WO2023116824A1 - 哒嗪酮类化合物及其制备方法、药物组合物和应用 - Google Patents

哒嗪酮类化合物及其制备方法、药物组合物和应用 Download PDF

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WO2023116824A1
WO2023116824A1 PCT/CN2022/141022 CN2022141022W WO2023116824A1 WO 2023116824 A1 WO2023116824 A1 WO 2023116824A1 CN 2022141022 W CN2022141022 W CN 2022141022W WO 2023116824 A1 WO2023116824 A1 WO 2023116824A1
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trifluoromethyl
amino
acid
piperazine
carbonyl
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PCT/CN2022/141022
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French (fr)
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徐云根
郝海平
古宏峰
严文昕
邹毅
汪勇
王洪
朱启华
许文博
杨解平
苏宇佩
刘备备
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中国药科大学
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • the present invention relates to a pyridazinone compound and its preparation method, pharmaceutical composition and application, in particular to a pyridazinone compound with antitumor activity, its preparation method, pharmaceutical composition and application.
  • PARP7 a member of the monoPARP protein family, is a novel negative regulator of nucleic acid sensors in cells and is overexpressed in tumors. Because cancer cells can use PARP7 to suppress interferon signaling, making it "hide” from the immune system, many cancer cells rely on PARP7 to survive. The study found that inhibiting PARP7 can restore intracellular interferon signaling, restore the body's innate and adaptive immunity, and thereby inhibit the growth of cancer cells. In cancer models such as lung cancer and colorectal cancer, PARP7 inhibitors showed durable tumor growth inhibition.
  • RBN-2397 developed by Ribon is the first compound with strong inhibitory activity and selectivity for PARP7.
  • RBN-2397 orally administered once a day has a significant anti-tumor effect at a dose of ⁇ 30 mg/kg in a dose-dependent manner, and has entered phase I clinical research (NCT04053673).
  • NCT04053673 phase I clinical research
  • the present invention aims to provide a pyridazinone compound with excellent in vivo and in vitro antitumor activity and pharmacokinetic properties and Its preparation method, pharmaceutical composition and application.
  • the pyridazinone compound of the present invention has the structure of formula (I), including its isomers, pharmaceutically acceptable salts or mixtures thereof:
  • n 0, 1, 2 or 3;
  • R 1 is selected from hydrogen, halogen, cyano, trifluoromethyl, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, methylthio, methylsulfonyl, carbamoyl;
  • R 2 or R 3 are independently selected from hydrogen, C 1 -C 6 alkyl, substituted C 3 -C 6 cycloalkyl or heterocycloalkyl, cyano, trifluoromethyl, or R 2 and R 3 Together with the connected carbon atoms, a C 3 -C 6 cycloalkyl group is formed; the substituent of the C 3 -C 6 cycloalkyl group is selected from hydrogen, methyl, trifluoromethyl, 2,2-difluoroethyl, Methoxy, halogen, cyano, amino, methylamino, dimethylamino, diethylamino, acetamido, hydroxyl, acetoxy, carboxyl or methoxycarbonyl, the substituents are one or more;
  • R is selected from substituted aryl, substituted heteroaryl or substituted 1,3-benzodioxanyl
  • the heteroaryl or 1,3-benzodioxanyl substituent is selected from hydrogen , halogen, cyano, trifluoromethyl, 2,2,-difluoroethyl, C 1 to C 6 alkyl, C 1 to C 6 alkoxy, C 3 to C 6 cycloalkyl, Aryl, hydroxyl, methoxy, amino, methylamino, dimethylamino, acetamido, carboxyl, methylsulfonyl, methoxycarbonyl or nitro, the substituents are one or more;
  • a 1 is selected from -NH-, -O-, -S-,
  • n 1 and n 2 are each independently selected from 0, 1 or 2;
  • R is selected from hydrogen, halogen, methyl, trifluoromethyl, cyano, hydroxyl , methoxy, amino, methylamino, dimethylamino, diethylamino or acetamido, and R is one or more;
  • X 1 represents -O-, -NH- or
  • X 2 and X 3 are independently selected from N or CH
  • R 6 , R 7 or R 8 are independently selected from hydrogen, methyl, trifluoromethyl, cyano, hydroxyl, methoxy, amino, Methylamino, dimethylamino, acetylamino, carboxyl or methoxycarbonyl.
  • n is selected from 0, 1 or 2;
  • R is selected from halogen, cyano or trifluoromethyl
  • R 2 or R 3 are independently selected from hydrogen, methyl or trifluoromethyl; when R 2 and R 3 are different, the carbon atom connected to R 2 and R 3 is racemic configuration, R configuration or S structure;
  • R4 is selected from Wherein, Y 1 or Y 2 are independently selected from CH or N, R 9 and R 10 are independently selected from trifluoromethyl, methyl, fluorine, chlorine, bromine, cyano, methoxy, methylsulfonyl , 2,2-difluoroethyl or 4-trifluoromethylphenyl, R 9 or R 10 is one or more;
  • a 1 is selected from -NH-;
  • n 0 or 2.
  • R 1 is trifluoromethyl
  • R 2 is hydrogen
  • R 3 is hydrogen or methyl
  • R 3 is hydrogen or methyl
  • the carbon atom connected to R 3 is in S configuration.
  • R4 is selected from
  • pyridazinone compounds are any of the following compounds:
  • the pharmaceutically acceptable salt of the above-mentioned pyridazinone compound is a salt formed by the above-mentioned pyridazinone compound and an acid, and the specific acid is hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, carbonic acid, methanesulfonic acid, benzenesulfonic acid, p- Toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid, succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid, or ferulic acid.
  • the preparation method of the above-mentioned pyridazinone compounds is any of the following methods:
  • R 1 is selected from trifluoromethyl, cyano or halogen
  • R 2 is hydrogen
  • R 3 is selected from methyl or hydrogen
  • the carbon atom connected to R 3 is in S configuration, or R 2 and R 3
  • R4 is A 1 represents -NH-
  • a 2 is n 1 or n 2 each independently represent 0 or 1
  • a 3 is A 4 is The preparation method of target compound IA is as follows:
  • Compound IV is prepared from compound II by dissolving II and III together in a solvent and adding an acid-binding agent for substitution reaction.
  • the reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably acetonitrile;
  • the acid-binding agent is Sodium carbonate, potassium carbonate, triethylamine or N,N-diisopropylethylamine (DIPEA), preferably DIPEA.
  • Compound V is prepared from compound IV by dissolving IV in a solvent and adding acid for reaction.
  • the reaction solvent is dichloromethane, tetrahydrofuran or 1,4-dioxane, preferably dichloromethane;
  • the acid used is a solution of ethyl acetate saturated with hydrogen chloride, a solution of 1,4-dioxane saturated with hydrogen chloride or trifluoroacetic acid , preferably trifluoroacetic acid.
  • Compound VII is prepared from compound V by dissolving V and VI in a solvent and adding an acid-binding agent for substitution reaction.
  • the reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably 1,4-diox Hexacyclic;
  • the acid-binding agent is sodium carbonate, potassium carbonate, triethylamine or DIPEA, preferably DIPEA.
  • Compound VIII is prepared from compound VII by dissolving VII in a solvent and adding a catalyst to carry out catalytic hydrogenation reaction.
  • the reaction solvent is tetrahydrofuran, methanol, ethanol or a mixed solvent of any two, preferably methanol;
  • the catalyst is palladium hydroxide or palladium carbon, preferably palladium carbon.
  • Compound X is prepared from compound VIII by dissolving VIII in a solvent, adding a condensing agent, and then adding a base and compound IX for condensation reaction.
  • the solvent is dichloromethane, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably N,N'-dimethylformamide; condensing agent Selected from N,N'-carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), N,N'-dicyclohexyl carbon Diimine (DCC), N,N'-diisopropylcarbodiimide (DIC), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (HATU), benzotri
  • the target compound I-A is prepared from compound X by dissolving X in a solvent and adding acid to react.
  • the solvent is tetrahydrofuran, acetonitrile or dichloromethane, preferably dichloromethane;
  • the acid is hydrochloric acid or trifluoroacetic acid or trifluoromethanesulfonic acid, preferably trifluoroacetic acid or trifluoromethanesulfonic acid.
  • R 1 is selected from trifluoromethyl, cyano or halogen
  • R 2 is hydrogen
  • R 3 is selected from methyl or hydrogen
  • the carbon atom connected to R 3 is in S configuration, or R 2 and R 3
  • R4 is A 1 is -NH-
  • a 2 is n 1 or n 2 are each independently selected from 0 or 1
  • a 3 is A 4 is The preparation method of target compound IB is as follows:
  • Compound XII is prepared from compound VIII by dissolving VIII in a solvent, adding a condensing agent, and then adding a base and compound XI for condensation reaction.
  • the solvent is dichloromethane, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane or acetonitrile, preferably N,N'-dimethylformamide;
  • the condensing agent is selected from N,N'- Carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), benzotriazo
  • the preparation of target compound I-B from compound XII is obtained by dissolving XII in a solvent and adding acid for reaction.
  • the solvent is tetrahydrofuran, acetonitrile or dichloromethane, preferably dichloromethane;
  • the acid is hydrochloric acid or trifluoroacetic acid or trifluoromethanesulfonic acid, preferably trifluoroacetic acid or trifluoromethanesulfonic acid.
  • R 1 represents trifluoromethyl, cyano or halogen
  • R 2 is hydrogen
  • R 3 is selected from methyl or hydrogen
  • the carbon atom connected to R 3 is in S configuration, or R 2 and R 3 form Cyclopropyl
  • R4 is A 1 is -NH-
  • a 2 is A 3 is A 4 is The preparation method of target compound IC is as follows:
  • Compound XIV is prepared from compound XIII by dissolving XIII in a solvent, adding a base, and then adding compound III for reaction.
  • the reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably N,N-dimethyl base formamide;
  • the base is sodium hydride, sodium carbonate, potassium carbonate, triethylamine or DIPEA, preferably sodium hydride.
  • the preparation of compound XV from compound XIV is obtained by dissolving XIV in a solvent and adding an aqueous base solution for hydrolysis.
  • the reaction solvent is tetrahydrofuran, methanol, acetonitrile or a mixed solvent of any two, preferably a mixed solvent of tetrahydrofuran and methanol;
  • the base is sodium hydroxide, lithium hydroxide or potassium hydroxide, preferably sodium hydroxide.
  • Compound XVI is prepared from compound XV by dissolving XV in a solvent, adding a condensing agent, and then adding a base and compound IX for condensation reaction.
  • the solvent is dichloromethane, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably N,N-dimethylformamide; From N,N'-carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), N,N'-dicyclohexylcarbodiimide Imine (DCC), N,N'-diisopropylcarbodiimide (DIC), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (HATU), benzotri
  • Compound XVII is prepared from compound XVI by dissolving XVI in a solvent and adding an acid for reaction.
  • the solvent is dichloromethane, tetrahydrofuran or 1,4-dioxane, preferably dichloromethane;
  • the acid is hydrochloric acid, trifluoroacetic acid or sulfuric acid, preferably trifluoroacetic acid.
  • the preparation of compound XVIII from compound XVII is obtained by dissolving XVII and compound VI in a solvent and adding a base for substitution reaction.
  • the reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably 1,4-diox Hexacyclic;
  • the base is sodium carbonate, potassium carbonate, triethylamine or DIPEA, preferably DIPEA.
  • Compound I-C is prepared from compound XVIII by dissolving XVIII in a solvent and adding an acid for reaction.
  • the solvent is tetrahydrofuran, acetonitrile or dichloromethane, preferably dichloromethane;
  • the acid is hydrochloric acid or trifluoroacetic acid or trifluoromethanesulfonic acid, preferably trifluoroacetic acid or trifluoromethanesulfonic acid.
  • R 1 is selected from trifluoromethyl, cyano or halogen
  • R 2 is hydrogen
  • R 3 is methyl
  • R 4 is A 1 is -NH-
  • a 2 is n 1 or n 2 are each independently selected from 0 or 1
  • a 3 is A 4 is
  • the preparation method of target compound ID is as follows:
  • Compound XXI is prepared from compound XIX by dissolving XIX in a solvent, adding a condensing agent, and then adding a base and compound XX for condensation reaction.
