WO2017028798A1 - 哒嗪酮类化合物、其制备方法、药物组合物及用途 - Google Patents

哒嗪酮类化合物、其制备方法、药物组合物及用途 Download PDF

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WO2017028798A1
WO2017028798A1 PCT/CN2016/095869 CN2016095869W WO2017028798A1 WO 2017028798 A1 WO2017028798 A1 WO 2017028798A1 CN 2016095869 W CN2016095869 W CN 2016095869W WO 2017028798 A1 WO2017028798 A1 WO 2017028798A1
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ring
group
substituents
straight
methyl
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PCT/CN2016/095869
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French (fr)
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胡有洪
左建平
陆栋
唐炜
邢唯强
杨莉
王浪
王亚娟
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中国科学院上海药物研究所
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Priority to CN201680040315.6A priority Critical patent/CN107848986A/zh
Publication of WO2017028798A1 publication Critical patent/WO2017028798A1/zh

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    • 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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/14—Oxygen atoms
    • 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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the invention belongs to the field of medicinal chemistry.
  • the present invention relates to a pyridazinone compound or a pharmaceutically acceptable salt thereof, a process for the preparation thereof, a pharmaceutical composition and use thereof.
  • Such compounds or pharmaceutical compositions thereof can be used in the preparation of hepatitis B virus inhibitors for the prevention and/or treatment of hepatitis B.
  • HBV hepatitis B virus
  • interferon and nucleoside anti-HBV drugs are the two main means of treating hepatitis B virus infection.
  • interferon has the disadvantages of poor tolerance, many adverse reactions, and high cost; and the six nucleoside drugs currently available (lamivudine, adefovir, entecaine, telbivudine, Both tenofovir and clafidine act on the reverse transcriptase of hepatitis B virus, which produces varying degrees of drug resistance and side effects during long-term treatment, greatly limiting the use of such drugs.
  • An object of the present invention is to provide a pyridazinone compound or a pharmaceutically acceptable salt thereof.
  • Another object of the invention is to provide a process for the preparation of the compounds of the invention.
  • Still another object of the present invention is to provide a pyridazinone compound of the present invention or a pharmaceutically acceptable salt thereof as a hepatitis B virus inhibitor and use for the preparation of a medicament for preventing and treating hepatitis B.
  • the present invention provides a pyridazinone compound of the formula I or a pharmaceutically acceptable salt thereof:
  • R 1 and R 2 are each independently H, a C1-C7 linear or branched alkyl group, a C3-C6 cycloalkyl group or a 6-10 membered aryl group, or R 1 and R 2 together with a carbon atom to be bonded a 5-7 membered heteroaryl ring or a non-aromatic heterocyclic ring selected from the group consisting of hetero atoms in N, O and S,
  • R 1 and R 2 are each independently H, C1-C4 linear or branched alkyl, C3-C6 cycloalkyl or phenyl, or R 1 and R 2 together with the attached carbon atom form 1 - 2 5-7 membered heteroaryl rings or non-aromatic heterocyclic rings selected from heteroatoms in N, O and S,
  • R 1 and R 2 are each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl, or R 1 and R 2 together with the attached carbon atom form a pyrrole ring, a thiophene ring. a furan ring, a pyrazine ring, a tetrahydropyrrole ring, a tetrahydrothiophene ring or a tetrahydrofuran ring;
  • A is a 6-10 membered aromatic ring or a 5-10 membered heteroaryl ring containing 1-3 hetero atoms selected from N, O and S,
  • A is a benzene ring or a 5-10 membered heteroaryl ring containing 1-2 heteroatoms selected from N, O and S,
  • A is a benzene ring, a pyridine ring, a pyrrole ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a thiophene ring, a furan ring, a pyrazole ring, an imidazole ring, an oxazole ring, a thiazole ring, an anthracene ring, Azaindole ring, naphthyridine ring, benzimidazole ring, imidazopyridine ring or imidazopyridine ring or quinoline ring;
  • A is a benzene ring, a pyridine ring, a pyrimidine ring, a pyrazine ring, a pyrazole ring, a pyridazine ring, an anthracene ring, an azaindole ring, a naphthyridine ring, an imidazo[1,2-a] a pyridine ring or an imidazo[1,2-a]pyrimidine ring or a quinoline ring;
  • R 3 represents one or more substituents, preferably 1 , 2 or 3 substituents, each independently selected from H, halogen, cyano, nitro, C1-C7 straight or branched alkyl a C1-C6 straight or branched alkoxy group, an amino group (preferably dimethylamino) substituted by two C1-C7 linear or branched alkyl groups, preferably a C1-C4 alkyl group, more preferably a C1-C2 alkyl group.
