润滑剂(例如硬脂酸镁、滑石、硬脂酸钙、固体聚乙二醇、十二烷基硫 酸钠等或其混合物)；表面活性或分散或润湿剂(例如月桂基硫酸钠、鲸蜡醇、单硬脂酸甘油酯)；及防腐剂(例如对羟基苯甲酸甲酯、对羟基苯甲酸丙酯、山梨酸)混合。模制片可以通过在合适的机器中将以惰性液体稀释剂湿润的含有本发明式(I)化合物、其药学上可接受的盐或立体异构体的粉末混合物塑型而制备。可以任选地将片剂包衣或刻划，并可以经过配制而提供其中所采用的本发明式(I)化合物的缓释或控释，例如使用不同比例的羟丙基甲基纤维素提供所需的释放特征。可以任选地提供具有肠衣的片剂，以供在除胃之外的部分肠内释放。Tablets suitable for oral administration can be prepared by conventional methods, for example, by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing a free-flowing form of a compound of formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof (e.g., a powder or granule) of the present invention in a suitable machine, a compound of formula (I) of the present invention. a pharmaceutically acceptable salt or stereoisomer thereof, optionally with a filler or diluent (eg, starch, lactose, sucrose, microcrystalline cellulose, calcium hydrogen phosphate); one or more binders (eg, Polyvinylpyrrolidone, hydroxymethylcellulose, starch, gelatin, gum arabic, sorbitol, tragacanth, hydroxypropylmethylcellulose, sucrose); disintegrants (eg sodium starch glycolate, crosslinked polyethylene) Pyrrolidone, croscarmellose sodium, agar, calcium carbonate, potato starch or tapioca starch, alginic acid); lubricants (such as magnesium stearate, talc, calcium stearate, solid polyethylene glycol, ten Sodium dialkyl sulfates and the like or mixtures thereof; surface active or dispersing or wetting agents (for example, sodium lauryl sulfate, cetyl alcohol, glyceryl monostearate); and preservatives (for example, methylparaben, Mix propylparaben, sorbic acid). Molded tablets may be made by molding in a suitable machine a powder mixture containing a compound of formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof, moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated to provide sustained or controlled release of a compound of formula (I) of the invention employed therein, for example, using different proportions of hydroxypropyl methylcellulose. The desired release characteristics. A tablet having a casing may optionally be provided for release in a portion of the intestine other than the stomach.
适于口服给药的液体剂型可通过常规方法制备，包括但不限于作为活性成分的本发明式(I)化合物、其药学上可接受的盐或立体异构体，本领域中常规采用的惰性稀释剂，如水和其他溶剂，增溶剂和乳化剂，例如，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1，3-丁二醇、二甲基甲酰胺以及油类，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油等或这些物质的混合物等。除了这些惰性稀释剂外，本发明液体剂型也可包含常规助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料等。Liquid dosage forms suitable for oral administration can be prepared by conventional methods including, but not limited to, the compounds of formula (I), pharmaceutically acceptable salts or stereoisomers thereof of the present invention as active ingredients, inert in the art conventionally employed Thinners such as water and other solvents, solubilizers and emulsifiers such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide and oils, especially It is cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame oil, etc. or a mixture of these substances. In addition to these inert diluents, the liquid dosage forms of the present invention may also contain conventional adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and flavoring agents.
适于局部给药(如透皮、鼻内、眼、口腔和舌下)的制剂包括软膏剂、栓剂、霜剂、悬液、洗剂、粉剂、溶液、凝胶剂等。作为活性成分的本发明式(I)化合物、其药学上可接受的盐或立体异构体在无菌条件下和生理上可接受的载体及任选的防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。Formulations suitable for topical administration (e.g., transdermal, intranasal, ocular, buccal, and sublingual) include ointments, suppositories, creams, suspensions, lotions, powders, solutions, gels, and the like. a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof of the present invention as an active ingredient under sterile conditions and a physiologically acceptable carrier and optionally a preservative, buffer, or if possible The propellants needed are mixed together.
适于口内局部给药的制剂包括锭剂(lozenge)，包括本发明式(I)化合物或其药学上可接受的盐或立体异构体、经过矫味的基质(例如蔗糖、阿拉伯胶)；锭剂(pastille)，包括本发明式(I)化合物或其药学上可接受的盐、惰性基质(例如明胶和甘油)；以及漱口剂，包括本发明式(I)化合物或其药学上可接受的盐或立体异构体、及合适的液体载体。Formulations suitable for intra-oral administration include lozenges, including a compound of formula (I) of the present invention, or a pharmaceutically acceptable salt or stereoisomer thereof, a flavored substrate (eg, sucrose, acacia); Pastille, comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, an inert matrix (such as gelatin and glycerin), and a mouthwash, including a compound of formula (I) of the present invention or a pharmaceutically acceptable compound thereof Accepted salts or stereoisomers, and suitable liquid carriers.
适于经由皮肤局部给药的制剂包括软膏剂、霜剂和乳剂。对于软膏剂，包括但不限于本发明式(I)化合物或其药学上可接受的盐或立体异构体、合适的基质(例如石蜡类、水混合性软膏基质)、皮肤渗透增强剂(例如二甲亚砜)；对于霜剂，包括但不限于本发明式(I)化合物或其药学上可接受的盐或立体异构体、合适的基质(例如水包 油型霜剂基质)；对于乳剂，包括但不限于本发明式(I)化合物或其药学上可接受的盐或立体异构体、合适的基质(例如乳化剂、乳化剂和脂肪、乳化剂和油、乳化剂和脂肪及油)。Formulations suitable for topical administration via the skin include ointments, creams and lotions. For ointments, including but not limited to the compounds of formula (I) of the present invention, or pharmaceutically acceptable salts or stereoisomers thereof, suitable matrices (e.g., paraffinic, water-mixable ointment bases), skin penetration enhancers (e.g., Dimethyl sulfoxide); for creams, including but not limited to the compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof, suitable matrices (eg, oil-in-water cream bases); Emulsions, including but not limited to the compounds of formula (I), or pharmaceutically acceptable salts or stereoisomers thereof, suitable matrices (eg, emulsifiers, emulsifiers and fats, emulsifiers and oils, emulsifiers, and fats) oil).
适于对眼睛局部给药的制剂包括滴眼剂，包括本发明式(I)化合物、其药学上可接受的盐或立体异构体，其溶解或悬浮于合适的载体中。Formulations suitable for topical administration to the eye include eye drops comprising a compound of formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, dissolved or suspended in a suitable carrier.
适于鼻给药的制剂包括载体是固体的粗粉，采取鼻吸的方式给药；载体是液体的水溶液或油溶液，例如鼻喷雾剂、滴鼻剂或通过雾化器以气雾剂给药等。Formulations suitable for nasal administration include a solid powder which is a solid, which is administered by nasal inhalation; the carrier is a liquid aqueous or oily solution, such as a nasal spray, nasal drops or aerosolized by a nebulizer Medicine, etc.
适于直肠给药的制剂包括栓剂，包括本发明式(I)化合物或其药学上可接受的盐或立体异构体、合适的基质(例如可可脂、水杨酸酯)。Formulations suitable for rectal administration include suppositories, including a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, a suitable matrix (e.g., cocoa butter, salicylate).
适于阴道给药的制剂包括阴道栓、喷雾剂、霜剂或凝胶剂等，包括本发明式(I)化合物或其药学上可接受的盐或立体异构体以及本领域已知的适当的载体。Formulations suitable for vaginal administration include pessaries, sprays, creams or gels, and the like, including a compound of formula (I), or a pharmaceutically acceptable salt or stereoisomer thereof, and suitable in the art a.
适于胃肠外(例如注射，包括表皮、皮下、肌肉内、静脉内和皮内)给药的制剂包括水性或非水性的生理上可接受的无菌注射溶液、分散液、悬浮液或乳液，以及用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。Formulations suitable for parenteral (eg, injection, including epidermal, subcutaneous, intramuscular, intravenous, and intradermal) include aqueous or non-aqueous, physiologically acceptable sterile injectable solutions, dispersions, suspensions or emulsions. And a sterile powder for reconstitution into a sterile injectable solution or dispersion. Suitable carriers, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
一般而言，本发明式(I)化合物的成人合适日剂量为0.1～500mg，优选0.1～250mg，进一步优选0.1～150mg、0.3～120mg、0.3～100mg、0.3～80mg、0.3～50mg、0.5～50mg、0.5～30mg或0.5～10mg等。当本发明式(I)化合物为盐、酯、前药等时，以母体化合物为基础计算施用量。In general, a suitable daily dose for the compound of the formula (I) of the present invention is 0.1 to 500 mg, preferably 0.1 to 250 mg, more preferably 0.1 to 150 mg, 0.3 to 120 mg, 0.3 to 100 mg, 0.3 to 80 mg, 0.3 to 50 mg, or 0.5 to 0.5%. 50 mg, 0.5 to 30 mg or 0.5 to 10 mg, and the like. When the compound of the formula (I) of the present invention is a salt, an ester, a prodrug or the like, the application amount is calculated on the basis of the parent compound.
本发明式(I)化合物、其药学上可接受的盐或立体异构体或其药物组合物可与电离辐射、一种或多种化疗药物或其组合组合施用用于治疗或预防癌症。确切来说，本发明式(I)化合物、其药学上可接受的盐或立体异构体或其药物组合物可强化大量癌症化学疗法的治疗作用。所述化疗药物包括用于治疗癌症的HDAC抑制剂(如辛二酰苯胺异羟肟酸(SAHA))，雌激素受体调节剂(如他莫昔芬、雷洛昔芬、艾多昔芬)，雄激素受体调节剂(如非那雄胺、乙酸阿比特龙)，类视黄醇受体调节剂(如贝沙罗汀)，细胞毒性/细胞生长抑制剂{如烷基 化试剂(例如环磷酰胺、卡莫司汀(BCNU)、替莫唑胺、顺铂、卡铂)，微管抑制剂/微管稳定剂(例如紫杉醇，硫酸长春地辛，长春新碱)，拓扑异构酶抑制剂(如伊立替康、拓扑替康和卢比替康(rubitecan))，蛋白酶体抑制剂(例如硼替佐米)和泛素连接酶抑制剂)}，抗增生剂(如卡培他滨、加洛他滨)，HMG-CoA还原酶抑制剂(洛伐他汀、辛伐他汀)，HIV蛋白酶抑制剂，血管生成抑制剂(如酪氨酸激酶抑制剂)，细胞增生和生存信号抑制剂(如EGFR的抑制剂如吉非替尼和厄洛替尼，ERB-2的抑制剂例如曲妥珠单抗，IGFR的抑制剂例如WO03/059951中公开的那些，细胞因子受体的抑制剂，PI3K的抑制剂例如LY294002，Raf激酶的抑制剂例如BAY-43-9006，MEK的抑制剂例如PD-098059)等。本发明化合物在与放射疗法共同施用时特别有效。The compound of the formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof of the present invention can be administered for treatment or prevention of cancer in combination with ionizing radiation, one or more chemotherapeutic drugs or a combination thereof. Specifically, the compound of the formula (I), a pharmaceutically acceptable salt or stereoisomer thereof, or a pharmaceutical composition thereof of the present invention can potentiate the therapeutic effects of a large number of cancer chemotherapy. The chemotherapeutic drugs include HDAC inhibitors for treating cancer (such as suberoylanilide hydroxamic acid (SAHA)), estrogen receptor modulators (such as tamoxifen, raloxifene, and iindoxifen). ), androgen receptor modulators (eg finasteride, abiraterone acetate), retinoid receptor modulators (eg, bexarotene), cytotoxicity/cytostatic agents {eg alkylating agents) (eg cyclophosphamide, carmustine (BCNU), temozolomide, cisplatin, carboplatin), microtubule inhibitors / microtubule stabilizers (eg paclitaxel, vindesine sulfate, vincristine), topoisomerase Inhibitors (such as irinotecan, topotecan and rubitecan), proteasome inhibitors (such as bortezomib) and ubiquitin ligase inhibitors), anti-proliferative agents (such as capecitabine, Carbopolamine), HMG-CoA reductase inhibitors (lovastatin, simvastatin), HIV protease inhibitors, angiogenesis inhibitors (such as tyrosine kinase inhibitors), cell proliferation and survival signal inhibitors ( Inhibitors such as EGFR such as gefitinib and erlotinib, inhibitors of ERB-2 such as trastuzumab, inhibitors of IGFR such as WO03/0 Those disclosed in 59951, inhibitors of cytokine receptors, inhibitors of PI3K such as LY294002, inhibitors of Raf kinase such as BAY-43-9006, inhibitors of MEK such as PD-098059) and the like. The compounds of the invention are particularly effective when administered in combination with radiation therapy.
本发明式(I)化合物、其药学上可接受的盐或立体异构体或其药物组合物同样可以与非抗癌药物联用。例如与PPAR-γ(PPAR-gamma)激动剂和PPAR-δ(PPAR-delta)激动剂的联合药物可用于治疗某些癌症；与抗病毒药(例如核苷类似物更昔洛韦)联合用于治疗癌症；与基因疗法联合用于治疗癌症；与转运蛋白的高水平表达有关的MDR的抑制剂(例如LY335979、维拉帕米)联合施用；与止吐药(如神经激肽-1受体拮抗剂或5HT3受体拮抗剂如昂丹司琼、格拉司琼)联合使用，治疗因单独使用或与放疗一起使用本发明化合物可能引起的恶心或呕吐，包括急性、迟发性、后期和早发性呕吐等等。The compound of the formula (I), a pharmaceutically acceptable salt or stereoisomer thereof or a pharmaceutical composition thereof of the present invention can also be used in combination with a non-anticancer drug. For example, a combination with a PPAR-gamma (PPAR-gamma) agonist and a PPAR-delta agonist can be used to treat certain cancers; in combination with an antiviral drug such as the nucleoside analog ganciclovir. For the treatment of cancer; in combination with gene therapy for the treatment of cancer; in combination with MDR inhibitors associated with high levels of transporter expression (eg LY335979, verapamil); with antiemetics (eg neurokinin-1) a combination of a body antagonist or a 5HT3 receptor antagonist such as ondansetron, granisetron, for the treatment of nausea or vomiting, including acute, delayed, late, and cerebral, may be caused by the use of a compound of the invention alone or in combination with radiation therapy. Early onset vomiting and so on.
试验证明本发明通式(I)化合物具有癌细胞增值抑制作用，可用于治疗癌症和制备用于治疗癌症的药物。本发明化合物抑制癌细胞增殖的药效可用常规方法测定，一种优选的评价方法为磺酰罗丹明B(SulforhodamIne B，SRB)蛋白染色法，通过测定药物作用于癌细胞后所产生的光吸收值的变化来计算药物对癌细胞增殖的抑制率。The test proves that the compound of the general formula (I) of the present invention has a cancer cell proliferation inhibitory effect and can be used for treating cancer and preparing a medicament for treating cancer. The pharmacological effect of the compound of the present invention for inhibiting the proliferation of cancer cells can be determined by a conventional method. A preferred evaluation method is Sulforhodam Ine B (SRB) protein staining method, and the light absorption produced by the action of the drug on cancer cells is determined. The change in value is used to calculate the rate of inhibition of cancer cell proliferation by the drug.
抑制率(％)＝[(空白对照OD-加药OD)/空白对照OD]×100％Inhibition rate (%) = [(blank control OD-dosing OD) / blank control OD] × 100%
空白对照OD：指没有药物作用正常生长的细胞的孔的OD值。Blank control OD: refers to the OD value of the wells of cells that do not have normal drug growth.
加药OD：指加入待筛选的化合物作用的细胞的孔的OD值。Dosing OD: refers to the OD value of the wells of the cells to which the compound to be screened is added.
半数抑制剂浓度(IC 50)值采用GraphPad公司PrIsm软件5.0版本，四参数拟合方法计算。每个实验重复3次，求出3次实验的平均IC 50值为抑制能力的最终指标。 The half-inhibitor concentration (IC 50 ) value was calculated using the GraphPad PrIsm software version 5.0, four-parameter fitting method. Each experiment was repeated 3 times, and the average IC 50 value of the 3 experiments was determined as the final index of inhibition ability.
本发明通式(I)化合物在分子水平对PARP-1和PARP-2酶具有 明显的抑制活性。本发明化合物在分子水平对PARP-1和PARP-2酶的抑制活性可通过常规方法测定，一种优选的方法为：组蛋白被包在96孔板中并4℃孵育过夜，用200μL PBST(磷酸盐缓冲液)溶液洗涤该板3次后，将其用封闭液封闭，室温孵育30分钟后，用PBST溶液洗涤3次。将被测试化合物处理加入孔板中，之后将20μL稀释的PARP-1(1nM)或20μL的PARP-2(3nM)溶液中加入到反应体系中孵育1或2小时。50μL链霉亲和素-HRP(辣根过氧化物酶)(1∶50)的混合液加入到孔板中并室温孵育30分钟后，PBST缓冲液洗涤三次。100μL HRP化学发光底物混合物加入孔板。立即到酶标仪(Envision，PerkinElmer)上读数。再通过计算获得化合物对PARP-1和PARP-2酶抑制活性的IC50值。The compound of the formula (I) of the present invention has significant inhibitory activity against PARP-1 and PARP-2 enzymes at the molecular level. The inhibitory activity of the compounds of the present invention on the PARP-1 and PARP-2 enzymes at the molecular level can be determined by a conventional method. A preferred method is that the histone is encapsulated in a 96-well plate and incubated overnight at 4 ° C with 200 μL of PBST ( After washing the plate 3 times with a phosphate buffer solution, it was blocked with a blocking solution, incubated at room temperature for 30 minutes, and then washed 3 times with a PBST solution. The test compound was treated to be added to the well plate, after which 20 μL of diluted PARP-1 (1 nM) or 20 μL of PARP-2 (3 nM) solution was added to the reaction system for 1 or 2 hours. A mixture of 50 μL streptavidin-HRP (horseradish peroxidase) (1:50) was added to the well plate and incubated for 30 minutes at room temperature, and washed three times with PBST buffer. 100 μL of HRP chemiluminescent substrate mixture was added to the well plates. Immediately read on a microplate reader (Envision, PerkinElmer). The IC50 value of the compound for PARP-1 and PARP-2 enzyme inhibitory activity was obtained by calculation.
本发明通式(I)化合物具有良好的药代动力学性质，测试方法为：健康SD大鼠，将本发明化合物按一定剂量灌胃给药。试验前禁食12h，自由饮水。给药后2h统一进食。灌胃给药后0.25h、0.5h、1h、2h、4h、6h、8h和24h，经大鼠眼球后静脉丛取静脉血，分离制备血浆，以液相色谱-串联质谱法测定血浆中化合物的浓度；健康SD大鼠，将本发明化合物按一定剂量静脉给药。试验前禁食12h，自由饮水。给药后2h统一进食。静脉给药后0.08h、0.25h、0.5h、1h、2h、4h、6h、8h和24h，经大鼠眼球后静脉丛取静脉血，分离制备血浆，以液相色谱-串联质谱法测定血浆中化合物的浓度。The compound of the formula (I) of the present invention has good pharmacokinetic properties, and the test method is: healthy SD rats, and the compound of the present invention is administered by a certain dose. Fasting for 12 hours before the test, free to drink water. Uniformly eaten 2 hours after administration. After 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h after intragastric administration, venous blood was taken from the posterior venous plexus of rats, and plasma was separated and determined by liquid chromatography-tandem mass spectrometry. Concentration; in healthy SD rats, the compounds of the invention are administered intravenously at a dose. Fasting for 12 hours before the test, free to drink water. Uniformly eaten 2 hours after administration. After intravenous administration, 0.08h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h, venous blood was taken from the posterior venous plexus of rats, and plasma was separated and plasma was determined by liquid chromatography-tandem mass spectrometry. The concentration of the compound in the medium.
本发明通式(I)化合物抑制动物移植瘤生长的药效可用常规方法测定，一种优选的评价方法为对人三阴性乳腺癌细胞MDA-MB-436裸小鼠皮下移植瘤的生长抑制作用。实验方法：人三阴性乳腺癌细胞MDA-MB-436细胞株(5×10 6个/只)接种于BALB/cA裸小鼠右侧背部皮下。待肿瘤生长至100-200mm 3时根据肿瘤大小和小鼠体重随机分组。测试化合物按一定剂量灌胃给药，溶剂对照组灌胃给予等量溶剂，每天给药一次，连续给药20天。整个实验过程中，每周测量两次小鼠的体重和肿瘤的大小，观察是否出现毒性反应。肿瘤体积(tumor volume)的计算公式为：TV＝1/2×a×b 2，其中a、b分别表示肿瘤长、宽。 The pharmacological effect of the compound of the general formula (I) of the present invention for inhibiting the growth of transplanted tumor of an animal can be determined by a conventional method, and a preferred evaluation method is the growth inhibitory effect on the subcutaneous transplantation tumor of human triple negative breast cancer cell MDA-MB-436 nude mice. . Experimental method: Human triple negative breast cancer cell MDA-MB-436 cell line (5×10 6 cells/only) was inoculated subcutaneously into the right side of BALB/cA nude mice. When the tumors were grown to 100-200 mm 3 , they were randomly grouped according to tumor size and mouse body weight. The test compound was administered by a certain dose, and the solvent control group was intragastrically administered with an equal amount of solvent, once a day for 20 days. The body weight and tumor size of the mice were measured twice a week during the entire experiment to see if a toxic reaction occurred. The formula for calculating the tumor volume is: TV = 1/2 × a × b 2 , where a and b represent the length and width of the tumor, respectively.
附图说明DRAWINGS
附图1是化合物56和LT-00628在1mg/kg给药剂量下的人三阴性 乳腺癌细胞MDA-MB-436裸小鼠皮下移植瘤的肿瘤体积变化曲线。BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a graph showing the tumor volume change of human 56-negative breast cancer cell MDA-MB-436 nude mouse subcutaneous xenografts of Compound 56 and LT-00628 at a dose of 1 mg/kg.
附图2是化合物56和LT-00628在1mg/kg给药剂量下的人三阴性乳腺癌细胞MDA-MB-436裸小鼠的体重变化曲线。Figure 2 is a graph showing body weight changes of human 56-negative breast cancer cells MDA-MB-436 nude mice at a dose of 1 mg/kg of Compound 56 and LT-00628.
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于举例说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则份数和百分比分别为重量份和重量百分比。The invention is further illustrated below in conjunction with specific embodiments. It is to be understood that the examples are not intended to limit the scope of the invention. The experimental methods in the following examples which do not specify the specific conditions are usually in accordance with conventional conditions or according to the conditions recommended by the manufacturer. Parts and percentages are by weight and by weight, respectively, unless otherwise stated.
具体实施方式detailed description
I.本发明化合物制备实施例I. Preparation Examples of Compounds of the Invention
中间体1a：5-氟-9-氯-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3-酮-7-羧酸叔丁酯(中间体1a)Intermediate 1a: 5-fluoro-9-chloro-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazin-3-one-7 - tert-butyl carboxylate (intermediate 1a)
Figure PCTCN2019078089-appb-000094
Figure PCTCN2019078089-appb-000094
步骤1：2-溴-5-氟-3-硝基苯甲酸叔丁酯Step 1: 2-Bromo-5-fluoro-3-nitrobenzoic acid tert-butyl ester
Figure PCTCN2019078089-appb-000095
Figure PCTCN2019078089-appb-000095
2-溴-5-氟-3-硝基苯甲酸(274g，1.038mol)和叔丁醇(660mL，7mol)溶于二氯甲烷(2L)，再加入无水硫酸镁(600g，5mol)和浓硫酸(55mL，1.038mol)。室温下搅拌反应2天。反应液用硅藻土过滤，二氯甲烷洗涤。二氯甲烷层依次用水、饱和碳酸氢钠溶液洗涤，无水硫酸镁干燥，过滤。滤液浓缩后残余物经硅胶柱层析(石油醚/乙酸乙酯＝20/1，v/v)纯化，得到产物132g(收率39.9％)。 1H NMR(400MHz，DMSO-d6)δ8.25(dd，J＝7.8，3.0Hz，1H)，7.93(dd，J＝8.2，3.0Hz，1H)，1.57(s，9H)。 2-Bromo-5-fluoro-3-nitrobenzoic acid (274 g, 1.038 mol) and tert-butanol (660 mL, 7 mol) were dissolved in dichloromethane (2 L), then anhydrous magnesium sulfate (600 g, 5 mol) and Concentrated sulfuric acid (55 mL, 1.038 mol). The reaction was stirred at room temperature for 2 days. The reaction solution was filtered through celite and washed with dichloromethane. The methylene chloride layer was washed with water and a saturated aqueous After the filtrate was concentrated, the residue was purified mjjjjjlililililililililililili 1 H NMR (400MHz, DMSO- d6) δ8.25 (dd, J = 7.8,3.0Hz, 1H), 7.93 (dd, J = 8.2,3.0Hz, 1H), 1.57 (s, 9H).
步骤2：2-(1-乙氧基乙烯基)-5-氟-3-硝基苯甲酸叔丁酯Step 2: 2-(1-Ethoxyvinyl)-5-fluoro-3-nitrobenzoic acid tert-butyl ester
Figure PCTCN2019078089-appb-000096
Figure PCTCN2019078089-appb-000096
2-溴-5-氟-3-硝基苯甲酸叔丁酯(72.4g，0.227mol)、三丁基(1-乙氧基乙烯基)锡(98g，0.27mol)、[1，1′-双(二苯基膦基)二茂铁]二氯化钯(6g，8.56mmol)溶于二氧六环(500mL)。氩气保护下升温到80℃反应5小时，冷却到室温。将二水氟化钾(21g)溶于250mL水的溶液加入反应液中，搅拌1小时。反应液用硅藻土过滤，乙酸乙酯洗涤。分出的有机层用水洗涤2次，无水硫酸镁干燥，过滤。减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝50/1，v/v)纯化，得70.6g产物(收率100％)。 1H NMR(400MHz，CDCl 3)δ7.58(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)。 tert-Butyl 2-bromo-5-fluoro-3-nitrobenzoate (72.4 g, 0.227 mol), tributyl(1-ethoxyvinyl)tin (98 g, 0.27 mol), [1,1' Bis(diphenylphosphino)ferrocene]palladium dichloride (6 g, 8.56 mmol) was dissolved in dioxane (500 mL). The reaction was heated to 80 ° C under argon for 5 hours and cooled to room temperature. A solution of potassium fluoride dihydrate (21 g) dissolved in 250 mL of water was added to the reaction solution, and the mixture was stirred for 1 hour. The reaction solution was filtered through Celite, and ethyl acetate. The separated organic layer was washed twice with water, dried over anhydrous magnesium sulfate and filtered. The residue was purified by silica gel chromatography chromatography eluting elut elut elut elut 1 H NMR (400MHz, CDCl 3 ) δ7.58 (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 = 7.0 Hz, 3H).
步骤3：2-乙酰基-3-氨基-5-氟苯甲酸叔丁酯Step 3: 2-Acetyl-3-amino-5-fluorobenzoic acid tert-butyl ester
Figure PCTCN2019078089-appb-000097
Figure PCTCN2019078089-appb-000097
2-(1-乙氧基乙烯基)-5-氟-3-硝基苯甲酸叔丁酯(36.5g，0.117mol)、还原铁粉(26.3g，0.47mol)和氯化铵(12.5g，0.235mol)加到乙醇(200mL)-水(50mL)混合溶剂中。升温到85℃反应过夜。反应液用硅藻土过滤，乙醇洗涤，减压浓缩。加入乙酸乙酯(750mL)，依次用饱和碳酸氢钠溶液、饱和氯化钠溶液洗涤。有机层用无水硫酸镁干燥、过滤。减压浓缩所得残余物经硅胶柱层析(石油醚/乙酸乙酯＝9/1，v/v)纯化，得27.5g产物(收率92.9％)。 1H NMR(400MHz，CDCl 3)δ6.84(dd，J＝8.8，2.4Hz，1H)，6.50(dd，J＝10.1，2.4Hz，1H)，4.74(s，2H)，1.55(s，9H)。 tert-Butyl 2-(1-ethoxyvinyl)-5-fluoro-3-nitrobenzoate (36.5 g, 0.117 mol), reduced iron powder (26.3 g, 0.47 mol) and ammonium chloride (12.5 g) 0.235 mol) was added to a mixed solvent of ethanol (200 mL)-water (50 mL). The temperature was raised to 85 ° C and allowed to react overnight. The reaction mixture was filtered with EtOAc EtOAc. Ethyl acetate (750 mL) was added and washed successively with saturated sodium hydrogen carbonate solution and saturated sodium chloride. The organic layer was dried over anhydrous magnesium sulfate and filtered. The residue was purified by silica gel column chromatography eluting elut elut elut elut elut 1 H NMR (400MHz, CDCl 3 ) δ6.84 (dd, J = 8.8,2.4Hz, 1H), 6.50 (dd, J = 10.1,2.4Hz, 1H), 4.74 (s, 2H), 1.55 (s, 9H).