  • the solvent is dichloromethane, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably N,N-dimethylformamide; From N,N'-carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), N,N'-dicyclohexylcarbodiimide Imine (DCC), N,N'-diisopropylcarbodiimide (DIC), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexafluorophosphate (HATU
  • Compound XXII can be prepared from compound XXI by dissolving XXI in a solvent and adding an aqueous base solution for hydrolysis.
  • the reaction solvent is tetrahydrofuran, methanol, acetonitrile or a mixed solvent of any two, preferably a mixed solvent of tetrahydrofuran and methanol;
  • the base is sodium hydroxide, lithium hydroxide or potassium hydroxide, preferably sodium hydroxide.
  • Compound XXIII is prepared from compound XXII by dissolving XXII in a solvent, adding a condensing agent, and then adding N,O-dimethylhydroxylamine hydrochloride for condensation reaction.
  • the solvent is dichloromethane, tetrahydrofuran, N,N-dimethylformamide, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably N,N-dimethylformamide; From N,N'-carbonyldiimidazole (CDI), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), N,N'-dicyclohexylcarbodiimide Imine (DCC), N,N'-diisopropylcarbodiimide (DIC), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyl Urea hexa
  • Compound XXIV is prepared from compound XXIII by dissolving XXIII in a solvent and adding methylmagnesium bromide at low temperature for reaction.
  • the reaction solvent is anhydrous tetrahydrofuran, anhydrous diethyl ether, anhydrous dichloromethane or anhydrous dioxane, preferably anhydrous tetrahydrofuran.
  • Compound XXV is prepared from compound XXIV by dissolving XXIV in a solvent, adding an ammonia source and reacting with a catalyst.
  • the solvent is methanol, ethanol, tetrahydrofuran or a mixed solvent of any two, preferably methanol
  • the ammonia source is ammonium formate or ammonium acetate, preferably ammonium formate
  • the catalyst is preferably dichloro(pentamethylcyclopentadienyl) rhodium (III) dimer.
  • Compound XXVI is prepared from compound XXV by dissolving XXV and compound VI in a solvent and adding a base for substitution reaction.
  • the reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably 1,4-diox Hexacyclic;
  • the base is sodium carbonate, potassium carbonate, triethylamine or DIPEA, preferably DIPEA.
  • the preparation of target compound I-D from compound XXVI is obtained by dissolving XXVI in a solvent and adding acid for reaction.
  • the solvent is tetrahydrofuran, acetonitrile, dichloromethane or a mixed solvent of any two, preferably dichloromethane;
  • the acid is hydrochloric acid or trifluoroacetic acid or trifluoromethanesulfonic acid, preferably trifluoroacetic acid or trifluoromethanesulfonic acid.
  • R 1 is selected from trifluoromethyl, cyano or halogen
  • R 2 and R 3 are hydrogen
  • R 4 is A 1 represents -NH-
  • a 2 is -NH- or -N(CH 3 )-
  • a 3 is A 4 is
  • the preparation method of target compound IE is as follows:
  • Compound XXVIII is prepared from compound IX by dissolving IX in a solvent, adding a base, and then adding compound XXVII for reaction.
  • the reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, dichloromethane or acetonitrile, preferably dichloromethane;
  • the base is sodium carbonate, Potassium carbonate, triethylamine or DIPEA, preferably triethylamine.
  • Compound XXX is prepared from compound XVIII by dissolving XVIII in a solvent, adding XXIX, and then adding a base to react.
  • the reaction solvent is tetrahydrofuran, N,N-dimethylformamide, N,N-dimethylacetamide or acetonitrile, preferably N,N-dimethylformamide;
  • the base is sodium hydroxide, potassium carbonate or sodium carbonate, Potassium carbonate is preferred.
  • Compound XXXI is prepared from compound XXX by dissolving XXX in a solvent and adding an acid for reaction.
  • the solvent is dichloromethane, tetrahydrofuran or 1,4-dioxane, preferably dichloromethane;
  • the acid is hydrochloric acid, trifluoroacetic acid or sulfuric acid, preferably trifluoroacetic acid.
  • Compound XXXII is prepared from compound XXXI by dissolving XXXI and compound VI in a solvent and adding a base for substitution reaction.
  • the reaction solvent is N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether or acetonitrile, preferably 1,4-diox Hexacyclic;
  • the base is sodium carbonate, potassium carbonate, triethylamine or DIPEA, preferably DIPEA.
  • Compound I-E is prepared from compound XXXII by dissolving XXXII in a solvent and adding an acid for reaction.
  • the solvent is dichloromethane, tetrahydrofuran or 1,4-dioxane, preferably dichloromethane;
  • the acid is hydrochloric acid, trifluoroacetic acid or sulfuric acid, preferably trifluoroacetic acid.
  • m, Y 1 , Y 2 , R 7 , R 8 , R 9 , R 10 are as defined above; Boc is tert-butoxycarbonyl; P is (trimethylsilyl)ethoxymethyl (SEM ) or p-methoxybenzyl (PMB);
  • the above-mentioned pharmaceutical composition comprises any one of the above-mentioned pyridazinone compounds and a pharmaceutically acceptable carrier.
  • Common pharmaceutical preparations can be made by adding pharmaceutically acceptable carriers, such as tablets, capsules, syrups, suspensions or injections.
  • Common pharmaceutical excipients such as spices, sweeteners, liquid/solid fillers, diluents, etc. can be added to the preparations .
  • the above-mentioned pyridazinone compounds and their pharmaceutical compositions can be prepared as PARP7 inhibitor drugs, specifically drugs for the treatment of tumors, more specifically for the treatment of lung squamous adenocarcinoma, colon cancer , breast cancer and other cancer drugs.
  • the present invention has the following significant advantages:
  • the pyridazinone compound has excellent in vivo pharmacokinetic properties, the half-life, in vivo exposure and bioavailability have been significantly improved, and has significant advantages in drug preparation; at the same time, it also has excellent in vivo pharmacodynamic properties, giving Significant tumor growth inhibitory activity can be achieved at a lower dose; in addition, it can also promote the release of immune factors, and can achieve significant curative effect without the need for combined medication;
  • the pyridazinone compound can effectively inhibit the enzyme activity of PARP7, and the enzyme inhibition IC 50 value is optimally less than 0.1 ⁇ M, reaching the nanomolar concentration level;
  • the pyridazinone compound and its pharmaceutical composition are widely used, can be prepared as anti-tumor drugs, and have better in vivo pharmacokinetic and pharmacodynamic properties;
  • Fig. 1 is the promoting effect of compound on the release of interferon
  • Figure 2 is the in vivo anti-tumor effect of the compound.
  • Azetidine-3-carboxylic acid benzyl ester (II-1) (16.0g, 83.7mmol) was dissolved in 70mL of acetonitrile, and (S)-(1-bromoprop-2-yl)carbamic acid tert-butyl ester was added (III-1) (21.9g, 92.0mmol) and DIPEA (32.4g, 251.1mmol) were heated up to 80°C for 2 hours.
  • Example 2 4-(trifluoromethyl)-5-(((S)-1-((S)-3-(4-(5-(trifluoromethyl)pyrimidin-2-yl)piperazine Synthesis of -1-carbonyl)pyrrolidin-1-yl)propan-2-yl)amino)pyridazin-3(2H)-one (I-A-18)
  • 10X PBS preparation Weigh 720mg KH 2 PO 4 , 45g NaCl and 5.311g Na 2 HPO 4 12H 2 O and dissolve them in 500mL deionized water, adjust the pH of the system to 7.4, and sterilize at 121°C for 30 minutes. After cooling, place it at 4°C for later use.
  • 1X PBS preparation Dilute 10X PBS 10 times with deionized water, that is, 1 part of 10X PBS is diluted with 9 parts of deionized water.
  • Wash buffer preparation 1X PBS containing 0.05% Tween-20.
  • 1X PARP buffer preparation (Prepare now) Use deionized water to dilute 10X PARP buffer 10 times, and place it on ice for later use.
  • the compound to be tested was diluted to the desired concentration with 100% DMSO, and then diluted 10 times with 1X PARP buffer to prepare a 10X compound working solution.
  • Compound number 100nM inhibition rate Compound number 100nM inhibition rate Compound number 100nM inhibition rate I-A-1 +++ I-A-16 +++ I-A-2 ++ I-A-17 +++ I-A-3 +++ I-A-18 ++ I-A-4 +++ I-A-19 ++ I-A-5 +++ I-A-20 +++ I-A-6 +++ I-A-21 ++ I-A-7 +++ I-A-22 ++ I-A-8 ++ I-A-23 ++ I-A-9 +++ I-A-24 ++
  • test compounds of the present invention have good enzyme inhibitory activity on PARP7, and the enzyme inhibition IC 50 values all reach the nanomolar concentration level.
  • compounds IA-1, IA-3 ⁇ IA-7, IA-9 ⁇ IA-10, IA-13, IA-15 ⁇ IA-17, IA-20, IB-1, IC-1, ID-1 , IE-1, IE-2 and IE-7 enzyme inhibition IC 50 values are less than 0.1 ⁇ M.
  • Embodiment 8 Compound promotes the release of interferon
  • the compound of the present invention can obviously promote the release of interferon ⁇ , so it can be used for immunotherapy of tumors, and the release amount is better than that of the active drug RBN-2397.
  • IV Indicates intravenous injection
  • PO Indicates intragastric administration
  • the experimental results show that the compound I-A-1 of the present invention has good pharmacokinetic properties in SD rats. Compared with the active drug RBN-2397, the compound of the present invention has a longer half-life, greater exposure in vivo, and better oral bioavailability.
  • IV Indicates intravenous injection
  • PO Indicates intragastric administration
  • the experimental results show that the compound I-A-1 of the present invention has good pharmacokinetic properties in ICR mice. Compared with the active drug RBN-2397, the compound of the present invention has a longer half-life, greater in vivo exposure, and the oral bioavailability even reaches 95.80%.
  • mice were subcutaneously inoculated with CT26 cells on the right flank to develop tumors. Four days after tumor inoculation, 24 mice with tumor sizes ranging from 55-75 mm 3 (mean tumor size 63 mm 3 ) were selected and randomly divided into 4 groups of 6 mice based on their tumor volume.
  • the drug was administered with vehicle (0.5% methylcellulose+0.2% Tween 80), compound RBN-2397 (500 mg/kg , once a day, administered by intragastric administration for 14 consecutive days), compound IA-1 (100mg/kg, once a day, administered by intragastric administration for 14 consecutive days), compound IA-1 (50mg/kg, administered twice a day, continuously 14 days of intragastric administration) were administered, and the tumor size was measured three times a week during the administration period. The entire study was terminated on the 14th day, and the drug efficacy results are shown in Figure 2.
  • the compound I-A-1 of the present invention has obvious anti-tumor activity in mice. Compared with the positive drug RBN-2397, the compound I-A-1 of the present invention can exert a better anti-tumor effect at a lower dose .