  • a 3-8 preferably 3-5)-membered saturated heterocyclic group (more preferably oxetanyl, azetidinyl) having 1-3 hetero atoms selected from N, O and S,
  • n is an integer selected from 0 to 10, preferably, n is an integer selected from 0 to 7, more preferably, n is 0, 1, 2, 3 or 4;
  • R 4 is H, halogen, C1-C7 straight or branched alkyl, C3-C6 cycloalkyl, 6-10 membered aryl, containing 1-3 heteroatoms selected from N, O and S a 10-membered heteroaryl group, a 3-8 membered saturated heterocyclic group having 1 to 3 hetero atoms selected from N, O and S, an amino group which is unsubstituted or substituted with 1-2 substituents;
  • the substituent in the "amino group substituted by 1-2 substituents" is a C1-C7 straight or branched alkyl group, preferably a methyl group, an ethyl group, a propyl group or a butyl group;
  • R 4 is H, halogen, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, cyclopropyl, oxetanyl, azetidin
  • the alkyl group is either an amino group substituted with 1-2 substituents selected from methyl, ethyl, propyl or butyl.
  • the pyridazinone compound of formula I is selected from compounds having the structure shown by one of the following formulae I-I to I-VIII:
  • R 1 , R 2 and R 3 are the same as defined in the formula I.
  • R 1 and R 2 are each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl, or R 1 and R 2 are taken together with the attached carbon atom.
  • R 3 represents 1, 2 or 3 substituents each independently selected from H, halogen.
  • R 4 is H, halogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or 1-2 selected from An amino group substituted with a substituent in a methyl group, an ethyl group, a propyl group or a butyl group.
  • R 1 and R 2 are each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl; and R 3 represents 1 or 2 substituents.
  • the substituents are each independently selected from the group consisting of H, halogen, cyano, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxy, and are straight-chained by two C1-C7 or A branched alkyl group, preferably a C1-C4 alkyl group, more preferably a C1-C2 alkyl-substituted amino group (preferably dimethylamino group) having 3 to 3 heteroatoms selected from N, O and S ( Preferred is a 3-5)membered saturated heterocyclic group (more preferably oxetanyl, azetidinyl), Wherein n is 0, 1, 2, 3 or 4; R 4 is H,
  • R 1 and R 2 are each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl; and R 3 represents 1 or 2 substituents.
  • the substituents are each independently selected from the group consisting of H, halogen, cyano, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxy, Wherein n is 0, 1, 2, 3 or 4; and R 4 is H, halogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl.
  • R 1 and R 2 are each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl; and R 3 represents 1 or 2 substituents.
  • the substituents are each independently selected from the group consisting of H, halogen, cyano, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxy or Wherein n is 0, 1, 2, 3 or 4; and R 4 is H, halogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl.
  • R 1 and R 2 are each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl; and R 3 represents 1 or 2 substituents, said substitution
  • the groups are each independently selected from the group consisting of H, halogen, cyano, nitro, C1-C6 straight or branched alkyl, C1-C6 straight or branched alkoxy, Wherein n is 0, 1, 2, 3 or 4; and R 4 is H, halogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl.
  • R 1 and R 2 are each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl; and R 3 represents 1 or 2 substituents.
  • the substituents are each independently selected from the group consisting of H, halogen, cyano, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxy, Wherein n is 0, 1, 2, 3 or 4; and R 4 is H, halogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl.
  • R 1 and R 2 are each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl; and R 3 represents 1 or 2 substituents.
  • the substituents are each independently selected from the group consisting of H, halogen, cyano, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxy or Wherein n is 0, 1, 2, 3 or 4; and R 4 is H, halogen, methyl, ethyl, propyl, isopropyl, butyl or isobutyl.
  • R 1 and R 2 are each independently H, methyl, n-propyl, cyclopropyl, cyclohexyl or phenyl; and R 3 represents 1 or 2 substituents.
  • the substituents are each independently selected from the group consisting of H, halogen, cyano, nitro, C1-C7 straight or branched alkyl or C1-C6 straight or branched alkoxy.
  • the halogen atom means F, Cl, Br or I.
  • the C1-C7 straight or branched alkyl group means a straight or branched alkyl group having 1 to 7 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, a n-propyl group, an isopropyl group, n-Butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2-methylbutyl, 3-methylbutyl, isopentyl, 1-ethylpropane Base, neopentyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethyl Butyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl,
  • the C1-C6 linear or branched alkoxy group refers to a linear or branched alkoxy group having 1 to 6 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, and a n-propoxy group. , isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3 -methylpentyloxy and the like.
  • the C3-C6 cycloalkyl group means an aliphatic carbocyclic group having 3 to 6 carbon atoms in the ring, and specific examples thereof include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and the like.
  • the 6-10 membered aryl group means an aromatic carbocyclic group having 6 to 10 carbon atoms in the ring, and specific examples thereof include a phenyl group, a naphthyl group and the like.
  • the 5-10 membered heteroaryl ring containing 1-3 hetero atoms selected from N, O and S means having 5 to 10 atoms in the ring and 1-3 selected from N, O,
  • An aromatic ring of a hetero atom in S which may be monocyclic or bicyclic, such as a pyridine ring, a pyrrole ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a thiophene ring, a furan ring, a pyrazole ring, an imidazole ring, or an evil
  • the 5-7 membered heteroaryl ring containing 1-3 hetero atoms selected from N, O and S means having 5 to 7 atoms on the ring and 1-3 selected from N, O,
  • the aromatic ring of the hetero atom in S for example, a pyridine ring, a pyrrole ring, a pyrimidine ring, a pyrazine ring, a pyridazine ring, a thiophene ring, a furan ring, a pyrazole ring, an imidazole ring, an oxazole ring, a thiazole ring or the like.
