WO2019174607A1 - Dérivé de dihydropyridophtalazinone, son procédé de préparation et son utilisation - Google Patents

Dérivé de dihydropyridophtalazinone, son procédé de préparation et son utilisation 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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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/zh
Publication of WO2019174607A1 publication Critical patent/WO2019174607A1/fr

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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
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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

La présente invention concerne un dérivé de dihydropyridophtalazinone représenté par la formule (I), son procédé de préparation et son utilisation. Dans la formule, R1, R2, R3, m, n, cycle A et cycle B sont tels que définis dans la description. Le dérivé de dihydropyridophtalazinone selon la présente invention a une bonne activité inhibitrice de PARP, et peut être utilisé pour traiter ou prévenir des maladies par inhibition de l'activité de PARP.
PCT/CN2019/078089 2018-03-14 2019-03-14 Dérivé de dihydropyridophtalazinone, son procédé de préparation et son utilisation WO2019174607A1 (fr)

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