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Abstract

本发明公开了一种哒嗪酮类化合物及其制备方法、药物组合物和应用。该哒嗪酮类化合物的结构如式(I)，包含其异构体、药学上可接受的盐或它们的混合物。该哒嗪酮类化合物在体内具有优异的药代动力学性质，还可以促进免疫因子释放，尤其是在体内也具有优异的抗肿瘤活性。此外，该哒嗪酮类化合物的制备方法简便易行。

Description

哒嗪酮类化合物及其制备方法、药物组合物和应用 技术领域
本发明涉及一种哒嗪酮类化合物及其制备方法、药物组合物和应用，尤其涉及一种具有抗肿瘤活性的哒嗪酮类化合物及其制备方法、药物组合物和应用。
背景技术
恶性肿瘤是人类健康的第一号杀手，严重危害着人类的生命健康。2020年中国新发癌症病例457万例，癌症死亡病例300万例，占全世界新发病例的23.7％。数十年来，手术、放疗、化疗和靶向治疗等极大地改善了癌症患者的治疗效果，但这些疗法均存在各自的局限性。不管是化疗还是靶向治疗，均难以根除体内的肿瘤细胞，且极易引起耐药，严重影响了治疗效果和预后。
研究表明人体大多数的PARP家族成员展现的是monoADP核糖转移酶活性。MonoPARP蛋白家族与癌症、炎症和神经退行性疾病的发展密切相关。PARP7是monoPARP蛋白家族的成员之一，它是一种新的细胞中核酸感应器的负调控因子，在肿瘤中过度表达。由于癌细胞可以借助PARP7来抑制干扰素信号，而使其“躲藏”在免疫系统之外，因此，许多癌细胞都依赖PARP7而存活。研究发现，抑制PARP7可恢复细胞内的干扰素信号传导，恢复机体的先天和适应性免疫，进而抑制癌细胞的生长。在肺癌、结直肠癌等癌症模型中，PARP7抑制剂表现出持久的肿瘤生长抑制作用。
目前尚未有PARP7抑制剂被批准上市，Ribon公司开发的RBN-2397是首个对PARP7具有较强抑制活性和选择性的化合物，在NCI-H1373细胞(人肺癌腺癌细胞)的异种移植瘤模型中，RBN-2397每天口服一次在≥30mg/kg的剂量下具有显著的抗肿瘤作用，并且呈剂量依赖性，目前已进入临床I期研究(NCT04053673)。但由于RBN-2397在体内具有较高的清除率，使其在体内的药物暴露量和口服生物利用度均较低。动物体内药效试验结果表明，单一给予RBN-2397很难起到抗肿瘤作用，必须与CYP450抑制剂联用来降低其清除速度才能发挥出良好的抗肿瘤作用。
发明内容
发明目的：针对现有化合物存在的药代动力学差、单药难以发挥作用等不足，本发明旨在提供一种体内外抗肿瘤活性、药代动力学性质均优异的哒嗪酮类化合物及其制备方法、药物组合物和应用。
技术方案：作为本发明涉及的第一方面，本发明的哒嗪酮类化合物具有式(I)的结构，包含其异构体、药学上可接受的盐或它们的混合物：
Figure PCTCN2022141022-appb-000001
其中：
m选自0、1、2或3；
R 1选自氢、卤素、氰基、三氟甲基、C 1～C 6的烷基、C 1～C 6的烷氧基、甲硫基、甲磺酰基、氨甲酰基；
R 2或R 3分别独立地选自氢、C 1～C 6烷基、取代的C 3～C 6环烷基或杂环烷基、氰基、三氟甲基，或者R 2和R 3与所连碳原子一起形成C 3～C 6环烷基；所述C 3～C 6环烷基的取代基选自氢、甲基、三氟甲基、2,2-二氟乙基、甲氧基、卤素、氰基、氨基、甲氨基、二甲氨基、二乙氨基、乙酰氨基、羟基、乙酰氧基、羧基或甲氧羰基，所述取代基为一个或多个；
R 4选自取代的芳基、取代的杂芳基或取代的1,3-苯并二噁烷基，所述杂芳基或1,3-苯并二噁烷基的取代基选自氢、卤素、氰基、三氟甲基、2,2,-二氟乙基、C 1～C 6的烷基、C 1～C 6的烷氧基、C 3～C 6的环烷基、芳基、羟基、甲氧基、氨基、甲氨基、二甲氨基、乙酰氨基、羧基、甲磺酰基、甲氧羰基或硝基，所述取代基为一个或多个；
A 1选自-NH-、-O-、-S-、
Figure PCTCN2022141022-appb-000002
A 2选自
Figure PCTCN2022141022-appb-000003
-NH-或-N(CH 3)-，其中，n 1和n 2各自独立地选自0、1或2；
R 5选自氢、卤素、甲基、三氟甲基、氰基、羟基、甲氧基、氨基、甲氨基、二甲氨基、二乙氨基或乙酰氨基，R 5为一个或多个；
A 3选自
Figure PCTCN2022141022-appb-000004
其中，X 1代表-O-、-NH-或
Figure PCTCN2022141022-appb-000005
A 4选自
Figure PCTCN2022141022-appb-000006
其中，X 2和X 3分别独立地选自N或CH，R 6、R 7或R 8分别独立地选自氢、甲基、三氟甲基、氰基、羟基、甲氧基、氨基、甲氨基、二甲氨基、乙酰氨基、羧基或甲氧羰基。
优选，上述哒嗪酮类化合物结构中：
m选自0、1或2；
R 1选自卤素、氰基或三氟甲基；
R 2或R 3分别独立地选自氢、甲基或三氟甲基；当R 2和R 3不同时，与R 2和R 3相连的碳原子为消旋构型、R构型或S构型；
R 4选自
Figure PCTCN2022141022-appb-000007
其中，Y 1或Y 2分别独立地选自CH或N，R 9、R 10分别独立地选自三氟甲基、甲基、氟、氯、溴、氰基、甲氧基、甲磺酰基、2,2-二氟乙基或4-三氟甲基苯基，R 9或R 10为一个或多个；
A 1选自-NH-；
A 2选自
Figure PCTCN2022141022-appb-000008
-NH-或-N(CH 3)-；
A 3选自
Figure PCTCN2022141022-appb-000009
A 4选自
Figure PCTCN2022141022-appb-000010
进一步优选，上述哒嗪酮类化合物结构中：
m为0或2。
进一步优选，上述哒嗪酮类化合物结构中：
R 1为三氟甲基，R 2为氢，R 3为氢或甲基，R 3为甲基时，与R 3相连的碳原子为S构型。
进一步优选，上述哒嗪酮类化合物结构中：
A 2选自
Figure PCTCN2022141022-appb-000011
或-NH-；A 3为
Figure PCTCN2022141022-appb-000012
A 4为
Figure PCTCN2022141022-appb-000013
进一步优选，上述哒嗪酮类化合物结构中：
R 4选自
Figure PCTCN2022141022-appb-000014
Figure PCTCN2022141022-appb-000015
更具体地，上述哒嗪酮类化合物为以下任一化合物：
Figure PCTCN2022141022-appb-000016
Figure PCTCN2022141022-appb-000017
Figure PCTCN2022141022-appb-000018
Figure PCTCN2022141022-appb-000019
Figure PCTCN2022141022-appb-000020
上述哒嗪酮类化合物的药学上可接受的盐为上述哒嗪酮类化合物与酸形成的盐，具体酸为盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸或阿魏酸。
作为本发明涉及的第二方面，上述哒嗪酮类化合物的制备方法为以下任一方法：
(1)当R 1选自三氟甲基、氰基或卤素，R 2为氢，R 3选自甲基或氢，与R 3相连的碳原子为S构型，或R 2和R 3形成环丙基，R 4为
Figure PCTCN2022141022-appb-000021
A 1代表-NH-，A 2为
Figure PCTCN2022141022-appb-000022
n 1或n 2各自独立地代表0或1，A 3为
Figure PCTCN2022141022-appb-000023
A 4为
Figure PCTCN2022141022-appb-000024
目标化合物I-A的制备方法如下：
Figure PCTCN2022141022-appb-000025
由化合物Ⅱ制备化合物Ⅳ，是将Ⅱ和Ⅲ共同溶于溶剂中，加入缚酸剂进行取代反应得到。反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、1,4-二氧六环、乙二醇二甲醚或乙腈，优选乙腈；缚酸剂为碳酸钠、碳酸钾、三乙胺或N,N-二异丙基乙胺(DIPEA)，优选DIPEA。
由化合物Ⅳ制备化合物Ⅴ，是将Ⅳ溶于溶剂中，加入酸进行反应得到。反应溶剂为二氯甲烷、四氢呋喃或1,4-二氧六环，优选二氯甲烷；所用酸为氯化氢饱和的乙酸乙酯溶液、氯化氢饱和的1,4-二氧六环溶液或三氟乙酸，优选三氟乙酸。
由化合物Ⅴ制备化合物Ⅶ，是将Ⅴ和Ⅵ溶于溶剂，加入缚酸剂进行取代反应得到。反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、1,4-二氧六环、乙二醇二甲醚或乙腈，优选1,4-二氧六环；缚酸剂为碳酸钠、碳酸钾、三乙胺或DIPEA，优选DIPEA。
由化合物Ⅶ制备化合物Ⅷ，是将Ⅶ溶于溶剂中，加入催化剂进行催化氢化反应得到。反应溶剂为四氢呋喃、甲醇、乙醇或任意两者的混合溶剂，优选甲醇；催化剂为氢氧化钯或钯碳，优选钯碳。
由化合物Ⅷ制备化合物Ⅹ，是将Ⅷ溶于溶剂中，加入缩合剂，再加入碱和化合物 Ⅸ进行缩合反应得到。溶剂为二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、1,4-二氧六环、乙二醇二甲醚或乙腈，优选N,N’-二甲基甲酰胺；缩合剂选自N,N'-羰基二咪唑(CDI)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、N,N'-二环己基碳二亚胺(DCC)、N,N'-二异丙基碳二亚胺(DIC)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基(PyBop)，优选EDCI；碱为三乙胺、碳酸氢钠、碳酸钠、碳酸钾或DIPEA，优选DIPEA。
由化合物Ⅹ制备目标化合物Ⅰ-A，是将Ⅹ溶于溶剂，加入酸反应得到。溶剂为四氢呋喃、乙腈或二氯甲烷，优选二氯甲烷；酸为盐酸或三氟乙酸或三氟甲磺酸，优选三氟乙酸或三氟甲磺酸。
(2)当R 1选自三氟甲基、氰基或卤素，R 2为氢，R 3选自甲基或氢，与R 3相连的碳原子为S构型，或R 2和R 3形成环丙基，R 4为
Figure PCTCN2022141022-appb-000026
A 1为-NH-，A 2为
Figure PCTCN2022141022-appb-000027
n 1或n 2各自独立地选自0或1，A 3为
Figure PCTCN2022141022-appb-000028
A 4为
Figure PCTCN2022141022-appb-000029
目标化合物I-B的制备方法如下：
Figure PCTCN2022141022-appb-000030
由化合物Ⅷ制备化合物Ⅻ，是将Ⅷ溶于溶剂中，加入缩合剂，再加入碱和化合物Ⅺ进行缩合反应得到。溶剂为二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、1,4-二氧六环或乙腈，优选N,N’-二甲基甲酰胺；缩合剂选自N,N'-羰基二咪唑(CDI)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、N,N'-二环己基碳二亚胺(DCC)、N,N'-二异丙基碳二亚胺(DIC)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)或六氟磷酸苯并三唑-1-基-氧基三吡 咯烷基(PyBop)，优选EDCI；碱为三乙胺、碳酸氢钠、碳酸钠、碳酸钾或DIPEA，优选DIPEA。
由化合物Ⅻ制备目标化合物Ⅰ-B，是将ⅩII溶于溶剂，加入酸进行反应得到。溶剂为四氢呋喃、乙腈或二氯甲烷，优选二氯甲烷；酸为盐酸或三氟乙酸或三氟甲磺酸，优选三氟乙酸或三氟甲磺酸。
(3)当R 1代表三氟甲基、氰基或卤素，R 2为氢，R 3选自甲基或氢，与R 3相连的碳原子为S构型，或R 2和R 3形成环丙基，R 4为
Figure PCTCN2022141022-appb-000031
A 1为-NH-，A 2为
Figure PCTCN2022141022-appb-000032
A 3为
Figure PCTCN2022141022-appb-000033
A 4为
Figure PCTCN2022141022-appb-000034
目标化合物I-C的制备方法如下：
Figure PCTCN2022141022-appb-000035
由化合物ⅩⅢ制备化合物ⅩⅣ，是将ⅩⅢ溶于溶剂，加入碱，再加入化合物Ⅲ进行反应得到。反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、1,4-二氧六环、乙二醇二甲醚或乙腈，优选N,N-二甲基甲酰胺；碱为氢化钠、碳酸钠、碳酸钾、三乙胺或DIPEA，优选氢化钠。
由化合物ⅩⅣ制备化合物ⅩⅤ，是将ⅩⅣ溶于溶剂，加入碱的水溶液进行水解得到。反应溶剂为四氢呋喃、甲醇、乙腈或任意两者的混合溶剂，优选四氢呋喃与甲醇混合溶剂；碱为氢氧化钠、氢氧化锂或氢氧化钾，优选氢氧化钠。
由化合物ⅩⅤ制备化合物ⅩⅥ，是将ⅩⅤ溶于溶剂，加入缩合剂，再加入碱和化合物Ⅸ进行缩合反应得到。溶剂为二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、1,4-二氧六环、乙二醇二甲醚或乙腈，优选N,N-二甲基甲酰胺；缩合剂选自N,N'-羰基二咪唑(CDI)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、N,N'-二环己基碳二亚胺(DCC)、N,N'-二异丙基碳二亚胺(DIC)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基(PyBop)，优选EDCI；碱为三乙胺、碳酸钠、碳酸钾或DIPEA，优选DIPEA。