  • the term "5-7 membered heteroaryl ring containing 1-2 heteroatoms selected from N, O and S" has a similar meaning.
  • the 5-7 membered non-aromatic heterocyclic ring comprising 1-3 heteroatoms selected from the group consisting of N, O and S refers to having 5 to 7 atoms in the ring and 1-3 selected from N,
  • a non-aromatic cyclic group of a hetero atom in O or S for example, a tetrahydropyrrole ring, a tetrahydrothiophene ring or a tetrahydrofuran ring.
  • the term "5-7 membered non-aromatic heterocyclic ring containing 1-2 heteroatoms selected from N, O and S" has a similar meaning.
  • a particularly preferred specific compound is one of the following compounds:
  • the pharmaceutically acceptable salt may, for example, be an alkali metal salt (for example, a sodium salt, a potassium salt, a lithium salt, a barium salt or the like); an alkaline earth metal salt (for example, a calcium salt, a magnesium salt, a barium salt, etc.); a salt with an organic base, for example, with a tri(lower)alkylamine (eg, trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, imidazole, methyl Pyridine, dimethylaminopyridine, dimethylaniline, N-(lower)alkylmorpholine (eg N-methylmorpholine, etc.), 1,5-diazabicyclo[4.3.0]nonene-5 ( a salt formed by DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2
  • the pharmaceutically acceptable salt of the pyridazinone compound of the formula I provided by the present invention can be reacted by dissolving the pyridazinone compound represented by the formula I in an alcohol solution saturated with the corresponding acid.
  • the pyridazinone compound provided by the present invention is dissolved in a HCl saturated methanol solution, stirred at room temperature for 30 minutes, and the solvent is evaporated to dryness to give the corresponding hydrochloride salt.
  • the pyridazinone compound of the present invention or a pharmaceutically acceptable salt thereof can be further used in the form of an isomer, a prodrug or a solvate thereof without affecting the application effect thereof, and those skilled in the art should understand
  • the above forms of the pyridazinone compounds of the present invention are also within the scope of the present invention.
  • the isomers include geometric isomers, stereoisomers and the like.
  • the prodrug refers to a compound obtained by chemically modifying a drug, which is inactive or less active in vitro, and exhibits pharmacological effects by enzymatic or non-enzymatic conversion in the body to release an active drug.
  • the form of the prodrug in the present invention is not particularly limited as long as it releases an active original drug by enzymatic or chemical action in the body to exert a desired pharmacological action, and may be a carrier prodrug or a biological precursor.
  • the solvate may be, for example, a hydrate, an ethanolate or the like, and a preferred solvate is a hydrate.
  • R 1 , R 2 , R 3 have the same definitions as in Formula I,
  • Route 1 a compound represented by Formula 1, which is condensed with pyruvic acid, hydrated to a guanidine ring to obtain a compound of Formula 2, and then subjected to nucleophilic substitution reaction with p-chlorobenzyl chloride to obtain a pyridazinone of Formula 4
  • Formula 1 a compound represented by Formula 1, which is condensed with pyruvic acid, hydrated to a guanidine ring to obtain a compound of Formula 2, and then subjected to nucleophilic substitution reaction with p-chlorobenzyl chloride to obtain a pyridazinone of Formula 4
  • the nucleophilic substitution reaction described in Scheme 1, Route 2, and Route 3 can be carried out, for example, in the presence of a base such as potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, potassium t-butoxide, sodium t-butoxide, sodium hydroxide or the like. It is carried out in a solvent such as acetonitrile, N,N-dimethylformamide or tetrahydrofuran;
  • a base such as potassium carbonate, cesium carbonate, sodium hydride, potassium hydride, potassium t-butoxide, sodium t-butoxide, sodium hydroxide or the like. It is carried out in a solvent such as acetonitrile, N,N-dimethylformamide or tetrahydrofuran;
  • the hydrolysis reaction conditions described in Scheme 2 are carried out in a solvent under acidic or basic conditions;
  • the acid is preferably one or more of acetic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid;
  • the base is preferably hydrogen
  • the solvent is preferably one or more of ethanol, methanol, water, acetic acid.
  • the coupling reaction conditions described in Scheme 2 are routine choices for those skilled in the art. In general, it is selected to be a solvent such as DMF (N,N-dimethylformamide), toluene or 1,4-dioxane in the presence of a metal catalyst, a base and a ligand under heating.
  • the heating conditions are well known to those skilled in the art, for example by heating under reflux or by microwave heating.
  • the base is well known to those skilled in the art, such as cesium carbonate, potassium carbonate, potassium t-butoxide, sodium t-butoxide, and the like.
  • the metal catalysts are well known to those skilled in the art, such as palladium acetate, Pd(PPh 3 ) 4 , Pd(dppf) 2 Cl 2 and the like.
  • the ligands are well known to those skilled in the art, such as triphenylphosphine, DPPP (1,1'-bis(diphenylphosphino)ferrocene), BINAP (binaphthalene diphenylphosphine), Sphos ( 2-Dicyclohexylphosphine-2',6'-dimethoxy-biphenyl), Davephos (2-dicyclohexylphosphino-2'-(N,N-dimethylamine)-biphenyl), and the like.