步骤4：(E)-2-乙酰基-5-氟-3-((4-氟苄叉)氨基)苯甲酸叔丁酯Step 4: (E)-2-Acetyl-5-fluoro-3-((4-fluorobenzylidene)amino)benzoic acid tert-butyl ester
Figure PCTCN2019078089-appb-000098
Figure PCTCN2019078089-appb-000098
2-乙酰基-3-氨基-5-氟苯甲酸叔丁酯(25.6g，101.2mmol)、对氟苯甲醛(12.55g，101.2mmol)和L-脯氨酸(3.5g，30.36mmol)溶于甲醇(100mL)。室温搅拌过夜。抽滤，收集析出的固体，固体用甲醇洗涤，得白色固体。滤液减压蒸除部分甲醇后，静置一天，又有固体析出。过滤，用甲醇洗涤得白色固体。合并过滤所得的白色固体得27.4g产物(收率75.4％)。 1H NMR(400MHz，CDCl 3)δ8.36(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)。 tert-Butyl 2-acetyl-3-amino-5-fluorobenzoate (25.6 g, 101.2 mmol), p-fluorobenzaldehyde (12.55 g, 101.2 mmol) and L-valine (3.5 g, 30.36 mmol) In methanol (100 mL). Stir at room temperature overnight. The solid which precipitated was collected by suction filtration, and the solid was washed with methanol to give a white solid. After the filtrate was distilled off under reduced pressure, a portion of methanol was allowed to stand for one day, and a solid precipitated. Filtration and washing with methanol gave a white solid. The white solid obtained by combined filtration gave 27.4 g of product (yield 75.4%). 1 H NMR (400MHz, CDCl 3 ) δ8.36 (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, 2.4 Hz, 1H), 2.63 (s, 3H), 1.58 (s, 9H).
步骤5：7-氟-2-(4-氟苯基)-2，3-二氢喹啉-4(1H)-酮-5-甲酸叔丁酯Step 5: 7-Fluoro-2-(4-fluorophenyl)-2,3-dihydroquinolin-4(1H)-one-5-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000099
Figure PCTCN2019078089-appb-000099
(E)-2-乙酰基-5-氟-3-((4-氟苄叉)氨基)苯甲酸叔丁酯(27.4g，76.3mmol)、碳酸铯(7.4g，22.9mmol)在乙腈(250mL)中加热到60℃反应5小时。过滤，滤液减压浓缩，残余物经硅胶层析柱(石油醚/乙酸乙酯＝4/1，v/v)纯化，得22.4g产物(收率81.8％)。MS(ESI)：358.1[M-H] -。 1H NMR(400MHz，DMSO-d6)δ7.62(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)。 (E) tert-Butyl 2-acetyl-5-fluoro-3-((4-fluorobenzylidene)amino)benzoate (27.4 g, 76.3 mmol), cesium carbonate (7.4 g, 22.9 mmol) in acetonitrile ( The reaction was heated to 60 ° C for 5 hours in 250 mL). Filtration and concentration of the filtrate under reduced pressure. The residue was purified on silica gel column ( petroleum ether/ethyl acetate=4/1, v/v) to give 22.4 g (yield: 81.8%). MS (ESI): 358.1 [MH] - . 1 H NMR (400MHz, DMSO- d6) δ7.62 (s, 1H), 7.54 (dd, J = 8.6,5.5Hz, 2H), 7.24 (t, J = 8.9Hz, 2H), 6.67 (dd, J = 9.0, 2.4 Hz, 1H), 6.38 (dd, J = 8.5, 2.4 Hz, 1H), 4.85 (dd, J = 12.1, 4.2 Hz, 1H), 2.88 (dd, J = 16.0, 12.2 Hz, 1H) , 2.67 (dd, J = 16.0, 3.8 Hz, 1H), 1.52 (s, 9H).
步骤6：N-叔丁氧基羰基-7-氟-2-(4-氟苯基)-2，3-二氢喹啉-4-酮-5-甲酸叔丁酯Step 6: N-tert-Butoxycarbonyl-7-fluoro-2-(4-fluorophenyl)-2,3-dihydroquinolin-4-one-5-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000100
Figure PCTCN2019078089-appb-000100
7-氟-2-(4-氟苯基)-2，3-二氢喹啉-4(1H)-酮-5-甲酸叔丁酯(21.4g，59.61mmol)、N，N-二异丙基乙胺(8.51g，65.97mmol)、4-二甲氨基吡啶(700mg，5.74mmol)和二碳酸二叔丁酯(14.3g，65.6mmol)溶于二氯甲烷(250mL)。室温搅拌过夜。减压浓缩，残余物经硅胶层析柱(石油醚/乙酸乙酯＝10/1，v/v)纯化得16g产物(收率58.5％)。 1H NMR(400MHz，DMSO-d6)δ7.71(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)。 7-Fluoro-2-(4-fluorophenyl)-2,3-dihydroquinolin-4(1H)-one-5-carboxylic acid tert-butyl ester (21.4 g, 59.61 mmol), N,N-diiso Propylethylamine (8.51 g, 65.97 mmol), 4-dimethylaminopyridine (700 mg, 5.74 mmol) and di-tert-butyl dicarbonate (14.3 g, 65.6 mmol) were dissolved in dichloromethane (250 mL). Stir at room temperature overnight. The organic layer was concentrated under reduced pressure. EtOAcjjjjjj 1 H NMR (400MHz, DMSO- d6) δ7.71 (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, 2.5 Hz, 1H), 6.03 (d, J = 5.2 Hz, 1H), 3.51 (dd, J = 17.8, 5.9 Hz, 1H), 3.29 (dd, J = 17.8, 2.1 Hz, 1H), 1.54 (s, 9H), 1.49 (s, 9H).
步骤7：7-氟-2-(4-氟苯基)-4-(叔丁基二甲基硅氧基)-1，2-二氢喹啉-1，5-二羧酸叔丁酯Step 7: 7-Fluoro-2-(4-fluorophenyl)-4-(tert-butyldimethylsilyloxy)-1,2-dihydroquinoline-1,5-dicarboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000101
Figure PCTCN2019078089-appb-000101
N-叔丁氧基羰基-7-氟-2-(4-氟苯基)-2，3-二氢喹啉-4-酮-5-甲酸叔丁酯(9g，19.61mmol)溶于四氢呋喃(100mL)，冷却到-70℃。滴加1mol/L的六甲基二硅基氨基锂四氢呋喃溶液(59mL，58.82mmol)，控制温度不超过-60℃。滴完后继续搅拌1小时。再滴加三氟甲磺酸叔丁基二甲硅烷酯(9.2g，34.88mmol)的四氢呋喃(50mL)溶液，控制滴加温度不超过-60℃，继续搅拌30分钟。加入饱和氯化铵(100mL)，自然升温到室温。加入乙酸乙酯(500mL)，分出有机层。有机层用饱和氯化钠溶液洗涤2次，无水硫酸镁干燥，过滤，减压浓缩，残余物经硅胶柱层析(石油醚/乙酸乙酯＝50/1，v/v)纯化得9.3g产物(收率 82.8％)。 1H NMR(400MHz，CDCl 3)δ7.39-7.32(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)。 N-tert-Butoxycarbonyl-7-fluoro-2-(4-fluorophenyl)-2,3-dihydroquinolin-4-one-5-carboxylic acid tert-butyl ester (9 g, 19.61 mmol) dissolved in tetrahydrofuran (100 mL), cooled to -70 °C. A 1 mol/L solution of hexamethyldisilazide lithium tetrahydrofuran (59 mL, 58.82 mmol) was added dropwise, and the temperature was controlled to not exceed -60 °C. Stirring was continued for 1 hour after the completion of the dropping. Further, a solution of t-butyldimethylsilane trifluoromethanesulfonate (9.2 g, 34.88 mmol) in tetrahydrofuran (50 mL) was added dropwise, and the dropwise addition temperature was controlled to -60 ° C, and stirring was continued for 30 minutes. Saturated ammonium chloride (100 mL) was added and the mixture was warmed to room temperature. Ethyl acetate (500 mL) was added and the organic layer was separated. The organic layer was washed twice with aq. EtOAc. g product (yield 82.8%). 1 H NMR (400MHz, CDCl 3 ) δ7.39-7.32 (m, 2H), 7.24-7.17 (m, 1H), 6.97-6.92 (m, 1H), 6.92-6.85 (m, 2H), 6.20 (d , J = 7.3 Hz, 1H), 5.55 (d, J = 7.5 Hz, 1H), 1.60 (s, 9H), 1.57 (s, 9H), 0.87 (s, 9H), 0.21 (s, 3H), 0.12 (s, 3H).
步骤8：7-氟-2-(4-氟苯基)-3-叔丁基二甲基硅氧基-2，3-二氢喹啉-4(1H)-酮-1，5-二羧酸叔丁酯Step 8: 7-Fluoro-2-(4-fluorophenyl)-3-tert-butyldimethylsilyl-2,3-dihydroquinolin-4(1H)-one-1,5-di Tert-butyl carboxylate
Figure PCTCN2019078089-appb-000102
Figure PCTCN2019078089-appb-000102
7-氟-2-(4-氟苯基)-4-(叔丁基二甲基硅氧基)-1，2-二氢喹啉-1，5-二羧酸叔丁酯(9g，15.71mmol)溶于二氯甲烷(70mL)中，再加入间氯过氧苯甲酸(5.4g，31.41mmol)，室温下搅拌反应5.5小时。反应液由澄清变为浑浊，过滤，二氯甲烷洗涤固体。滤液依次用10％亚硫酸氢钠溶液洗涤1次、饱和氯化钠溶液洗涤2次，无水硫酸镁干燥，过滤，减压浓缩得产物，直接用于下一步反应。MS(ESI)：590.2[M+H] +。 1H NMR(400MHz，CDCl 3)δ7.69(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)。 7-Fluoro-2-(4-fluorophenyl)-4-(tert-butyldimethylsilyloxy)-1,2-dihydroquinoline-1,5-dicarboxylic acid tert-butyl ester (9 g, 15.71 mmol) was dissolved in dichloromethane (70 mL), then m-chloroperoxybenzoic acid (5.4 g, 31.41 mmol) was added, and the reaction was stirred at room temperature for 5.5 hours. The reaction mixture turned from clarification to turbidity, filtered, and washed with dichloromethane. The filtrate was washed once with 10% sodium hydrogen sulfite solution, twice with saturated sodium chloride solution, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the product. MS (ESI): 590.2 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ7.69 (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, 2.4 Hz, 1H), 5.88 (d, J = 3.2 Hz, 1H), 4.43 (d, J = 3.5 Hz, 1H), 1.58 (s, 9H), 1.56 (s, 9H), 0.90 (s, 9H), 0.20 (s, 3H), 0.12 (s, 3H).
步骤9：5-氟-8-(4-氟苯基)-9-叔丁基二甲基硅氧基-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3-酮-7-羧酸叔丁酯Step 9: 5-Fluoro-8-(4-fluorophenyl)-9-tert-butyldimethylsilyloxy-8,9-dihydro-2H-pyrido[4,3,2-de]fluorene Pyrazin-3-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000103
Figure PCTCN2019078089-appb-000103
将上一步制备的7-氟-2-(4-氟苯基)-3-叔丁基二甲基硅氧基-2，3-二氢喹啉-4(1H)-酮-1，5-二羧酸叔丁酯中溶于甲醇(200mL)，加入80％水合肼(10mL，206mmol)，室温下反应过夜。减压浓缩，残余物经 硅胶柱层析(石油醚/乙酸乙酯＝5/1，v/v)纯化得5.1g产物(61.4％，两步收率)。MS(ESI)：530.2[M+H] +。 1H NMR(400MHz，CDCl 3)δ11.52(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)。 7-Fluoro-2-(4-fluorophenyl)-3-tert-butyldimethylsilyloxy-2,3-dihydroquinolin-4(1H)-one-1,5 prepared in the previous step The tert-butyl dicarboxylate was dissolved in methanol (200 mL), and 80% hydrazine hydrate (10 mL, 206 mmol) was added and allowed to react at room temperature overnight. The residue was purified by silica gel chromatography chromatography eluting elut elut elut elut MS (ESI): 530.2 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ11.52 (s, 1H), 8.15 (d, J = 9.3Hz, 1H), 7.75 (dd, J = 7.9,2.4Hz, 1H), 7.05 (dd, J = 8.5, 5.2 Hz, 2H), 6.93-6.85 (m, 2H), 6.07 (s, 1H), 5.14 (d, J = 3.0 Hz, 1H), 1.62 (s, 9H), 0.88 (d, J = 2.7) Hz, 9H), 0.28 (s, 3H), 0.01 (s, 3H).
步骤10：5-氟-8-(4-氟苯基)-9-羟基-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3-酮-7-羧酸叔丁酯Step 10: 5-Fluoro-8-(4-fluorophenyl)-9-hydroxy-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazin-3-one-7- Tert-butyl carboxylate
Figure PCTCN2019078089-appb-000104
Figure PCTCN2019078089-appb-000104
5-氟-8-(4-氟苯基)-9-叔丁基二甲基硅氧基-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3-酮-7-羧酸叔丁酯(2.8g，5.29mmol)溶于四氢呋喃(20mL)，加入四丁基氟化铵(2.07g，7.94mmol)，在室温下搅拌反应4.5小时。减压浓缩，残余物经硅胶层析柱(石油醚/乙酸乙酯＝1/2，v/v)纯化得到2.1g产物(收率95.7％)。MS(ESI)：416.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.75(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)。 5-fluoro-8-(4-fluorophenyl)-9-tert-butyldimethylsilyl-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3 The ketone-7-carboxylic acid tert-butyl ester (2.8 g, 5.29 mmol) was dissolved in tetrahydrofuran (20 mL), tetrabutylammonium fluoride (2.07 g, 7.94 mmol) was added, and the reaction was stirred at room temperature for 4.5 hours. The organic layer was concentrated under reduced pressure. EtOAcjjjjjj MS (ESI): 416.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.75 (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 = 3.9 Hz, 1H), 6.00-5.94 (m, 1H), 5.07-4.99 (m, 1H), 1.53 (s, 9H) ).
步骤11：5-氟-9-氯-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3-酮-7-羧酸叔丁酯(中间体1a)Step 11: 5-Fluoro-9-chloro-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazin-3-one-7- Tert-butyl carboxylate (intermediate 1a)
Figure PCTCN2019078089-appb-000105
Figure PCTCN2019078089-appb-000105
5-氟-8-(4-氟苯基)-9-羟基-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3-酮-7-羧酸叔丁酯(3.8g，9.157mmol)、三乙胺(3.8mL，27.47mmol)溶于四氢呋喃(30mL)。冷却到0℃左右，加入甲磺酰氯(0.8mL，10.34mmol)，然后在室温下反应1.5小时。加入乙酸乙酯(120mL)， 依次用10％柠檬酸溶液、饱和食盐水洗涤，无水硫酸镁干燥，过滤，减压浓缩，残余物中加入乙酸乙酯，打浆处理得2.6g白色固体(收率57.6％)。MS(ESI)：434.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.96(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)。 5-fluoro-8-(4-fluorophenyl)-9-hydroxy-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazin-3-one-7-carboxylic acid Butyl ester (3.8 g, 9.157 mmol) and triethylamine (3.8 mL, 27.47 mmol) were dissolved in tetrahydrofuran (30 mL). After cooling to about 0 ° C, methanesulfonyl chloride (0.8 mL, 10.34 mmol) was added, followed by a reaction at room temperature for 1.5 hours. Ethyl acetate (120 mL) was added, and the mixture was washed with EtOAc EtOAc. The rate is 57.6%). MS (ESI): 434.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 8.22 (dd, J = 11.7, 2.4 Hz, 1H), 7.65 (dd, J = 8.2, 2.5 Hz, 1H), 7.33 (dd , J=8.4, 5.4 Hz, 2H), 7.09 (dd, J = 12.3, 5.4 Hz, 2H), 6.23 (s, 1H), 6.08 (d, J = 2.8 Hz, 1H), 1.55 (s, 9H) .
实施例1：5-氟-8-(4-氟苯基)-9-(1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物1)Example 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyrido[4 ,3,2-de]pyridazine-3(7H)-one (Compound 1)
Figure PCTCN2019078089-appb-000106
Figure PCTCN2019078089-appb-000106
步骤1：5-氟-8-(4-氟苯基)-9-(1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000107
Figure PCTCN2019078089-appb-000107
5-氟-9-氯-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3-酮-7-羧酸叔丁酯(中间体1a，50mg，0.115mmol)、1，2，4-三氮唑(21mg，0.303mmol)和碳酸钾(41mg，0.3mmol)中加入N，N-二甲基甲酰胺(0.5mL)，室温下搅拌反应过夜。加入乙酸乙酯，依次用水、饱和食盐水洗涤，无水硫酸镁干燥，过滤，减压浓缩，残余物经制备薄层色谱纯化(石油醚/乙酸乙酯＝1/2，v/v)，得到产物39mg(收率72％)。MS(ESI)：467.1[M+H] +。 1H NMR(400MHz，CDCl 3)δ8.82(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)。 5-fluoro-9-chloro-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazin-3-one-7-carboxylic acid N,N-dimethylformamide (0.5) was added to the butyl ester (intermediate 1a, 50 mg, 0.115 mmol), 1,2,4-triazole (21 mg, 0.303 mmol) and potassium carbonate (41 mg, 0.3 mmol). (mL), the reaction was stirred at room temperature overnight. Ethyl acetate was added, and the mixture was washed with EtOAc EtOAc. The product was obtained in 39 mg (yield: 72%). MS (ESI): 467.1 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ8.82 (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, 5.4 Hz, 2H), 7.13 (dd, J = 12.2, 5.4 Hz, 2H), 6.51 (d, J = 2.3 Hz, 1H), 6.29 (s, 1H), 1.36 (s, 9H).
步骤2：5-氟-8-(4-氟苯基)-9-(1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000108
Figure PCTCN2019078089-appb-000108
5-氟-8-(4-氟苯基)-9-(1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3-酮-7-羧酸叔丁酯(36mg，0.077mmol)溶于二氯甲烷(1mL)，加入三氟乙酸(0.5mL)，室温下搅拌反应2小时。减压蒸除溶剂，残留物溶于乙酸乙酯(20mL)，依次用饱和碳酸氢钠溶液、水洗涤，无水硫酸钠干燥，过滤浓缩，残留物经制备薄层色谱纯化(二氯甲烷/甲醇＝20/1，v/v)，得产物25mg(收率88％)。MS(ESI)：367.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.51(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)。 5-fluoro-8-(4-fluorophenyl)-9-(1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyrido[4,3,2 -de] pyrazin-3-one-7-carboxylic acid tert-butyl ester (36 mg, 0.077 mmol) was dissolved in dichloromethane (1 mL), trifluoroacetic acid (0.5 mL) was added, and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure. EtOAc EtOAc m. Methanol = 20/1, v/v) gave product 25 mg (yield 88%). MS (ESI): 367.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.51 (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 = 8.7 Hz, 2H), 7.12 (dd, J = 8.9, 2.0 Hz, 1H), 6.96 (dd, J = 11.0, 2.0 Hz, 1H), 6.08 (d, J = 10.1 Hz, 1H), 5.15 (d, J = 10.1 Hz, 1H).
实施例2：5-氟-8-(4-氟苯基)-9-(5-三氟甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物2)Example 2: 5-Fluoro-8-(4-fluorophenyl)-9-(5-trifluoromethyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 2)
Figure PCTCN2019078089-appb-000109
Figure PCTCN2019078089-appb-000109
步骤1：5-氟-8-(4-氟苯基)-9-(5-三氟甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(5-trifluoromethyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000110
Figure PCTCN2019078089-appb-000110
同实施例1的步骤1。由5-三氟甲基-1H-1，2，4-三唑和中间体1a反应制备。MS(ESI)：535.1[M+H] +。 Same as step 1 of the embodiment 1. Prepared by the reaction of 5-trifluoromethyl-1H-1,2,4-triazole with intermediate 1a. MS (ESI): 535.1 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(5-三氟甲基-1H-1，2，4-三唑-1-基) -8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(5-trifluoromethyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000111
Figure PCTCN2019078089-appb-000111
同实施例1的步骤2。MS(ESI)：435.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.51(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)。 Same as step 2 of the embodiment 1. MS (ESI): 435.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.51 (s, 1H), 8.42 (s, 1H), 7.92 (s, 1H), 7.47 (dd, J = 8.5,5.5Hz, 2H), 7.20 (t , J = 8.8 Hz, 2H), 7.14 (dd, J = 8.9, 2.3 Hz, 1H), 6.98 (dd, J = 11.1, 2.4 Hz, 1H), 6.15 (d, J = 10.7 Hz, 1H), 5.26 (d, J = 10.7 Hz, 1H).
实施例3：5-氟-8-(4-氟苯基)-9-(3，5-二甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物3)Example 3: 5-Fluoro-8-(4-fluorophenyl)-9-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 3)
Figure PCTCN2019078089-appb-000112
Figure PCTCN2019078089-appb-000112
步骤1：5-氟-8-(4-氟苯基)-9-(3，5-二甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000113
Figure PCTCN2019078089-appb-000113
同实施例1的步骤1。由3，5-二甲基-1H-1，2，4-三唑和中间体1a反应制备。收率为53％。MS(ESI)：495.2[M+H] +。 1H NMR(400MHz，CDCl 3)δ11.08(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)。 Same as step 1 of the embodiment 1. It is prepared by reacting 3,5-dimethyl-1H-1,2,4-triazole with intermediate 1a. The yield was 53%. MS (ESI): 495.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 11.08 (s, 1H), 7.99 (d, J = 9.5 Hz, 1H), 7.78 (dd, J = 8.0, 2.4 Hz, 1H), 7.16 (dd, J = 8.7, 5.1 Hz, 2H), 6.98 (t, J = 8.5 Hz, 2H), 6.25 (s, 1H), 5.74 (d, J = 1.8 Hz, 1H), 2.66 (s, 3H), 2.19 (s, 3H), 1.51 (s, 9H).
步骤2：5-氟-8-(4-氟苯基)-9-(3，5-二甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000114
Figure PCTCN2019078089-appb-000114
同实施例1的步骤2。收率为80％。MS(ESI)：395.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.45(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)。 Same as step 2 of the embodiment 1. The yield was 80%. MS (ESI): 395.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.45 (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, 2.3 Hz, 1H), 6.95 (dd, J = 11.1, 2.4 Hz, 1H), 5.93 (d, J = 11.0 Hz, 1H), 5.05 (d, J = 11.0 Hz) , 1H), 2.14 (s, 3H), 2.04 (s, 3H).
实施例4：5-氟-8-(4-氟苯基)-9-(2-甲基-1H-咪唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物4)Example 4: 5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-1H-imidazol-1-yl)-8,9-dihydro-2H-pyrido[4,3 ,2-de]pyridazine-3(7H)-one (Compound 4)
Figure PCTCN2019078089-appb-000115
Figure PCTCN2019078089-appb-000115
步骤1：5-氟-8-(4-氟苯基)-9-(2-甲基-1H-咪唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-1H-imidazol-1-yl)-8,9-dihydro-2H-pyrido[4,3, 2-de]pyridazine-3(7H)-keto-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000116
Figure PCTCN2019078089-appb-000116
同实施例1的步骤1。由2-甲基-1H-咪唑和中间体1a反应制备。MS(ESI)：480.2[M+H] +。 1H NMR(400MHz，DMSO-d6)δ13.04(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)。 Same as step 1 of the embodiment 1. Prepared by the reaction of 2-methyl-1H-imidazole with intermediate 1a. MS (ESI): 480.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ13.04 (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, 5.3 Hz, 2H), 7.13 (t, J=8.8 Hz, 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).
步骤2：5-氟-8-(4-氟苯基)-9-(2-甲基-1H-咪唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-1H-imidazol-1-yl)-8,9-dihydro-2H-pyrido[4,3, 2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000117
Figure PCTCN2019078089-appb-000117
同实施例1的步骤2。MS(ESI)：380.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.48(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)。 Same as step 2 of the embodiment 1. MS (ESI): 380.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.48 (s, 1H), 7.86 (s, 1H), 7.44 (dd, J = 8.5,5.5Hz, 2H), 7.25 (s, 1H), 7.19 (t , J = 8.8 Hz, 2H), 7.12 (dd, J = 8.9, 2.4 Hz, 1H), 6.97 (dd, J = 11.1, 2.4 Hz, 1H), 6.78 (s, 1H), 5.74 (d, J = 11.1 Hz, 1H), 5.03 (d, J = 11.1 Hz, 1H), 1.96 (s, 3H).
实施例5：5-氟-8-(4-氟苯基)-9-(3-三氟甲基-5，6-二氢-[1，2，4]三唑[4，3-a]吡嗪-7(8H)-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物5)Example 5: 5-Fluoro-8-(4-fluorophenyl)-9-(3-trifluoromethyl-5,6-dihydro-[1,2,4]triazole [4,3-a Pyrazin-7(8H)-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 5)
Figure PCTCN2019078089-appb-000118
Figure PCTCN2019078089-appb-000118
步骤1：5-氟-8-(4-氟苯基)-9-(3-三氟甲基-5，6-二氢-[1，2，4]三唑[4，3-a]吡嗪-7(8H)-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(3-trifluoromethyl-5,6-dihydro-[1,2,4]triazole [4,3-a] Pyrazin-7(8H)-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000119
Figure PCTCN2019078089-appb-000119
同实施例1的步骤1。由3-(三氟甲基)-5，6，7，8-四氢-[1，2，4]三唑并[4，3-a]吡嗪盐酸盐和中间体1a反应制备。MS(ESI)：590.2[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.85(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)。 Same as step 1 of the embodiment 1. Prepared by the reaction of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride and Intermediate 1a. MS (ESI): 590.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.85 (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, 5.4 Hz, 2H), 7.06 (dd, J = 12.3, 5.4 Hz, 2H), 6.36 (s, 1H), 4.41 (d, J = 2.5 Hz, 1H), 4.24 (d, J = 15.6 Hz, 1H), 4.15-4.04 (m, 2H), 4.04-3.96 (m, 1H), 3.27 (dt, J = 18.6, 5.7 Hz, 1H), 3.18-3.09 (m, 1H), 1.45 (s) , 9H).
步骤2：5-氟-8-(4-氟苯基)-9-(3-三氟甲基-5，6-二氢-[1，2，4]三唑[4，3-a]吡嗪-7(8H)-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(3-trifluoromethyl-5,6-dihydro-[1,2,4]triazole [4,3-a] Pyrazin-7(8H)-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000120
Figure PCTCN2019078089-appb-000120
同实施例1的步骤2。MS(ESI)：490.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.53(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)。 Same as step 2 of the embodiment 1. MS (ESI): 490.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.53 (s, 1H), 7.81 (d, J = 2.1Hz, 1H), 7.38 (dd, J = 8.7,5.5Hz, 2H), 7.15 (t, J = 8.8 Hz, 2H), 7.01 (dd, J = 9.0, 2.4 Hz, 1H), 6.93 (dd, J = 11.2, 2.4 Hz, 1H), 5.09 (dd, J = 4.8, 2.1 Hz, 1H), 4.33 (d, J = 15.7 Hz, 1H), 4.21 (d, J = 5.2 Hz, 1H), 4.16 (d, J = 15.7 Hz, 1H), 4.03 (dd, J = 8.8, 3.5 Hz, 2H), 3.40 -3.31 (m, 1H), 3.13 - 3.02 (m, 1H).