由化合物ⅩⅥ制备化合物ⅩⅦ，是将ⅩⅥ溶于溶剂中，加入酸进行反应得到。溶剂为二氯甲烷、四氢呋喃或1,4-二氧六环，优选二氯甲烷；酸为盐酸、三氟乙酸或硫酸，优选三氟乙酸。
由化合物ⅩⅦ制备化合物ⅩⅧ，是将ⅩⅦ和化合物Ⅵ溶于溶剂，加入碱进行取代反应得到。反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、1,4-二氧六环、乙二醇二甲醚或乙腈，优选1,4-二氧六环；碱为碳酸钠、碳酸钾、三乙胺或DIPEA，优选DIPEA。
由化合物ⅩⅧ制备化合物Ⅰ-C，是将ⅩⅧ溶于溶剂，加入酸进行反应得到。溶剂为四氢呋喃、乙腈或二氯甲烷，优选二氯甲烷；酸为盐酸或三氟乙酸或三氟甲磺酸，优选三氟乙酸或三氟甲磺酸。
(4)当m＝0，R 1选自三氟甲基、氰基或卤素，R 2为氢，R 3为甲基，R 4为
Figure PCTCN2022141022-appb-000036
A 1为-NH-，A 2为
Figure PCTCN2022141022-appb-000037
n 1或n 2各自独立地选自0或1，A 3为
Figure PCTCN2022141022-appb-000038
A 4为
Figure PCTCN2022141022-appb-000039
目标化合物I-D的制备方法如下：
Figure PCTCN2022141022-appb-000040
Figure PCTCN2022141022-appb-000041
由化合物ⅩⅨ制备化合物ⅩⅩⅠ，是将ⅩⅨ溶于溶剂，加入缩合剂，再加入碱和化合物ⅩⅩ进行缩合反应得到。溶剂为二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、1,4-二氧六环、乙二醇二甲醚或乙腈，优选N,N-二甲基甲酰胺；缩合剂选自N,N'-羰基二咪唑(CDI)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、N,N'-二环己基碳二亚胺(DCC)、N,N'-二异丙基碳二亚胺(DIC)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)、六氟磷酸苯并三唑-1-基-氧基三吡咯烷基(PyBop)，优选EDCI；碱为三乙胺、碳酸钠、碳酸钾或DIPEA，优选DIPEA。
由化合物ⅩⅩⅠ制备化合物ⅩⅩⅡ，是将ⅩⅩⅠ溶于溶剂，加入碱的水溶液进行水解得到。反应溶剂为四氢呋喃、甲醇、乙腈或任意两者的混合溶剂，优选四氢呋喃与甲醇混合溶剂；碱为氢氧化钠、氢氧化锂或氢氧化钾，优选氢氧化钠。
由化合物ⅩⅩⅡ制备化合物ⅩⅩⅢ，是将ⅩⅩⅡ溶于溶剂，加入缩合剂，再加入N,O-二甲基羟胺盐酸盐进行缩合反应得到。溶剂为二氯甲烷、四氢呋喃、N,N-二甲基甲酰胺、1,4-二氧六环、乙二醇二甲醚或乙腈，优选N,N-二甲基甲酰胺；缩合剂选自N,N'-羰基二咪唑(CDI)、1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)、N,N'-二环己基碳二亚胺(DCC)、N,N'-二异丙基碳二亚胺(DIC)、2-(7-偶氮苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯(HATU)、苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐(HBTU)或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基(PyBop)，优选CDI。
由化合物ⅩⅩⅢ制备化合物ⅩⅩⅣ，是将ⅩⅩⅢ溶于溶剂，在低温下加入甲基溴化镁反应得到。反应溶剂为无水四氢呋喃、无水乙醚、无水二氯甲烷或无水二氧六环，优选无水四氢呋喃。
由化合物XXIV制备化合物XXV，是将XXIV溶于溶剂，加入氨源和催化剂反应得到。溶剂为甲醇、乙醇、四氢呋喃或任意两者的混合溶剂，优选甲醇，氨源为甲酸铵或乙酸铵，优选甲酸铵，催化剂优选二氯(五甲基环戊二烯基)合铑(III)二聚体。
由化合物ⅩXV制备化合物XXVI，是将XXV和化合物Ⅵ溶于溶剂，加入碱进行取代反应得到。反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、1,4-二氧六环、乙二醇二甲醚或乙腈，优选1,4-二氧六环；碱为碳酸钠、碳酸钾、三乙胺或DIPEA，优选DIPEA。
由化合物XXVI制备目标化合物Ⅰ-D，是将XXVI溶于溶剂，加入酸进行反应得到。溶剂为四氢呋喃、乙腈、二氯甲烷或任意两者的混合溶剂，优选二氯甲烷；酸为盐酸或三氟乙酸或三氟甲磺酸，优选三氟乙酸或三氟甲磺酸。
(5)当R 1选自三氟甲基、氰基或卤素，R 2和R 3为氢，R 4为
Figure PCTCN2022141022-appb-000042
A 1代表-NH-，A 2为-NH-或-N(CH 3)-，A 3为
Figure PCTCN2022141022-appb-000043
A 4为
Figure PCTCN2022141022-appb-000044
目标化合物I-E的制备方法如下：
Figure PCTCN2022141022-appb-000045
由化合物IX制备化合物XXVIII，是将IX溶于溶剂，加入碱，再加入化合物XXVII进行反应得到。反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、1,4-二氧六环、二氯甲烷或乙腈，优选二氯甲烷；碱为碳酸钠、碳酸钾、三乙胺或DIPEA，优选三乙胺。
由化合物XVIII制备化合物ⅩXX，是将ⅩVIII溶于溶剂，加入XXIX，再加入碱反应得到。反应溶剂为四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺或乙腈，优选N,N-二甲基甲酰胺；碱为氢氧化钠、碳酸钾或碳酸钠，优选碳酸钾。
由化合物XXX制备化合物XXXI，是将ⅩXX溶于溶剂中，加入酸进行反应得到。溶剂为二氯甲烷、四氢呋喃或1,4-二氧六环，优选二氯甲烷；酸为盐酸、三氟乙酸或硫酸，优选三氟乙酸。
由化合物ⅩXXI制备化合物ⅩXXII，是将ⅩXXI和化合物Ⅵ溶于溶剂，加入碱进行取代反应得到。反应溶剂为N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、四氢呋喃、1,4-二氧六环、乙二醇二甲醚或乙腈，优选1,4-二氧六环；碱为碳酸钠、碳酸钾、三乙胺或DIPEA，优选DIPEA。
由化合物ⅩXXII制备化合物I-E，是将XXXII溶于溶剂中，加入酸进行反应得到。溶剂为二氯甲烷、四氢呋喃或1,4-二氧六环，优选二氯甲烷；酸为盐酸、三氟乙酸或硫酸，优选三氟乙酸。
其中，m、Y 1、Y 2、R 7、R 8、R 9、R 10的定义如前所述；Boc为叔丁氧羰基；P为(三甲基硅)乙氧基甲基(SEM)或对甲氧基苄基(PMB)；
将相应的酸与以上方法制备的化合物(I)成盐，即得上述哒嗪酮类化合物的药学上可接受的盐。
作为本发明涉及的第三方面，上述药物组合物包含上述任一哒嗪酮类化合物以及药学上可接受的载体。可以添加药学上可接受的载体制成常见的药用制剂，如片剂、胶囊、糖浆、悬浮剂或注射剂，制剂可以加入香料、甜味剂、液体/固体填料、稀释剂等常用药用辅料。
作为本发明涉及的第四方面，上述哒嗪酮类化合物及其药物组合物可制备为PARP7抑制剂药物，具体为用于治疗肿瘤的药物，更具体为用于治疗肺鳞腺癌、结肠癌、乳腺癌等癌症的药物。
有益效果：与现有技术相比，本发明具有如下显著优点：
1、该哒嗪酮类化合物具有优异的体内药代动力学性质，半衰期、体内暴露量及生物利用度均得到显著提升，具有显著的成药优势；同时还具有优异的体内药效学性质，给予较低的剂量即可实现显著的肿瘤生长抑制活性；此外还可以促进免疫因子释放，无需联合用药，单独用药即可实现显著的疗效；
2、该哒嗪酮类化合物可有效抑制PARP7酶活性，酶抑制IC 50值最优小于0.1μM，达到纳摩尔浓度级别；
3、该哒嗪酮类化合物及其药物组合物应用广泛，可制备为抗肿瘤药物，具有更优异的体内药代动力学和药效学性质；
4、化合物制备方法简便易行。
附图说明
图1为化合物对干扰素释放的促进作用；
图2为化合物的体内抗肿瘤作用。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。
实施例1：(S)-4-(三氟甲基)-5-((1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-1)的合成
(S)-1-(2-((叔丁氧羰基)氨基)丙基)氮杂环丁烷-3-甲酸苄酯(IV-1)的合成
将氮杂环丁烷-3-甲酸苄酯(II-1)(16.0g,83.7mmol)溶于70mL乙腈中，加入(S)-(1-溴丙-2-基)氨基甲酸叔丁酯(III-1)(21.9g,92.0mmol)和DIPEA(32.4g,251.1mmol)，升温至80℃反应2小时。薄层色谱(V石油醚：V乙酸乙酯＝1:1)监测反应完全， 加入200mL水，乙酸乙酯(100mL×3)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品通过硅胶柱层析(V石油醚：V乙酸乙酯＝3:1)纯化得25.4g无色油状物(IV-1)，收率87.0％。ESI-MS[M+H] +349.2； 1H NMR(300MHz,DMSO-d 6)δ7.40-7.30(m,5H),5.14(s,2H),3.65-3.50(m,3H),3.40-3.30(m,3H),2.45(dd,J 1＝6Hz,J 2＝1.8Hz,2H),1.44(s,9H),1.08(d,J＝6.6Hz,3H)。
(S)-1-(2-氨基丙基)氮杂环丁烷-3-甲酸苄酯(V-1)的合成
将化合物IV-1(6.9g,20.0mmol)溶于30mL二氯甲烷，加入20mL三氟乙酸，室温搅拌0.5小时，薄层色谱(V二氯甲烷：V甲醇＝15:1)监测反应完全，减压蒸除溶剂，加入饱和碳酸氢钠水溶液调pH至7～8。用二氯甲烷(50mL×7)萃取，合并有机相，用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩得浅黄色油状物(V-1)4.40g，收率88.7％。ESI-MS[M+H] +249.2。
(S)-1-(2-((6-氧代-5-三氟甲基-1-((2-(三甲基硅基)乙氧基)甲基)-1,6-二氢哒嗪-4-基)氨基)丙基)氮杂环丁烷-3-甲酸苄酯(VII-1)的合成
将化合物V-1(2.2g,9.0mmol)溶于10mL 1,4-二氧六环中，加入5-氯-4-三氟甲基-2-((2-(三甲基硅基)乙氧基)甲基)哒嗪-3(2H)-酮(VI-1)(3.3g,10.0mmol)和DIPEA(3.5g,27.0mmol)，升温至90℃反应2小时，薄层色谱(V石油醚：V乙酸乙酯＝1:1)监测反应完全。加入40mL水，乙酸乙酯(20mL×3)萃取，合并有机相，依次用饱和食盐水洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品通过硅胶柱层析(V石油醚：V乙酸乙酯＝3:1)纯化得4.1g无色油状物VII-1，收率83.7％。ESI-MS[M+H] +541.2； 1H NMR(300MHz,DMSO-d 6)δ7.61(s,1H),7.38-7.32(m,5H),6.15-6.05(m,1H),5.37(dd,J 1＝14.1Hz,J 2＝9.9Hz,2H),5.14(s,2H),3.74-3.55(m,5H),3.45-3.35(m,3H),2.72-2.54(m,2H),1.23(d,J＝6.6Hz,3H),0.99-0.91(m,2H),-0.01(s,9H)。
(S)-1-(2-((6-氧代-5-三氟甲基-1-((2-(三甲基硅基)乙氧基)甲基)-1,6-二氢哒嗪-4-基)氨基)丙基)氮杂环丁-3-甲酸(VIII-1)的合成
将化合物VII-1(4.0g,7.4mmol)溶于20mL无水甲醇中，加入500mg钯碳，反应体系用氢气置换后，在室温下反应30分钟，薄层色谱(V二氯甲烷：V甲醇＝15:1)监测反应完全，抽滤，滤饼用10mL甲醇洗涤，干燥后得白色固体(VIII-1)3.2g，收率96.1％。ESI-MS[M+H] +451.2； 1H NMR(300MHz,DMSO-d 6)δ11.4(s,1H),7.62(s,1H),6.45-6.35(m,1H),5.37(dd,J 1＝14.1Hz,J 2＝9.9Hz,2H),3.74-3.55(m,5H),3.45-3.35(m,3H),2.72-2.54(m,2H),1.23(d,J＝6.6Hz,3H),0.99-0.91(m,2H),-0.01(s,9H)。
(S)-4-三氟甲基-5-((1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-氨基)-2-((2-(三甲基硅基)乙氧基)甲基)哒嗪-3(2H)-酮(X-1)的合成
将化合物VIII-1(480.0mg,1.1mmol)溶于5mL二氯甲烷中，分别加入1-羟基苯并三唑(HOBt，180.0mg,1.3mmol)和EDCI(210.0mg,1.3mmol)，在室温下反应0.5小时后，再依次加入2-(哌嗪-1-基)-5-三氟甲基嘧啶(IX-1)(280.0mg,1.2mmol)和DIPEA(430.0mg,3.3mmol)，继续在室温下反应1小时，薄层色谱(V二氯甲烷：V甲醇＝15:1)监测反应完全。加入10mL水，二氯甲烷(5mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品通过硅胶柱层析(V石油醚：V乙酸乙酯＝1:2)纯化得白色固体(X-1)560.0mg，收率76.6％。ESI-MS[M+H] +665.2； 1H NMR(300MHz,DMSO-d 6)δ8.73(s,2H),8.00(s,1H),6.65-6.55(m,1H),5.21(s,2H),4.20-4.00(m,1H),3.83-3.74(m,4H),3.66-3.45(m,8H),3.28-3.13(m,5H),1.24(t,J＝7.2Hz,1H),1.18(d,J＝6.3Hz,3H),0.84(t,J＝8.1Hz,2H),-0.04(s,9H)。