  • the format reagent R 1 MgBr described in Scheme 3 is well known to those skilled in the art, such as alkyl magnesium bromide, cycloalkyl magnesium bromide, aryl magnesium bromide, such as methyl magnesium bromide, ethyl bromide.
  • alkyl magnesium bromide such as alkyl magnesium bromide, cycloalkyl magnesium bromide, aryl magnesium bromide, such as methyl magnesium bromide, ethyl bromide.
  • the Michael addition reaction conditions described in Scheme 3 are carried out under solvent; the solvent is preferably tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, toluene, benzene.
  • a pyridazinone compound of the formula I or a pharmaceutically acceptable salt thereof for the preparation of a hepatitis B virus inhibitor, and for preparation for prevention and / or use in drugs for the treatment of hepatitis B disease.
  • the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of one or more of a pyridazinone compound of the formula I or a pharmaceutically acceptable salt thereof .
  • the pharmaceutical composition may be used as a hepatitis B virus inhibitor for the prevention and/or treatment of hepatitis B. Further, the pharmaceutical composition may optionally comprise a pharmaceutically acceptable carrier or excipient.
  • the above pharmaceutically acceptable carrier means a conventional pharmaceutical carrier in the pharmaceutical field, such as a diluent such as water; a filler such as starch, sucrose, etc.; a binder such as a cellulose derivative, an alginate, gelatin, or a poly a vinylpyrrolidone; a wetting agent such as glycerin; a disintegrating agent such as agar, calcium carbonate and sodium hydrogencarbonate; an absorption enhancer such as a quaternary ammonium compound; a surfactant such as cetyl alcohol; and an adsorption carrier such as kaolin and soap clay.
  • Lubricants such as talc, calcium stearate and magnesium stearate, and polyethylene glycol.
  • other adjuvants such as a flavoring agent and a sweetener may be added to the above pharmaceutical composition.
  • the present invention provides a method for preventing and/or treating hepatitis B diseases, which comprises administering a therapeutically effective amount of a pyridazinone compound of the formula I or a pharmaceutically acceptable compound thereof One or more of the accepted salts or the above pharmaceutical compositions of the invention are administered to a patient.
  • the compounds or compositions provided herein can be administered to a patient in need of such treatment by oral, rectal or parenteral administration.
  • a patient in need of such treatment by oral, rectal or parenteral administration.
  • it can be prepared into a conventional solid preparation such as a tablet, a powder, a granule, a capsule, etc., or as a liquid preparation, such as a water or oil suspension, or other liquid preparation, such as a syrup;
  • parenteral administration it may be prepared as a solution for injection, water or an oily suspension, or the like.
  • the inventors By detecting the toxicity of the compound of the present invention to HepG2.2.15 cells and the activity of inhibiting HBV DNA, the inventors have found that among the compounds represented by the above formula I, the HBV DNA inhibitory activity of a plurality of compounds is 3 ⁇ M or less, and the best compound is inhibited. The activity is less than 0.4 ⁇ M.
  • the compound of formula I is a potent hepatitis B virus inhibitor.
  • the nuclear magnetic resonance spectrum was recorded using a Bruker AMX-400 type, a Gemini-300 type or an AMX-600 type nuclear magnetic resonance apparatus, and the unit of the chemical shift ⁇ was ppm.
  • the specific optical rotation was measured by a Perkin-Elmer Model 241 automatic polarimeter, and the microwave used was a CEM-discovery microwave reactor. All reaction solvents were purified according to a conventional method unless otherwise specified. Column chromatography with silica gel (200-300 mesh) is produced by Qingdao Ocean Chemical Branch. Thin layer chromatography was performed using the GF254 high efficiency plate for the Yantai Institute of Chemical Industry.
  • Preparative thin-layer chromatography plates were prepared by Shanghai Institute of Materia Medica, Chinese Academy of Sciences.
  • the stationary phase was prepared using GF254 (HG/T2354-92) silica gel and sodium carboxymethylcellulose (800-1200), respectively, Qingdao Marine Chemical Co., Ltd. and China National Pharmaceutical (Group) Shanghai Chemical Reagent Company produces.
  • all solvents are analytically pure reagents, and the reagents used are all purchased from Sinopharm Chemical Reagent Co., Ltd. Color development was carried out by iodine or ultraviolet fluorescence.
  • the organic solvent was distilled off under reduced pressure in a rotary evaporator.
  • step 1
  • step 1
  • step 1
  • step 1
  • step 1
  • step 1
  • Test Example 1 Effect of the compound prepared in the examples of the present invention on the DNA replication ability of hepatitis B virus
  • HepG2.2.15 cell line stably transfected with full-length HBV (provided by Institute of Materia Medica, Chinese Academy of Sciences)
  • Incubator (ThermoForma 3111); microplate reader (Molecular Devices Spectra Max 190); electronic balance; microscope; biosafety cabinet (Heal Force safe 15); centrifuge (Eppendorf Centrifuge 5810R); Real-Time PCR (FASTA GEN-DNA fast2000)
  • Lamivudine (3TC) composed of the medicinal chemistry of the Shanghai Institute of Materia Medica, Chinese Academy of Sciences, was configured into a 40 mM stock solution for use with DMEM/High Glucose medium (Dulbecco's modified Eagle's medium, Hyclone).