实施例6：5-氟-8-(4-氟苯基)-9-(1H-吲唑基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物6)Example 6: 5-Fluoro-8-(4-fluorophenyl)-9-(1H-carbazolyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine -3(7H)-one (Compound 6)
Figure PCTCN2019078089-appb-000121
Figure PCTCN2019078089-appb-000121
步骤1：5-氟-8-(4-氟苯基)-9-(1H-吲唑基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1H-carbazolyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine- 3(7H)-keto-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000122
Figure PCTCN2019078089-appb-000122
同实施例1的步骤1。由吲唑和中间体1a反应制备。收率为46％。MS(ESI)：516.2[M+H] +。 1H NMR(400MHz，CDCl 3)δ11.16(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)。 Same as step 1 of the embodiment 1. It is prepared by reacting carbazole with intermediate 1a. The yield was 46%. MS (ESI): 516.2 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ11.16 (s, 1H), 8.12 (d, J = 9.2Hz, 1H), 7.82 (dd, J = 7.9,2.4Hz, 1H), 7.71 (d, J = 8.7 Hz, 1H), 7.59 (s, 1H), 7.54 (d, J = 8.5 Hz, 1H), 7.33 - 7.29 (m, 1H), 7.23 (dd, J = 8.5, 5.1 Hz, 2H), 7.06 ( Dd, J = 8.0, 7.0 Hz, 1H), 6.98 (t, J = 8.6 Hz, 2H), 6.73 (s, 1H), 6.31 (d, J = 2.3 Hz, 1H), 1.22 (s, 9H).
步骤2：5-氟-8-(4-氟苯基)-9-(1H-吲唑基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1H-carbazolyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine- 3(7H)-ketone
Figure PCTCN2019078089-appb-000123
Figure PCTCN2019078089-appb-000123
同实施例1的步骤2。MS(ESI)：416.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.45(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)。 Same as step 2 of the embodiment 1. MS (ESI): 416.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.45 (s, 1H), 8.33 (s, 1H), 7.87 (s, 1H), 7.64 (d, J = 8.4Hz, 1H), 7.60-7.54 (d , J=8.8 Hz, 1H), 7.47 (dd, J=8.6, 5.5 Hz, 2H), 7.24-7.17 (m, 1H), 7.16-7.09 (m, 3H), 7.03-6.96 (m, 2H), 6.24 (d, J = 9.4 Hz, 1H), 5.43 (d, J = 9.5 Hz, 1H).
实施例7：5-氟-8-(4-氟苯基)-9-(吡咯烷-2，5-二酮-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物7)Example 7: 5-Fluoro-8-(4-fluorophenyl)-9-(pyrrolidine-2,5-dione-1-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one (compound 7)
Figure PCTCN2019078089-appb-000124
Figure PCTCN2019078089-appb-000124
步骤1：5-氟-8-(4-氟苯基)-9-(吡咯烷-2，5-二酮-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(pyrrolidine-2,5-dione-1-yl)-8,9-dihydro-2H-pyrido[4,3 ,2-de]pyridazine-3(7H)-keto-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000125
Figure PCTCN2019078089-appb-000125
同实施例1的步骤1。由琥珀酰亚胺和中间体1a反应制备。MS(ESI)：497.1[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting succinimide with intermediate 1a. MS (ESI): 497.1 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(吡咯烷-2，5-二酮-1-基)-8，9-二氢 -2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(pyrrolidine-2,5-dione-1-yl)-8,9-dihydro-2H-pyrido[4,3 ,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000126
Figure PCTCN2019078089-appb-000126
同实施例1的步骤2。MS(ESI)：397.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.46(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)。 Same as step 2 of the embodiment 1. MS (ESI): 397.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.46 (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, 2.4 Hz, 1H), 6.92 (dd, J = 11.1, 2.4 Hz, 1H), 5.35 (d, J = 11.5 Hz, 1H), 5.11 (d, J = 11.5 Hz) , 1H), 2.77-2.54 (m, 4H).
实施例8：5-氟-8-(4-氟苯基)-9-(4，7-环氧六氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物8)Example 8: 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxyhexahydroisoindol-1,3(2H)-dione-2-yl)-8, 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 8)
Figure PCTCN2019078089-appb-000127
Figure PCTCN2019078089-appb-000127
步骤1：5-氟-8-(4-氟苯基)-9-(4，7-环氧六氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxyhexahydroisoindol-1,3(2H)-dione-2-yl)-8,9 -Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000128
Figure PCTCN2019078089-appb-000128
同实施例1的步骤1。由4，7-环氧六氢异吲哚-1，3(2H)-二酮和中间体1a反应制备。MS(ESI)：565.1[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 4,7-epoxyhexahydroisoindol-1,3(2H)-dione with intermediate 1a. MS (ESI): 565.1 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(4，7-环氧六氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxyhexahydroisoindol-1,3(2H)-dione-2-yl)-8,9 -dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000129
Figure PCTCN2019078089-appb-000129
同实施例1的步骤2。MS(ESI)：465.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.44(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)。 Same as step 2 of the embodiment 1. MS (ESI): 465.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.44 (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, 2.3 Hz, 1H), 6.90 (dd, J = 11.1, 2.3 Hz, 1H), 5.29 (d, J = 11.4 Hz, 1H), 5.03 (d, J = 11.5 Hz) , 1H), 4.65 (s, 1H), 4.37 (s, 1H), 3.07 (d, J = 7.2 Hz, 1H), 2.99 (d, J = 7.2 Hz, 1H), 1.65-1.48 (m, 4H) .
实施例9：5-氟-8-(4-氟苯基)-9-(4，7-环氧-3a，4，7，7a-四氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物9)Example 9: 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxy-3a,4,7,7a-tetrahydroisoindol-1,3(2H)-di Keto-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 9)
Figure PCTCN2019078089-appb-000130
Figure PCTCN2019078089-appb-000130
步骤1：5-氟-8-(4-氟苯基)-9-(4，7-环氧-3a，4，7，7a-四氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxy-3a,4,7,7a-tetrahydroisoindole-1,3(2H)-dione 2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000131
Figure PCTCN2019078089-appb-000131
同实施例1的步骤1。由4，7-环氧-3a，4，7，7a-四氢异吲哚-1，3(2H)-二酮和中间体1a反应制备。MS(ESI)：563.1[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 4,7-epoxy-3a,4,7,7a-tetrahydroisoindole-1,3(2H)-dione with intermediate 1a. MS (ESI): 563.1 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(4，7-环氧-3a，4，7，7a-四氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxy-3a,4,7,7a-tetrahydroisoindol-1,3(2H)-dione -2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000132
Figure PCTCN2019078089-appb-000132
同实施例1的步骤2。MS(ESI)：463.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.45(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)。 Same as step 2 of the embodiment 1. MS (ESI): 463.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.45 (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, 2.4 Hz, 1H), 6.91 (dd, J = 11.1, 2.4 Hz, 1H), 6.50 (qd, J = 5.7, 1.5 Hz, 2H), 5.33 (d, J = 11.3 Hz, 1H), 5.10 (s, 1H), 5.04 (d, J = 11.4 Hz, 1H), 4.84 (s, 1H), 2.99 (d, J = 6.6 Hz, 1H), 2.89 (d, J = 6.6 Hz, 1H).
实施例10：5-氟-8-(4-氟苯基)-9-(4，7-环氧-5-羟基六氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物10)Example 10: 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxy-5-hydroxyhexahydroisoindol-1,3(2H)-dione-2-yl )-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 10)
Figure PCTCN2019078089-appb-000133
Figure PCTCN2019078089-appb-000133
步骤1：5-氟-8-(4-氟苯基)-9-(4，7-环氧-5羟基六氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxy-5hydroxyhexahydroisoindole-1,3(2H)-dione-2-yl)- 8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000134
Figure PCTCN2019078089-appb-000134
同实施例1的步骤1。由4，7-环氧-5羟基六氢异吲哚-1，3(2H)-二酮和中间体1a反应制备。MS(ESI)：581.1[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 4,7-epoxy-5hydroxyhexahydroisoindol-1,3(2H)-dione with Intermediate 1a. MS (ESI): 581.1 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(4，7-环氧-5-羟基六氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-epoxy-5-hydroxyhexahydroisoindol-1,3(2H)-dione-2-yl) -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000135
Figure PCTCN2019078089-appb-000135
同实施例1的步骤2。MS(ESI)：481.1[M+H] +。 1H NMR(400MHz，DMSO)δ12.46(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)。 Same as step 2 of the embodiment 1. MS (ESI): 481.1 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.46 (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, 2.4 Hz, 1H), 6.91 (dd, J = 11.1, 2.4 Hz, 1H), 5.31 (d, J = 11.5 Hz, 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).
实施例11：5-氟-8-(4-氟苯基)-9-(异吲哚-1，3-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物11)Example 11: 5-Fluoro-8-(4-fluorophenyl)-9-(isoindole-1,3-dione-2-yl)-8,9-dihydro-2H-pyrido[4 ,3,2-de]pyridazine-3(7H)-one (Compound 11)
Figure PCTCN2019078089-appb-000136
Figure PCTCN2019078089-appb-000136
步骤1：5-氟-8-(4-氟苯基)-9-(异吲哚-1，3-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(isoindole-1,3-dione-2-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000137
Figure PCTCN2019078089-appb-000137
同实施例1的步骤1。由邻苯二甲酰亚胺钾盐和中间体1a反应制备。收率为33％。MS(ESI)：545.2[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.99(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)。 Same as step 1 of the embodiment 1. It is prepared by reacting potassium phthalimide with intermediate 1a. The yield was 33%. MS (ESI): 545.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.99 (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).
步骤2：5-氟-8-(4-氟苯基)-9-(异吲哚-1，3-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(isoindole-1,3-dione-2-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000138
Figure PCTCN2019078089-appb-000138
同实施例1的步骤2。收率为59％。MS(ESI)：445.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.39(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)。 Same as step 2 of the embodiment 1. The yield was 59%. MS (ESI): 445.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.39 (s, 1H), 7.88 (m, 4H), 7.74 (s, 1H), 7.53 (dd, J = 8.3,5.5Hz, 2H), 7.20 (t , J = 8.7 Hz, 2H), 7.12 (dd, J = 8.9, 2.1 Hz, 1H), 6.94 (dd, J = 11.1, 2.1 Hz, 1H), 5.60 (d, J = 11.8 Hz, 1H), 5.23 (d, J = 11.8 Hz, 1H).
实施例12：5-氟-8-(4-氟苯基)-9-(2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物12)Example 12: 5-Fluoro-8-(4-fluorophenyl)-9-(2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4,3 ,2-de]pyridazine-3(7H)-one (Compound 12)
Figure PCTCN2019078089-appb-000139
Figure PCTCN2019078089-appb-000139
步骤1：5-氟-8-(4-氟苯基)-9-(2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4,3, 2-de]pyridazine-3(7H)-keto-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000140
Figure PCTCN2019078089-appb-000140
同实施例1的步骤1。由2，4-咪唑啉二酮和中间体1a反应制备。MS(ESI)：498.2[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.95(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)。 Same as step 1 of the embodiment 1. It is prepared by reacting 2,4-imidazolidinone with Intermediate 1a. MS (ESI): 498.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.95 (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, 5.4 Hz, 2H), 7.15-7.08 (m, 2H), 6.13 (s, 1H), 5.46 (d, J = 1.8 Hz, 1H), 4.03 (d, J = 18.1 Hz, 1H), 3.90 (d, J = 18.1 Hz, 1H), 1.47 (s, 9H).
步骤2：5-氟-8-(4-氟苯基)-9-(2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(2,4-imidazolidin-2-one-3-yl)-8,9-dihydro-2H-pyrido[4,3, 2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000141
Figure PCTCN2019078089-appb-000141
同实施例1的步骤2。MS(ESI)：398.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.50(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)。 Same as step 2 of the embodiment 1. MS (ESI): 398.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.50 (s, 1H), 8.20 (s, 1H), 7.66 (s, 1H), 7.51 (dd, J = 8.5,5.5Hz, 2H), 7.27 (t , J = 8.8 Hz, 2H), 7.11 (dd, J = 8.9, 2.3 Hz, 1H), 6.92 (dd, J = 11.1, 2.4 Hz, 1H), 5.27 (d, J = 11.7 Hz, 1H), 5.17 (d, J = 11.7 Hz, 1H), 3.95 (d, J = 18.3 Hz, 1H), 3.88 (d, J = 18.4 Hz, 1H).
实施例13：5-氟-8-(4-氟苯基)-9-(1-甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物13)Example 13: 5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one (compound 13)
Figure PCTCN2019078089-appb-000142
Figure PCTCN2019078089-appb-000142
步骤1：5-氟-8-(4-氟苯基)-9-(1-甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000143
Figure PCTCN2019078089-appb-000143
同实施例1的步骤1。由1-甲基-2，4-咪唑啉二酮和中间体1a反应制备。收率为45％。MS(ESI)：512.2[M+H] +。 1H NMR(400MHz，CDCl 3)δ10.90(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)。 Same as step 1 of the embodiment 1. It is prepared by reacting 1-methyl-2,4-imidazolidinone with Intermediate 1a. The yield was 45%. MS (ESI): 512.2 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ10.90 (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, 5.2 Hz, 2H), 6.97-6.90 (m, 2H), 6.28 (s, 1H), 5.64 (d, J = 1.7 Hz, 1H), 3.93 (d, J = 17.5 Hz, 1H), 3.86 (d, J = 17.5 Hz, 1H), 2.98 (s, 3H), 1.55 (s, 9H).
步骤2：5-氟-8-(4-氟苯基)-9-(1-甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000144
Figure PCTCN2019078089-appb-000144
同实施例1的步骤2。MS(ESI)：412.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.46(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)。 Same as step 2 of the embodiment 1. MS (ESI): 412.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.46 (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, 2.4 Hz, 1H), 6.92 (dd, J = 11.1, 2.4 Hz, 1H), 5.30 (d, J = 11.6 Hz, 1H), 5.16 (d, J = 11.6 Hz) , 1H), 4.04 ((d, J = 18.4 Hz, 1H), 3.96 (d, J = 18.4 Hz, 1H), 2.81 (s, 3H).
手性拆分化合物13得到(8R，9R)-5-氟-8-(4-氟苯基)-9-(1-甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物13a)和(8S，9S)-5-氟-8-(4-氟苯基)-9-(1-甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物13b)Chiral resolution of compound 13 affords (8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4-imidazolidin-2-one)-8 ,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 13a) and (8S,9S)-5-Fluoro-8-(4-fluorobenzene 9-(1-methyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3 ( 7H)-ketone (compound 13b)
Figure PCTCN2019078089-appb-000145
Figure PCTCN2019078089-appb-000145
将5-氟-8-(4-氟苯基)-9-(1-甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物13)溶解在甲醇/二氯甲烷混合溶剂中，采用超临界流体色谱(SFC)进行手性拆分得到一对对映异构体。手性柱为
Figure PCTCN2019078089-appb-000146
Cellulose-2，洗脱剂为二氧化碳(55％)和甲醇(45％，含0.1％氨水)。 5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4] , 3,2-de]pyridazine-3(7H)-one (compound 13) was dissolved in a methanol/dichloromethane mixed solvent and subjected to chiral resolution by supercritical fluid chromatography (SFC) to obtain a pair of enantiomers. Structure. Chiral column
Figure PCTCN2019078089-appb-000146
Cellulose-2, eluent is carbon dioxide (55%) and methanol (45%, containing 0.1% ammonia).
实施例14：5-氟-8-(4-氟苯基)-9-(1-异丙基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物14)Example 14: 5-Fluoro-8-(4-fluorophenyl)-9-(1-isopropyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 14)
Figure PCTCN2019078089-appb-000147
Figure PCTCN2019078089-appb-000147
步骤1：5-氟-8-(4-氟苯基)-9-(1-异丙基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1-isopropyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000148
Figure PCTCN2019078089-appb-000148
同实施例1的步骤1。由1-异丙基-2，4-咪唑啉二酮和中间体1a反应制备。MS(ESI)：540.2[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 1-isopropyl-2,4-imidazolidinone with Intermediate 1a. MS (ESI): 540.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(1-异丙基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1-isopropyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000149
Figure PCTCN2019078089-appb-000149
同实施例1的步骤2。MS(ESI)：440.2[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.46(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)。 Same as step 2 of the embodiment 1. MS (ESI): 440.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.46 (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, 2.3 Hz, 1H), 6.92 (dd, J = 11.1, 2.3 Hz, 1H), 5.25 (d, J = 11.6 Hz, 1H), 5.12 (d, J = 11.6 Hz) , 1H), 4.06-4.01 (m, 1H), 4.00-3.85 (m, 2H), 1.07 (d, J = 6.7 Hz, 3H), 1.01 (d, J = 6.7 Hz, 3H).
实施例15：5-氟-8-(4-氟苯基)-9-(1-(2-羟乙基)-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物15)Example 15: 5-Fluoro-8-(4-fluorophenyl)-9-(1-(2-hydroxyethyl)-2,4-imidazolidin-2-one)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 15)
Figure PCTCN2019078089-appb-000150
Figure PCTCN2019078089-appb-000150
步骤1：5-氟-8-(4-氟苯基)-9-(1-(2-羟乙基)-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1-(2-hydroxyethyl)-2,4-imidazolinedion-3-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000151
Figure PCTCN2019078089-appb-000151
同实施例1的步骤1。由1-(2-羟乙基)-2，4-咪唑啉二酮和中间体1a反应制备。MS(ESI)：542.1[M+H] +。 Same as step 1 of the embodiment 1. Prepared by the reaction of 1-(2-hydroxyethyl)-2,4-imidazolidinone with Intermediate 1a. MS (ESI): 542.1 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(1-(2-羟乙基)-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1-(2-hydroxyethyl)-2,4-imidazolinedion-3-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000152
Figure PCTCN2019078089-appb-000152
同实施例1的步骤2。MS(ESI)：442.1[M+H] +。 1H NMR(400MHz，DMSO)δ12.48(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)。 Same as step 2 of the embodiment 1. MS (ESI): 442.1 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.48 (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, 2.3 Hz, 1H), 7.00-6.85 (m, 1H), 5.27 (d, J = 11.5 Hz, 1H), 5.14 (d, J = 11.5 Hz, 1H), 4.82 (t , J = 5.0 Hz, 1H), 4.13 - 3.92 (m, 2H), 3.52-3.42 (m, 2H), 3.32-3.15 (m, 2H).
实施例16：5-氟-8-(4-氟苯基)-9-(1-环丙基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物16)Example 16: 5-Fluoro-8-(4-fluorophenyl)-9-(1-cyclopropyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 16)
Figure PCTCN2019078089-appb-000153
Figure PCTCN2019078089-appb-000153
步骤1：5-氟-8-(4-氟苯基)-9-(1-环丙基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1-cyclopropyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000154
Figure PCTCN2019078089-appb-000154
同实施例1的步骤1。由1-环丙基-2，4-咪唑啉二酮和中间体1a反应制备。MS(ESI)：538.1[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 1-cyclopropyl-2,4-imidazolidinone with Intermediate 1a. MS (ESI): 538.1 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(1-环丙基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1-cyclopropyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000155
Figure PCTCN2019078089-appb-000155
同实施例1的步骤2。MS(ESI)：438.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.47(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)。 Same as step 2 of the embodiment 1. MS (ESI): 438.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.47 (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, 2.4 Hz, 1H), 6.92 (dd, J = 11.1, 2.4 Hz, 1H), 5.26 (d, J = 11.5 Hz, 1H), 5.12 (d, J = 11.5 Hz) , 1H), 4.05-3.90 (m, 2H), 2.65-2.55 (m, 1H), 0.72-0.52 (m, 4H).
实施例17：5-氟-8-(4-氟苯基)-9-(1-环戊基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物17)Example 17: 5-Fluoro-8-(4-fluorophenyl)-9-(1-cyclopentyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 17)
Figure PCTCN2019078089-appb-000156
Figure PCTCN2019078089-appb-000156
步骤1：5-氟-8-(4-氟苯基)-9-(1-环戊基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1-cyclopentyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000157
Figure PCTCN2019078089-appb-000157
同实施例1的步骤1。由1-环戊基-2，4-咪唑啉二酮和中间体1a反应制备。MS(ESI)：566.2[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 1-cyclopentyl-2,4-imidazolidinone with Intermediate 1a. MS (ESI): 566.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(1-环戊基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1-cyclopentyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000158
Figure PCTCN2019078089-appb-000158
同实施例1的步骤2。MS(ESI)：466.2[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.46(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)。 Same as step 2 of the embodiment 1. MS (ESI): 466.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.46 (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, 2.3 Hz, 1H), 6.92 (dd, J = 11.1, 2.3 Hz, 1H), 5.25 (d, J = 11.6 Hz, 1H), 5.13 (d, J = 11.6 Hz) , 1H), 4.17 (p, J = 7.1, 6.7 Hz, 1H), 4.07-3.89 (m, 2H), 1.82-1.36 (m, 8H).
实施例18：5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物18)Example 18: 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-imidazolidin-2-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 18)
Figure PCTCN2019078089-appb-000159
Figure PCTCN2019078089-appb-000159
步骤1：5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000160
Figure PCTCN2019078089-appb-000160
同实施例1的步骤1。由5，5-二甲基-2，4-咪唑啉二酮和中间体1a反应制备。收率为35％。MS(ESI)：526.1[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 5,5-dimethyl-2,4-imidazolidinone with Intermediate 1a. The yield was 35%. MS (ESI): 526.1 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000161
Figure PCTCN2019078089-appb-000161
同实施例1的步骤2。收率为35％。MS(ESI)：426.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.48(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)。 Same as step 2 of the embodiment 1. The yield was 35%. MS (ESI): 426.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.48 (s, 1H), 8.34 (s, 1H), 7.66 (s, 1H), 7.49 (dd, J = 8.4,5.6Hz, 2H), 7.28 (t , J = 8.8 Hz, 2H), 7.11 (dd, J = 8.9, 2.3 Hz, 1H), 6.92 (dd, J = 11.1, 2.3 Hz, 1H), 5.19 (d, J = 11.8 Hz, 1H), 5.15 (d, J = 11.8 Hz, 1H), 1.19 (s, 3H), 1.08 (s, 3H).
手性拆分化合物18得到(8R，9R)-5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物18a)和(8S，9S)-5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物18b)Chiral resolution of compound 18 affords (8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-imidazolidin-2-one-3-yl )-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (compound 18a) and (8S,9S)-5-fluoro-8-(4) -fluorophenyl)-9-(5,5-dimethyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de Pyridazine-3(7H)-one (compound 18b)
Figure PCTCN2019078089-appb-000162
Figure PCTCN2019078089-appb-000162
将5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物18)溶解在甲醇/二甲亚砜混合溶剂中，采用超临界流体色谱(SFC)进行手性拆分得到一对对映异构体。手性柱为
Figure PCTCN2019078089-appb-000163
Cellulose-2，洗脱剂为二氧化碳(60％)和甲醇(40％，含0.1％氨水)。 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one (Compound 18) was dissolved in methanol/dimethyl sulfoxide mixed solvent and chiral resolution by supercritical fluid chromatography (SFC). Enantiomers. Chiral column
Figure PCTCN2019078089-appb-000163
Cellulose-2, eluent is carbon dioxide (60%) and methanol (40%, containing 0.1% ammonia).
实施例19：5-氟-8-(4-氟苯基)-9-(1，5，5-三甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物19)Example 19: 5-Fluoro-8-(4-fluorophenyl)-9-(1,5,5-trimethyl-2,4-imidazolidin-2-one)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 19)
Figure PCTCN2019078089-appb-000164
Figure PCTCN2019078089-appb-000164
步骤1：5-氟-8-(4-氟苯基)-9-(1，5，5-三甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1,5,5-trimethyl-2,4-imidazolidin-2-one)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000165
Figure PCTCN2019078089-appb-000165
同实施例1的步骤1。由1，5，5-三甲基-2，4-咪唑啉二酮和中间体1a反应制备。收率为74％。MS(ESI)：540.2[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 1,5,5-trimethyl-2,4-imidazolidinone with Intermediate 1a. The yield was 74%. MS (ESI): 540.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(1，5，5-三甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1,5,5-trimethyl-2,4-imidazolidin-2-one)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000166
Figure PCTCN2019078089-appb-000166
同实施例1的步骤2。MS(ESI)：440.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.46(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)。 Same as step 2 of the embodiment 1. MS (ESI): 440.1 [M + H] +. 1 H NMR (400MHz, DMSO- d6) δ12.46 (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, 2.4 Hz, 1H), 6.92 (dd, J = 11.1, 2.4 Hz, 1H), 5.25 (d, J = 11.7 Hz, 1H), 5.15 (d, J = 11.8 Hz) , 1H), 2.74 (s, 3H), 1.21 (s, 3H), 1.09 (s, 3H).
实施例20：5-氟-8-(4-氟苯基)-9-(1-异丙基-5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物20)Example 20: 5-Fluoro-8-(4-fluorophenyl)-9-(1-isopropyl-5,5-dimethyl-2,4-imidazolinedion-3-yl)-8 ,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 20)
Figure PCTCN2019078089-appb-000167
Figure PCTCN2019078089-appb-000167
步骤1：5-氟-8-(4-氟苯基)-9-(1-异丙基-5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1-isopropyl-5,5-dimethyl-2,4-imidazolidindione-3-yl)-8, 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000168
Figure PCTCN2019078089-appb-000168
同实施例1的步骤1。由1-异丙基-5，5-二甲基-2，4-咪唑啉二酮和中间体1a反应制备。收率为41％。MS(ESI)：568.2[M+H] +。 Same as step 1 of the embodiment 1. Prepared by the reaction of 1-isopropyl-5,5-dimethyl-2,4-imidazolidinone with Intermediate 1a. The yield was 41%. MS (ESI): 568.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(1-异丙基-5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1-isopropyl-5,5-dimethyl-2,4-imidazolidindione-3-yl)-8, 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000169
Figure PCTCN2019078089-appb-000169
同实施例1的步骤2。MS(ESI)：468.2[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.47(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)。 Same as step 2 of the embodiment 1. MS (ESI): 468.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.47 (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, 2.4 Hz, 1H), 6.92 (dd, J = 11.1, 2.4 Hz, 1H), 5.21 (d, J = 11.7 Hz, 1H), 5.12 (d, J = 11.7 Hz) , 1H), 3.52 (dt, J = 13.5, 6.7 Hz, 1H), 1.29 (d, J = 6.7 Hz, 3H), 1.20 (s, 3H), 1.16 (d, J = 6.7 Hz, 3H), 1.06 (s, 3H).
实施例21：5-氟-8-(4-氟苯基)-9-(5-甲基-5-苯基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物21)Example 21: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-5-phenyl-2,4-imidazolidin-2-one)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 21)
Figure PCTCN2019078089-appb-000170
Figure PCTCN2019078089-appb-000170
步骤1：5-氟-8-(4-氟苯基)-9-(5-甲基-5-苯基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-5-phenyl-2,4-imidazolidin-2-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000171
Figure PCTCN2019078089-appb-000171
同实施例1的步骤1。由5-甲基-5-苯基-2，4-咪唑啉二酮和中间体1a反应制备。MS(ESI)：588.2[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 5-methyl-5-phenyl-2,4-imidazolidinone with Intermediate 1a. MS (ESI): 588.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(5-甲基-5-苯基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-5-phenyl-2,4-imidazolidin-2-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000172
Figure PCTCN2019078089-appb-000172
同实施例1的步骤2。MS(ESI)：488.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.54(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)。 Same as step 2 of the embodiment 1. MS (ESI): 488.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.54 (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, 2.4 Hz, 1H), 6.91 (dd, J = 11.1, 2.4 Hz, 1H), 5.27 (d, J = 11.8 Hz, 1H), 5.20 (d, J=11.8 Hz, 1H), 1.60 (s, 3H).