(S)-4-(三氟甲基)-5-((1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-1)的合成
将化合物X-1(531.2mg,0.8mmol)溶于3mL二氯甲烷，加入3mL三氟乙酸，在室温下反应3小时。薄层色谱(V二氯甲烷：V甲醇＝15:1)监测反应完全，减压蒸除溶剂，加入饱和碳酸氢钠水溶液调pH至7～8，加入10mL水，二氯甲烷(10mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品通过硅胶柱层析(V二氯甲烷：V甲醇＝40:1)纯化得白色固体(I-A-1)332.4mg，收率77.8％。ESI-MS[M+H] +535.2； 1H NMR(300MHz,DMSO-d 6)δ12.50(s,1H),8.73(s,2H),7.90(s,1H),6.49-6.35(m,1H),4.10-3.90(m,1H),3.88-3.72(m,4H),3.62-3.42(m,11H),1.16(d,J＝6.3Hz,3H)。
参照实施例1的制备方法，制备得到以下化合物：
Figure PCTCN2022141022-appb-000046
Figure PCTCN2022141022-appb-000047
Figure PCTCN2022141022-appb-000048
实施例2：4-(三氟甲基)-5-(((S)-1-((S)-3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)吡咯烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-18)的合成
1-((S)-2-((叔丁氧羰基)氨基)丙基)吡咯烷-3-甲酸苄酯(IV-2)的合成
将吡咯烷-3-羧酸苄酯(II-2)(17.2g,83.7mmol)溶于70mL乙腈中，加入化合物III-1(21.9g,92.0mmol)和DIPEA(32.4g,251.1mmol)，升温至80℃反应2小时。薄层色谱(V石油醚：V乙酸乙酯＝1:1)监测反应完全，加入200mL水，乙酸乙酯(100mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品通过硅胶柱层析(V石油醚：V乙酸乙酯＝3:1)纯化得25.4g无色油状物(IV-2)，收率83.8％。ESI-MS[M+H] +363.2。
1-((S)-2-氨基丙基)吡咯烷-3-甲酸苄酯(V-2)的合成
将化合物IV-2(7.2g,19.9mmol)溶于30mL二氯甲烷，加入20mL三氟乙酸，室温搅拌0.5小时，薄层色谱(V二氯甲烷：V甲醇＝15:1)监测反应完全，减压蒸除溶剂，加入饱和碳酸氢钠水溶液调pH至7～8。加二氯甲烷(50mL×5)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩得浅黄色油状物(V-2)4.4g，收率84.6％。ESI-MS[M+H] +263.2。
1-((S)-2-((6-氧代-5-(三氟甲基)-1-((2-(三甲基硅基)乙氧基)甲基)-1,6-二氢哒嗪-4-基)氨基)丙基)吡咯烷-3-甲酸苄酯(VII-3)的合成
将化合物V-2(2.4g,9.0mmol)溶于10mL 1,4-二氧六环中，加入化合物VI-1(3.3g,10.0mmol)和DIPEA(3.5g,27.0mmol)，升温至90℃反应2小时，薄层色谱(V石油醚：V乙酸乙酯＝1:1)监测反应完全。加入40mL水，乙酸乙酯(20mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品通过硅胶柱层析(V石油醚：V乙酸乙酯＝3:1)纯化得4.2g无色油状物(VII-3)，收率84.4％。ESI-MS[M+H] +555.3。
1-((S)-2-((6-氧代-5-三氟甲基-1-((2-三甲基硅基乙氧基)甲基)-1,6-二氢哒嗪-4-基)氨基)丙基)吡咯烷-3-甲酸(VIII-3)的合成
将化合物VII-3(4.1g,7.4mmol)溶于20mL无水甲醇中，加入500mg钯碳，反应体系用氢气置换后，室温下反应30分钟，薄层色谱(V二氯甲烷：V甲醇＝15:1)监测反应完全，抽滤，滤饼用10mL甲醇洗涤，干燥后得白色固体(VIII-3)3.2g，收率93.3％。ESI-MS[M+H] +465.2。
4-三氟甲基-5-((2S)-1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)吡咯烷-1-基)丙-2-基)氨基)-2-((2-三甲基硅基乙氧基)甲基)哒嗪-3(2H)-酮(X-18)的合成
以化合物VIII-3(139.2mg,0.3mmol)与化合物IX-1(70.0mg,0.3mmol)为原料，制备过程参考化合物X-1，得到白色固体(X-18)129.0mg，收率63.5％。ESI-MS:[M+H] +679.3。
4-(三氟甲基)-5-(((S)-1-((S)-3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)吡咯烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-18)的合成
以化合物X-18(88.0mg,0.13mmol)为原料，制备过程参考化合物I-A-1，得到50.0mg白色固体(I-A-18)，收率70.4％。ESI-MS[M+H] +549.2； 1H NMR(300MHz,DMSO-d 6)δ12.32(s,1H),8.71(s,2H),7.53(s,1H),6.19(t,J＝1.8Hz,1H),4.50-4.40(m,1H),4.10-4.05(m,2H),3.81-3.70(m,4H),3.67-3.60(m,4H),1.92-1.22(m,11H),1.22(d,J＝6.3Hz,3H)。
参照实施例2的制备方法，制备得到以下化合物：
Figure PCTCN2022141022-appb-000049
Figure PCTCN2022141022-appb-000050
实施例3：(S)-5-((1-(3-(4-(2,2-二氟苯并[d][1,3]二氧杂-5-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(I-B-1)的合成
以化合物X-25(113.0mg,0.17mmol)为原料，制备过程参考化合物I-A-1，得到80.0mg白色固体(I-B-1)，收率86.5％。ESI-MS[M+H] +545.2； 1H NMR(400MHz,DMSO-d 6)δ12.46(s,1H),7.89(s,1H),7.22(d,J＝8.8Hz,1H),7.09(d,J＝2.4Hz,1H),6.70(dd,J 1＝8.8Hz,J 2＝2.4Hz,1H),6.45-6.35(m,1H),4.00-3.90(m,1H),3.65-3.45(m,4H),3.45-3.35(m,3H),3.26-3.18(m,2H),3.10-3.00(m,4H),2.65-2.54(m,2H),1.12(d,J＝6.3Hz,3H)。
实施例4：(S)-4-(三氟甲基)-5-((1-(3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)-1H-吡咯-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-C-1)的合成
(S)-1-(2-(叔丁氧羰基氨基)丙基)-1H-吡咯-3-甲酸甲酯(XIV-1)的合成
将1H-吡咯-3-甲酸甲酯(XIII-1)(1.3g,10.3mmol)溶于5mL无水DMF，冰浴下加入氢化钠(0.8g,20.0mmol)，加毕，升至室温搅拌1小时，随后在冰浴下加入化合物III-1(3.6g,15.0mmol)，加毕，升温至50℃反应6小时。薄层色谱(V石油醚：V丙酮＝8:1)监测反应完全。加入10mL冰水淬灭反应，乙酸乙酯(20mL×3)萃取，合并有机相，用饱和氯化钠溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品用柱层析(V石油醚：V丙酮＝11:1)纯化得2.4g白色固体(XIV-1)，收率82.8％。ESI-MS[M+H] +283.1； 1H NMR(300MHz,CDCl 3)δ7.23(t,J＝2.1Hz,1H),6.55(d,J＝2.1Hz,2H),4.49(d,J＝6.9Hz,1H),3.92-3.84(m,2H),3.77(s,3H),1.41(s,9H),1.07(d,J＝6.9Hz,3H)。
(S)-1-(2-(叔丁氧羰基氨基)丙基)-1H-吡咯-3-甲酸(XV-1)的合成
将化合物XIV-1(2.4g,8.5mmol)溶于20mL四氢呋喃和甲醇的混合溶剂(V四氢呋喃：V甲醇＝1:1)，再将一水合氢氧化锂(1.8g,42.5mmol)溶于4mL水中所得的溶液加到上述反应液中，升温至60℃反应12小时。薄层色谱(V石油醚：V乙酸乙酯＝4:1)监测反应完全，加入20mL水，乙酸乙酯(20mL×2)萃取，收集水相，用2mol/L稀盐酸调pH至5～6，乙酸乙酯(20mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩得白色固体(XV-1)1.9g，收率83.4％。ESI-MS[M+H] +269.1； 1H NMR(300MHz,DMSO-d 6)δ11.65(s,1H),7.30(t,J＝2.1Hz,1H),6.86(d,J＝10.8Hz,1H),6.71(t,J＝2.4Hz,1H),6.32(t,J＝2.1Hz,1H),3.96-3.66(m,3H),1.33 (s,9H),0.98(d,J＝6.6Hz,3H)。
(S)-(1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)-1H-吡咯-1-基)丙-2-基)氨基甲酸叔丁酯(XVI-1)的合成
将化合物XV-1(1.0g,3.9mmol)溶于6mL二氯甲烷中，加入HATU(1.6g,4.3mmol)，室温搅拌15分钟，随后依次加入化合物IX-1(1.0g,4.3mmol)和DIPEA(1.0g,7.80mmol)，室温反应30分钟。薄层色谱(V石油醚：V乙酸乙酯＝1:1)监测反应完全，加入20mL水，用乙酸乙酯(10mL×3)萃取，合并有机相，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。用柱层析(V石油醚：V乙酸乙酯＝3:1)纯化得1.4g白色固体(XVI-1)，收率74.5％。ESI-MS[M+H] +483.2； 1H NMR(300MHz,DMSO-d 6)δ8.71(s,2H),7.14(t,J＝2.1Hz,1H),6.90(d,J＝10.8Hz,1H),6.73(t,J＝2.4Hz,1H),6.25(t,J＝2.1Hz,1H),3.94-3.66(m,11H),1.33(s,9H),0.98(d,J＝6.6Hz,3H)。
(S)-(1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)-1H-吡咯-1-基)丙-2-基)氨基(XVII-1)的合成
将化合物XVI-1(1.4g,2.9mmol)溶于5mL二氯甲烷中，加入3mL三氟乙酸，室温反应15分钟，薄层色谱(V二氯甲烷：V甲醇＝5:1)监测反应完全，减压蒸除溶剂，加入饱和碳酸氢钠溶液使体系的pH至7～8，二氯甲烷(20mL×5)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩得浅黄色固体(XVII-1)0.9g，收率90.9％。ESI-MS[M+H] +383.2； 1H NMR(300MHz,DMSO-d 6)δ8.74(s,2H),7.21(t,J＝2.1Hz,1H),6.81(t,J＝2.4Hz,1H),6.27(t,J＝2.1Hz,1H),3.94-3.66(m,11H),0.98(d,J＝6.6Hz,3H)。
(S)-4-三氟甲基-5-((1-(3-(4-(5-三氟甲基)嘧啶-2-基)哌嗪-1-羰基)-1H-吡咯-1-基)丙-2-基)氨基)-2-((2-三甲基硅基乙氧基)甲基)哒嗪-3(2H)-酮(XVIII-1)的合成
将化合物VI-1(1.0g,3.2mmol)溶于6mL1,4-二氧六环中，加入化合物XVII-1(1.1g,2.9mmol)和DIPEA(1.1g,8.6mmol)，升温至90℃反应2小时，薄层色谱(V石油醚：V乙酸乙酯＝1:1)监测反应完全，加入20mL水，乙酸乙酯(10mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品用柱层析(V石油醚：V乙酸乙酯＝3:1)纯化得到1.5g白色固体(XVIII-1)，收率69.4％。ESI-MS[M+H] +675.2； 1H NMR(300MHz,DMSO-d 6)δ8.74(s,2H),7.63(s,1H),7.14(t,J＝2.1Hz,1H),6.75(t,J＝2.7Hz,1H),6.73-6.66(m,1H),6.21-6.17(m,1H),5.18-5.10(m,2H),4.50-4.40(m,1H),4.10-4.05(m,2H),3.88-3.80(m,4H),3.67-3.60(m,4H),3.53(t,J＝8.1Hz,2H),1.24(d,J＝6.3Hz,3H),1.18(t,J＝7.2Hz,1H),0.81(t,J＝8.1Hz,2H),-0.06(s,9H)。