  • DMEM/High Glucose medium Dulbecco's modified Eagle's medium 1 ⁇ (Hyclone) phosphate buffer (PBS, pH 7.3, 1 L): NaCl, 8.0 g; Na 2 HPO 4 , 1.16 g; KH 2 PO 4 , 0.2 g; KCl: 0.2 g;
  • MTT solution MTT (Sigma), formulated with PBS 5mg / ml;
  • HepG2.2.15 cells were cultured and passaged in a conventional manner.
  • the medium used was DMEM containing 10% (v/v) bovine serum and the selected antibiotic G418, and cultured in an incubator at 37 ° C, 5% CO 2 for 8 days (diversion on the 4th day).
  • Hyclone TM Fetal Bovine Serum free DMEM was formulated to specify a maximum concentration and dilution; positive drug lamivudine, likewise containing 10% Hyclone TM Fetal Bovine Serum's DMEM medium was formulated to the specified concentration.
  • HepG2.2.15 cells were seeded in 96-well plates at 5 ⁇ 10 3 cells/well, cultured under the action of the above method for eight days, 200 ⁇ l of the supernatant was removed, MTT solution was added, and the lysate was added after 4 hours of culture. After 12 hours of culture, the enzyme was used. The OD 570 was measured by a standard instrument, and the absorbance of the control well was compared, the percentage of viable cells was calculated, and the concentration CC 50 required for half of the cytotoxicity was calculated.
  • HepG2.2.15 cells were treated with different concentrations of compounds for 8 days (diversion on day 4), and the culture supernatant was aspirated, and the HBV DNA contained in the mature virions in the supernatant was quantitatively detected by real-time PCR.
  • step 4) Add all the liquid from step 3) to the DNeasy Mini spin column (Qiagen, placed in a 2 ml waste collection tube). Blood&Tissue Kit), centrifuge at 6000rcf*1min, discard the supernatant;
  • the second step 55 ° C, 1 min
  • Second step 55 ° C, 45 s
  • Table 1 Toxicity of HepG2.2.15 cells and inhibition of HBV DNA activity by some of the compounds of the examples of the present invention
  • I-55 >100 13.6 I-56 67.7 7.8 I-57 >100 15.8 I-58 50.6 16.8 I-59 46.9 11.3 I-60 77.9 3.2 I-61 33.5 1.6 I-62 >100 6.9 I-63 >100 4.7 I-64 >100 22.4 I-65 >100 20.1 I-66 44.9 4.4 I-67 34.4 1.6 I-68 >100 0.5 I-69 >100 2.9 I-70 >100 0.05 I-71 >100 10.8 I-72 38.8 4.6 I-73 >100 5.1 I-74 >100 1.3 I-75 37.3 4.9 I-76 33.3 30 I-77 >100 1.1 I-78 8.1 1.6 I-79 34.4 0.2
  • CC 50 is the effect of sample drug on the growth of HepG2.2.15 cells, half (50%) lethal concentration.