实施例22：5-氟-8-(4-氟苯基)-9-((7aS)-四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物22)Example 22: 5-Fluoro-8-(4-fluorophenyl)-9-((7aS)-tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione -2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 22)
Figure PCTCN2019078089-appb-000173
Figure PCTCN2019078089-appb-000173
步骤1：5-氟-8-(4-氟苯基)-9-((7aS)-四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-((7aS)-tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione- 2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000174
Figure PCTCN2019078089-appb-000174
同实施例1的步骤1。由(7aS)-四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮和中间体1a反应制备。MS(ESI)：538.2[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting (7aS)-tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione with Intermediate 1a. MS (ESI): 538.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-((7aS)-四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-((7aS)-tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione- 2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000175
Figure PCTCN2019078089-appb-000175
同实施例1的步骤2。MS(ESI)：438.1[M+H] +。 Same as step 2 of the embodiment 1. MS (ESI): 438.1 [M+H] + .
实施例23：5-氟-8-(4-氟苯基)-9-((S)-7a-甲基四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物23)Example 23: 5-Fluoro-8-(4-fluorophenyl)-9-((S)-7a-methyltetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3 (2H )-Dione-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 23)
Figure PCTCN2019078089-appb-000176
Figure PCTCN2019078089-appb-000176
步骤1：5-氟-8-(4-氟苯基)-9-((S)-7a-甲基四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-((S)-7a-methyltetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H) -dione-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000177
Figure PCTCN2019078089-appb-000177
同实施例1的步骤1。由(S)-7a-甲基四氢-1H-吡咯并[1，2-c]咪唑 -1，3(2H)-二酮和中间体1a反应制备。收率为68％。MS(ESI)：552.2[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting (S)-7a-methyltetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione with Intermediate 1a. The yield was 68%. MS (ESI): 552.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-((S)-7a-甲基四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-((S)-7a-methyltetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H) -dione-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000178
Figure PCTCN2019078089-appb-000178
同实施例1的步骤2。收率为33％。MS(ESI)：452.2[M+H] +。 Same as step 2 of the embodiment 1. The yield was 33%. MS (ESI): 452.2 [M+H] + .
实施例24：5-氟-8-(4-氟苯基)-9-((6R，7aS)-6-羟基四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物24)Example 24: 5-Fluoro-8-(4-fluorophenyl)-9-((6R,7aS)-6-hydroxytetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3 ( 2H)-dione-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 24)
Figure PCTCN2019078089-appb-000179
Figure PCTCN2019078089-appb-000179
步骤1：5-氟-8-(4-氟苯基)-9-((6R，7aS)-6-羟基四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-((6R,7aS)-6-hydroxytetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3 (2H )-Dione-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000180
Figure PCTCN2019078089-appb-000180
同实施例1的步骤1。由(6R，7aS)-6-羟基四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮和中间体1a反应制备。MS(ESI)：554.2[M+H] +。 Same as step 1 of the embodiment 1. Prepared by the reaction of (6R,7aS)-6-hydroxytetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione with Intermediate 1a. MS (ESI): 554.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-((6R，7aS)-6-羟基四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-((6R,7aS)-6-hydroxytetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3 (2H )-dione-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000181
Figure PCTCN2019078089-appb-000181
同实施例1的步骤2。MS(ESI)：454.1[M+H] +。 Same as step 2 of the embodiment 1. MS (ESI): 454.1 [M+H] + .
实施例25：5-氟-8-(4-氟苯基)-9-(1，3-二氮杂螺[3.4]辛烷-6，8-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物25)Example 25: 5-Fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[3.4]octane-6,8-dione-3-yl)-8,9 -Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 25)
Figure PCTCN2019078089-appb-000182
Figure PCTCN2019078089-appb-000182
步骤1：5-氟-8-(4-氟苯基)-9-(1，3-二氮杂螺[3.4]辛烷-6，8-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[3.4]octane-6,8-dione-3-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000183
Figure PCTCN2019078089-appb-000183
同实施例1的步骤1。由1，3-二氮杂螺[3.4]辛烷-6，8-二酮和中间体1a反应制备。收率为52％。MS(ESI)：536.2[M-H] -。 1H NMR(400MHz，CDCl 3)δ11.07(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)。 Same as step 1 of the embodiment 1. It is prepared by reacting 1,3-diazaspiro[3.4]octane-6,8-dione with intermediate 1a. The yield was 52%. MS (ESI): 536.2 [MH] - . 1 H NMR (400 MHz, CDCl 3 ) δ 11.07 (s, 1H), 7.98 (dd, J = 10.9, 2.3 Hz, 1H), 7.75 (dd, J = 8.0, 2.4 Hz, 1H), 7.18 (dd, J = 8.4, 5.2 Hz, 2H), 6.93 (t, J = 8.6 Hz, 2H), 6.43 (s, 1H), 6.27 (s, 1H), 5.60 (d, J = 1.6 Hz, 1H), 2.56 ( Dd, J = 10.5, 6.6 Hz, 2H), 2.36 (dd, J = 11.7, 6.6 Hz, 2H), 2.14-1.98 (m, 1H), 1.88-1.75 (m, 1H), 1.55 (s, 9H) .
步骤2：5-氟-8-(4-氟苯基)-9-(1，3-二氮杂螺[3.4]辛烷-6，8-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[3.4]octane-6,8-dione-3-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000184
Figure PCTCN2019078089-appb-000184
同实施例1的步骤2。MS(ESI)：438.2[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.46(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)。 Same as step 2 of the embodiment 1. MS (ESI): 438.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.46 (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 = 11.7 Hz, 1H), 2.35-2.15 (m, 3H), 2.01 (dd, J = 14.1, 6.8 Hz, 1H), 1.85 (dd, J = 19.0, 9.8 Hz, 1H), 1.76- 1.65 (m, 1H).
实施例26：5-氟-8-(4-氟苯基)-9-(1，3-二氮杂螺[4.4]壬烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物26)Example 26: 5-Fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[4.4]nonane-2,4-dione-3-yl)-8,9 -Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 26)
Figure PCTCN2019078089-appb-000185
Figure PCTCN2019078089-appb-000185
步骤1：5-氟-8-(4-氟苯基)-9-(1，3-二氮杂螺[4.4]壬烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[4.4]nonane-2,4-dione-3-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000186
Figure PCTCN2019078089-appb-000186
同实施例1的步骤1。由1，3-二氮杂螺[4.4]壬烷-2，4-二酮和中间体1a反应制备。MS(ESI)：550.3[M-H] -。 1H NMR(400MHz，CDCl 3)δ11.38(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)。 Same as step 1 of the embodiment 1. It is prepared by reacting 1,3-diazaspiro[4.4]nonane-2,4-dione with intermediate 1a. MS (ESI): 550.3 [MH] - . 1 H NMR (400MHz, CDCl 3 ) δ11.38 (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, 5.2 Hz, 2H), 6.96-6.90 (m, 2H), 6.80 (s, 1H), 6.28 (s, 1H), 5.62 (d, J = 1.8 Hz, 1H), 2.11 (dd, J =13.5, 6.4 Hz, 2H), 1.92-1.63 (m, 6H), 1.55 (s, 9H).
步骤2：5-氟-8-(4-氟苯基)-9-(1，3-二氮杂螺[4.4]壬烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[4.4]nonane-2,4-dione-3-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000187
Figure PCTCN2019078089-appb-000187
同实施例1的步骤2。MS(ESI)：452.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.49(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)。 Same as step 2 of the embodiment 1. MS (ESI): 452.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.49 (s, 1H), 8.54 (s, 1H), 7.67 (s, 1H), 7.48 (dd, J = 8.5,5.5Hz, 2H), 7.28 (t , J = 8.8 Hz, 2H), 7.11 (dd, J = 8.9, 2.3 Hz, 1H), 6.92 (dd, J = 11.1, 2.3 Hz, 1H), 5.21 (d, J = 11.7 Hz, 1H), 5.13 (d, J = 11.7 Hz, 1H), 1.91-1.84 (m, 1H), 1.68 (br s, 4H), 1.59-1.50 (m, 3H).
实施例27：5-氟-8-(4-氟苯基)-9-(1，3-二氮杂螺[4.5]癸烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物27)Example 27: 5-Fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[4.5]decane-2,4-dione-3-yl)-8,9 -Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 27)
Figure PCTCN2019078089-appb-000188
Figure PCTCN2019078089-appb-000188
步骤1：5-氟-8-(4-氟苯基)-9-(1，3-二氮杂螺[4.5]癸烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[4.5]decane-2,4-dione-3-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000189
Figure PCTCN2019078089-appb-000189
同实施例1的步骤1。由1，3-二氮杂螺[4.5]癸烷-2，4-二酮和中间体1a反应制备。MS(ESI)：566.2[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 1,3-diazaspiro[4.5]nonane-2,4-dione with intermediate 1a. MS (ESI): 566.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(1，3-二氮杂螺[4.5]癸烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[4.5]decane-2,4-dione-3-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000190
Figure PCTCN2019078089-appb-000190
同实施例1的步骤2。收率为38％。MS(ESI)：466.2[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.45(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)。 Same as step 2 of the embodiment 1. The yield was 38%. MS (ESI): 466.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.45 (s, 1H), 8.74 (s, 1H), 7.64 (s, 1H), 7.47 (dd, J = 8.6,5.5Hz, 2H), 7.27 (t , J = 8.8 Hz, 2H), 7.10 (dd, J = 8.9, 2.4 Hz, 1H), 6.91 (dd, J = 11.1, 2.4 Hz, 1H), 5.18 (d, J = 11.8 Hz, 1H), 5.14 (d, J = 11.8 Hz, 1H), 1.68-1.20 (m, 10H).
实施例28：5-氟-8-(4-氟苯基)-9-(2-氧-5，7-二氮杂螺[3.4]辛烷-6，8-二酮-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物28)Example 28: 5-Fluoro-8-(4-fluorophenyl)-9-(2-oxo-5,7-diazaspiro[3.4]octane-6,8-dione-7-yl) -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 28)
Figure PCTCN2019078089-appb-000191
Figure PCTCN2019078089-appb-000191
步骤1：5-氟-8-(4-氟苯基)-9-(2-氧-5，7-二氮杂螺[3.4]辛烷-6，8-二酮-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(2-oxo-5,7-diazaspiro[3.4]octane-6,8-dione-7-yl)- 8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000192
Figure PCTCN2019078089-appb-000192
同实施例1的步骤1。由2-氧-5，7-二氮杂螺[3.4]辛烷-6，8-二酮和中间体1a反应制备。收率为32％。MS(ESI)：538.1[M-H] -。 1H NMR(400MHz，CDCl 3)δ11.57(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)。 Same as step 1 of the embodiment 1. Prepared by the reaction of 2-oxo-5,7-diazaspiro[3.4]octane-6,8-dione with intermediate 1a. The yield was 32%. MS (ESI): 538.1 [MH] - . 1 H NMR (400MHz, CDCl 3 ) δ11.57 (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, 5.1 Hz, 2H), 6.93 (t, J = 8.6 Hz, 2H), 6.27 (s, 1H), 5.63 (d, J = 1.7 Hz, 1H), 4.96 ( d, J = 7.0 Hz, 2H), 4.73 (t, J = 7.1 Hz, 2H), 1.54 (s, 9H).
步骤2：5-氟-8-(4-氟苯基)-9-(2-氧-5，7-二氮杂螺[3.4]辛烷-6，8-二酮-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(2-oxo-5,7-diazaspiro[3.4]octane-6,8-dione-7-yl)- 8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000193
Figure PCTCN2019078089-appb-000193
同实施例1的步骤2。收率为70％。MS(ESI)：440.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.45(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)。 Same as step 2 of the embodiment 1. The yield was 70%. MS (ESI): 440.1 [M + H] +. 1 H NMR (400MHz, DMSO- d6) δ12.45 (s, 1H), 9.27 (s, 1H), 7.69 (s, 1H), 7.47 (dd, J = 8.6,5.5Hz, 2H), 7.25 (t , J = 8.8 Hz, 2H), 7.12 (dd, J = 8.9, 2.4 Hz, 1H), 6.93 (dd, J = 11.1, 2.4 Hz, 1H), 5.24 (d, J = 11.6 Hz, 1H), 5.09 (d, J = 11.6 Hz, 1H), 4.72 (d, J = 6.7 Hz, 1H), 4.62 (dd, J = 6.5, 4.6 Hz, 2H), 4.44 (d, J = 5.3 Hz, 1H).
实施例29：5-氟-8-(4-氟苯基)-9-(2，5，7-三氮杂螺[3.4]辛烷-6，8-二酮-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物29)Example 29: 5-Fluoro-8-(4-fluorophenyl)-9-(2,5,7-triazaspiro[3.4]octane-6,8-dione-7-yl)-8 ,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 29)
Figure PCTCN2019078089-appb-000194
Figure PCTCN2019078089-appb-000194
步骤1：5-氟-8-(4-氟苯基)-9-(2-叔丁氧基羰基-2，5，7-三氮杂螺[3.4]辛烷-6，8-二酮-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(2-tert-butoxycarbonyl-2,5,7-triazaspiro[3.4]octane-6,8-dione -7-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000195
Figure PCTCN2019078089-appb-000195
同实施例1的步骤1。由2-叔丁氧基羰基-2，5，7-三氮杂螺[3.4]辛烷 -6，8-二酮和中间体1a反应制备。 1H NMR(400MHz，DMSO-d6)δ12.95(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)。 Same as step 1 of the embodiment 1. Prepared by the reaction of 2-tert-butoxycarbonyl-2,5,7-triazaspiro[3.4]octane-6,8-dione and intermediate 1a. 1 H NMR (400MHz, DMSO- d6) δ12.95 (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, 5.4 Hz, 2H), 7.12 (t, J = 8.8 Hz, 2H), 6.12 (s, 1H), 5.45 (d, J = 1.9 Hz, 1H), 4.05 -3.87 (m, 4H), 1.47 (s, 9H), 1.37 (s, 9H).
步骤2：5-氟-8-(4-氟苯基)-9-(2，5，7-三氮杂螺[3.4]辛烷-6，8-二酮-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(2,5,7-triazaspiro[3.4]octane-6,8-dione-7-yl)-8, 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000196
Figure PCTCN2019078089-appb-000196
同实施例1的步骤2。MS(ESI)：439.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.48(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)。 Same as step 2 of the embodiment 1. MS (ESI): 439.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.48 (s, 1H), 9.22 (s, 2H), 7.71 (s, 1H), 7.48 (dd, J = 8.6,5.5Hz, 2H), 7.26 (t , J = 8.8 Hz, 2H), 7.11 (dd, J = 8.9, 2.4 Hz, 1H), 6.93 (dd, J = 11.1, 2.4 Hz, 1H), 5.27 (d, J = 11.3 Hz, 1H), 5.03 (d, J = 11.3 Hz, 1H), 4.23 (d, J = 11.5 Hz, 1H), 4.17 (d, J = 12.5 Hz, 2H), 3.80 (d, J = 11.3 Hz, 1H).
实施例30：5-氟-8-(4-氟苯基)-9-(2，4-噻唑烷二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物30)Example 30: 5-Fluoro-8-(4-fluorophenyl)-9-(2,4-thiazolidinedione-3-yl)-8,9-dihydro-2H-pyrido[4,3 ,2-de]pyridazine-3(7H)-one (compound 30)
Figure PCTCN2019078089-appb-000197
Figure PCTCN2019078089-appb-000197
步骤1：5-氟-8-(4-氟苯基)-9-(2，4-噻唑烷二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(2,4-thiazolidinedione-3-yl)-8,9-dihydro-2H-pyrido[4,3, 2-de]pyridazine-3(7H)-keto-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000198
Figure PCTCN2019078089-appb-000198
同实施例1的步骤1。由2，4-噻唑烷二酮和中间体1a反应制备。MS(ESI)：515.1[M+H] +。 1H NMR(400MHz，CDCl 3)δ12.10(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)。 Same as step 1 of the embodiment 1. It is prepared by reacting 2,4-thiazolidinedione with intermediate 1a. MS (ESI): 515.1 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 12.10 (s, 1H), 7.91 (dd, J = 10.7, 2.4 Hz, 1H), 7.77 (dd, J = 8.0, 2.5 Hz, 1H), 7.19 (dd, J=8.5, 5.1 Hz, 2H), 6.97-6.88 (m, 2H), 6.25 (s, 1H), 5.76 (d, J = 1.6 Hz, 1H), 4.03 (d, J = 17.6 Hz, 1H), 3.95 (d, J = 17.6 Hz, 1H), 1.55 (s, 9H).
步骤2：5-氟-8-(4-氟苯基)-9-(2，4-噻唑烷二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(2,4-thiazolidinedione-3-yl)-8,9-dihydro-2H-pyrido[4,3, 2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000199
Figure PCTCN2019078089-appb-000199
同实施例1的步骤2。MS(ESI)：415.0[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.51(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)。 Same as step 2 of the embodiment 1. MS (ESI): 415.0 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.51 (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, 2.3 Hz, 1H), 6.92 (dd, J = 11.1, 2.4 Hz, 1H), 5.54 (d, J = 11.5 Hz, 1H), 5.14 (d, J = 11.5 Hz) , 1H), 4.35 (d, J = 18.3 Hz, 1H), 4.23 (d, J = 18.3 Hz, 1H).
实施例31：5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-噻唑烷二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物31)Example 31: 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-thiazolidinedione-3-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 31)
Figure PCTCN2019078089-appb-000200
Figure PCTCN2019078089-appb-000200
步骤1：5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-噻唑烷二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-thiazolidinedione-3-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000201
Figure PCTCN2019078089-appb-000201
同实施例1的步骤1。由5，5-二甲基-2，4-噻唑烷二酮和中间体1a 反应制备。MS(ESI)：543.2[M+H] +。 1H NMR(400MHz，CDCl 3)δ11.07(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)。 Same as step 1 of the embodiment 1. It is prepared by reacting 5,5-dimethyl-2,4-thiazolidinedione with intermediate 1a. MS (ESI): 543.2 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ11.07 (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, 5.1 Hz, 2H), 6.98-6.89 (m, 2H), 6.28 (s, 1H), 5.72 (d, J = 1.6 Hz, 1H), 1.74 (s, 6H), 1.56 (s, 9H) ).
步骤2：5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-噻唑烷二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-thiazolidinedione-3-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000202
Figure PCTCN2019078089-appb-000202
同实施例1的步骤2。收率为74％。MS(ESI)：443.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.51(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)。 Same as step 2 of the embodiment 1. The yield was 74%. MS (ESI): 443.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.51 (s, 1H), 7.72 (s, 1H), 7.57-7.45 (m, 2H), 7.30 (t, J = 8.5Hz, 2H), 7.13 (d , J = 7.5 Hz, 1H), 6.92 (d, J = 10.9 Hz, 1H), 5.52 (d, J = 11.6 Hz, 1H), 5.13 (d, J = 11.6 Hz, 1H), 1.57 (s, 3H) ), 1.36 (s, 3H).
实施例32：5-氟-8-(4-氟苯基)-9-(噁唑烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物32)Example 32: 5-Fluoro-8-(4-fluorophenyl)-9-(oxazolidine-2,4-dione-3-yl)-8,9-dihydro-2H-pyrido[4 ,3,2-de]pyridazine-3(7H)-one (Compound 32)
Figure PCTCN2019078089-appb-000203
Figure PCTCN2019078089-appb-000203
步骤1：5-氟-8-(4-氟苯基)-9-(噁唑烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(oxazolidine-2,4-dione-3-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000204
Figure PCTCN2019078089-appb-000204
同实施例1的步骤1。由2，4-噁唑烷二酮和中间体1a反应制备。MS(ESI)：499.1[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 2,4-oxazolidinedione with intermediate 1a. MS (ESI): 499.1 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(噁唑烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(oxazolidine-2,4-dione-3-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000205
Figure PCTCN2019078089-appb-000205
同实施例1的步骤2。MS(ESI)：399.1[M+H] +。 1H NMR(400MHz，DMSO)δ12.57(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)。 Same as step 2 of the embodiment 1. MS (ESI): 399.1 [M+H] + . 1 H NMR (400MHz, DMSO) δ12.57 (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, 2.4 Hz, 1H), 6.93 (dd, J = 11.1, 2.4 Hz, 1H), 5.45 (d, J = 11.5 Hz, 1H), 5.10 (d, J = 11.6 Hz, 1H) ), 5.05 (q, J = 16.8 Hz, 2H).
实施例33：5-氟-8-(4-氟苯基)-9-(5，5-二甲基噁唑烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物33)Example 33: 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyloxazolidine-2,4-dione-3-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 33)
Figure PCTCN2019078089-appb-000206
Figure PCTCN2019078089-appb-000206
步骤1：5-氟-8-(4-氟苯基)-9-(5，5-二甲基噁唑烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyloxazolidine-2,4-dione-3-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000207
Figure PCTCN2019078089-appb-000207
同实施例1的步骤1。由5，5-二甲基-2，4-噁唑烷二酮和中间体1a反应制备。MS(ESI)：527.2[M+H] +。 1H NMR(400MHz，DMSO-d6)δ11.53(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)。 Same as step 1 of the embodiment 1. It is prepared by reacting 5,5-dimethyl-2,4-oxazolidinedione with intermediate 1a. MS (ESI): 527.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.53 (s, 1H), 7.78 (dd, J = 10.8, 2.4 Hz, 1H), 7.77 (dd, J = 8.0, 2.5 Hz, 1H), 7.15 (dd , J=8.5, 5.1 Hz, 2H), 6.99-6.83 (m, 2H), 6.32 (s, 1H), 5.58 (d, J = 1.8 Hz, 1H), 1.59 (s, 3H), 1.58 (s, 3H), 1.55 (s, 9H).
步骤2：5-氟-8-(4-氟苯基)-9-(5，5-二甲基噁唑烷-2，4-二酮-3-基) -8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyloxazolidine-2,4-dione-3-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000208
Figure PCTCN2019078089-appb-000208
同实施例1的步骤2。MS(ESI)：427.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.56(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)。 Same as step 2 of the embodiment 1. MS (ESI): 427.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.56 (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, 2.4 Hz, 1H), 6.93 (dd, J = 11.1, 2.4 Hz, 1H), 5.37 (d, J = 11.7 Hz, 1H), 5.09 (d, J = 11.8 Hz) , 1H), 1.44 (s, 3H), 1.30 (s, 3H).
实施例34：5-氟-8-(4-氟苯基)-9-(2H-苯并[e][1，3]噁嗪-2，4(3H)-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物34)Example 34: 5-Fluoro-8-(4-fluorophenyl)-9-(2H-benzo[e][1,3]oxazine-2,4(3H)-dione-3-yl) -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (compound 34)
Figure PCTCN2019078089-appb-000209
Figure PCTCN2019078089-appb-000209
步骤1：5-氟-8-(4-氟苯基)-9-(2H-苯并[e][1，3]噁嗪-2，4(3H)-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(2H-benzo[e][1,3]oxazine-2,4(3H)-dione-3-yl)- 8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000210
Figure PCTCN2019078089-appb-000210
同实施例1的步骤1。由2H-苯并[e][1，3]噁嗪-2，4(3H)-二酮和中间体1a反应制备。MS(ESI)：561.2[M+H] +。 1H NMR(400MHz，CDCl 3)δ11.67(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)。 Same as step 1 of the embodiment 1. Prepared by the reaction of 2H-benzo[e][1,3]oxazine-2,4(3H)-dione with Intermediate 1a. MS (ESI): 561.2 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ11.67 (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).
步骤2：5-氟-8-(4-氟苯基)-9-(2H-苯并[e][1，3]噁嗪-2，4(3H)-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(2H-benzo[e][1,3]oxazine-2,4(3H)-dione-3-yl)- 8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000211
Figure PCTCN2019078089-appb-000211
同实施例1的步骤2。MS(ESI)：461.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.42(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)。 Same as step 2 of the embodiment 1. MS (ESI): 461.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.42 (s, 1H), 8.05-7.82 (m, 2H), 7.72 (s, 1H), 7.63-7.42 (m, 4H), 7.22 (t, J = 8.7 Hz, 2H), 7.14 (dd, J = 8.9, 2.4 Hz, 1H), 6.95 (dd, J = 11.1, 2.4 Hz, 1H), 6.35 (d, J = 10.9 Hz, 1H), 5.34 (d, J = 10.9 Hz, 1H).
实施例35：5-氟-8-(4-氟苯基)-9-(苯并[d]异噻唑-3(2H)-酮-1，1-二氧化物-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物35)Example 35: 5-Fluoro-8-(4-fluorophenyl)-9-(benzo[d]isothiazole-3(2H)-one-1,1-dioxide-2-yl)-8 ,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 35)
Figure PCTCN2019078089-appb-000212
Figure PCTCN2019078089-appb-000212
步骤1：5-氟-8-(4-氟苯基)-9-(苯并[d]异噻唑-3(2H)-酮-1，1-二氧化物-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(benzo[d]isothiazole-3(2H)-one-1,1-dioxide-2-yl)-8, 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000213
Figure PCTCN2019078089-appb-000213
同实施例1的步骤1。由邻苯甲酰磺酰胺钠和中间体1a反应制备。收率为40％。 1H NMR(400MHz，CDCl 3)δ10.63(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)。 Same as step 1 of the embodiment 1. It is prepared by reacting sodium o-benzoylsulfonamide with intermediate 1a. The yield was 40%. 1 H NMR (400MHz, CDCl 3 ) δ10.63 (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, 2.5 Hz, 1H), 7.22 (dd, J = 8.5, 5.1 Hz, 2H), 7.02-6.93 (m, 2H), 6.55 (s, 1H), 5.88 (d, J = 1.8 Hz) , 1H), 1.43 (s, 9H).
步骤2：5-氟-8-(4-氟苯基)-9-(苯并[d]异噻唑-3(2H)-酮-1，1-二氧化物-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(benzo[d]isothiazole-3(2H)-one-1,1-dioxide-2-yl)-8, 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000214
Figure PCTCN2019078089-appb-000214
同实施例1的步骤2。MS(ESI)：481.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.49(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)。 Same as step 2 of the embodiment 1. MS (ESI): 481.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.49 (s, 1H), 8.23 (d, J = 7.3Hz, 1H), 8.12 (d, J = 7.6Hz, 1H), 8.03 (dtd, J = 21.4 , 7.5, 1.1 Hz, 2H), 7.78 (s, 1H), 7.59 (dd, J = 8.6, 5.5 Hz, 2H), 7.22 (t, J = 8.9 Hz, 2H), 7.12 (dd, J = 8.9, 2.4 Hz, 1H), 6.95 (dd, J = 11.1, 2.4 Hz, 1H), 5.58 (d, J = 11.1 Hz, 1H), 5.28 (d, J = 11.1 Hz, 1H).
实施例36：5-氟-8-(4-氟苯基)-9-(5-甲基-3-氨基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物36)Example 36: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-3-amino-1H-1,2,4-triazol-1-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 36)
Figure PCTCN2019078089-appb-000215
Figure PCTCN2019078089-appb-000215
步骤1：5-氟-9-肼基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-9-mercapto-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)- Keto-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000216
Figure PCTCN2019078089-appb-000216
5-氟-9-氯-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯(中间体1a，1.0g，2.31mmol)溶于10mL乙醇，加入水合肼(2mL)，加热至60℃反应2小时。减压蒸除溶剂，残留物溶于乙酸乙酯，水洗2次。有机相用无水硫酸镁干燥，过滤。滤液减 压蒸干，残留物经硅胶柱层析(二氯甲烷/甲醇＝20∶1，v/v)，得到800mg产物(收率为81％)。MS(ESI)：430.1[M+H] +。 1H NMR(400MHz，CDCl 3)δ11.80(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)。 5-fluoro-9-chloro-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7- The tert-butyl carboxylate (intermediate 1a, 1.0 g, 2.31 mmol) was dissolved in 10 mL of ethanol, hydrazine hydrate (2 mL) was added, and the mixture was heated to 60 ° C for 2 hours. The solvent was evaporated under reduced pressure. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated to drynesshhhhhhhhhhhhhhhhhhhhhhhhhhh MS (ESI): 430.1 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ11.80 (s, 1H), 8.08 (d, J = 10.9Hz, 1H), 7.68 (dd, J = 7.9,2.2Hz, 1H), 7.10 (dd, J = 8.6, 5.2 Hz, 2H), 6.92-6.82 (m, 2H), 6.35 (s, 1H), 4.28 (s, 1H), 3.82 (br s, 3H), 1.59 (s, 9H).