(S)-4-(三氟甲基)-5-((1-(3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)-1H-吡咯-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-C-1)
将化合物XVIII-1(674.0mg,1.0mmol)溶于5mL二氯甲烷中，加入三氟乙酸4mL，室温反应3小时，薄层色谱监测(V石油醚：V乙酸乙酯＝1:4)反应完全，减压蒸除溶剂，加入饱和碳酸氢钠溶液使其pH至7～8，加入10mL水，二氯甲烷(10mL×3)萃取，合并有机相，无水硫酸钠干燥，抽滤，滤液浓缩。粗品用柱层析(V石油醚：V乙酸乙酯＝1:1)分离纯化得白色固体(I-C-1)350.0mg，收率64.3％。ESI-MS[M+H] +544.2； 1H NMR(300MHz,DMSO-d 6)δ12.37(s,1H),8.73(s,2H),7.90(s,1H),7.14(t,J＝1.5Hz,1H),6.74(t,J＝2.4Hz,1H),6.54-6.45(m,1H),6.19(t,J＝1.8Hz,1H),4.50-4.40(m,1H),4.10-4.05(m,2H),3.88-3.80(m,4H),3.67-3.60(m,4H),1.22(d,J＝6.3Hz,3H)。
实施例5：4-(三氟甲基)-5-((1-(1-(1-(5-(三氟甲基)嘧啶-2-基)哌啶-4-羰基)氮杂环丁-3-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-D-1)的合成
2-(1-(1-(5-三氟甲基嘧啶-2-基)哌啶-4-羰基)氮杂环丁烷-3-基)乙酸甲酯(XXI-1)的合成
将1-(5-三氟甲基嘧啶-2-基)哌啶-4-甲酸(XIX-1)(1.1g,4.0mmol)溶于5mL二氯甲烷中，加入HATU(1.7g,4.4mmol)，室温搅拌15分钟，加入2-(氮杂环丁烯-3-基)乙酸甲酯(XX-1)(0.5g,4.0mmol)和DIPEA(1.0g,8.0mmol)，加毕，在室温下反应30分钟，薄层色谱监测(V石油醚：V乙酸乙酯＝3:1)反应完全，加10mL水，二氯甲烷(5mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品用柱层析(V石油醚：V乙酸乙酯＝1:1)纯化得白色固体(XXI-1)1.5g，收率97.1％。ESI-MS[M+H] +387.2； 1HNMR(300MHz,CDCl 3)δ8.45(s,2H),4.88-4.78(m,2H),4.38(t,J＝8.4Hz,1H),4.16(t,J＝9.6Hz,1H),3.95-3.87(m,1H),3.69(s,3H),3.06-2.95(m,3H),2.70-2.64(m,2H),2.50-2.40(m,1H),1.80-1.70(m,4H)。
2-(1-(1-(5-三氟甲基嘧啶-2-基)哌啶-4-羰基)氮杂环丁烷-3-基)乙酸(XXII-1)的合成
将化合物XXI-1(1.5g,3.8mmol)溶于5mL四氢呋喃中，加入甲醇5mL，再加入5mol/L氢氧化钠水溶液2mL，加毕，室温反应1小时，薄层色谱监测(V石油醚：V乙酸乙酯＝1:1)反应完全。加水20mL，乙酸乙酯(10mL×2)萃取，水层用稀盐酸调pH至4，析出白色固体，抽滤，滤饼用5mL水洗涤，收集滤饼，真空干燥得白色固体(XXII-1)1.2g，收率83.5％。ESI-MS[M+H] +373.2； 1HNMR(300MHz,CDCl 3)δ8.45(s,2H),4.82(dt,J 1＝13.5Hz,J 2＝3.9Hz,2H),4.38(t,J＝8.4Hz,1H),4.16(t,J＝9.6Hz,1H),3.95-3.87(m,1H),3.06-2.95(m,3H),2.70-2.64(m,2H),2.50-2.40(m,1H),1.80-1.70(m,4H)。
N-甲氧基-N-甲基-2-(1-(1-(5-三氟甲基嘧啶-2-基)哌啶-4-羰基)氮杂环丁烷-3-基)乙酰胺(XXIII-1)的合成
将化合物XXII-1(1.5g,4.0mmol)溶于6mL二氯甲烷中，依次加入CDI(1.0g,6.0mmol)和二甲羟胺盐酸盐(1.2g,12.0mmol)，加毕，室温反应1小时，薄层色谱监测(V二氯甲烷：V甲醇＝15:1)反应完全，加入10mL水，二氯甲烷(8mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品用柱层析(V石油醚：V乙酸乙酯＝1:1)纯化得白色固体(XXIII-1)1.2g，收率69.9％。ESI-MS[M+H] +416.2； 1HNMR(300MHz,CDCl 3)δ8.45(s,2H),4.88-4.78(m,2H),4.38(t,J＝8.4Hz,1H),4.16(t,J＝9.6Hz,1H),3.95-3.87(m,1H),3.69(s,3H),3.06-2.95(m,3H),2.72(s,3H),2.70-2.64(m,2H),2.50-2.40(m,1H),1.80-1.70(m,4H)。
1-(1-(1-(5-三氟甲基嘧啶-2-基)哌啶-4-羰基)氮杂环丁烷-3-基)丙-2-酮(XXIV-1)的合成
将化合物XXIII-1(0.8g,2.0mmol)溶于5mL无水四氢呋喃中，在-15℃下加入甲基溴化镁(1mol/L,4.0mL)，加毕，保温反应4小时，薄层色谱监测(V二氯甲烷：V甲醇＝15:1)反应完全。加入10mL水淬灭反应，室温搅拌15分钟，乙酸乙酯(8mL×3)萃取，合并有机相，饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品用柱层析(V石油醚：V乙酸乙酯＝1:1)纯化得白色固体(XXIV-1)450.0mg，收率60.8％。ESI-MS[M+H] +371.2； 1HNMR(300MHz,CDCl 3)δ8.45(s,2H),4.88-4.78(m,2H),4.38(t,J＝8.4Hz,1H),4.16(t,J＝9.6Hz,1H),3.95-3.87(m,1H),3.06-2.95(m,3H),2.70-2.64(m,2H),2.50-2.40(m,1H),2.20(s,3H),1.80-1.70(m,4H)。
(3-(2-氨基丙基)氮杂环丁烷-1-基)(1-(5-三氟甲基嘧啶-2-基)哌啶-4-基)甲酮(XXV-1)的合成
将化合物XXIV-1(0.5g,1.4mmol)溶于5mL甲醇中，依次加入甲酸铵(0.4g,7.0mmol)和二氯(五甲基环戊二烯基)合铑(III)二聚体(43.0mg,0.07mmol)，加毕，升温至70℃下反应3小时，薄层色谱监测(V二氯甲烷：V甲醇＝10:1)反应完全，冷却至室温，减压蒸除溶剂，加入2mol/L盐酸调pH至1～2，室温搅拌10分钟。乙酸乙酯(5mL×2)萃取，水层用5mol/L氢氧化钠水溶液调pH至8～9，再次用乙酸乙酯(10mL×5)萃取，合并有机层，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品用柱层析(V二氯甲烷：V甲醇＝10:1)纯化得白色固体(XXV-1)370.0mg，收率71.3％。ESI-MS[M+H] +372.2； 1HNMR(300MHz,DMSO-d 6)δ8.70(s,2H),4.79-4.69(m,2H),4.34(t,J＝8.4Hz,1H),4.01-3.91(m,5H),3.55-3.45(m,1H),3.15-2.95(m,3H),2.78-2.68(m,1H),1.80-1.65(m,3H),1.51-1.36(m,2H),1.11(d,J＝6.3Hz,3H)。
4-三氟甲基-5-((1-(1-(1-(5-三氟甲基嘧啶-2-基)哌啶-4-羰基)氮杂环丁烷-3-基)丙-2-氨基)-2-((2-三甲基硅基乙氧基)甲基)哒嗪-3(2H)-酮(XXVI-1)的合成
将化合物XXV-1(372.0mg,1.0mmol)溶于4mL 1,4-二氧六环中，加入化合物VI-1(350.0mg,1.1mmol)，再加入DIPEA(388.0mg,3.0mmol)，加毕，升温至90℃反应3小时，薄层色谱监测(V二氯甲烷：V甲醇＝15:1)反应完全。冷却至室温，加水10mL，乙酸乙酯(8mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品用柱层析(V二氯甲烷：V甲醇＝70:1)纯化得白色固体(XXVI-1)370.0mg，收率56.7％。ESI-MS[M+H] +654.3； 1H NMR(300MHz,DMSO-d 6)δ8.73(s,2H),8.00(s,1H),6.59(s,1H),5.21(s,2H),4.05-3.95(m,1H),3.83-3.74(m,4H),3.66-3.45(m,9H),3.28-3.13(m,5H),1.24(t,J＝7.2Hz,1H),1.18(d,J＝6.3Hz,3H),0.81(t,J＝8.1Hz,2H),-0.06(s,9H)。
4-(三氟甲基)-5-((1-(1-(1-(5-(三氟甲基)嘧啶-2-基)哌啶-4-羰基)氮杂环丁-3-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-D-1)的合成
将化合物XXVI-1(327.0mg,0.5mmol)溶于3mL二氯甲烷中，加入三氟乙酸2mL，在室温下反应3小时，薄层色谱监测(V二氯甲烷：V甲醇＝15:1)反应完全，减压蒸除溶剂，加入饱和碳酸氢钠水溶液调pH至7～8，再加入10mL水，二氯甲烷(10mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品用柱层析(V石油醚：V乙酸乙酯＝1:1)纯化得白色固体(I-D-1)230.0mg，收率86.1％。ESI-MS[M+H] +534.2； 1H NMR(400MHz,DMSO-d 6)δ12.48(s,1H),8.67(s,2H),7.92(s,1H),6.43-6.35(m,1H),4.70-4.60(m,2H),4.30-4.20(m,1H),4.05-3.95(m,1H),3.90-3.82(m,1H),3.55-3.46(m,1H),3.10-3.00(m,2H),2.66-2.53(m,2H),2.03-1.95(m,1H),1.82-1.65(m,3H),1.50-1.35(m,2H),1.17(d,J＝6.3Hz,3H)。
实施例6：N-(4-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丁基)-4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-甲酰胺(I-E-1)的合成
4-硝基苯基4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羧酸酯(XXVIII-1)的合成
将化合物IX-1(464.0mg,2.0mmol)溶于3mL二氯甲烷中，加入三乙胺(404.0mg,4.0mmol)，0℃下加入化合物XXVII-1(442.2mg,2.2mmol)，加毕室温反应1小时，薄层色谱监测(V石油醚：V乙酸乙酯＝4:1)反应完全，加入5mL水，二氯甲烷(5mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品用柱层析(V石油醚：V乙酸乙酯＝10:1)纯化得黄色固体(XXVIII-1)710.0mg，收率89.4％，ESI-MS[M+H] +398.1。
叔丁基(4-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-甲酰氨基)丁基)氨基甲酸酯(XXX-1) 的合成
将化合物XXVIII-1(397.3mg,1.0mmol)溶于4mL 1,4-二氧六环中，加入化合物XXIX-1(207.0mg,1.1mmol)，再加入碳酸钾(414.0mg,3.0mmol)，加毕，升温至90℃反应7小时，薄层色谱监测(V二氯甲烷：V甲醇＝15:1)反应完全。冷却至室温，加水5mL，乙酸乙酯(5mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品用柱层析(纯EA)纯化得白色固体(XXX-1)350.0mg，收率78.0％，ESI-MS[M+H] +447.2。
N-(4-氨基丁基)-4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-甲酰胺(XXXI-1)的合成
将化合物XXXI-1(223.0mg,0.5mmol)溶于3mL二氯甲烷中，加入三氟乙酸3mL，室温反应0.5小时，薄层色谱监测(V石油醚：V乙酸乙酯＝1:4)反应完全，减压蒸除溶剂，加入饱和碳酸氢钠溶液使其pH至7～8，加入4mL水，二氯甲烷(5mL×7)萃取，合并有机相，无水硫酸钠干燥，抽滤，滤液浓缩得白色固体(XXXI-1)120.0mg，收率69.4％，ESI-MS[M+H] +347.2。
N-(4-((6-氧代-5-(三氟甲基)-1-((2-(三甲基甲硅烷基)乙氧基)甲基)-1,6-二氢哒嗪-4-基)氨基)丁基)-4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-甲酰胺(XXXII-1)的合成
将化合物XXXI-1(346.4mg,1.0mmol)溶于4mL 1,4-二氧六环中，加入化合物VI-1(350.0mg,1.1mmol)，再加入DIPEA(388.0mg,3.0mmol)，加毕，升温至90℃反应3小时，薄层色谱监测(V二氯甲烷：V甲醇＝15:1)反应完全。冷却至室温，加水10mL，乙酸乙酯(8mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品用柱层析(V二氯甲烷：V甲醇＝70:1)纯化得白色固体(XXXII-1)490.0mg，收率76.8％，ESI-MS[M+H] +639.3。