  • the IC 50 is the concentration at which half of the inhibition of hepatitis B virus DNA replication by the sample drug (50%).

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Abstract

一种如下通式I所示的哒嗪酮类化合物或其药学上可接受的盐、其制备方法、药物组合物及其在制备乙型肝炎病毒抑制剂和预防和/或治疗乙型肝炎的药物中的用途。

Description

哒嗪酮类化合物、其制备方法、药物组合物及用途
交叉引用
本申请要求于2015年8月19日向中国国家知识产权局提交的发明专利申请CN201510512718.3的优先权和权益，该申请的全部内容通过引入并入本文，如同记载在本文中一样。
技术领域
本发明属于药物化学领域。具体而言，本发明涉及一种哒嗪酮类化合物或其药学上可接受的盐、其制备方法、药物组合物及用途。该类化合物或其药物组合物可用于制备乙型肝炎病毒抑制剂，来预防和/或治疗乙型肝炎。
背景技术
据世界卫生组织的统计，目前全世界已经有20亿人感染过乙型肝炎病毒(HBV)，并且大约有3.5-4.0亿人属于慢性感染。每年大约有100万人因感染乙肝病毒而死于肝硬化、肝功能代谢不全、肝癌等并发症。因此，乙型肝炎病毒感染仍是一种严重危害公众健康的世界性疾病。
目前，干扰素和核苷类抗乙肝病毒药是治疗乙型肝炎病毒感染的两种主要手段。但是干扰素存在耐受性差、不良反应多、费用昂贵等缺点；而目前已上市的6种核苷类药物(拉米夫定、阿德福韦酯、恩替卡恩、替比夫定、替诺福韦和克拉夫定)均作用于乙型肝炎病毒的逆转录酶，在长期治疗中会产生不同程度的耐药性和副作用，大大限制了这类药物的应用。
因此，研究和开发更多作用于新靶点、新机制及全新结构母核的非核苷类小分子抗乙型肝炎病毒药物日益迫切，是目前药物化学领域研究的热点，且具有十分重要的理论、经济和社会意义。
发明内容
本发明的一个目的是提供一种哒嗪酮类化合物或其药学上可接受的盐。
本发明的另一个目的是提供本发明化合物的制备方法。
本发明的又一个目的是提供本发明的哒嗪酮类化合物或其药学上可接受的盐作为乙型肝炎病毒抑制剂以及在制备预防和治疗乙型肝炎的药物中的用途。
本发明的再一个目的是提供一种预防和/或治疗乙型肝炎的方法。
根据本发明的一个方面，本发明提供了一种如下通式I所示的哒嗪酮类化合物或其药学上可接受的盐：
Figure PCTCN2016095869-appb-000001
其中，
R1、R2各自独立地为H、C1-C7直链或支链烷基、C3-C6环烷基或6-10元芳基，或者R1和R2与相连的碳原子一起形成含有1-3个选自N、O和S中的杂原子的5-7元杂芳环或者非芳香性杂环，
优选地，R1、R2各自独立地为H、C1-C4直链或支链烷基、C3-C6环烷基或苯基，或者R1和R2与相连的碳原子一起形成含有1-2个选自N、O和S中杂原子的5-7元杂芳环或者非芳香性杂环，
更优选地，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基，或者R1和R2与相连的碳原子一起形成吡咯环、噻吩环、呋喃环、吡嗪环、四氢吡咯环、四氢噻吩环或四氢呋喃环；
A为6-10元芳环或含有1-3个选自N、O和S中的杂原子的5-10元杂芳环，
优选地，A为苯环或含有1-2个选自N、O和S中的杂原子的5-10元杂芳环，
更优选地，A为苯环、吡啶环、吡咯环、嘧啶环、吡嗪环、哒嗪环、噻吩环、呋喃环、吡唑环、咪唑环、噁唑环、噻唑环、吲哚环、氮杂吲哚环、萘啶环、苯并咪唑环、咪唑并吡啶环或咪唑并嘧啶环或喹啉环；
更优选地，A为苯环、吡啶环、嘧啶环、吡嗪环、吡唑环、哒嗪环、吲哚环、氮杂吲哚环、萘啶环、咪唑并[1,2-a]吡啶环或咪唑并[1,2-a]嘧啶环或喹啉环；
R3表示一个或多个取代基，优选表示1、2或3个取代基，所述取代基各自独立地选自H，卤素，氰基，硝基，C1-C7直链或支链烷基，C1-C6直链或支链烷氧基，被两个C1-C7直链或支链烷基，优选C1-C4烷基，更优选C1-C2烷基取代的氨基(优选二甲氨基)，含有1-3个选自N、O和S中的杂原子的3-8(优选3-5)元饱和杂环基(更优选氧杂环丁烷基、氮杂环丁烷基)，
Figure PCTCN2016095869-appb-000002
Figure PCTCN2016095869-appb-000003
其中，n为选自0至10的整数，优选地，n为选自0至7的整数，更优选地，n为0、1、2、3或4；
R4为H，卤素，C1-C7直链或支链烷基，C3-C6环烷基，6-10元芳基，含有1-3个选自N、O和S中的杂原子的5-10元杂芳基，含有1-3个选自N、O和S中的杂原子的3-8元饱和杂环基，未取代或被1-2个取代基取代的氨基；其中，所述“被1-2个取代基取代的氨基”中的取代基为C1-C7直链或支链烷基，优选为甲基、乙基、丙基或丁基；
优选地，R4为H、卤素、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、氧杂环丁烷基、氮杂环丁烷基或者为被1-2个选自甲基、乙基、丙基或丁基中的取代基取代的氨基。
优选地，通式I所示的哒嗪酮类化合物选自具有如下通式I-I至I-VIII之一所示的结构的化合物：
Figure PCTCN2016095869-appb-000004
其中，R1、R2、R3的定义与通式I中的定义相同。