步骤2：5-氟-8-(4-氟苯基)-9-(5-甲基-3-叔丁氧基羰基氨基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-3-tert-butoxycarbonylamino-1H-1,2,4-triazol-1-yl)- 8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000217
Figure PCTCN2019078089-appb-000217
5-氟-9-肼基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3-酮-7-羧酸叔丁酯(100mg，0.233mmol)和乙酰氨基(甲硫基)亚甲基氨基甲酸叔丁酯(46mg，0.85mmol)溶于N，N-二甲基甲酰胺(0.5mL)，加入二异丙基乙胺(52μL，1.28mmol)，室温反应过夜。加入10mL乙酸乙酯，水洗两次。有机相用无水硫酸镁干燥，过滤，滤液减压浓缩，残留物用制备薄层色谱分离纯化(二氯甲烷/甲醇＝20/1，v/v)，得到60mg产物(收率43％)。MS(ESI)：596.2[M+H] +。 1H NMR(400MHz，MeOD)δ8.08(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)。 5-fluoro-9-mercapto-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazin-3-one-7-carboxylic acid tert-Butyl ester (100 mg, 0.233 mmol) and tert-butyl acetamido(methylthio)methylenecarbamate (46 mg, 0.85 mmol) were dissolved in N,N-dimethylformamide (0.5 mL). Propylethylamine (52 μL, 1.28 mmol) was reacted overnight at room temperature. 10 mL of ethyl acetate was added and washed twice with water. The organic phase was dried over anhydrous magnesium sulfate, filtered, evaporated, evaporated, evaporated, . MS (ESI): 596.2 [M+H] + . 1 H NMR (400MHz, MeOD) δ8.08 (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 = 2.2 Hz, 1H), 2.70 (s, 3H), 1.49 (s, 9H), 1.40 (d, J = 9.1 Hz, 9H).
步骤3：5-氟-8-(4-氟苯基)-9-(5-甲基-3-氨基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 3: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-3-amino-1H-1,2,4-triazol-1-yl)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000218
Figure PCTCN2019078089-appb-000218
5-氟-8-(4-氟苯基)-9-(5-甲基-3-叔丁氧基羰基氨基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯 (60mg，0.101mmol)溶于2mL二氯甲烷和1mL三氟乙酸，室温反应3小时。减压蒸除溶剂，加入10mL乙酸乙酯，依次用饱和碳酸氢钠水溶液、水洗涤，无水硫酸镁干燥，过滤。滤液减压蒸除，加入少量乙酸乙酯，析出白色固体。过滤，固体干燥得到20mg产物(收率50％)。MS(ESI)：396.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.46(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)。 5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-3-tert-butoxycarbonylamino-1H-1,2,4-triazol-1-yl)-8,9 -Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester (60 mg, 0.101 mmol) dissolved in 2 mL dichloromethane and 1 mL trifluoro Acetic acid was reacted at room temperature for 3 hours. The solvent was evaporated under reduced pressure. EtOAc was evaporated. The filtrate was evaporated under reduced pressure and a small amount of ethyl acetate was added to precipitate a white solid. Filtration and solid drying gave 20 mg of product (yield 50%). MS (ESI): 396.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.46 (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, 2.3 Hz, 1H), 6.93 (dd, J = 11.1, 2.4 Hz, 1H), 5.74 (d, J = 10.9 Hz, 1H), 5.12 (s, 2H), 4.98 (d, J = 10.9 Hz, 1H), 1.92 (s, 3H).
实施例37：5-氟-8-(4-氟苯基)-9-(5-异丙基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物37)Example 37: 5-Fluoro-8-(4-fluorophenyl)-9-(5-isopropyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 37)
Figure PCTCN2019078089-appb-000219
Figure PCTCN2019078089-appb-000219
步骤1：5-氟-8-(4-氟苯基)-9-(5-异丙基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(5-isopropyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000220
Figure PCTCN2019078089-appb-000220
异丁酰胺(61mg，0.701mmol)和N，N-二甲基甲酰胺二甲基缩醛(100μL，0.754mmol)溶于N，N-二甲基乙酰胺(0.3mL)，反应物加热至80℃反应2小时。再向反应液中加入5-氟-9-肼基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯(100mg，0.233mmol)和2mL乙酸，继续反应2小时。将反应液冷却至室温，加入20mL乙酸乙酯。再用水洗涤，无水硫酸镁干燥，过滤。滤液减压浓缩，残余物用制备薄层色谱分离纯化(石油醚/乙酸乙酯＝1/1，v/v)，得到80mg产物(收率68％)。MS(ESI)：509.2[M+H] +。 Isobutyramide (61 mg, 0.701 mmol) and N,N-dimethylformamide dimethyl acetal (100 μL, 0.754 mmol) were dissolved in N,N-dimethylacetamide (0.3 mL). The reaction was carried out at 80 ° C for 2 hours. Further, 5-fluoro-9-mercapto-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3 was added to the reaction solution. 7H)-keto-7-carboxylic acid tert-butyl ester (100 mg, 0.233 mmol) and 2 mL of acetic acid, and the reaction was continued for 2 hr. The reaction solution was cooled to room temperature, and 20 mL of ethyl acetate was added. It was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified (jjjjjjjj MS (ESI): 509.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(5-异丙基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(5-isopropyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000221
Figure PCTCN2019078089-appb-000221
同实施例1的步骤2。MS(ESI)：409.2[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.43(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)。 Same as step 2 of the embodiment 1. MS (ESI): 409.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.43 (s, 1H), 7.86 (s, 1H), 7.79 (s, 1H), 7.44 (dd, J = 8.4,5.6Hz, 2H), 7.19 (t , J = 8.8 Hz, 2H), 7.12 (dd, J = 8.9, 2.2 Hz, 1H), 6.96 (dd, J = 11.1, 2.3 Hz, 1H), 6.06 (d, J = 11.1 Hz, 1H), 5.12 (d, J = 11.1 Hz, 1H), 2.94 (hept, J = 6.7 Hz, 1H), 1.12 (d, J = 6.7 Hz, 3H), 0.71 (d, J = 6.7 Hz, 3H).
实施例38：5-氟-8-(4-氟苯基)-9-(5-甲基-1H-吡唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物38)Example 38: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-pyrazol-1-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one (compound 38)
Figure PCTCN2019078089-appb-000222
Figure PCTCN2019078089-appb-000222
步骤1：5-氟-8-(4-氟苯基)-9-(5-甲基-1H-吡唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-pyrazol-1-yl)-8,9-dihydro-2H-pyrido[4,3 ,2-de]pyridazine-3(7H)-keto-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000223
Figure PCTCN2019078089-appb-000223
同实施例37的步骤1。由4，4-二甲氧基-2-丁酮和5-氟-9-肼基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯反应制备。MS(ESI)：480.2[M+H] +。 1H NMR(400MHz，CDCl3)δ11.06(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)。 Same as step 1 of Example 37. From 4,4-dimethoxy-2-butanone and 5-fluoro-9-mercapto-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3, Preparation of 2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester. MS (ESI): 480.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 11.06 (s, 1H), 8.13 (d, J = 11.1 Hz, 1H), 7.77 (dt, J = 11.4, 5.7 Hz, 1H), 7.18 (dd, J = 8.5 , 5.2 Hz, 2H), 6.94 (t, J = 8.6 Hz, 2H), 6.90 (d, J = 2.1 Hz, 1H), 6.54 (s, 1H), 6.01 (d, J = 2.2 Hz, 1H), 5.92d, J = 2.3 Hz, 1H), 2.31 (s, 3H), 1.46 (s, 9H).
步骤2：5-氟-8-(4-氟苯基)-9-(5-甲基-1H-吡唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-pyrazol-1-yl)-8,9-dihydro-2H-pyrido[4,3 ,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000224
Figure PCTCN2019078089-appb-000224
同实施例1的步骤2。MS(ESI)：380.2[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.48(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)。 Same as step 2 of the embodiment 1. MS (ESI): 380.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.48 (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 = 7.8 Hz, 1H), 6.94 (d, J = 10.3 Hz, 1H), 5.91 (s, 1H), 5.72 (d, J = 9.2 Hz, 1H), 5.14 (d, J) = 9.1 Hz, 1H), 2.10 (s, 3H).
实施例39：5-氟-8-(4-氟苯基)-9-(5-甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物39)Example 39: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one (compound 39)
Figure PCTCN2019078089-appb-000225
Figure PCTCN2019078089-appb-000225
乙酰胺(1.18g，20mmol)和N，N-二甲基甲酰胺二甲基缩醛(3mL，22.6mmol)溶于20mL二氧六环，加热至90℃反应3小时。冷却至室温，减压蒸除溶剂，加入少量石油醚，析出固体，过滤得到N-(二甲氨基)亚甲基乙酰胺。Acetamide (1.18 g, 20 mmol) and N,N-dimethylformamide dimethyl acetal (3 mL, 22.6 mmol) were dissolved in 20 mL of dioxane and heated to 90 ° C for 3 hours. After cooling to room temperature, the solvent was evaporated under reduced pressure, and a small amount of petroleum ether was added to precipitate a solid, which was filtered to give N-(dimethylamino)methyleneacetamide.
5-氟-9-肼基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯(100mg，0.233mmol)和N-(二甲氨基)亚甲基乙酰胺(50mg，0.439mmol)溶于1mL乙酸，于95℃反应6小时。冷却至室温，再加入1mL三氟乙酸，室温下反应2小时。反应液减压浓缩，残留物溶于20mL乙酸乙酯，依次用饱和碳酸氢钠溶液、水洗涤，无水硫酸镁干燥，过滤，浓缩，制备薄层色谱纯化(二氯甲烷/甲醇＝20/1，v/v)，得到20mg产物(收率23％)。MS(ESI)：381.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.47(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＝10.9 Hz，1H)，5.09(d，J＝10.9Hz，1H)，2.12(s，3H)。 5-fluoro-9-mercapto-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7 - tert-butyl carboxylate (100 mg, 0.233 mmol) and N-(dimethylamino)methyleneacetamide (50 mg, 0.439 mmol) were dissolved in 1 mL of acetic acid and reacted at 95 ° C for 6 hours. After cooling to room temperature, 1 mL of trifluoroacetic acid was further added, and the mixture was reacted at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure. EtOAcjjjjjjjjjjjjjjj 1, v/v), 20 mg of product was obtained (yield 23%). MS (ESI): 381.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.47 (s, 1H), 7.86 (s, 1H), 7.83 (s, 1H), 7.46 (dd, J = 8.6,5.6Hz, 2H), 7.19 (t , J = 8.8 Hz, 2H), 7.12 (dd, J = 8.9, 2.4 Hz, 2H), 6.98 (dd, J = 11.1, 2.4 Hz, 1H), 6.05 (d, J = 10.9 Hz, 1H), 5.09 (d, J = 10.9 Hz, 1H), 2.12 (s, 3H).
手性拆分化合物39得到(8R，9R)-5-氟-8-(4-氟苯基)-9-(5-甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物39a)和(8S，9S)-5-氟-8-(4-氟苯基)-9-(5-甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物39b)Chiral resolution of compound 39 affords (8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-1,2,4-triazol-1-yl) -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (compound 39a) and (8S,9S)-5-fluoro-8-(4- Fluorophenyl)-9-(5-methyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]酞Pyrazin-3(7H)-one (compound 39b)
Figure PCTCN2019078089-appb-000226
Figure PCTCN2019078089-appb-000226
将5-氟-8-(4-氟苯基)-9-(5-甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物39)溶解在甲醇/二氯甲烷混合溶剂中，采用超临界流体色谱(SFC)进行手性拆分得到一对对映异构体。手性柱为ChiralCel OD，洗脱剂为二氧化碳(55％)和甲醇(45％，含0.1％氨水)。5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one (Compound 39) was dissolved in a methanol/methylene chloride mixed solvent and subjected to chiral separation by supercritical fluid chromatography (SFC) to obtain a pair. Isomer. The chiral column was ChiralCel OD and the eluent was carbon dioxide (55%) and methanol (45% with 0.1% ammonia).
实施例40：5-氟-8-(2，4-二氟苯基)-9-(5-甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物40)Example 40: 5-Fluoro-8-(2,4-difluorophenyl)-9-(5-methyl-1H-1,2,4-triazol-1-yl)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 40)
Figure PCTCN2019078089-appb-000227
Figure PCTCN2019078089-appb-000227
步骤1：2-溴-5-氟-3-硝基苯甲酸甲酯Step 1: Methyl 2-bromo-5-fluoro-3-nitrobenzoate
Figure PCTCN2019078089-appb-000228
Figure PCTCN2019078089-appb-000228
2-溴-5-氟-3-硝基苯甲酸(315g，1.19mol)溶于1L甲醇，加入50mL浓硫酸，80℃反应过夜。冰水浴冷却，析出黄色固体。过滤，滤饼用200mL甲醇洗涤得到2-溴-5-氟-3-硝基苯甲酸甲酯(70g，收率21％)。 1H NMR(400MHz，CDCl 3)δ7.63(dd，J＝7.8，3.0Hz，1H)，7.54(dd，J＝6.9，3.0Hz，1H)，3.99(s，3H)。 2-Bromo-5-fluoro-3-nitrobenzoic acid (315 g, 1.19 mol) was dissolved in 1 L of methanol, and 50 mL of concentrated sulfuric acid was added thereto, and the mixture was reacted at 80 ° C overnight. The ice water bath was cooled and a yellow solid precipitated. After filtration, the cake was washed with 200 mL of methanol to give ethyl 2-bromo-5-fluoro-3-nitrobenzoate (70 g, yield 21%). 1 H NMR (400 MHz, CDCl 3 ) δ 7.63 (dd, J = 7.8, 3.0 Hz, 1H), 7.54 (dd, J = 6.9, 3.0 Hz, 1H), 3.99 (s, 3H).
步骤2：2-(1-乙氧基乙烯基)-5-氟-3-硝基苯甲酸甲酯Step 2: Methyl 2-(1-ethoxyvinyl)-5-fluoro-3-nitrobenzoate
Figure PCTCN2019078089-appb-000229
Figure PCTCN2019078089-appb-000229
2-溴-5-氟-3-硝基苯甲酸甲酯(100g，0.36mol)、三丁基(1-乙氧基乙烯基)锡(134mL，0.397mol)、二(三苯基膦)氯化钯(8g，0.011mol)溶于二氧六环(500mL)。氩气保护下于95℃反应3小时，冷却到室温。向反应液中加入100g二水氟化钾溶于300mL水的溶液，搅拌2小时。过滤，滤液减压浓缩。残留物溶于400mL乙酸乙酯，依次用水和饱和食盐水洗涤。有机相用无水硫酸镁干燥，过滤。滤液浓缩得到2-(1-乙氧基乙烯基)-5-氟-3-硝基苯甲酸甲酯。 1H NMR(400MHz，CDCl 3)δ7.62(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)。 Methyl 2-bromo-5-fluoro-3-nitrobenzoate (100 g, 0.36 mol), tributyl(1-ethoxyvinyl)tin (134 mL, 0.397 mol), bis(triphenylphosphine) Palladium chloride (8 g, 0.011 mol) was dissolved in dioxane (500 mL). The reaction was carried out at 95 ° C for 3 hours under argon atmosphere and cooled to room temperature. A solution of 100 g of potassium fluoride dihydrate in 300 mL of water was added to the reaction mixture, and the mixture was stirred for 2 hours. Filtration and concentration of the filtrate under reduced pressure. The residue was dissolved in ethyl acetate (400 mL). The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to give methyl 2-(1-ethoxyvinyl)-5-fluoro-3-nitrobenzoate. 1 H NMR (400MHz, CDCl 3 ) δ7.62 (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 = 3.2 Hz, 1H), 3.93 - 3.84 (m, 5H), 1.32 (t, J = 7.0 Hz, 3H).
步骤3：2-乙酰基-3-氨基-5-氟苯甲酸甲酯Step 3: Methyl 2-acetyl-3-amino-5-fluorobenzoate
Figure PCTCN2019078089-appb-000230
Figure PCTCN2019078089-appb-000230
同中间体1a的步骤3。黄色固体，收率为70％。Same as step 3 of intermediate 1a. Yellow solid with a yield of 70%.
步骤4：(E)-2-乙酰基-5-氟-3-((2，4-二氟苄叉)氨基)苯甲酸甲酯Step 4: (E)-2-Acetyl-5-fluoro-3-((2,4-difluorobenzylidene)amino)benzoic acid methyl ester
Figure PCTCN2019078089-appb-000231
Figure PCTCN2019078089-appb-000231
上步骤产物与2，4-二氟苯甲醛反应，同中间体1a的步骤4。白色固体，收率为63％。 1H NMR(400MHz，CDCl 3)δ8.80(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 product of the above step is reacted with 2,4-difluorobenzaldehyde, as in step 4 of intermediate 1a. White solid with a yield of 63%. 1 H NMR (400 MHz, CDCl 3 ) δ 8.80 (s, 1H), 8.05 (dd, J = 15.4, 8.4 Hz, 1H), 7.70 (dd, J = 9.8, 2.2 Hz, 1H), 7.58 (dd, J = 8.8, 2.3 Hz, 1H), 7.52-7.42 (m, 1H), 7.33-7.24 (m, 1H), 3.84 (s, 3H), 2.51 (s, 3H).
步骤5：7-氟-2-(2，4-二氟苯基)-2，3-二氢喹啉-4(1H)-酮-5-甲酸甲酯Step 5: Methyl 7-fluoro-2-(2,4-difluorophenyl)-2,3-dihydroquinolin-4(1H)-one-5-carboxylate
Figure PCTCN2019078089-appb-000232
Figure PCTCN2019078089-appb-000232
(E)-2-乙酰基-5-氟-3-((2，4-二氟苄叉)氨基)苯甲酸甲酯(6.8g，20.3mmol)溶于100mL二氯甲烷，再加入三氟甲基磺酸钪(3.5g，7.1mmol)。室温反应1.5小时。反应液依次以水、饱和食盐水洗涤，有机相减压浓缩，残留物硅胶柱层析得到6.07g白色固体(收率为89％)。 1H NMR(400MHz，DMSO-d6)δ7.73(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)。 Methyl (E)-2-acetyl-5-fluoro-3-((2,4-difluorobenzylidene)amino)benzoate (6.8 g, 20.3 mmol) was dissolved in dichloromethane (100 mL) Bismuth methanesulfonate (3.5 g, 7.1 mmol). The reaction was carried out at room temperature for 1.5 hours. The reaction mixture was washed with water and aq. 1 H NMR (400MHz, DMSO- d6) δ7.73 (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, 2.1 Hz, 1H), 6.72 (dd, J = 11.0, 2.4 Hz, 1H), 6.49 (dd, J = 8.5, 2.4 Hz, 1H), 5.07 (dd, J = 11.2, 4.7 Hz, 1H), 3.75 (s, 3H), 2.88 (dd, J = 16.1, 11.3 Hz, 1H), 2.75 (dd, J = 16.1, 4.5 Hz, 1H).
步骤6：N-叔丁氧基羰基-7-氟-2-(2，4-二氟苯基)-2，3-二氢喹啉-4-酮-5-甲酸甲酯Step 6: Methyl N-tert-butoxycarbonyl-7-fluoro-2-(2,4-difluorophenyl)-2,3-dihydroquinolin-4-one-5-carboxylate
Figure PCTCN2019078089-appb-000233
Figure PCTCN2019078089-appb-000233
同中间体1a的步骤6。收率为50％。 1H NMR(400MHz，DMSO-d6)δ7.81(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)。 Same as step 6 of intermediate 1a. The yield was 50%. 1 H NMR (400MHz, DMSO- d6) δ7.81 (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, 3.8 Hz, 1H), 6.19 (d, J = 5.8 Hz, 1H), 3.82 (dd, J = 7.5, 6.0 Hz, 1H), 3.77 (s, 3H), 3.61 (dd, J = 17.6, 6.5 Hz, 1H), 3.01 (dd, J = 17.6, 1.6 Hz, 1H), 1.49 (s, 9H).
步骤7：N-叔丁氧基羰基-7-氟-2-(2，4-二氟苯基)-4-(叔丁基二甲基硅氧基)-1，2-二氢喹啉-5-甲酸甲酯Step 7: N-tert-Butoxycarbonyl-7-fluoro-2-(2,4-difluorophenyl)-4-(tert-butyldimethylsilyloxy)-1,2-dihydroquinoline -5-methyl formate
Figure PCTCN2019078089-appb-000234
Figure PCTCN2019078089-appb-000234
同中间体1a的步骤7。淡黄色固体。收率为83％。 1H NMR(400MHz，DMSO-d6)δ7.43(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)。 Same as step 7 of intermediate 1a. Light yellow solid. The yield was 83%. 1 H NMR (400 MHz, DMSO-d6) δ 7.43 (d, J = 8.4 Hz, 1H), 7.29-7.17 (m, 1H), 7.11 (br s, 2H), 6.93 (t, J = 6.9 Hz, 1H), 6.40 (d, J = 6.6 Hz, 1H), 5.60 (d, J = 6.8 Hz, 1H), 3.80 (s, 3H), 1.46 (s, 9H), 0.82 (s, 9H), 0.18 ( s, 3H), 0.16 (s, 3H).
步骤8：N-叔丁氧基羰基-3-溴-7-氟-2-(2，4-二氟苯基)-4-氧代-3，4-二氢喹啉-1，5(2H)-5-甲酸甲酯Step 8: N-tert-Butoxycarbonyl-3-bromo-7-fluoro-2-(2,4-difluorophenyl)-4-oxo-3,4-dihydroquinoline-1,5 ( 2H)-5-carboxylic acid methyl ester
Figure PCTCN2019078089-appb-000235
Figure PCTCN2019078089-appb-000235
将N-叔丁氧基羰基-7-氟-2-(2，4-二氟苯基)-4-(叔丁基二甲基硅氧基)-1，2-二氢喹啉-5-甲酸甲酯(200mg，0.36mmol)溶于5mL四氢呋喃，反应液冷却到-30℃，加入N-溴代丁二酰亚胺(65mg，0.36mmol)，反应40分钟。向反应液中加入40mL乙酸乙酯，依次用水、饱和食盐水洗涤。有机相用无水硫酸镁干燥，过滤，滤液减压浓缩，产物不经纯化直接用于下一步反应。MS(ESI)：514，516[M+H] +。 N-tert-Butoxycarbonyl-7-fluoro-2-(2,4-difluorophenyl)-4-(tert-butyldimethylsilyloxy)-1,2-dihydroquinoline-5 Methyl formate (200 mg, 0.36 mmol) was dissolved in 5 mL of tetrahydrofuran, the reaction mixture was cooled to -30 ° C, and N-bromosuccinimide (65 mg, 0.36 mmol) was added and reacted for 40 minutes. 40 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and brine. The organic phase was dried over anhydrous magnesium sulfate, filtered and evaporated. MS (ESI): 514, 516 [M+H] + .
步骤9：5-氟-9-肼基-8-(2，4-二氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 9: 5-Fluoro-9-mercapto-8-(2,4-difluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3 ( 7H)-keto-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000236
Figure PCTCN2019078089-appb-000236
上一步反应产物溶于甲醇(5mL)，加入水合肼(45μL，1.44mmol)，室温下反应2小时。向反应液中加入20mL乙酸乙酯，依次用水和饱和食盐水洗涤。有机相用无水硫酸镁干燥，过滤，滤液减压浓缩，残 留物用制备薄层色谱纯化(二氯甲烷/甲醇＝20/1，v/v)，得到95mg白色固体(两步收率58％)。MS(ESI)：448.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.79(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 reaction product of the previous step was dissolved in methanol (5 mL), and hydrazine hydrate (45 μL, 1.44 mmol) was added and allowed to react at room temperature for 2 hours. 20 mL of ethyl acetate was added to the reaction mixture, and the mixture was washed successively with water and brine. The organic phase was dried over anhydrous MgSO~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ %). MS (ESI): 448.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.79 (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 = 8.4 Hz, 1H), 6.70 (dd, J = 15.1, 8.6 Hz, 1H), 6.50 (s, 1H), 4.11 (s, 3H), 3.89 (s, 1H), 1.49 (s, 9H).
步骤10：5-氟-8-(2，4-二氟苯基)-9-(5-甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 10: 5-Fluoro-8-(2,4-difluorophenyl)-9-(5-methyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000237
Figure PCTCN2019078089-appb-000237
5-氟-9-肼基-8-(2，4-二氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯(93mg，0.21mmol)和N-(二甲氨基亚甲基)乙酰胺(29mg，0.25mmol)溶于冰乙酸(3mL)，然后于90℃反应2小时。向反应液中加入3mL三氟乙酸，40℃搅拌2小时。减压蒸除溶剂，残留物溶于50mL乙酸乙酯，依次用饱和碳酸氢钠和饱和氯化钠溶液洗涤，制备薄层色谱纯化(二氯甲烷/甲醇＝30/1，v/v)，得到40mg淡黄色固体(收率48％)。MS(ESI)：399.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.49(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)。 5-fluoro-9-mercapto-8-(2,4-difluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)- Ketone-7-carboxylic acid tert-butyl ester (93 mg, 0.21 mmol) and N-(dimethylaminomethylene)acetamide (29 mg, 0.25 mmol) were dissolved in glanic acid (3 mL) and then reacted at 90 ° C for 2 hours. 3 mL of trifluoroacetic acid was added to the reaction liquid, and the mixture was stirred at 40 ° C for 2 hours. The solvent was evaporated under reduced pressure. EtOAc EtOAc m. 40 mg of a pale yellow solid were obtained (yield: 48%). MS (ESI): 399.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.49 (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 = 10.6 Hz, 1H), 5.38 (d, J = 10.6 Hz, 1H), 2.25 (s, 3H).
实施例41：5-氟-8-(4-氟苯基)-9-(1-甲基-2，4，5-咪唑啉三酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物41)Example 41: 5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4,5-imidazolin-3-one-3-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 41)
Figure PCTCN2019078089-appb-000238
Figure PCTCN2019078089-appb-000238
步骤1：5-氟-8-(4-氟苯基)-9-(1-甲基-2，4，5-咪唑啉三酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4,5-imidazolin-3-one-3-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000239
Figure PCTCN2019078089-appb-000239
同实施例1的步骤1。由1-甲基-2，4，5-咪唑啉三酮和中间体1a反应制备。MS(ESI)：526.1[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 1-methyl-2,4,5-imidazolidinone with Intermediate 1a. MS (ESI): 526.1 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(1-甲基-2，4，5-咪唑啉三酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4,5-imidazolin-3-one-3-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000240
Figure PCTCN2019078089-appb-000240
同实施例1的步骤2。MS(ESI)：426.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.52(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)。 Same as step 2 of the embodiment 1. MS (ESI): 426.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.52 (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, 2.3 Hz, 1H), 6.93 (dd, J = 11.1, 2.3 Hz, 1H), 5.61 (d, J = 10.8 Hz, 1H), 5.09 (d, J = 10.8 Hz) , 1H), 3.30 (s, 3H).
实施例42：5-氟-8-(4-氟苯基)-9-(1-环丁基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物42)Example 42: 5-Fluoro-8-(4-fluorophenyl)-9-(1-cyclobutyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 42)
Figure PCTCN2019078089-appb-000241
Figure PCTCN2019078089-appb-000241
步骤1：5-氟-8-(4-氟苯基)-9-(1-环丁基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1-cyclobutyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000242
Figure PCTCN2019078089-appb-000242
同实施例1的步骤1。由1-环丁基-2，4-咪唑啉二酮和中间体1a反应制备。MS(ESI)：552.1[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 1-cyclobutyl-2,4-imidazolidinone with Intermediate 1a. MS (ESI): 552.1 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(1-环丁基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1-cyclobutyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000243
Figure PCTCN2019078089-appb-000243
同实施例1的步骤2。MS(ESI)：452.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.46(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)。 Same as step 2 of the embodiment 1. MS (ESI): 452.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.46 (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, 2.4 Hz, 1H), 6.92 (dd, J = 11.1, 2.4 Hz, 1H), 5.28 (d, J = 11.5 Hz, 1H), 5.13 (d, J = 11.6 Hz) , 1H), 4.43-4.30 (m, 1H), 4.19-4.01 (m, 2H), 2.15 (q, J = 9.8 Hz, 2H), 2.09-1.91 (m, 2H), 1.66-1.51 (m, 2H) ).