N-(4-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丁基)-4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-甲酰胺(I-E-1)的合成
将化合物XXII-1(314.0mg,0.5mmol)溶于3mL二氯甲烷中，加入三氟乙酸2mL，在室温下反应3小时，薄层色谱监测(V二氯甲烷：V甲醇＝15:1)反应完全，减压蒸除溶剂，加入饱和碳酸氢钠水溶液调pH至7～8，再加入10mL水，二氯甲烷(10mL×3)萃取，合并有机相，用饱和氯化钠水溶液洗涤，无水硫酸钠干燥，抽滤，滤液浓缩。粗品用柱层析(V石油醚：V乙酸乙酯＝1:1)纯化得白色固体(I-E-1)210.0mg，收率82.7％。ESI-MS[M+H] +509.2； 1H NMR(300MHz,DMSO)δ12.43(s,1H),8.71(s,2H),7.87(s,1H),7.10(s,1H),6.64(s,1H),3.90-3.70(m,4H),3.55-3.41(m,6H),3.12-3.02(m,2H),1.60-1.40(m,4H)。
参照实施例6的制备方法，制备得到以下化合物：
Figure PCTCN2022141022-appb-000051
实施例7：化合物对PARP7酶的抑制活性
实验材料：PARP7Chemiluminescent Assay Kit，BPS Bioscience；DMSO，国药，Nivo,PerkinElmer。
实验方法：
(1)溶液与缓冲液的配置：
10X PBS配制：分别称取720mg KH 2PO 4,45g NaCl和5.311g Na 2HPO 4·12H 2O溶解在500mL去离子水中，将体系的pH调为7.4，在121℃下灭菌30分钟，冷却后放置于4℃备用。
1X PBS配制：将10X PBS用去离子水稀释10倍，即1份10X PBS加入9份去离子水稀释。
Wash buffer配制：1X PBS含有0.05％Tween-20。
1X PARP buffer配制：(现用现配)使用去离子水将10X PARP buffer进行10倍稀释，放置在冰上备用。
(2)化合物工作液浓度的配制：
根据检测要求，将待测化合物用100％DMSO稀释至所需浓度，然后用1X PARP buffer进行10倍稀释，配制成10X的化合物工作液。
(3)实验步骤：
a.实验前一天，冰上解冻5X histone mixture；
b.1X histone mixture配制，使用1X PBS将5X histone mixture配制成1X histone mixture；每孔取25μL 1X histone mixture到测试板中，在4℃下孵育过夜；
c.每孔取100μL Blocking buffer加入到测试板中，在25℃下孵育90分钟；
d.结束孵育后，甩干测试板中液体，重复洗板3次；
e.每孔取2.5μL的化合物工作液，按照实验排布图加入到测试板中；阳性对照孔中(Positive control)加入相应体积含有10％DMSO的1X PARP buffer，空白对照(Blank)中加入相应体积的1X PARP buffer；
f.酶完全溶解后，用1X PARP buffer将酶原液稀释到6ng/μL；
g.取10μL每孔酶溶液加入到测试孔板中，空白对照孔加入对应体积的1X PARP buffer，此时酶量为60ng每孔。注意：此步骤需要在冰上操作；
h.向测试板的各个孔中加入12.5μL master mixture(12.5μL master mixture包括1.25μL 10X PARP buffer,1.25μL Opti-PARP 10X Assay mixture和10μL水)；将测试板封膜置于25℃下孵育60分钟；
i.孵育结束后，甩干测试板中的液体，重复洗板3次；
j.将试剂盒中的Streptavidin-HRP用Blocking buffer溶液稀释50倍，每孔各25μL加入到测试板中，在25℃下孵育30分钟；
k.孵育结束后，甩干测试板中的液体，重复洗板3次；
l.按照1:1混合试剂盒中的ELISA ECL Substrate A和ELISA ECL Substrate B，向测试板中加入每孔50μL混合液，并且马上使用Nivo进行Luminescence检测，读取发光值(RLU)；
m.酶率计算：％Enzyme Activity＝(RLU(Sample)-RLU(Blank))/(RLU(Pos.Ctrl)-RLU(Blank))×100％；酶抑制率＝1-％Enzyme Activity，具体结果如下表1所示。
表1.受试化合物对PARP7的酶抑制活性数据
化合物编号 100nM抑制率 化合物编号 100nM抑制率
I-A-1 +++ I-A-16 +++
I-A-2 ++ I-A-17 +++
I-A-3 +++ I-A-18 ++
I-A-4 +++ I-A-19 ++
I-A-5 +++ I-A-20 +++
I-A-6 +++ I-A-21 ++
I-A-7 +++ I-A-22 ++
I-A-8 ++ I-A-23 ++
I-A-9 +++ I-A-24 ++
I-A-10 +++ I-B-1 +++
I-A-11 ++ I-C-1 +++
I-A-12 ++ I-D-1 +++
I-A-13 +++ I-E-1 +++
I-A-14 ++ I-E-2 +++
I-A-15 +++ I-E-7 +++
注：“+++”为IC 50＜0.1μM；“++”为IC 50≥0.1μM且＜0.5μM；“+”为IC 50≥0.5μM。
如表1所示，本发明所有测试化合物均表现出对PARP7具有良好的酶抑制活性，酶抑制IC 50值均达到纳摩尔浓度级别。其中，化合物I-A-1、I-A-3～I-A-7、I-A-9～I-A-10、I-A-13、I-A-15～I-A-17、I-A-20、I-B-1、I-C-1、I-D-1、I-E-1、I-E-2和I-E-7的酶抑制IC 50值均小于0.1μM。
实施例8：化合物对干扰素释放的促进作用
在STING激动剂DMXAA存在的条件下，对RAW264.7通过PARP7抑制剂诱导干扰素-β水平。将生长至对数生长期的RAW264.7细胞涂铺于96孔板中，37℃，5％CO 2培养箱中孵育过夜至贴壁。细胞用剂量滴定的PARP7抑制剂和50μg/mL DMXAA共处理24小时并收集上清液，通过ELISA(R&D,Mouse IFN--beta DuoSet Elisa)根据试剂盒说明书进行处理，结果参见图1。
由图1可见，本发明化合物能明显促进干扰素β释放，因而可以用于肿瘤的免疫治疗，并且释放量优于阳性药RBN-2397。
实施例9：化合物的大鼠体内药代动力学研究
实验过程：选取雄性SD大鼠12只，6只口服给药(RBN-2397和I-A-1各3只，10mg/kg)，6只静脉注射(RBN-2397和I-A-1各3只，1mg/kg)，分别采集0分钟、2分钟、5分钟、10分钟、20分钟、30分钟、60分钟、2小时、4小时、6小时、8小时血样，离心(3000转/5分钟)，采集上清液使用LC-MS-MS进行分析，结果使用WinNonlin软件进行分析，具体结果如下表2所示。
表2.受试化合物在SD大鼠体内的药代动力学数据
Figure PCTCN2022141022-appb-000052
IV：表示静脉注射，PO：表示灌胃给药
实验结果表明，本发明的化合物I-A-1在SD大鼠上具有良好的药代动力学性质。 相较于阳性药RBN-2397，本发明化合物具有更长的半衰期，更大的体内暴露量，更好的口服生物利用度。
实施例10：化合物的小鼠体内药代动力学研究
实验过程：选取雄性ICR小鼠12只，6只口服给药(RBN-2397和I-A-1各3只，10mg/kg)，6只静脉注射(RBN-2397和I-A-1各3只，1mg/kg),分别采集0分钟、2分钟、5分钟、10分钟、20分钟、30分钟、60分钟、2小时、4小时、6小时、8小时血样，离心(3000转/5分钟)，采集上清液使用LC-MS-MS进行分析，结果使用WinNonlin软件进行分析，具体结果如下表3所示。
表3.受试化合物在ICR小鼠体内的药代动力学数据
Figure PCTCN2022141022-appb-000053
IV：表示静脉注射，PO：表示灌胃给药
实验结果表明，本发明的化合物I-A-1在ICR小鼠上具有良好的药代动力学性质。相较于阳性药RBN-2397，本发明化合物具有更长的半衰期，更大的体内暴露量，口服生物利用度更是达到了95.80％。
实施例11：化合物的小鼠体内药效研究
对BALB/c小鼠在右侧腹皮下接种CT26细胞以发展肿瘤。在肿瘤接种后四天，选择肿瘤尺寸在55-75mm 3(平均肿瘤尺寸63mm 3)范围内的24只小鼠并且基于其肿瘤体积，随机划分为4组，每组6只小鼠。在随机分组后的第二天(将随机分组当天定义为第0天)开始给药，分别用媒介物(0.5％甲基纤维素+0.2％吐温80)、化合物RBN-2397(500mg/kg，每天1次，连续14天灌胃给药)、化合物I-A-1(100mg/kg，每天1次，连续14天灌胃给药)、化合物I-A-1(50mg/kg，每天2次，连续14天灌胃给药)进行给药，在给药期间每周测量肿瘤尺寸三次。整个研究在第14天终止，其药效结果参见图2。
由图2可见，本发明化合物I-A-1在小鼠体内有着明显的抗肿瘤活性，相较于阳性药RBN-2397，本发明化合物I-A-1在更低剂量就能发挥更好的抗肿瘤作用。

Claims (12)

  1. 一种哒嗪酮类化合物，其特征在于，具有式(I)的结构，所述哒嗪酮类化合物包含其异构体、药学上可接受的盐或它们的混合物：
    Figure PCTCN2022141022-appb-100001
    其中：
    m选自0、1、2或3；
    R 1选自氢、卤素、氰基、三氟甲基、C 1～C 6的烷基、C 1～C 6的烷氧基、甲硫基、甲磺酰基、氨甲酰基；
    R 2或R 3分别独立地选自氢、C 1～C 6烷基、取代的C 3～C 6环烷基或杂环烷基、氰基、三氟甲基，或者R 2和R 3与所连碳原子一起形成C 3～C 6环烷基；所述C 3～C 6环烷基的取代基选自氢、甲基、三氟甲基、2,2-二氟乙基、甲氧基、卤素、氰基、氨基、甲氨基、二甲氨基、二乙氨基、乙酰氨基、羟基、乙酰氧基、羧基或甲氧羰基，所述取代基为一个或多个；
    R 4选自取代的芳基、取代的杂芳基或取代的1,3-苯并二噁烷基，所述杂芳基或1,3-苯并二噁烷基的取代基选自氢、卤素、氰基、三氟甲基、2,2,-二氟乙基、C 1～C 6的烷基、C 3～C 6的环烷基、芳基、C 1～C 6的烷氧基、羟基、甲氧基、氨基、甲氨基、二甲氨基、乙酰氨基、羧基、甲磺酰基、甲氧羰基或硝基，所述取代基为一个或多个；
    A 1选自-NH-、-O-、-S-、
    Figure PCTCN2022141022-appb-100002
    A 2选自
    Figure PCTCN2022141022-appb-100003
    -NH-或-N(CH 3)-，其中，n 1和n 2各自独立地选自0、1或2；
    R 5选自氢、卤素、甲基、三氟甲基、氰基、羟基、甲氧基、氨基、甲氨基、二甲氨基、二乙氨基或乙酰氨基，R 5为一个或多个；
    A 3选自
    Figure PCTCN2022141022-appb-100004
    其中，X 1代表-O-、-NH-或
    Figure PCTCN2022141022-appb-100005
    A 4选自
    Figure PCTCN2022141022-appb-100006
    其中，X 2和X 3分别独立地选 自N或CH，R 6、R 7或R 8分别独立地选自氢、甲基、三氟甲基、氰基、羟基、甲氧基、氨基、甲氨基、二甲氨基、乙酰氨基、羧基或甲氧羰基。
  2. 根据权利要求1所述的哒嗪酮类化合物，其特征在于，所述结构中：
    m选自0、1或2；
    R 1选自卤素、氰基或三氟甲基；
    R 2或R 3分别独立地选自氢、甲基或三氟甲基；当R 2和R 3不同时，与R 2和R 3相连的碳原子为消旋构型、R构型或S构型；
    R 4选自
    Figure PCTCN2022141022-appb-100007
    其中，Y 1或Y 2分别独立地选自CH或N，R 9、R 10分别独立地选自三氟甲基、甲基、氟、氯、溴、氰基、甲氧基、甲磺酰基、2,2-二氟乙基或4-三氟甲基苯基，R 9或R 10为一个或多个；
    A 1选自-NH-；
    A 2选自
    Figure PCTCN2022141022-appb-100008
    -NH-或-N(CH 3)-；
    A 3选自
    Figure PCTCN2022141022-appb-100009
    A 4选自
    Figure PCTCN2022141022-appb-100010
  3. 根据权利要求1或2所述的哒嗪酮类化合物，其特征在于，所述结构中：
    m为0或2。
  4. 根据权利要求1或2所述的哒嗪酮类化合物，其特征在于，所述结构中：
    R 1为三氟甲基，R 2为氢，R 3为氢或甲基，其中，当R 3为甲基时，与R 3相连的碳原子为S构型。
  5. 根据权利要求1或2所述的哒嗪酮类化合物，其特征在于，所述结构中：
    A 2选自
    Figure PCTCN2022141022-appb-100011
    或-NH-；A 3为
    Figure PCTCN2022141022-appb-100012
    A 4为
    Figure PCTCN2022141022-appb-100013
  6. 根据权利要求1或2所述的哒嗪酮类化合物，其特征在于，所述结构中：
    R 4选自
    Figure PCTCN2022141022-appb-100014
    Figure PCTCN2022141022-appb-100015