优选地，在通式I-I中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基，或者R1和R2与相连的碳原子一起形成吡咯环、噻吩环、呋喃环、吡嗪环、四氢吡咯环、四氢噻吩环或四氢呋喃环；R3表示1、2或3个取代基，所述取代基各自独立地选自H、卤素、氰基、硝基、C1-C7直链或支链烷基、C1-C6直链或支链烷氧基、
Figure PCTCN2016095869-appb-000005
其中，n为0、1、2、3或4；R4为H、卤素、甲基、乙基、丙基、异丙基、丁基、异丁基、或者为被1-2个选自甲基、乙基、丙基或丁基中的取代基取代的氨基。
优选地，在通式I-II中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基 或苯基；R3表示1或2个取代基，所述取代基各自独立地选自H，卤素，氰基，硝基，C1-C7直链或支链烷基，C1-C6直链或支链烷氧基，被两个C1-C7直链或支链烷基，优选C1-C4烷基，更优选C1-C2烷基取代的氨基(优选二甲氨基)，含有1-3个选自N、O和S中的杂原子的3-8(优选3-5)元饱和杂环基(更优选氧杂环丁烷基、氮杂环丁烷基)，
Figure PCTCN2016095869-appb-000006
其中，n为0、1、2、3或4；R4为H，卤素，甲基，乙基，丙基，异丙基，正丁基，叔丁基，环丙基，氧杂环丁烷基，氮杂环丁烷基或异丁基。
优选地，在通式I-III中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基；R3表示1或2个取代基，所述取代基各自独立地选自H、卤素、氰基、硝基、C1-C7直链或支链烷基、C1-C6直链或支链烷氧基、
Figure PCTCN2016095869-appb-000007
其中，n为0、1、2、3或4；R4为H、卤素、甲基、乙基、丙基、异丙基、丁基或异丁基。
优选地，在通式I-IV中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基；R3表示1或2个取代基，所述取代基各自独立地选自H、卤素、氰基、硝基、C1-C7直链或支链烷基、C1-C6直链或支链烷氧基或
Figure PCTCN2016095869-appb-000008
其中，n为0、1、2、3或4；R4为H、卤素、甲基、乙基、丙基、异丙基、丁基或异丁基。
优选地，在通式I-V中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基；R3表示1或2个取代基，所述取代基各自独立地选自H、卤素、氰基、硝基、C1-C6直链或支链烷基、C1-C6直链或支链烷氧基、
Figure PCTCN2016095869-appb-000009
其中，n为0、1、2、3或4；R4为H、卤素、甲基、乙基、丙基、异丙基、丁基或异丁基。
优选地，在通式I-VI中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基；R3表示1或2个取代基，所述取代基各自独立地选自H、卤素、氰基、硝基、 C1-C7直链或支链烷基、C1-C6直链或支链烷氧基、
Figure PCTCN2016095869-appb-000010
其中，n为0、1、2、3或4；R4为H、卤素、甲基、乙基、丙基、异丙基、丁基或异丁基。
优选地，在通式I-VII中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基；R3表示1或2个取代基，所述取代基各自独立地选自H、卤素、氰基、硝基、C1-C7直链或支链烷基、C1-C6直链或支链烷氧基或
Figure PCTCN2016095869-appb-000011
其中，n为0、1、2、3或4；R4为H、卤素、甲基、乙基、丙基、异丙基、丁基或异丁基。
优选地，在通式I-VIII中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基；R3表示1或2个取代基，所述取代基各自独立地选自H、卤素、氰基、硝基、C1-C7直链或支链烷基或C1-C6直链或支链烷氧基。
在本发明中，除非另有具体说明外，对于取代基的含义做出如下定义：
所述卤素原子指的是F、Cl、Br或I。
所述C1-C7直链或支链烷基指的是具有1至7个碳原子的直链或支链烷基，其具体的实例包括甲基、乙基、正丙基、异丙基、正丁基、异丁基、叔丁基、仲丁基、正戊基，1-甲基丁基、2-甲基丁基、3-甲基丁基、异戊基、1-乙基丙基、新戊基、正己基、1-甲基戊基、2-甲基戊基、3-甲基戊基、异己基、1,1-二甲基丁基、2,2-二甲基丁基、3,3-二甲基丁基、1,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、正庚基、2-甲基己基、3-甲基己基、2,2-二甲基戊基、3,3-二甲基戊基、2,3-二甲基戊基、2,4-二甲基戊基、3-乙基戊基、2,2,3-三甲基丁基等。术语“C1-C4直链或支链烷基”具有类似的含义。
所述C1-C6直链或支链烷氧基指的是具有1至6个碳原子的直链或支链烷氧基，其具体的实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基、异戊氧基、新戊氧基、正己氧基、异己氧基、3-甲基戊氧基等。
所述C3-C6环烷基指的是环上具有3至6个碳原子的脂肪族碳环基，其具体的实例包括环丙基、环丁基、环戊基、环己基等。
所述6-10元芳基指的是环上具有6至10个碳原子的芳香性碳环基，其具体的实例包括苯基、萘基等。