实施例43：5-氟-8-(4-氟苯基)-9-(1-(氮杂环丁-3-基)-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物43)Example 43: 5-Fluoro-8-(4-fluorophenyl)-9-(1-(azetidin-3-yl)-2,4-imidazolidindione-3-yl)-8, 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 43)
Figure PCTCN2019078089-appb-000244
Figure PCTCN2019078089-appb-000244
步骤1：5-氟-8-(4-氟苯基)-9-(1-(1-叔丁氧羰基氮杂环丁-3-基)-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1-(1-tert-butoxycarbonylazetidin-3-yl)-2,4-imidazolidin-2-one-3- ,8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000245
Figure PCTCN2019078089-appb-000245
同实施例1的步骤1。由1-(1-叔丁氧羰基氮杂环丁-3-基)-2，4- 咪唑啉二酮和中间体1a反应制备。MS(ESI)：653.2[M+H] +。 Same as step 1 of the embodiment 1. Prepared by the reaction of 1-(1-tert-butoxycarbonylazetidin-3-yl)-2,4-imidazolidinone with Intermediate 1a. MS (ESI): 653.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(1-(氮杂环丁-3-基)-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1-(azetidin-3-yl)-2,4-imidazolidindione-3-yl)-8,9 -dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000246
Figure PCTCN2019078089-appb-000246
同实施例1的步骤2。MS(ESI)：453.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.48(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)。 Same as step 2 of the embodiment 1. MS (ESI): 453.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.48 (s, 1H), 9.00 (s, 1H), 7.67 (s, 1H), 7.49 (dd, J = 8.5,5.5Hz, 2H), 7.25 (t , J = 8.8 Hz, 2H), 7.11 (dd, J = 8.9, 2.3 Hz, 1H), 6.93 (dd, J = 11.1, 2.3 Hz, 1H), 5.32 (d, J = 11.3 Hz, 1H), 5.10 (d, J = 11.3 Hz, 1H), 4.99 - 4.82 (m, 1H), 4.33 (q, J = 18.0 Hz, 2H), 4.25 - 4.19 (m, 2H), 4.17 - 4.04 (m, 2H).
实施例44：5-氟-8-(4-氟苯基)-9-(1-(哌啶-4-基)-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物44)Example 44: 5-Fluoro-8-(4-fluorophenyl)-9-(1-(piperidin-4-yl)-2,4-imidazolidin-2-one-3-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 44)
Figure PCTCN2019078089-appb-000247
Figure PCTCN2019078089-appb-000247
步骤1：5-氟-8-(4-氟苯基)-9-(1-(1-叔丁氧羰基哌啶-4-基)-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(1-(1-tert-butoxycarbonylpiperidin-4-yl)-2,4-imidazolinedion-3-yl) -8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000248
Figure PCTCN2019078089-appb-000248
同实施例1的步骤1。由1-(1-叔丁氧羰基哌啶-4-基)-2，4-咪唑啉二酮和中间体1a反应制备。MS(ESI)：681.3[M+H] +。 Same as step 1 of the embodiment 1. Prepared by the reaction of 1-(1-tert-butoxycarbonylpiperidin-4-yl)-2,4-imidazolidinone with Intermediate 1a. MS (ESI): 681.3 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(1-(哌啶-4-基)-2，4-咪唑啉二酮 -3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(1-(piperidin-4-yl)-2,4-imidazolidin-2-one)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000249
Figure PCTCN2019078089-appb-000249
同实施例1的步骤2。MS(ESI)：481.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.47(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)。 Same as step 2 of the embodiment 1. MS (ESI): 481.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.47 (s, 1H), 8.55 (s, 1H), 7.68 (s, 1H), 7.49 (dd, J = 8.5,5.6Hz, 2H), 7.25 (t , J = 8.8 Hz, 2H), 7.12 (dd, J = 8.9, 2.3 Hz, 1H), 6.93 (dd, J = 11.1, 2.3 Hz, 1H), 5.27 (d, J = 11.5 Hz, 1H), 5.12 (d, J = 11.5 Hz, 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).
实施例45：5-氟-8-(4-氟苯基)-9-(3-甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物45)Example 45: 5-Fluoro-8-(4-fluorophenyl)-9-(3-methyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 45)
Figure PCTCN2019078089-appb-000250
Figure PCTCN2019078089-appb-000250
步骤1：5-氟-9-叠氮基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-9-azido-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3 (7H) -keto-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000251
Figure PCTCN2019078089-appb-000251
5-氟-9-氯-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯(中间体1a，3.0g，6.91mmol)溶于N，N-二甲基甲酰胺(40mL)，加入叠氮化钠(0.9g，13.82mmol)，加热至50℃反应3小时。反应液加入100mL水及100mL乙酸乙酯，分出有机相，有机相再用水洗两次，无水硫酸镁干燥，过滤。滤液减压浓缩得到3.06g淡黄色固体(收率100％)。MS(ESI)：441.1[M+H] +。 5-fluoro-9-chloro-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7- The tert-butyl carboxylate (intermediate 1a, 3.0 g, 6.91 mmol) was dissolved in N,N-dimethylformamide (40 mL), sodium azide (0.9 g, 13.82 mmol) was added and heated to 50 ° C. hour. The reaction mixture was poured into 100 mL of water and ethyl acetate (100 mL), and the organic phase was separated. The filtrate was concentrated under reduced pressure to give 3.06 g (yield: 100%). MS (ESI): 441.1 [M+H] + .
步骤2：5-氟-9-氨基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 2: 5-Fluoro-9-amino-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one -7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000252
Figure PCTCN2019078089-appb-000252
5-氟-9-叠氮基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯(3.06g，6.91mmol)溶于甲醇(40mL)，加入10％钯碳(0.6g)，室温下用氢气球氢化反应2天。反应液通过硅藻土抽滤，滤液减压浓缩，残留物用石油醚-乙酸乙酯(5/1，v/v)打浆处理，得到产物1.86g(收率65％)。MS(ESI)：415.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.65(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)。 5-fluoro-9-azido-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one- 7-Carboxylic acid tert-butyl ester (3.06 g, 6.91 mmol) was dissolved in methanol (40 mL), 10% palladium carbon (0.6 g) was added, and hydrogenated with hydrogen balloon at room temperature for 2 days. The reaction mixture was filtered with EtOAc (EtOAc)EtOAc.EtOAc. MS (ESI): 415.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.65 (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 = 2.6 Hz, 1H), 2.41 (brs, 2H), 1.54 (s, 9H).
步骤3：5-氟-9-异硫氰基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 3: 5-Fluoro-9-isothiocyanato-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3 (7H )-keto-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000253
Figure PCTCN2019078089-appb-000253
5-氟-9-氨基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯(250mg，0.6mmol)及三乙胺(0.21mL，1.5mmol)溶于二氯甲烷(10mL)，反应物冷却到0℃，加入硫光气(64μL，0.84mmol)，继续于0℃反应2小时。反应物减压浓缩，残留物不经纯化直接用于下一步反应。MS(ESI)：457.1[M+H] +。 5-fluoro-9-amino-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7- tert-Butyl carboxylic acid ester (250 mg, 0.6 mmol) and triethylamine (0.21 mL, 1.5 mmol) were dissolved in dichloromethane (10 mL), and the reaction was cooled to 0 ° C, and sulphur phosgene (64 μL, 0.84 mmol) was added. The reaction was carried out at 0 ° C for 2 hours. The reaction was concentrated under reduced pressure. MS (ESI): 457.1 [M+H] + .
步骤4：5-氟-8-(4-氟苯基)-9-(3-甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 4: 5-Fluoro-8-(4-fluorophenyl)-9-(3-methyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000254
Figure PCTCN2019078089-appb-000254
上一步反应产物溶于乙醇(10mL)，加入N-甲基甘氨酸(122mg，1.38mmol)，加热回流反应2小时。反应物减压蒸去溶剂，加入15mL水，用24mL乙酸乙酯萃取，有机相用无水硫酸镁干燥，过滤，滤液减压浓缩，所得残留物硅胶柱层析(石油醚/乙酸乙酯＝2/1，v/v)，得到81mg黄色固体。MS(ESI)：528.1[M+H] +。 The reaction product of the previous step was dissolved in ethanol (10 mL), and N-methylglycine (122 mg, 1.38 mmol) was added, and the mixture was refluxed for 2 hours. The solvent was evaporated under reduced pressure. EtOAc was evaporated, evaporated, evaporated. 2/1, v/v) gave 81 mg of a yellow solid. MS (ESI): 528.1 [M+H] + .
步骤5：5-氟-8-(4-氟苯基)-9-(3-甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 5: 5-Fluoro-8-(4-fluorophenyl)-9-(3-methyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000255
Figure PCTCN2019078089-appb-000255
5-氟-8-(4-氟苯基)-9-(3-甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯(70mg，0.13mmol)溶于二氯甲烷(2mL)，再加入三氟乙酸(1mL)，室温下搅拌反应1小时。反应液减压蒸干，残留物溶于乙酸乙酯(20mL)，依次用饱和碳酸氢钠溶液、水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，残留物经制备薄层色谱纯化(二氯甲烷/甲醇＝30/1，v/v)，得产物28mg(收率50％)。MS(ESI)：428.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.46(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)。 5-fluoro-8-(4-fluorophenyl)-9-(3-methyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester (70 mg, 0.13 mmol) was dissolved in dichloromethane (2 mL). The reaction was stirred at room temperature for 1 hour. The reaction mixture was evaporated to drynesshhhhhhhhhhhhhhhhhhhhh Methyl chloride / methanol = 30/1, v / v), product 28 mg (yield 50%). MS (ESI): 428.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.46 (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).
实施例46：5-氟-8-(4-氟苯基)-9-(5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物46)Example 46: 5-Fluoro-8-(4-fluorophenyl)-9-(5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H-pyrido[ 4,3,2-de]pyridazine-3(7H)-one (compound 46)
Figure PCTCN2019078089-appb-000256
Figure PCTCN2019078089-appb-000256
步骤1：5-氟-8-(4-氟苯基)-9-(5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H-pyrido[4 ,3,2-de]pyridazine-3(7H)-keto-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000257
Figure PCTCN2019078089-appb-000257
同实施例45的步骤4。由甘氨酸乙酯盐酸盐和5-氟-9-异硫氰基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯反应制备。MS(ESI)：514.1[M+H] +。 Same as step 4 of Example 45. From glycine ethyl ester hydrochloride and 5-fluoro-9-isothiocyanato-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de]酞Prepared by the reaction of azin-3(7H)-one-7-carboxylic acid tert-butyl ester. MS (ESI): 514.1 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H-pyrido[4 ,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000258
Figure PCTCN2019078089-appb-000258
同实施例45的步骤5。MS(ESI)：414.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.47(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)。 Same as step 5 of Example 45. MS (ESI): 414.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.47 (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 = 11.0 Hz, 1H), 5.25 (d, J = 11.0 Hz, 1H), 4.17 (s, 2H).
实施例47：5-氟-8-(4-氟苯基)-9-(4，4-二甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物47)Example 47: 5-Fluoro-8-(4-fluorophenyl)-9-(4,4-dimethyl-5-oxo-2-thioimidazolin-1-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 47)
Figure PCTCN2019078089-appb-000259
Figure PCTCN2019078089-appb-000259
步骤1：5-氟-8-(4-氟苯基)-9-(4，4-二甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(4,4-dimethyl-5-oxo-2-thioimidazolin-1-yl)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000260
Figure PCTCN2019078089-appb-000260
同实施例45的步骤4。由2-氨基异丁酸甲酯盐酸盐和5-氟-9-异硫氰基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯反应制备。MS(ESI)：542.2[M+H] +。 Same as step 4 of Example 45. From 2-aminoisobutyrate methyl ester hydrochloride and 5-fluoro-9-isothiocyanato-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3, Preparation of 2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester. MS (ESI): 542.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(4，4-二甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(4,4-dimethyl-5-oxo-2-thioimidazolin-1-yl)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000261
Figure PCTCN2019078089-appb-000261
同实施例45的步骤5。MS(ESI)：441.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.47(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)。 Same as step 5 of Example 45. MS (ESI): 441.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.47 (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 = 11.2 Hz, 1H), 5.24 (d, J = 11.2 Hz, 1H), 1.30 (s, 3H), 1.15 (s, 3H).
实施例48：5-氟-8-(4-氟苯基)-9-(8-氧代-6-硫代-5，7-二氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物48)Example 48: 5-Fluoro-8-(4-fluorophenyl)-9-(8-oxo-6-thio-5,7-diazaspiro[3.4]octane-7-yl)- 8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 48)
Figure PCTCN2019078089-appb-000262
Figure PCTCN2019078089-appb-000262
步骤1：5-氟-8-(4-氟苯基)-9-(8-氧代-6-硫代-5，7-二氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(8-oxo-6-thio-5,7-diazaspiro[3.4]octane-7-yl)-8 , 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000263
Figure PCTCN2019078089-appb-000263
同实施例45的步骤4。由1-氨基环丁基甲酸甲酯盐酸盐和5-氟-9-异硫氰基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯反应制备。MS(ESI)：554.2[M+H] +。 Same as step 4 of Example 45. From 1-aminocyclobutylcarboxylic acid methyl ester hydrochloride and 5-fluoro-9-isothiocyanato-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3 , 2-de] pyridazine-3 (7H)-keto-7-carboxylic acid tert-butyl ester reaction preparation. MS (ESI): 554.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(8-氧代-6-硫代-5，7-二氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(8-oxo-6-thio-5,7-diazaspiro[3.4]octane-7-yl)-8 ,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000264
Figure PCTCN2019078089-appb-000264
同实施例45的步骤5。MS(ESI)：454.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.44(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)。 Same as step 5 of Example 45. MS (ESI): 454.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.44 (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 = 11.3 Hz, 1H), 5.25 (d, J = 11.5 Hz, 1H), 2.31 (m, 4H), 1.88 (m, 2H).
实施例49：5-氟-8-(4-氟苯基)-9-((S)-1-氧代-3-硫代四氢-1H-吡咯并[1，2-c]咪唑-2(3H)-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物49)Example 49: 5-Fluoro-8-(4-fluorophenyl)-9-((S)-1-oxo-3-thiotetrahydro-1H-pyrrolo[1,2-c]imidazole- 2(3H)-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 49)
Figure PCTCN2019078089-appb-000265
Figure PCTCN2019078089-appb-000265
步骤1：5-氟-8-(4-氟苯基)-9-((S)-1-氧代-3-硫代四氢-1H-吡咯并[1，2-c]咪唑-2(3H)-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-((S)-1-oxo-3-thiotetrahydro-1H-pyrrolo[1,2-c]imidazole-2 (3H)-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000266
Figure PCTCN2019078089-appb-000266
同实施例45的步骤4。由L-脯氨酸甲酯盐酸盐和5-氟-9-异硫氰基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯反应制备。MS(ESI)：554.2[M+H] +。 Same as step 4 of Example 45. From L-valine methyl ester hydrochloride and 5-fluoro-9-isothiocyanato-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2 -de] Preparation of pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester. MS (ESI): 554.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-((S)-1-氧代-3-硫代四氢-1H-吡咯并[1，2-c]咪唑-2(3H)-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-((S)-1-oxo-3-thiotetrahydro-1H-pyrrolo[1,2-c]imidazole-2 (3H)-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000267
Figure PCTCN2019078089-appb-000267
同实施例45的步骤5。MS(ESI)：454.1[M+H] +。 Same as step 5 of Example 45. MS (ESI): 454.1 [M+H] + .
实施例50：5-氟-8-(4-氟苯基)-9-(3-环丙基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物50)Example 50: 5-Fluoro-8-(4-fluorophenyl)-9-(3-cyclopropyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 50)
Figure PCTCN2019078089-appb-000268
Figure PCTCN2019078089-appb-000268
步骤1：5-氟-8-(4-氟苯基)-9-(3-环丙基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(3-cyclopropyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000269
Figure PCTCN2019078089-appb-000269
同实施例45的步骤4。由N-环丙基甘氨酸乙酯和5-氟-9-异硫氰基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔 丁酯反应制备。MS(ESI)：554.2[M+H] +。 Same as step 4 of Example 45. From N-cyclopropylglycine ethyl ester and 5-fluoro-9-isothiocyanato-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4,3,2-de The preparation of pyridazine-3 (7H)-keto-7-carboxylic acid tert-butyl ester. MS (ESI): 554.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(3-环丙基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(3-cyclopropyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000270
Figure PCTCN2019078089-appb-000270
同实施例45的步骤5。MS(ESI)：454.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.46(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)。 Same as step 5 of Example 45. MS (ESI): 454.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.46 (s, 1H), 7.68 (s, 1H), 7.48 (m, 2H), 7.24 (m, 2H), 7.12 (m, 1H), 6.94 (d , J = 10.7 Hz, 1H), 6.06 (d, J = 10.3 Hz, 1H), 5.18 (d, J = 10.4 Hz, 1H), 4.26 (s, 2H), 3.12 (m, 1H), 0.83-0.70 (m, 4H).
实施例51：5-氟-8-(4-氟苯基)-9-(7-氧代-5-硫代-4，6-二氮杂螺[2.4]庚烷-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物51)Example 51: 5-Fluoro-8-(4-fluorophenyl)-9-(7-oxo-5-thio-4,6-diazaspiro[2.4]heptane-6-yl)- 8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 51)
Figure PCTCN2019078089-appb-000271
Figure PCTCN2019078089-appb-000271
步骤1：5-氟-8-(4-氟苯基)-9-(7-氧代-5-硫代-4，6-二氮杂螺[2.4]庚烷-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(7-oxo-5-thio-4,6-diazaspiro[2.4]heptane-6-yl)-8 , 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000272
Figure PCTCN2019078089-appb-000272
同实施例45的步骤4。由1-氨基环丙基-1-羧酸乙酯盐酸盐和5-氟-9-异硫氰基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯反应制备。MS(ESI)：540.1[M+H] +。 Same as step 4 of Example 45. From 1-aminocyclopropyl-1-carboxylic acid ethyl ester hydrochloride and 5-fluoro-9-isothiocyanato-8-(4-fluorophenyl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester was prepared by reaction. MS (ESI): 540.1 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(7-氧代-5-硫代-4，6-二氮杂螺[2.4] 庚烷-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(7-oxo-5-thio-4,6-diazaspiro[2.4]heptane-6-yl)-8 ,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000273
Figure PCTCN2019078089-appb-000273
同实施例45的步骤5。MS(ESI)：440.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.55(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)。 Same as step 5 of Example 45. MS (ESI): 440.1 [M + H] +. 1 H NMR (400MHz, DMSO- d6) δ12.55 (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, 2.0 Hz, 1H), 6.95 (dd, J = 11.2, 2.0 Hz, 1H), 5.09 (t, J = 7.3 Hz, 1H), 4.83 (d, J = 6.5 Hz) , 1H), 1.56-1.42 (m, 4H).
实施例52：5-氟-8-(4-氟苯基)-9-(3，4，4-三甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物52)Example 52: 5-Fluoro-8-(4-fluorophenyl)-9-(3,4,4-trimethyl-5-oxo-2-thioimidazolin-1-yl)-8, 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 52)
Figure PCTCN2019078089-appb-000274
Figure PCTCN2019078089-appb-000274
步骤1：5-氟-8-(4-氟苯基)-9-(3，4，4-三甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(3,4,4-trimethyl-5-oxo-2-thioimidazolin-1-yl)-8,9 -Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000275
Figure PCTCN2019078089-appb-000275
同实施例45的步骤4。由2-甲基-2-甲氨基丙酸乙酯和5-氟-9-异硫氰基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯反应制备。MS(ESI)：556.2[M+H] +。 Same as step 4 of Example 45. From 2-methyl-2-methylaminopropionic acid ethyl ester and 5-fluoro-9-isothiocyanato-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4, Preparation of 3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester. MS (ESI): 556.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(3，4，4-三甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(3,4,4-trimethyl-5-oxo-2-thioimidazolin-1-yl)-8,9 -dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000276
Figure PCTCN2019078089-appb-000276
同实施例45的步骤5。MS(ESI)：456.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.45(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)。 Same as step 5 of Example 45. MS (ESI): 456.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.45 (s, 1H), 7.73 (s, 1H), 7.47 (m, 2H), 7.25 (t, J = 8.7Hz, 2H), 7.13 (dd, J = 8.9, 2.2 Hz, 1H), 6.94 (d, J = 9.2 Hz, 1H), 6.08 (d, J = 11.6 Hz, 1H), 5.25 (d, J = 11.6 Hz, 1H), 3.09 (s, 3H) ), 1.36 (s, 3H), 1.21 (s, 3H).
实施例53：5-氟-8-(4-氟苯基)-9-(5-甲基-8-氧代-6-硫代-5，7-二氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物53)Example 53: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-8-oxo-6-thio-5,7-diazaspiro[3.4]octane- 7-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 53)
Figure PCTCN2019078089-appb-000277
Figure PCTCN2019078089-appb-000277
步骤1：5-氟-8-(4-氟苯基)-9-(5-甲基-8-氧代-6-硫代-5，7-二氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-8-oxo-6-thio-5,7-diazaspiro[3.4]octane-7 -yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000278
Figure PCTCN2019078089-appb-000278
同实施例45的步骤4。由1-甲氨基环丁基-1-羧酸乙酯和5-氟-9-异硫氰基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯反应制备。MS(ESI)：568.2[M+H] +。 Same as step 4 of Example 45. From ethyl 1-methylaminocyclobutyl-1-carboxylate and 5-fluoro-9-isothiocyanato-8-(4-fluorophenyl)-8,9-dihydro-2H-pyrido[4 , 3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester reaction preparation. MS (ESI): 568.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(5-甲基-8-氧代-6-硫代-5，7-二氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-8-oxo-6-thio-5,7-diazaspiro[3.4]octane-7 -yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000279
Figure PCTCN2019078089-appb-000279
同实施例45的步骤5。MS(ESI)：468.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.43(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)。 Same as step 5 of Example 45. MS (ESI): 468.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.43 (s, 1H), 7.71 (s, 1H), 7.48 (m, 2H), 7.23 (m, 2H), 7.13 (m, 1H), 6.94 (d , J=9.7 Hz, 1H), 6.04 (d, J = 11.5 Hz, 1H), 5.28 (d, J = 11.3 Hz, 1H), 3.24 (s, 3H), 2.64 (m, 2H), 2.23 (m) , 2H), 1.92 (m, 2H).
手性拆分化合物53得到(8R，9R)-5-氟-8-(4-氟苯基)-9-(5-甲基-8-氧代-6-硫代-5，7-二氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物53a)和(8S，9S)-5-氟-8-(4-氟苯基)-9-(5-甲基-8-氧代-6-硫代-5，7-二氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物53b)Chiral resolution of compound 53 affords (8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-8-oxo-6-thio-5,7-di Azaspiro[3.4]octane-7-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (compound 53a) and (8S , 9S)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-8-oxo-6-thio-5,7-diazaspiro[3.4]octane- 7-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (compound 53b)
Figure PCTCN2019078089-appb-000280
Figure PCTCN2019078089-appb-000280
将5-氟-8-(4-氟苯基)-9-(5-甲基-8-氧代-6-硫代-5，7-二氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物53)溶解在甲醇/二氯甲烷混合溶剂中，采用超临界流体色谱(SFC)进行手性拆分得到一对对映异构体。手性柱为ChiralCel OD，洗脱剂为二氧化碳(55％)和甲醇(45％，含0.1％氨水)。5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-8-oxo-6-thio-5,7-diazaspiro[3.4]octane-7-yl )-8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 53) is dissolved in a methanol/methylene chloride mixed solvent using a supercritical fluid Chromatography (SFC) is carried out by chiral separation to give a pair of enantiomers. The chiral column was ChiralCel OD and the eluent was carbon dioxide (55%) and methanol (45% with 0.1% ammonia).
实施例54：5-氟-8-(4-氟苯基)-9-(4-氧代-2-硫代-1，3-二氮杂螺[4.4]壬烷-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物54)Example 54: 5-Fluoro-8-(4-fluorophenyl)-9-(4-oxo-2-thio-1,3-diazaspiro[4.4]decane-3-yl)- 8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 54)
Figure PCTCN2019078089-appb-000281
Figure PCTCN2019078089-appb-000281
步骤1：5-氟-8-(4-氟苯基)-9-(4-氧代-2-硫代-1，3-二氮杂螺[4.4]壬烷-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(4-oxo-2-thio-1,3-diazaspiro[4.4]decane-3-yl)-8 , 9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000282
Figure PCTCN2019078089-appb-000282
同实施例45的步骤4。由1-氨基环戊基-1-羧酸乙酯盐酸盐和5-氟-9-异硫氰基-8-(4-氟苯基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯反应制备。MS(ESI)：568.2[M+H] +。 Same as step 4 of Example 45. From 1-aminocyclopentyl-1-carboxylic acid ethyl ester hydrochloride and 5-fluoro-9-isothiocyanato-8-(4-fluorophenyl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester was prepared by reaction. MS (ESI): 568.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(4-氧代-2-硫代-1，3-二氮杂螺[4.4]壬烷-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(4-oxo-2-thio-1,3-diazaspiro[4.4]decane-3-yl)-8 ,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000283
Figure PCTCN2019078089-appb-000283
同实施例45的步骤5。MS(ESI)：468.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.47(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)。 Same as step 5 of Example 45. MS (ESI): 468.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.47 (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).
实施例55：5-氟-8-(4-氟苯基)-9-(4，7-亚甲基-3a，4，7，7a-四氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物55)Example 55: 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-methylene-3a,4,7,7a-tetrahydroisoindole-1,3(2H)- Diketo-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 55)
Figure PCTCN2019078089-appb-000284
Figure PCTCN2019078089-appb-000284
步骤1：5-氟-8-(4-氟苯基)-9-(4，7-亚甲基-3a，4，7，7a-四氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮 -7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-methylene-3a,4,7,7a-tetrahydroisoindol-1,3(2H)-di Keto-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000285
Figure PCTCN2019078089-appb-000285
同实施例1的步骤1。由4，7-亚甲基-3a，4，7，7a-四氢异吲哚-1，3(2H)-二酮和中间体1a反应制备。MS(ESI)：561.1[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 4,7-methylene-3a,4,7,7a-tetrahydroisoindol-1,3(2H)-dione with intermediate 1a. MS (ESI): 561.1 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(4，7-亚甲基-3a，4，7，7a-四氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(4,7-methylene-3a,4,7,7a-tetrahydroisoindol-1,3(2H)-di Keto-2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000286
Figure PCTCN2019078089-appb-000286
同实施例1的步骤2。MS(ESI)：461.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.47(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)。 Same as step 2 of the embodiment 1. MS (ESI): 461.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.47 (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, 2.4 Hz, 1H), 5.67 (s, 1H), 5.39 (d, J = 11.7 Hz, 1H), 5.08 (s, 1H), 5.02 (d, J = 11.8 Hz) , 1H), 3.38 (dd, J = 7.8, 4.5 Hz, 1H), 3.27 (dd, J = 7.8, 4.5 Hz, 1H), 3.15 (s, 1H), 3.10 (s, 1H), 1.45 (q, J = 8.5 Hz, 2H).
实施例56：5-氟-8-(4-氟苯基)-9-(2-甲基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物56)Example 56: 5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene-3 -yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 56)
Figure PCTCN2019078089-appb-000287
Figure PCTCN2019078089-appb-000287
步骤1：5-氟-8-(4-氟苯基)-9-(2-甲基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene-3- ,8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000288
Figure PCTCN2019078089-appb-000288
同实施例1的步骤1。由2-甲基-1，3-二氮杂螺-[4.4]壬-1-烯-4-酮和中间体1a反应制备。MS(ESI)：550.2[M+H] +。 Same as step 1 of the embodiment 1. Prepared by the reaction of 2-methyl-1,3-diazaspiro-[4.4]non-1-en-4-one with intermediate 1a. MS (ESI): 550.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(2-甲基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene-3- -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000289
Figure PCTCN2019078089-appb-000289
同实施例1的步骤2。MS(ESI)：450.2[M+H] +。 Same as step 2 of the embodiment 1. MS (ESI): 450.2 [M+H] + .