  7. 根据权利要求1或2所述的哒嗪酮类化合物，其特征在于，所述哒嗪酮类化合物为以下任一化合物：
    (S)-4-(三氟甲基)-5-((1-(3-(4-(5-三氟甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-1)，
    (S)-4-(三氟甲基)-5-((1-(3-(4-(5-(4-三氟甲基)苯基)嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)-丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-2)，
    (S)-2-(4-(1-(2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙基)氮杂环丁烷-3-羰基)哌嗪-1-基)嘧啶-5-腈(I-A-3)，
    (S)-5-((1-(3-(4-(5-甲磺酰基)嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(I-A-4)，
    (S)-5-((1-(3-(4-(5-氯嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(I-A-5)，
    (S)-5-((1-(3-(4-(5-甲基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(I-A-6)，
    (S)-5-((1-(3-(4-(5-溴嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(I-A-7)，
    (S)-5-((1-(3-(4-(5-氟嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(I-A-8)，
    (S)-5-((1-(3-(4-(5-甲氧基嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(I-A-9)，
    (S)-4-(三氟甲基)-5-((1-(3-(4-(5-三氟甲基)吡啶-2-基)哌嗪-1-羰基)氮杂环丁烷 -1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-10)，
    (S)-4-(三氟甲基)-5-((1-(3-(4-(4-三氟甲基)苯基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-11)，
    (S)-5-((1-(3-(4-(二苯并[b,d]呋喃-4-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(I-A-12)，
    (S)-4-(三氟甲基)-5-((1-(3-(4-(4-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-13)，
    (S)-5-((1-(3-(4-(嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙基-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(I-A-14)，
    (S)-1-(2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙基)-N-(1-(5-(三氟甲基)嘧啶-2-基)氮杂环丁烷-3-基)氮杂环丁烷-3-甲酰胺(I-A-15)，
    (S)-N-甲基-1-(2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙基)-N-(1-(5-三氟甲基)嘧啶-2-基)氮杂环丁烷-3-基)氮杂环丁烷-3-甲酰胺(I-A-16)，
    5-(((2S)-1-(3-(2,6-二甲基-4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(I-A-17)，
    4-(三氟甲基)-5-(((S)-1-((S)-3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)吡咯烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-18)，
    (S)-4-(三氟甲基)-5-((1-(4-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)哌啶-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-19)，
    4-(三氟甲基)-5-((2-(3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)乙基)氨基)哒嗪-3(2H)-酮(I-A-20)，
    (S)-4-(三氟甲基)-5-((4-(3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丁-2-基)氨基)哒嗪-3(2H)-酮(I-A-21)，
    (S)-4-氯-5-((1-(3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-22)，
    (S)-4-溴-5-((1-(3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-A-23)，
    4-(三氟甲基)-5-((1-((3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)氮杂环丁烷-1-基)甲基)环丙基)氨基)哒嗪-3(2H)-酮(I-A-24)，
    (S)-5-((1-(3-(4-(2,2-二氟苯并[d][1,3]二氧杂-5-基)哌嗪-1-羰基)氮杂环丁烷-1-基)丙-2-基)氨基)-4-(三氟甲基)哒嗪-3(2H)-酮(I-B-1)，
    (S)-4-(三氟甲基)-5-((1-(3-(4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-羰基)-1H-吡咯 -1-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-C-1)，
    4-(三氟甲基)-5-((1-(1-(1-(5-(三氟甲基)嘧啶-2-基)哌啶-4-羰基)氮杂环丁-3-基)丙-2-基)氨基)哒嗪-3(2H)-酮(I-D-1)，
    N-(4-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丁基)-4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-甲酰胺(I-E-1)，
    (E)-N-(4-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丁-2-烯-1-基)-4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-甲酰胺(I-E-2)，
    N-(3-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙基)-4-(2-(三氟甲基)嘧啶-5-基)哌嗪-1-甲酰胺(I-E-3)，
    N-(2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)乙基)-4-(2-(三氟甲基)嘧啶-5-基)哌嗪-1-甲酰胺(I-E-4)，
    N-(3-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)丙基)-4-(嘧啶-5-基)哌嗪-1-甲酰胺(I-E-5)，
    N-(2-((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)乙基)-4-(嘧啶-5-基)哌嗪-1-甲酰胺(I-E-6)，
    N-(3-(((6-氧代-5-(三氟甲基)-1,6-二氢哒嗪-4-基)氨基)甲基)苯基)-4-(5-(三氟甲基)嘧啶-2-基)哌嗪-1-甲酰胺(I-E-7)。
  8. 根据权利要求1或2所述的哒嗪酮类化合物，其特征在于，所述药学上可接受的盐为所述哒嗪酮类化合物与酸形成的盐，所述酸为盐酸、氢溴酸、硫酸、磷酸、碳酸、甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、柠檬酸、酒石酸、乳酸、丙酮酸、乙酸、马来酸、琥珀酸、富马酸、水杨酸、苯基乙酸、杏仁酸或阿魏酸。
  9. 一种权利要求1～8任一所述的哒嗪酮类化合物的制备方法，其特征在于，所述制备方法为以下任一方法：
    (1)当R 1选自三氟甲基、氰基或卤素，R 2为氢，R 3选自甲基或氢，与R 3相连的碳原子为S构型，或R 2和R 3形成环丙基，R 4为
    Figure PCTCN2022141022-appb-100016
    A 1代表-NH-，A 2为
    Figure PCTCN2022141022-appb-100017
    n 1或n 2各自独立地代表0或1，A 3为
    Figure PCTCN2022141022-appb-100018
    A 4为
    Figure PCTCN2022141022-appb-100019
    目标化合物I-A的制备方法如下：
    Figure PCTCN2022141022-appb-100020
    (2)当R 1选自三氟甲基、氰基或卤素，R 2为氢，R 3选自甲基或氢，与R 3相连的碳原子为S构型，或R 2和R 3形成环丙基，R 4为
    Figure PCTCN2022141022-appb-100021
    A 1为-NH-，A 2为
    Figure PCTCN2022141022-appb-100022
    n 1或n 2各自独立地选自0或1，A 3为
    Figure PCTCN2022141022-appb-100023
    A 4为
    Figure PCTCN2022141022-appb-100024
    目标化合物I-B的制备方法如下：
    Figure PCTCN2022141022-appb-100025
    (3)当R 1代表三氟甲基、氰基或卤素，R 2为氢，R 3选自甲基或氢，与R 3相连的碳原子为S构型，或R 2和R 3形成环丙基，R 4为
    Figure PCTCN2022141022-appb-100026
    A 1为-NH-，A 2为
    Figure PCTCN2022141022-appb-100027
    A 3为
    Figure PCTCN2022141022-appb-100028
    A 4为
    Figure PCTCN2022141022-appb-100029
    目标化合物I-C的制备方法如下：
    Figure PCTCN2022141022-appb-100030
    (4)当m＝0，R 1选自三氟甲基、氰基或卤素，R 2为氢，R 3为甲基，R 4为
    Figure PCTCN2022141022-appb-100031
    A 1为-NH-，A 2为
    Figure PCTCN2022141022-appb-100032
    n 1或n 2各自独立地选自0或1，A 3为
    Figure PCTCN2022141022-appb-100033
    A 4为
    Figure PCTCN2022141022-appb-100034
    目标化合物I-D的制备方法如下：
    Figure PCTCN2022141022-appb-100035
    Figure PCTCN2022141022-appb-100036
    (5)当R 1选自三氟甲基、氰基或卤素，R 2和R 3为氢，R 4为
    Figure PCTCN2022141022-appb-100037
    A 1代表-NH-，A 2为-NH-或-N(CH 3)-，A 3为
    Figure PCTCN2022141022-appb-100038
    A 4为
    Figure PCTCN2022141022-appb-100039
    目标化合物I-E的制备方法如下：
    Figure PCTCN2022141022-appb-100040
    其中，m、Y 1、Y 2、R 7、R 8、R 9、R 10的定义如权利要求1～7任一所述；Boc为叔丁氧羰基；P为(三甲基硅)乙氧基甲基或对甲氧基苄基；
    将相应的酸与以上方法制备的化合物(I)成盐，即得所述哒嗪酮类化合物的药学上可接受的盐。
  10. 一种药物组合物，其特征在于，所述药物组合物包含权利要求1～8任一所述哒嗪酮类化合物以及药学上可接受的载体。
  11. 一种权利要求1～8任一所述的哒嗪酮类化合物或权利要求10所述的药物组合物在制备PARP7抑制剂药物中的应用。
  12. 根据权利要求11所述的应用，其特征在于，所述药物为抗肿瘤药物。
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WO2019055966A2 (en) * 2017-09-18 2019-03-21 Goldfinch Bio, Inc. PYRIDAZINONES AND METHODS OF USE
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