手性拆分化合物56得到(8R，9R)-5-氟-8-(4-氟苯基)-9-(2-甲基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物56a)和(8S，9S)-5-氟-8-(4-氟苯基)-9-(2-甲基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物56b)Chiral resolution of compound 56 affords (8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(2-methyl-4-oxo-1,3-diazaspiro-[ 4.4] 壬-1-en-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 56a) and (8S, 9S)-5-fluoro-8-(4-fluorophenyl)-9-(2-methyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene-3- ,8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (compound 56b)
Figure PCTCN2019078089-appb-000290
Figure PCTCN2019078089-appb-000290
将5-氟-8-(4-氟苯基)-9-(2-甲基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物56)溶解在甲醇/二氯甲烷混合溶剂中，采用超临界流体色谱(SFC)进行手性拆分得到一对对映异构体。手性柱为ChiralCel OD，洗脱剂为二氧化碳(55％)和甲醇(45％，含0.1％氨水)。5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-4-oxo-1,3-diazaspiro-[4.4]non-1-en-3-yl) -8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazin-3(7H)-one (Compound 56) was dissolved in a methanol/methylene chloride mixed solvent using supercritical fluid chromatography Chiral resolution (SFC) gave a pair of enantiomers. The chiral column was ChiralCel OD and the eluent was carbon dioxide (55%) and methanol (45% with 0.1% ammonia).
实施例57：5-氟-8-(4-氟苯基)-9-(2-丁基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化 合物57)Example 57: 5-Fluoro-8-(4-fluorophenyl)-9-(2-butyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene-3 -yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 57)
Figure PCTCN2019078089-appb-000291
Figure PCTCN2019078089-appb-000291
步骤1：5-氟-8-(4-氟苯基)-9-(2-丁基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(2-butyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene-3- ,8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000292
Figure PCTCN2019078089-appb-000292
同实施例1的步骤1。由2-丁基-1，3-二氮杂螺-[4.4]壬-1-烯-4-酮盐酸盐和中间体1a反应制备。MS(ESI)：592.3[M+H] +。 Same as step 1 of the embodiment 1. Prepared by the reaction of 2-butyl-1,3-diazaspiro-[4.4]non-1-en-4-one hydrochloride with Intermediate 1a. MS (ESI): 592.3 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(2-丁基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(2-butyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene-3- -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000293
Figure PCTCN2019078089-appb-000293
同实施例1的步骤2。MS(ESI)：492.2[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.48(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)。 Same as step 2 of the embodiment 1. MS (ESI): 492.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.48 (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, 2.1 Hz, 1H), 6.93 (dd, J = 11.0, 2.1 Hz, 1H), 5.27 (m, 2H), 2.00-1.65 (m, 6H), 1.55-1.04 (m, 8H), 0.77 (t, J = 7.2 Hz, 3H).
手性拆分化合物57得到(8R，9R)-5-氟-8-(4-氟苯基)-9-(2-丁基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并 [4，3，2-de]酞嗪-3(7H)-酮(化合物57a)和(8S，9S)-5-氟-8-(4-氟苯基)-9-(2-丁基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物57b)Chiral resolution of compound 57 affords (8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(2-butyl-4-oxo-1,3-diazaspiro-[ 4.4] 壬-1-en-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 57a) and (8S, 9S)-5-fluoro-8-(4-fluorophenyl)-9-(2-butyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene-3- ,8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (compound 57b)
Figure PCTCN2019078089-appb-000294
Figure PCTCN2019078089-appb-000294
将5-氟-8-(4-氟苯基)-9-(2-丁基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物57)溶解在甲醇/二氯甲烷混合溶剂中，采用超临界流体色谱(SFC)进行手性拆分得到一对对映异构体。手性柱为ChiralCel OD，洗脱剂为二氧化碳(55％)和甲醇(45％，含0.1％氨水)。5-Fluoro-8-(4-fluorophenyl)-9-(2-butyl-4-oxo-1,3-diazaspiro-[4.4]non-1-en-3-yl) -8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 57) was dissolved in a methanol/methylene chloride mixed solvent using supercritical fluid chromatography Chiral resolution (SFC) gave a pair of enantiomers. The chiral column was ChiralCel OD and the eluent was carbon dioxide (55%) and methanol (45% with 0.1% ammonia).
实施例58：5-氟-8-(4-氟苯基)-9-(6-甲基-8-氧代-5，7-二氮杂螺-[3.4]辛-5-烯-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物58)Example 58: 5-Fluoro-8-(4-fluorophenyl)-9-(6-methyl-8-oxo-5,7-diazaspiro-[3.4]oct-5-ene-7 -yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (compound 58)
Figure PCTCN2019078089-appb-000295
Figure PCTCN2019078089-appb-000295
步骤1：5-氟-8-(4-氟苯基)-9-(6-甲基-8-氧代-5，7-二氮杂螺-[3.4]辛-5-烯-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(6-methyl-8-oxo-5,7-diazaspiro-[3.4]oct-5-ene-7- ,8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000296
Figure PCTCN2019078089-appb-000296
同实施例1的步骤1。由6-甲基-5，7-二氮杂螺-[3.4]辛-5-烯-8-酮和中间体1a反应制备。MS(ESI)：536.2[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 6-methyl-5,7-diazaspiro-[3.4]oct-5-en-8-one with intermediate 1a. MS (ESI): 536.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(6-甲基-8-氧代-5，7-二氮杂螺-[3.4]辛-5-烯-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(6-methyl-8-oxo-5,7-diazaspiro-[3.4]oct-5-ene-7- -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000297
Figure PCTCN2019078089-appb-000297
同实施例1的步骤2。MS(ESI)：436.2[M+H] +。 Same as step 2 of the embodiment 1. MS (ESI): 436.2 [M+H] + .
手性拆分化合物58得到(8R，9R)-5-氟-8-(4-氟苯基)-9-(6-甲基-8-氧代-5，7-二氮杂螺-[3.4]辛-5-烯-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物58a)和(8S，9S)-5-氟-8-(4-氟苯基)-9-(6-甲基-8-氧代-5，7-二氮杂螺-[3.4]辛-5-烯-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物58b)Chiral resolution of compound 58 affords (8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(6-methyl-8-oxo-5,7-diazaspiro-[ 3.4] oct-5-en-7-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (compound 58a) and (8S, 9S)-5-fluoro-8-(4-fluorophenyl)-9-(6-methyl-8-oxo-5,7-diazaspiro-[3.4]oct-5-ene-7- ,8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (compound 58b)
Figure PCTCN2019078089-appb-000298
Figure PCTCN2019078089-appb-000298
将5-氟-8-(4-氟苯基)-9-(6-甲基-8-氧代-5，7-二氮杂螺-[3.4]辛-5-烯-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物58)溶解在甲醇/二氯甲烷混合溶剂中，采用超临界流体色谱(SFC)进行手性拆分得到一对对映异构体。手性柱为ChiralCel OD，洗脱剂为二氧化碳(55％)和甲醇(45％，含0.1％氨水)。5-Fluoro-8-(4-fluorophenyl)-9-(6-methyl-8-oxo-5,7-diazaspiro-[3.4]oct-5-ene-7-yl) -8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 58) was dissolved in a methanol/methylene chloride mixed solvent using supercritical fluid chromatography Chiral resolution (SFC) gave a pair of enantiomers. The chiral column was ChiralCel OD and the eluent was carbon dioxide (55%) and methanol (45% with 0.1% ammonia).
实施例59：5-氟-8-(4-氟苯基)-9-(5-甲基-7-氧代-4，6-二氮杂螺-[2.4]庚-4-烯-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物59)Example 59: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-7-oxo-4,6-diazaspiro-[2.4]hept-4-ene-6 -yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 59)
Figure PCTCN2019078089-appb-000299
Figure PCTCN2019078089-appb-000299
步骤1：5-氟-8-(4-氟苯基)-9-(5-甲基-7-氧代-4，6-二氮杂螺-[2.4] 庚-4-烯-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-7-oxo-4,6-diazaspiro-[2.4]hept-4-ene-6- ,8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000300
Figure PCTCN2019078089-appb-000300
同实施例1的步骤1。由5-甲基-4，6-二氮杂螺-[2.4]庚-4-烯-7-酮和中间体1a反应制备。MS(ESI)：522.2[M+H] +。 Same as step 1 of the embodiment 1. It is prepared by reacting 5-methyl-4,6-diazaspiro-[2.4]hept-4-en-7-one with Intermediate 1a. MS (ESI): 522.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(5-甲基-7-氧代-4，6-二氮杂螺-[2.4]庚-4-烯-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-7-oxo-4,6-diazaspiro-[2.4]hept-4-ene-6- -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000301
Figure PCTCN2019078089-appb-000301
同实施例1的步骤2。MS(ESI)：421.1[M+H] +。 Same as step 2 of the embodiment 1. MS (ESI): 421.1 [M+H] + .
手性拆分化合物59得到8R，9R)-5-氟-8-(4-氟苯基)-9-(5-甲基-7-氧代-4，6-二氮杂螺-[2.4]庚-4-烯-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物59a)和(8S，9S)-5-氟-8-(4-氟苯基)-9-(5-甲基-7-氧代-4，6-二氮杂螺-[2.4]庚-4-烯-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物59b)Chiral resolution of compound 59 affords 8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-7-oxo-4,6-diazaspiro-[2.4 Hept-4-ene-6-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 59a) and (8S, 9S -5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-7-oxo-4,6-diazaspiro-[2.4]hept-4-ene-6-yl )-8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 59b)
Figure PCTCN2019078089-appb-000302
Figure PCTCN2019078089-appb-000302
将5-氟-8-(4-氟苯基)-9-(5-甲基-7-氧代-4，6-二氮杂螺-[2.4]庚-4-烯-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物59)溶解在甲醇/二氯甲烷混合溶剂中，采用超临界流体色谱(SFC)进行手性拆分得到一对对映异构体。手性柱为ChiralCel OD，洗脱剂为二氧化碳(55％)和甲醇(45％，含0.1％氨水)。5-Fluoro-8-(4-fluorophenyl)-9-(5-methyl-7-oxo-4,6-diazaspiro-[2.4]hept-4-en-6-yl) -8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 59) was dissolved in a methanol/methylene chloride mixed solvent using supercritical fluid chromatography Chiral resolution (SFC) gave a pair of enantiomers. The chiral column was ChiralCel OD and the eluent was carbon dioxide (55%) and methanol (45% with 0.1% ammonia).
实施例60：5-氟-8-(4-氟苯基)-9-(2，4，4-三甲基-5-氧代-4，5-二氢-1H-咪唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物60)Example 60: 5-Fluoro-8-(4-fluorophenyl)-9-(2,4,4-trimethyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl )-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 60)
Figure PCTCN2019078089-appb-000303
Figure PCTCN2019078089-appb-000303
步骤1：5-氟-8-(4-氟苯基)-9-(2，4，4-三甲基-5-氧代-4，5-二氢-1H-咪唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(2,4,4-trimethyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl) -8,9-Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000304
Figure PCTCN2019078089-appb-000304
同实施例1的步骤1。由2，4，4-三甲基-1H-咪唑-5(4H)-酮和中间体1a反应制备。MS(ESI)：524.2[M+H] +。 Same as step 1 of the embodiment 1. Prepared by the reaction of 2,4,4-trimethyl-1H-imidazole-5(4H)-one with intermediate 1a. MS (ESI): 524.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(2，4，4-三甲基-5-氧代-4，5-二氢-1H-咪唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(2,4,4-trimethyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl) -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000305
Figure PCTCN2019078089-appb-000305
同实施例1的步骤2。MS(ESI)：424.2[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.49(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)。 Same as step 2 of the embodiment 1. MS (ESI): 424.2 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.49 (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, 2.3 Hz, 1H), 6.88 (dd, J = 11.1, 2.3 Hz, 1H), 5.28 (d, J = 11.6 Hz, 1H), 5.11 (d, J = 10.8 Hz) , 1H), 1.87 (s, 3H), 1.04 (s, 3H), 0.98 (s, 3H).
实施例61：5-氟-8-(4-氟苯基)-9-(2-甲基-5-氧代-4，5-二氢-1H-咪唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮(化合物61)Example 61: 5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-8,9 -Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one (Compound 61)
Figure PCTCN2019078089-appb-000306
Figure PCTCN2019078089-appb-000306
步骤1：5-氟-8-(4-氟苯基)-9-(2-甲基-5-氧代-4，5-二氢-1H-咪唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮-7-羧酸叔丁酯Step 1: 5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one-7-carboxylic acid tert-butyl ester
Figure PCTCN2019078089-appb-000307
Figure PCTCN2019078089-appb-000307
同实施例1的步骤1。由2-甲基-1H-咪唑-5(4H)-酮和中间体1a反应制备。MS(ESI)：496.2[M+H] +。 Same as step 1 of the embodiment 1. Prepared by the reaction of 2-methyl-1H-imidazole-5(4H)-one with intermediate 1a. MS (ESI): 496.2 [M+H] + .
步骤2：5-氟-8-(4-氟苯基)-9-(2-甲基-5-氧代-4，5-二氢-1H-咪唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮Step 2: 5-Fluoro-8-(4-fluorophenyl)-9-(2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one
Figure PCTCN2019078089-appb-000308
Figure PCTCN2019078089-appb-000308
同实施例1的步骤2。MS(ESI)：396.1[M+H] +。 1H NMR(400MHz，DMSO-d6)δ12.58(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)。 Same as step 2 of the embodiment 1. MS (ESI): 396.1 [M+H] + . 1 H NMR (400MHz, DMSO- d6) δ12.58 (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, 2.4 Hz, 1H), 5.68 (d, J = 11.4 Hz, 1H), 4.83 (d, J = 11.4 Hz, 1H), 3.97 (q, J = 19.3 Hz, 2H) ), 1.96 (s, 3H).
II.本发明化合物活性测试实施例II. Example of activity test of the compound of the present invention
测试实施例1：细胞增殖抑制活性研究Test Example 1: Study on cell proliferation inhibitory activity
如下药理实验用于测定本发明的化合物在体外对人三阴性乳腺癌细胞株MDA-MB-436(BRCA1突变)以及雌激素受体阴性(ER -)、孕激素受体阴性(PR -)的炎性乳腺癌细胞株SUM149PT(BRCA1突变)的增殖抑制活性。 Following pharmacological test compounds for in vitro assays of the invention on human triple negative breast cancer cell line MDA-MB-436 (BRCA1 mutation) and estrogen receptor negative (ER -), negative progesterone receptor (PR -) of Proliferative inhibitory activity of the inflammatory breast cancer cell line SUM149PT (BRCA1 mutation).
实验过程(磺酰罗丹明B染色法)：取处于对数生长期的肿瘤细 胞接种于96孔培养板(180μL/孔)，37℃、5％CO 2培养24小时使细胞贴壁。各化合物已事先溶解在DMSO中配制成10mM的储存液。当检测时再用完全培养基在另一96孔板中稀释到目的浓度的10倍，然后在接种细胞的96孔板中加入稀释化合物20μL/孔，即到达目的浓度。每个浓度设3个复孔，并设空白对照。继续在37℃、5％CO 2中继续培养120小时。终止培养，每孔加入50μL预冷(4℃)的50％三氯乙酸即TCA(终浓度10％)，放置在4℃固定1小时，用纯化水洗涤至少5次，空气中自然干燥或60℃烘箱干燥。每孔加入100μL用含1％冰乙酸的纯化水配制4mg/mL的磺酰罗丹明B(SRB)溶液，室温染色1小时，弃染色液，用1％冰乙酸洗涤至少5次，干燥待用。每孔加入150μL的10mM的Tris-HCl溶液溶解，在510nm波长处测OD值，再通过计算获得化合物对肿瘤细胞增殖抑制的IC 50值。实验结果见表一。 Experimental procedure (sulfonhodamine B staining): Tumor cells in the logarithmic growth phase were seeded in 96-well culture plates (180 μL/well), and cultured at 37 ° C, 5% CO 2 for 24 hours to adhere the cells. Each compound was previously dissolved in DMSO to prepare a 10 mM stock solution. When assayed, the medium was further diluted to another 10-fold concentration of the target in another 96-well plate, and then 20 μL/well of the diluted compound was added to the 96-well plate inoculated with the cells to reach the target concentration. Three replicate wells were set for each concentration and a blank control was set. Continue to incubate for 120 hours at 37 ° C, 5% CO 2 . The culture was terminated, 50 μL of pre-cooled (4 ° C) 50% trichloroacetic acid, ie TCA (final concentration 10%), was added to each well, placed at 4 ° C for 1 hour, washed with purified water at least 5 times, naturally dried in the air or 60 °C oven drying. Add 100 μL of purified water containing 1% glacial acetic acid to each well to prepare a 4 mg/mL solution of sulforhodamine B (SRB), stain at room temperature for 1 hour, discard the staining solution, wash at least 5 times with 1% glacial acetic acid, and dry for use. . 150 μL of 10 mM Tris-HCl solution was added to each well to dissolve, and the OD value was measured at a wavelength of 510 nm, and the IC 50 value of the compound for inhibiting tumor cell proliferation was obtained by calculation. The experimental results are shown in Table 1.
表一Table I
Figure PCTCN2019078089-appb-000309
Figure PCTCN2019078089-appb-000309
Figure PCTCN2019078089-appb-000310
Figure PCTCN2019078089-appb-000310
注：LT-00628(制备方法参考CN102171214B实施例94)、Talazoparib(制备方法参考CN102171214B实施例155)和Olaparib(制备方法参考CN1788000B实施例9的化合物168)为文献报道的PARP抑制剂。LT-00628为Talazoparib的外消旋体。Note: LT-00628 (preparation method reference CN102171214B Example 94), Talazoparib (preparation method reference CN102171214B Example 155) and Olaparib (preparation method reference CN1788000B Example 9 compound 168) are reported PARP inhibitors. LT-00628 is the racemate of Talazoparib.
试验结果表明：本发明化合物对人三阴性乳腺癌细胞株MDA-MB-436和雌激素受体阴性(ER -)、孕激素受体阴性(PR -)的炎性乳腺癌细胞株SUM149PT具有明显的增殖抑制活性。 The test results show that the compound of the present invention has obvious effects on human triple negative breast cancer cell line MDA-MB-436 and estrogen receptor negative (ER - ) and progesterone receptor negative (PR - ) inflammatory breast cancer cell line SUM149PT. Proliferation inhibitory activity.
测试实施例2：PARP-1和PARP-2酶抑制活性研究Test Example 2: PARP-1 and PARP-2 enzyme inhibitory activities
如下药理实验用于测定本发明的化合物在分子水平对PARP-1和 PARP-2酶的抑制活性。The following pharmacological experiments were used to determine the inhibitory activity of the compounds of the invention on the PARP-1 and PARP-2 enzymes at the molecular level.
实验过程：组蛋白被包在96孔板中并4℃孵育过夜。用200μL PBST(磷酸盐缓冲液)溶液洗涤该板3次后，将其用封闭液封闭，室温孵育30分钟后，用PBST溶液洗涤3次。将被测试化合物处理加入孔板中，之后将20μL稀释的PARP-1(1nM)或20μL的PARP-2(3nM)溶液中加入到反应体系中孵育1或2小时。50μL链霉亲和素-HRP(辣根过氧化物酶)(1∶50)的混合液加入到孔板中并室温孵育30分钟后，PBST缓冲液洗涤三次。100μLHRP化学发光底物混合物加入孔板。立即到酶标仪(Envision，PerkinElmer)上读数。再通过计算获得化合物对PARP-1和PARP-2酶抑制活性的IC 50值。实验结果见表二。 Experimental procedure: Histones were packaged in 96-well plates and incubated overnight at 4 °C. After washing the plate 3 times with 200 μL of PBST (phosphate buffer) solution, it was blocked with a blocking solution, incubated at room temperature for 30 minutes, and then washed 3 times with a PBST solution. The test compound was treated to be added to the well plate, after which 20 μL of diluted PARP-1 (1 nM) or 20 μL of PARP-2 (3 nM) solution was added to the reaction system for 1 or 2 hours. A mixture of 50 μL streptavidin-HRP (horseradish peroxidase) (1:50) was added to the well plate and incubated for 30 minutes at room temperature, and washed three times with PBST buffer. 100 μL of HRP chemiluminescent substrate mixture was added to the well plates. Immediately read on a microplate reader (Envision, PerkinElmer). Then 50 values obtained for Compound PARP-1 and PARP-2 inhibitory activity is calculated by the IC. The experimental results are shown in Table 2.
表二Table II
Figure PCTCN2019078089-appb-000311
Figure PCTCN2019078089-appb-000311
注：LT-00628为Talazoparib的外消旋体，制备方法参考CN102171214B实施例94。Note: LT-00628 is a racemate of Talazoparib. For the preparation method, refer to Example 94 of CN102171214B.
试验结果表明：本发明化合物在分子水平对PARP-1和PARP-2酶具有明显的抑制活性。The test results indicate that the compound of the present invention has significant inhibitory activity against PARP-1 and PARP-2 enzymes at the molecular level.
测试实施例3：药代动力学性质研究Test Example 3: Study on pharmacokinetic properties
如下实验方案用于研究本发明化合物在大鼠体内的药代动力学行为，评价其药动学特征。The following experimental protocol was used to study the pharmacokinetic behavior of the compounds of the invention in rats and to evaluate their pharmacokinetic characteristics.
实验方案：健康SD大鼠3只，雄性，体重180-200g，灌胃给予10mg/kg的化合物，给药体积为10mL/kg，以5％DMSO/15％聚乙二醇-15羟基硬脂酸酯/80％羟丙基-β-环糊精(羟丙基-β-环糊精为20％水溶液，w/v)配制。试验前禁食12h，自由饮水。给药后2h统-进食。Experimental protocol: 3 healthy SD rats, male, weighing 180-200 g, given 10 mg/kg of compound by intragastric administration, the dosage volume was 10 mL/kg, and 5% DMSO/15% polyethylene glycol-15 hydroxystearate The ester/80% hydroxypropyl-β-cyclodextrin (hydroxypropyl-β-cyclodextrin was 20% aqueous solution, w/v) was formulated. Fasting for 12 hours before the test, free to drink water. 2 hours after administration - eating - eating.
健康SD大鼠3只，雄性，体重180-200g，静脉注射给予5mg/kg的化合物，给药体积为5mL/kg，5％DMSO/15％聚乙二醇-15羟基硬脂酸酯/80％羟丙基-β-环糊精(羟丙基-β-环糊精为20％水溶液，w/v)配制。试验前禁食12h，自由饮水。给药后2h统一进食。3 healthy SD rats, male, weighing 180-200 g, administered intravenously with 5 mg/kg of compound at a dose of 5 mL/kg, 5% DMSO/15% polyethylene glycol-15 hydroxystearate/80 % Hydroxypropyl-β-cyclodextrin (hydroxypropyl-β-cyclodextrin in 20% aqueous solution, w/v). Fasting for 12 hours before the test, free to drink water. Uniformly eaten 2 hours after administration.
分别于灌胃给药后0.25h、0.5h、1h、2h、4h、6h、8h、24h以及静脉给药后0.08h、0.25h、0.5h、1h、2h、4h、6h、8h、24h经大鼠眼球后静脉丛取静脉血0.1mL，置肝素化试管中，11000rpm离心5min，分离血浆，以液相色谱-串联质谱法测定血浆中化合物的浓度。实验结果见表三。0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h after intragastric administration and 0.08h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h, 24h after intravenous administration 0.1 mL of venous blood was taken from the posterior venous plexus of the rat, placed in a heparinized tube, centrifuged at 11,000 rpm for 5 min, plasma was separated, and the concentration of the compound in the plasma was determined by liquid chromatography-tandem mass spectrometry. The experimental results are shown in Table 3.
表三Table 3
Figure PCTCN2019078089-appb-000312
Figure PCTCN2019078089-appb-000312
试验结果表明：本发明化合物清除率低，血浆暴露量高，口服生物利用度高，具有良好的药代动力学性质。The test results show that the compound of the invention has low clearance rate, high plasma exposure, high oral bioavailability and good pharmacokinetic properties.
测试实施例4：对人三阴性乳腺癌细胞MDA-MB-436裸小鼠皮下移植瘤的生长抑制作用Test Example 4: Growth inhibition of human triple negative breast cancer cell MDA-MB-436 subcutaneous xenograft in nude mice
如下试验方案用于研究本发明化合物和LT-00628对人三阴性乳腺癌细胞MDA-MB-436裸小鼠皮下移植瘤的抑制作用以及安全性情况。The following protocol was used to investigate the inhibitory effect and safety of the compound of the present invention and LT-00628 on subcutaneous xenografts of human triple negative breast cancer cells MDA-MB-436 nude mice.
细胞培养：MDA-MB-436培养在加有10％胎牛血清的改良Eagle培养基-莱博维茨培养基混合液(1/1，v/v)中，放在37℃含有5％CO 2的恒温培养箱中培养。收取指数生长期的细胞并计数，以供接种。 Cell culture: MDA-MB-436 was cultured in a modified Eagle medium-Lybowitz medium mixture (1/1, v/v) supplemented with 10% fetal bovine serum and placed at 37 ° C containing 5% CO 2 culture incubator. Cells in the exponential growth phase are collected and counted for inoculation.
试验动物：BALB/cA裸小鼠，15只，雌性，5周龄，18±2g，购自北京维通利华实验动物技术有限公司。Test animals: BALB/cA nude mice, 15 females, 5 weeks old, 18±2 g, purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
设3个试验组，分别为：10％二甲基乙酰胺/5％聚乙二醇-15羟基硬脂酸酯/85％磷酸缓冲盐溶液溶剂对照组，化合物56的1mg/kg组和LT-00628的1mg/kg组。Three test groups were set up: 10% dimethylacetamide/5% polyethylene glycol-15 hydroxystearate/85% phosphate buffered saline solvent control group, compound 56 1 mg/kg group and LT -00628 of the 1 mg/kg group.
试验方案：人三阴性乳腺癌细胞MDA-MB-436细胞株(5×10 6个/只)接种于BALB/cA裸小鼠右侧背部皮下，每只小鼠接种量是2mL，定期观察肿瘤生长情况，待肿瘤生长至100-200mm 3时根据肿瘤大小和小鼠体重随机分组。化合物56和对照化合物LT-00628(LT-00628为Talazoparib的外消旋体)各自按1mg/kg灌胃给药，溶剂对照组灌胃给予等量溶剂，每天给药一次，连续20天。整个实验过程中，每周测量两次小鼠的体重和肿瘤的大小，观察是否出现毒性反应。 Test protocol: Human triple-negative breast cancer cell line MDA-MB-436 (5×10 6 cells/only) was inoculated subcutaneously into the right side of BALB/cA nude mice. The inoculation amount of each mouse was 2 mL, and the tumor was observed regularly. The growth was randomized according to tumor size and mouse body weight when the tumor grew to 100-200 mm 3 . Compound 56 and the control compound LT-00628 (LT-00628 is a racemate of Talazoparib) were each administered intragastrically at 1 mg/kg, and the solvent control group was intragastrically administered with an equal amount of solvent once a day for 20 consecutive days. The body weight and tumor size of the mice were measured twice a week during the entire experiment to see if a toxic reaction occurred.
肿瘤体积(tumor volume)的计算公式为：TV＝1/2×a×b 2，其中a、b分别表示肿瘤长、宽。 The formula for calculating the tumor volume is: TV = 1/2 × a × b 2 , where a and b represent the length and width of the tumor, respectively.
三个试验组肿瘤体积变化曲线和小鼠体重变化曲线见附图1和附图2。结果表明本发明化合物对MDA-MB-436裸小鼠皮下移植瘤的生长具有良好的抑制作用，并且对裸小鼠体重影响较小，显示出较好的安全性。The tumor volume change curve and the mouse body weight change curve of the three test groups are shown in Fig. 1 and Fig. 2. The results showed that the compound of the present invention has a good inhibitory effect on the growth of subcutaneous xenografts of MDA-MB-436 nude mice, and has little effect on the body weight of nude mice, showing good safety.
在本文中提及的所有文献均通过引用被并入本申请中。此外还应指明的是，在阅读了本申请的上述公开内容之后，本领域技术人员可以无需背离本发明的精神和范围，对本发明作出各种修饰、改动或修改，但这些变化形式同样都应落于本申请所附权利要求书所记载的范围。All documents mentioned herein are incorporated herein by reference. In addition, it should be noted that after reading the above disclosure of the present application, those skilled in the art can make various modifications, changes or modifications to the present invention without departing from the spirit and scope of the invention. It is within the scope of the claims appended hereto.

Claims (24)

  1. 如下式(I)化合物、其药学上可接受的盐或立体异构体，a compound of the formula (I), a pharmaceutically acceptable salt or a stereoisomer thereof,
    Figure PCTCN2019078089-appb-100001
    Figure PCTCN2019078089-appb-100001
    式中：In the formula:
    环A为含有1～5个选自N、O或S的环杂原子的含氮脂杂环基或含氮芳杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连；Ring A is a nitrogen-containing aliphatic heterocyclic group or a nitrogen-containing aromatic heterocyclic group having 1 to 5 ring hetero atoms selected from N, O or S, and is bonded to the dihydropyridinopyrazine ketone through a ring N atom. ;
    环B为芳基或芳杂环基；Ring B is an aryl or an aromatic heterocyclic group;
    R 1选自氢、C 1-C 6烷基、C 1-C 6烷氧基、卤素、卤代C 1-C 6烷基、C 2-C 6烯基、C 2-C 6炔基、3～7元环烷基、-CN、-OH、-NO 2或-NR 5R 6； R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogen, halogenated C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl , 3 to 7-membered cycloalkyl, -CN, -OH, -NO 2 or -NR 5 R 6 ;
    R 5、R 6各自独立地选自H、C 1-C 6烷基或卤代C 1-C 6烷基； R 5 and R 6 are each independently selected from H, C 1 -C 6 alkyl or halo C 1 -C 6 alkyl;
    R 2各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-NH 2、卤素、氘、氘代C 1-C 6烷基、-(CH 2) qOH、3～7元环烷基、
    Figure PCTCN2019078089-appb-100002
    Figure PCTCN2019078089-appb-100003
    芳基或被1～3个选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-OH、-NH 2或卤素的取代基取代的芳基；     R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -NH 2 , halogen, hydrazine, deuterated C 1 -C 6 alkane Base, -(CH 2 ) q OH, 3- to 7-membered cycloalkyl,
    Figure PCTCN2019078089-appb-100002
    Figure PCTCN2019078089-appb-100003
    The aryl group is substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -OH, -NH 2 or halogen Aryl;
    R 3各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-OH、-NH 2或卤素； R 3 are each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -OH, -NH 2 or halogen;
    q为0、1、2或3；q is 0, 1, 2 or 3;
    n为0、1、2、3或4；n is 0, 1, 2, 3 or 4;
    m为0、1、2或3。m is 0, 1, 2 or 3.
  2. 如权利要求1所述的化合物、其药学上可接受的盐或立体异构体，其特征在于所述化合物为式(II)化合物，其中各取代基定义与权利要求1中的含义相同，The compound, a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 1, wherein the compound is a compound of the formula (II), wherein each substituent has the same meaning as defined in claim 1.
    Figure PCTCN2019078089-appb-100004
    Figure PCTCN2019078089-appb-100004
  3. 如权利要求1或2所述的化合物、其药学上可接受的盐或立体异构体，其特征在于R 1选自氢、C 1-C 6烷基或卤素。 The compound, pharmaceutically acceptable salt or stereoisomer thereof according to claim 1 or 2, wherein R 1 is selected from the group consisting of hydrogen, C 1 -C 6 alkyl or halogen.
  4. 如权利要求1或2所述的化合物、其药学上可接受的盐或立体异构体，其特征在于环B为苯基或吡啶基，R 3各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-OH、-NH 2或卤素，m为0、1、2或3。 The compound according to claim 1 or 2, a pharmaceutically acceptable salt or a stereoisomer thereof, wherein ring B is a phenyl group or a pyridyl group, and R 3 is each independently selected from a C 1 -C 6 alkyl group. , C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -OH, -NH 2 or halogen, m is 0, 1, 2 or 3.
  5. 如权利要求4所述的化合物、其药学上可接受的盐或立体异构体，其特征在于所述R 3为卤素，m为1或2。 The compound, pharmaceutically acceptable salt or stereoisomer thereof according to claim 4, wherein R 3 is halogen and m is 1 or 2.
  6. 如权利要求1或2所述的化合物、其药学上可接受的盐或立体异构体，其特征在于环A为含有1～5个选自N、O或S的环杂原子的含氮单环脂杂环基、含氮稠环脂杂环基、含氮桥环稠环脂杂环基或含氮螺环脂杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连；其中，R 2各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-NH 2、卤素、-(CH 2) qOH、3～7元环烷基、
    Figure PCTCN2019078089-appb-100005
    Figure PCTCN2019078089-appb-100006
    芳基或被1～3个选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-OH、-NH 2或卤素的取代基取代的芳基，q为0、1、2或3，n为0、1、2、3或4。     A compound, a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 1 or 2, wherein ring A is a nitrogen-containing single containing 1 to 5 ring heteroatoms selected from N, O or S. a cycloaliphatic heterocyclic group, a nitrogen-containing fused ring heterocyclic group, a nitrogen-containing bridged ring fused ring heterocyclic group or a nitrogen-containing spirocyclic heterocyclic group, through a ring N atom and a dihydropyridinopyridinone nucleus And wherein R 2 is each independently selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halo C 1 -C 6 alkyl, -NH 2 , halogen, -(CH 2 ) q OH, 3 to 7-membered cycloalkyl,
    Figure PCTCN2019078089-appb-100005
    Figure PCTCN2019078089-appb-100006
    The aryl group is substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -OH, -NH 2 or halogen An aryl group, q is 0, 1, 2 or 3, and n is 0, 1, 2, 3 or 4.
  7. 如权利要求6所述的化合物、其药学上可接受的盐或立体异构体，其特征在于所述含氮单环脂杂环基、含氮稠环脂杂环基、含氮桥环稠环脂杂环基、含氮螺环脂杂环基选自
    Figure PCTCN2019078089-appb-100007
    The compound, a pharmaceutically acceptable salt or stereoisomer thereof according to claim 6, wherein the nitrogen-containing monocyclic heterocyclic group, the nitrogen-containing fused ring heterocyclic group, and the nitrogen-containing bridged ring are thick. a cycloaliphatic heterocyclic group, a nitrogen-containing spirocyclic heterocyclic group selected from the group consisting of
    Figure PCTCN2019078089-appb-100007
    Figure PCTCN2019078089-appb-100008
    Figure PCTCN2019078089-appb-100009
    Figure PCTCN2019078089-appb-100008
    Figure PCTCN2019078089-appb-100009
  8. 如权利要求7所述的化合物、其药学上可接受的盐或立体异构体，其特征在于所述含氮单环脂杂环基、含氮稠环脂杂环基、含氮桥环稠环脂杂环基、含氮螺环脂杂环基选自
    Figure PCTCN2019078089-appb-100010
    Figure PCTCN2019078089-appb-100011
    The compound according to claim 7, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that the nitrogen-containing monocyclic heterocyclic group, the nitrogen-containing fused ring heterocyclic group, and the nitrogen-containing bridged ring are thick. a cycloaliphatic heterocyclic group, a nitrogen-containing spirocyclic heterocyclic group selected from the group consisting of
    Figure PCTCN2019078089-appb-100010
    Figure PCTCN2019078089-appb-100011
  9. 如权利要求6所述的化合物、其药学上可接受的盐或立体异构体，其特征在于所述R 2各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-NH 2、卤素、-(CH 2) qOH、3～7元环烷基、
    Figure PCTCN2019078089-appb-100012
    Figure PCTCN2019078089-appb-100013
    苯基或被1～3个选自C 1-C 6烷基、-OH、-NH 2或卤素的取代基取代的苯基，q为0、1或2，n为0、1、2或3。     The compound according to claim 6, or a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that said R 2 are each independently selected from a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group. , halogenated C 1 -C 6 alkyl, -NH 2 , halogen, -(CH 2 ) q OH, 3- to 7-membered cycloalkyl,
    Figure PCTCN2019078089-appb-100012
    Figure PCTCN2019078089-appb-100013
    Phenyl or phenyl substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, -OH, -NH 2 or halogen, q is 0, 1 or 2, n is 0, 1, 2 or 3.
  10. 如权利要求1或2所述的化合物、其药学上可接受的盐或立体异构体，其特征在于环A为含有1～5个选自N、O或S的环杂原子的含氮单环芳杂环基或含氮稠环芳杂环基，通过环上N原子与二氢吡啶并酞嗪酮母核相连；其中，R 2各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-NH 2、卤素、-(CH 2) qOH、3～7元环烷基、
    Figure PCTCN2019078089-appb-100014
    Figure PCTCN2019078089-appb-100015
    芳基或被1～3个选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-OH、-NH 2或卤素的取代基取代的芳基，q为0、1、2或3，n为0、1、2、3或4。     A compound, a pharmaceutically acceptable salt or a stereoisomer thereof according to claim 1 or 2, wherein ring A is a nitrogen-containing single containing 1 to 5 ring heteroatoms selected from N, O or S. a cyclic aromatic heterocyclic group or a nitrogen-containing fused ring aromatic heterocyclic group, which is bonded to the dihydropyridazinone nucleus via a N atom on the ring; wherein R 2 is each independently selected from a C 1 -C 6 alkyl group, C 1- C 6 alkoxy, halogenated C 1 -C 6 alkyl, -NH 2 , halogen, -(CH 2 ) q OH, 3- to 7-membered cycloalkyl,
    Figure PCTCN2019078089-appb-100014
    Figure PCTCN2019078089-appb-100015
    The aryl group is substituted by 1 to 3 substituents selected from C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogenated C 1 -C 6 alkyl, -OH, -NH 2 or halogen An aryl group, q is 0, 1, 2 or 3, and n is 0, 1, 2, 3 or 4.
  11. 如权利要求10所述的化合物、其药学上可接受的盐或立体异构体，其特征在于所述含氮单环芳杂环基、含氮稠环芳杂环基选自
    Figure PCTCN2019078089-appb-100016
    The compound according to claim 10, a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that the nitrogen-containing monocyclic aromatic heterocyclic group and the nitrogen-containing fused ring aromatic heterocyclic group are selected from
    Figure PCTCN2019078089-appb-100016
  12. 如权利要求11所述的化合物、其药学上可接受的盐或立体异构体，其特征在于所述含氮单环芳杂环基、含氮稠环芳杂环基选自
    Figure PCTCN2019078089-appb-100017
    The compound, a pharmaceutically acceptable salt or stereoisomer thereof according to claim 11, wherein the nitrogen-containing monocyclic aromatic heterocyclic group and the nitrogen-containing fused ring aromatic heterocyclic group are selected from
    Figure PCTCN2019078089-appb-100017
  13. 如权利要求10所述的化合物、其药学上可接受的盐或立体异构体，其特征在于所述R 2各自独立地选自C 1-C 6烷基、C 1-C 6烷氧基、卤代C 1-C 6烷基、-(CH 2) qOH、-NH 2、卤素或苯基，q为0、1或2，n为0、1、2或3。 The compound according to claim 10, a pharmaceutically acceptable salt or stereoisomer thereof, characterized in that said R 2 are each independently selected from a C 1 -C 6 alkyl group, a C 1 -C 6 alkoxy group. , halogenated C 1 -C 6 alkyl, -(CH 2 ) q OH, -NH 2 , halogen or phenyl, q is 0, 1 or 2, and n is 0, 1, 2 or 3.
  14. 如权利要求1或2所述的化合物、其药学上可接受的盐或立体异构体，它选自：A compound, a pharmaceutically acceptable salt or a stereoisomer thereof, according to claim 1 or 2, which is selected from the group consisting of:
    5-氟-8-(4-氟苯基)-9-(1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyrido[4,3,2 -de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(5-三氟甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-trifluoromethyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(3，5-二甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(3,5-dimethyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(2-甲基-1H-咪唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2-methyl-1H-imidazol-1-yl)-8,9-dihydro-2H-pyrido[4,3,2-de Pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(3-三氟甲基-5，6-二氢-[1，2，4]三唑[4，3-a]吡嗪-7(8H)-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(3-trifluoromethyl-5,6-dihydro-[1,2,4]triazolo[4,3-a]pyrazine- 7(8H)-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(1H-吲唑基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1H-carbazolyl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3 (7H )-ketone;
    5-氟-8-(4-氟苯基)-9-(吡咯烷-2，5-二酮-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(pyrrolidine-2,5-dione-1-yl)-8,9-dihydro-2H-pyrido[4,3,2- De]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(4，7-环氧六氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(4,7-epoxyhexahydroisoindol-1,3(2H)-dione-2-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(4，7-环氧-3a，4，7，7a-四氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(4,7-epoxy-3a,4,7,7a-tetrahydroisoindole-1,3(2H)-dione-2- ,8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(4，7-环氧-5-羟基六氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(4,7-epoxy-5-hydroxyhexahydroisoindole-1,3(2H)-dione-2-yl)-8, 9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(异吲哚-1，3-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(isoindole-1,3-dione-2-yl)-8,9-dihydro-2H-pyrido[4,3,2 -de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de Pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(1-甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4, 3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(1-异丙基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-isopropyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4 , 3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(1-(2-羟乙基)-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-(2-hydroxyethyl)-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(1-环丙基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-cyclopropyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4 , 3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(1-环戊基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-cyclopentyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4 , 3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(1，5，5-三甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1,5,5-trimethyl-2,4-imidazolidin-2-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(1-异丙基-5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-isopropyl-5,5-dimethyl-2,4-imidazolidin-2-yl)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(5-甲基-5-苯基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-5-phenyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-((7aS)-四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-((7aS)-tetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione-2-yl -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-((S)-7a-甲基四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-((S)-7a-methyltetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-dione -2-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-((6R，7aS)-6-羟基四氢-1H-吡咯并[1，2-c]咪唑-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H) -酮； 5-fluoro-8-(4-fluorophenyl)-9-((6R,7aS)-6-hydroxytetrahydro-1H-pyrrolo[1,2-c]imidazole-1,3(2H)-di one-2-yl) -8,9-dihydro -2H- pyrido [4,3,2-de] phthalazin--3 (7H) - one;
    5-氟-8-(4-氟苯基)-9-(1，3-二氮杂螺[3.4]辛烷-6，8-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[3.4]octane-6,8-dione-3-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(1，3-二氮杂螺[4.4]壬烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[4.4]nonane-2,4-dione-3-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(1，3-二氮杂螺[4.5]癸烷-2，4-二酮-3-基)-8，9- 二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1,3-diazaspiro[4.5]decane-2,4-dione-3-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(2-氧-5，7-二氮杂螺[3.4]辛烷-6，8-二酮-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2-oxo-5,7-diazaspiro[3.4]octane-6,8-dione-7-yl)-8,9 - dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(2，5，7-三氮杂螺[3.4]辛烷-6，8-二酮-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2,5,7-triazaspiro[3.4]octane-6,8-dione-7-yl)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(2，4-噻唑烷二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2,4-thiazolidinedione-3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de Pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-噻唑烷二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-thiazolidinedione-3-yl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(噁唑烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(oxazolidine-2,4-dione-3-yl)-8,9-dihydro-2H-pyrido[4,3,2 -de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(5，5-二甲基噁唑烷-2，4-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyloxazolidine-2,4-dione-3-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(2H-苯并[e][1，3]噁嗪-2，4(3H)-二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2H-benzo[e][1,3]oxazine-2,4(3H)-dione-3-yl)-8,9 - dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(苯并[d]异噻唑-3(2H)-酮-1，1-二氧化物-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(benzo[d]isothiazole-3(2H)-one-1,1-dioxide-2-yl)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(5-甲基-3-氨基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-3-amino-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(5-异丙基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-isopropyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(5-甲基-1H-吡唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-pyrazol-1-yl)-8,9-dihydro-2H-pyrido[4,3,2- De]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(5-甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H-pyrido[ 4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(2，4-二氟苯基)-9-(5-甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(2,4-difluorophenyl)-9-(5-methyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro-2H- Pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(1-甲基-2，4，5-咪唑啉三酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4,5-imidazolin-3-one-3-yl)-8,9-dihydro-2H-pyrido[ 4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(1-环丁基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-cyclobutyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H-pyrido[4 , 3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(1-(氮杂环丁-3-基)-2，4-咪唑啉二酮-3- 基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-(azetidin-3-yl)-2,4-imidazolinedion-3-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(1-(哌啶-4-基)-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(1-(piperidin-4-yl)-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(3-甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(3-methyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H-pyridine [4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H-pyrido[4,3, 2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(4，4-二甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(4,4-dimethyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(8-氧代-6-硫代-5，7-二氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(8-oxo-6-thio-5,7-diazaspiro[3.4]octane-7-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-((S)-1-氧代-3-硫代四氢-1H-吡咯并[1，2-c]咪唑-2(3H)-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-((S)-1-oxo-3-thiotetrahydro-1H-pyrrolo[1,2-c]imidazole-2(3H) -yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(3-环丙基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(3-cyclopropyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro-2H-pyridine And [4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(7-氧代-5-硫代-4，6-二氮杂螺[2.4]庚烷-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(7-oxo-5-thio-4,6-diazaspiro[2.4]heptane-6-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(3，4，4-三甲基-5-氧代-2-硫代咪唑啉-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(3,4,4-trimethyl-5-oxo-2-thioimidazolin-1-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(5-甲基-8-氧代-6-硫代-5，7-二氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-8-oxo-6-thio-5,7-diazaspiro[3.4]octane-7-yl) -8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(4-氧代-2-硫代-1，3-二氮杂螺[4.4]壬烷-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(4-oxo-2-thio-1,3-diazaspiro[4.4]decane-3-yl)-8,9- Dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(4，7-亚甲基-3a，4，7，7a-四氢异吲哚-1，3(2H)-二酮-2-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(4,7-methylene-3a,4,7,7a-tetrahydroisoindole-1,3(2H)-dione-2 -yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(2-甲基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2-methyl-4-oxo-1,3-diazaspiro-[4.4]non-1-en-3-yl)- 8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(2-丁基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2-butyl-4-oxo-1,3-diazaspiro-[4.4]non-1-en-3-yl)- 8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(6-甲基-8-氧代-5，7-二氮杂螺-[3.4]辛-5-烯-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(6-methyl-8-oxo-5,7-diazaspiro-[3.4]oct-5-ene-7-yl)- 8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(5-甲基-7-氧代-4，6-二氮杂螺-[2.4]庚-4-烯 -6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-7-oxo-4,6-diazaspiro-[2.4]hept-4-ene-6-yl)- 8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(2，4，4-三甲基-5-氧代-4，5-二氢-1H-咪唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2,4,4-trimethyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-8, 9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    5-氟-8-(4-氟苯基)-9-(2-甲基-5-氧代-4，5-二氢-1H-咪唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；5-fluoro-8-(4-fluorophenyl)-9-(2-methyl-5-oxo-4,5-dihydro-1H-imidazol-1-yl)-8,9-dihydro- 2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8R，9R)-5-氟-8-(4-氟苯基)-9-(1-甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8S，9S)-5-氟-8-(4-氟苯基)-9-(1-甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(1-methyl-2,4-imidazolinedion-3-yl)-8,9-dihydro-2H -pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8R，9R)-5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-imidazolidin-2-one)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8S，9S)-5-氟-8-(4-氟苯基)-9-(5，5-二甲基-2，4-咪唑啉二酮-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(5,5-dimethyl-2,4-imidazolidin-2-one)-8,9-di Hydrogen-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8R，9R)-5-氟-8-(4-氟苯基)-9-(5-甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8S，9S)-5-氟-8-(4-氟苯基)-9-(5-甲基-1H-1，2，4-三唑-1-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-1H-1,2,4-triazol-1-yl)-8,9-dihydro -2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8R，9R)-5-氟-8-(4-氟苯基)-9-(5-甲基-8-氧代-6-硫代-5，7-二氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-8-oxo-6-thio-5,7-diazaspiro[3.4]xin Alkan-7-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8S，9S)-5-氟-8-(4-氟苯基)-9-(5-甲基-8-氧代-6-硫代-5，7-二氮杂螺[3.4]辛烷-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-8-oxo-6-thio-5,7-diazaspiro[3.4]xin Alkan-7-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8R，9R)-5-氟-8-(4-氟苯基)-9-(2-甲基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(2-methyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene 3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8S，9S)-5-氟-8-(4-氟苯基)-9-(2-甲基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(2-methyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene 3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8R，9R)-5-氟-8-(4-氟苯基)-9-(2-丁基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(2-butyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene 3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8S，9S)-5-氟-8-(4-氟苯基)-9-(2-丁基-4-氧代-1，3-二氮杂螺-[4.4]壬-1-烯-3-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(2-butyl-4-oxo-1,3-diazaspiro-[4.4]non-1-ene 3-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8R，9R)-5-氟-8-(4-氟苯基)-9-(6-甲基-8-氧代-5，7-二氮杂螺-[3.4]辛-5-烯-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(6-methyl-8-oxo-5,7-diazaspiro-[3.4]oct-5-ene -7-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8S，9S)-5-氟-8-(4-氟苯基)-9-(6-甲基-8-氧代-5，7-二氮杂螺-[3.4] 辛-5-烯-7-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(6-methyl-8-oxo-5,7-diazaspiro-[3.4]oct-5-ene -7-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8R，9R)-5-氟-8-(4-氟苯基)-9-(5-甲基-7-氧代-4，6-二氮杂螺-[2.4]庚-4-烯-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮；(8R,9R)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-7-oxo-4,6-diazaspiro-[2.4]hept-4-ene -6-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one;
    (8S，9S)-5-氟-8-(4-氟苯基)-9-(5-甲基-7-氧代-4，6-二氮杂螺-[2.4]庚-4-烯-6-基)-8，9-二氢-2H-吡啶并[4，3，2-de]酞嗪-3(7H)-酮。(8S,9S)-5-fluoro-8-(4-fluorophenyl)-9-(5-methyl-7-oxo-4,6-diazaspiro-[2.4]hept-4-ene -6-yl)-8,9-dihydro-2H-pyrido[4,3,2-de]pyridazine-3(7H)-one.
  15. 如权利要求2所述式(II)化合物的制备方法，其包括以下步骤，A method of preparing a compound of formula (II) according to claim 2, which comprises the steps of
    Figure PCTCN2019078089-appb-100018
    Figure PCTCN2019078089-appb-100018
    其中，环A、环B、R 1、R 2、R 3、m、n与权利要求2中的含义相同； Wherein ring A, ring B, R 1 , R 2 , R 3 , m, n have the same meanings as in claim 2;
    原料(a)经酯化反应得到化合物(b)；化合物(b)与三丁基(1-乙氧基乙烯基)锡在催化剂作用下反应得到化合物(c)；化合物(c)经还原水解得到化合物(d)；化合物(d)与化合物(e)经缩合反应得到化合物(f)；化合物(f)经关环反应得到化合物(g)；化合物(g)经Boc保护得到化合物(h)；在碱存在下化合物(h)与三氟甲磺酸叔丁基二甲硅烷酯反应得到化合物(i)；化合物(i)被氧化得到 化合物(j)；化合物(j)与水合肼经成环反应得到化合物(k)；化合物(k)脱保护得到化合物(1)；化合物(1)经氯化反应得到中间体1；中间体1与
    Figure PCTCN2019078089-appb-100019
    进行取代反应得到化合物(m)；化合物(m)脱除Boc保护基得到式(II)化合物。     The raw material (a) is esterified to obtain the compound (b); the compound (b) is reacted with tributyl (1-ethoxyvinyl) tin under the action of a catalyst to obtain a compound (c); and the compound (c) is subjected to reduction hydrolysis The compound (d) is obtained; the compound (d) is reacted with the compound (e) to obtain a compound (f); the compound (f) is subjected to a ring closure reaction to obtain a compound (g); and the compound (g) is protected by Boc to obtain a compound (h). Compound (h) is reacted with tert-butyldimethylsilane trifluoromethanesulfonate in the presence of a base to obtain compound (i); compound (i) is oxidized to give compound (j); compound (j) is hydrated with hydrazine The ring reaction gives the compound (k); the compound (k) is deprotected to obtain the compound (1); the compound (1) is chlorinated to obtain the intermediate 1; the intermediate 1 and
    Figure PCTCN2019078089-appb-100019
    Substitution reaction is carried out to give compound (m); compound (m) is removed from the Boc protecting group to give a compound of formula (II).
  16. 如下式结构的中间体1化合物，An intermediate 1 compound of the formula:
    Figure PCTCN2019078089-appb-100020
    Figure PCTCN2019078089-appb-100020
    其中，R 1为卤素，环B为苯基，R 3为卤素，m为1或2。 Wherein R 1 is halogen, ring B is phenyl, R 3 is halogen, and m is 1 or 2.
  17. 一种药物组合物，包括权利要求1～14之任一项所述的化合物、其药学上可接受的盐或立体异构体，以及药学上可接受载体、赋形剂或稀释剂。A pharmaceutical composition comprising a compound according to any one of claims 1 to 14, a pharmaceutically acceptable salt or stereoisomer thereof, and a pharmaceutically acceptable carrier, excipient or diluent.
  18. 权利要求1～14之任一项所述的化合物、其药学上可接受的盐或立体异构体，或权利要求17所述的药物组合物在制备治疗或预防因抑制PARP活性而改善的疾病的药物中的应用。The compound according to any one of claims 1 to 14, a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition according to claim 17 for the treatment or prevention of a disease which is improved by inhibiting PARP activity The application of the drug.
  19. 权利要求1～14之任一项所述的化合物、其药学上可接受的盐或立体异构体，或权利要求17所述的药物组合物在制备用于治疗或预防癌症的药物中的应用。Use of the compound according to any one of claims 1 to 14, a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition according to claim 17 for the preparation of a medicament for treating or preventing cancer .
  20. 如权利要求19所述的应用，所述药物与电离辐射、一种或多种化疗药物或其组合组合施用。The use according to claim 19, wherein the medicament is administered in combination with ionizing radiation, one or more chemotherapeutic agents, or a combination thereof.
  21. 权利要求1～14之任一项所述的化合物、其药学上可接受的盐或立体异构体，或权利要求17所述的药物组合物在制备用于治疗或预防同源重组(HR)依赖性DNA双链断裂(DSB)修复途径缺失的癌症的药物中的应用。The compound according to any one of claims 1 to 14, a pharmaceutically acceptable salt or stereoisomer thereof, or the pharmaceutical composition according to claim 17 in the preparation for the treatment or prevention of homologous recombination (HR) The use of drugs that rely on DNA double-strand break (DSB) repair pathways for the loss of cancer.
  22. 如权利要求19或21所述的应用，所述癌症包含一种或多种癌细胞，所述癌细胞具有相对于正常细胞降低或废除的利用HR修复DNA DSB的能力。The use according to claim 19 or 21, wherein the cancer comprises one or more cancer cells having the ability to repair DNA DSB using HR reduced or abolished relative to normal cells.
  23. 如权利要求22所述的应用，所述癌细胞具有BRCA1或BRCA2 缺失表型。The use of claim 22, wherein the cancer cell has a BRCA1 or BRCA2 deletion phenotype.
  24. 如权利要求19或21所述的应用，所述癌症包括乳腺癌、卵巢癌、子宫内膜癌、宫颈癌、肺癌、前列腺癌、胰腺癌、血癌、胃癌、胆囊癌、肝癌、头颈癌、食管癌、肾癌、脑癌、白血病、结肠癌、肠肿瘤、胶质母细胞瘤、淋巴瘤或黑色素瘤。The invention according to claim 19 or 21, wherein the cancer comprises breast cancer, ovarian cancer, endometrial cancer, cervical cancer, lung cancer, prostate cancer, pancreatic cancer, blood cancer, stomach cancer, gallbladder cancer, liver cancer, head and neck cancer, esophagus Cancer, kidney cancer, brain cancer, leukemia, colon cancer, intestinal tumor, glioblastoma, lymphoma or melanoma.
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