所述含有1-3个选自N、O和S中的杂原子的5-10元杂芳环指的是在环上具有5至10个原子且包含1-3个选自N、O、S中的杂原子的芳香性环，其可以为单环或双环，例如吡啶环、吡咯环、嘧啶环、吡嗪环、哒嗪环、噻吩环、呋喃环、吡唑环、咪唑环、噁唑环、噻唑环、吲哚环、氮杂吲哚环、萘啶环、苯并咪唑环、吡啶并咪唑环、嘧啶并咪唑环或喹啉环等。术语“含有1-2个选自N、O和S中的杂原子的5-10元杂芳环”具有类似的含义。
所述含有1-3个选自N、O和S中的杂原子的5-7元杂芳环指的是在环上具有5至7个原子且包含1-3个选自N、O、S中的杂原子的芳香性环，例如吡啶环、吡咯环、嘧啶环、吡嗪环、哒嗪环、噻吩环、呋喃环、吡唑环、咪唑环、噁唑环、噻唑环等。术语“含有1-2个选自N、O和S中的杂原子的5-7元杂芳环”具有类似的含义。
所述包含1-3个选自N、O和S中的杂原子的5-7元非芳香性杂环指的是在环上具有5至7个原子且包含1-3个选自N、O、S中的杂原子的非芳香性环基，例如四氢吡咯环、四氢噻吩环或四氢呋喃环等。术语“含有1-2个选自N、O和S中的杂原子的5-7元非芳香性杂环”具有类似的含义。
在本发明中，特别优选的具体化合物为下列化合物之一：
Figure PCTCN2016095869-appb-000012
Figure PCTCN2016095869-appb-000013
Figure PCTCN2016095869-appb-000014
Figure PCTCN2016095869-appb-000015
Figure PCTCN2016095869-appb-000016
Figure PCTCN2016095869-appb-000017
Figure PCTCN2016095869-appb-000018
Figure PCTCN2016095869-appb-000019
所述药学上可接受的盐，例如可以是碱金属盐(例如，钠盐、钾盐、锂盐、铯盐等)；碱土金属盐(例如钙盐、镁盐、锶盐等)等；铵盐；与有机碱所成的盐，例如与三(低级)烷基胺(例如三甲胺、三乙胺、N-乙基二异丙胺等)、吡啶、喹啉、哌啶、咪唑、甲基吡啶、二甲氨基吡啶、二甲基苯胺、N-(低级)烷基吗啉(例如N-甲基吗啉等)、1,5-二氮杂双环[4.3.0]壬烯-5(DBN)、1,8-二氮杂双环[5.4.0]十一碳烯-7(DBU)、1,4-二氮杂双环[2.2.2]辛烷(DABCO)等所成的盐；无机酸盐，例如盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硝酸盐、磷酸盐、碳酸盐等；有机酸盐，例如甲酸盐、乙酸盐、丙酸 盐、草酸盐、丙二酸盐、琥珀酸盐、富马酸盐、马来酸盐、乳酸盐、苹果酸盐、柠檬酸盐、枸橼酸盐、酒石酸盐、碳酸盐、苦味酸盐、甲磺酸盐、乙磺酸盐、对甲苯磺酸盐、谷氨酸盐、双羟萘酸盐等。
本发明提供的通式I所示的哒嗪酮类化合物的药学上可接受的盐可以通过将通式I所示的哒嗪酮类化合物溶于用相应的酸饱和的醇溶液中进行反应而制备，例如：将本发明提供的哒嗪酮类化合物溶于HCl饱和的甲醇溶液，室温搅拌30分钟，将溶剂蒸干，即制得相应的盐酸盐。
本发明的哒嗪酮类化合物或其药学上可接受的盐在不影响其应用效果的情况下，可以进一步以其异构体、前药或溶剂合物等形式使用，本领域技术人员应当理解本发明的哒嗪酮类化合物的上述形式也在本发明的保护范围之内。
所述异构体包括几何异构体、立体异构体等。
所述前药是指药物经过化学结构修饰后得到的在体外无活性或活性较小、在体内经酶或非酶的转化释放出活性药物而发挥药效的化合物。本发明中的前药形式不做特别限定，只要其在体内经酶或化学作用释放具有活性的原药，从而发挥预期的药理作用即可，可以是载体前体药物或生物前体。
所述溶剂合物，例如可以是水合物、乙醇合物等，优选的溶剂合物为水合物。
根据本发明的另一方面，本发明提供了通式I所示的哒嗪酮类化合物的制备方法，该方法通过以下反应式之一实现：
线路1：
Figure PCTCN2016095869-appb-000020
线路2：
Figure PCTCN2016095869-appb-000021
线路3：
Figure PCTCN2016095869-appb-000022
其中A、R1、R2、R3的定义与其在通式I中的定义相同，
各路线具体如下：
路线1：通式1所示的化合物，与丙酮酸缩合后水合肼关环得到通式2所示化合物，再与对氯苄氯进行亲核取代反应得到通式4所示的哒嗪酮类化合物；
路线2：通式5所示的化合物，水解后得到通式6和7所示的化合物，通式7所示的化合物与对氯苄氯进行亲核取代反应得到通式8所示的化合物，最后在金属催化剂或者碱的作用下，通过偶联反应(suzuki reaction)，得到通式9所示的哒嗪酮类化合物；
路线3：通式1所示的化合物，与乙醛酸缩合后水合肼关环得到通式10所示的化合物，与格式试剂R1MgBr进行Michael加成反应得通式11所示的化合物，最后与对氯苄氯进行亲核取代反应得到通式12所示的哒嗪酮类化合物。
路线1、路线2和路线3中所述的亲核取代反应可以在例如碳酸钾、碳酸铯、氢化钠、氢化钾、叔丁醇钾、叔丁醇钠、氢氧化钠等碱存在下在例如乙腈、N,N-二甲基甲酰胺、四氢呋喃等溶剂中进行；
路线2中所述的水解反应条件为在酸性或者碱性条件下在溶剂中进行；所述酸优选为醋酸、盐酸、硫酸、三氟乙酸中的一种或多种；所述碱优选为氢氧化钾、氢氧化钠、乙酸钾、乙酸钠、叔丁醇钾、叔丁醇钠中的一种或多种；所述溶剂优选为乙醇、甲醇、水、乙酸中的一种或多种。
路线2中所述的偶联反应条件，为本领域技术人员的常规选择。一般而言，选择如DMF(N,N-二甲基甲酰胺)、甲苯、1,4-二氧六环为溶剂，在金属催化剂、碱及配体存在下在加热条件下进行。所述加热条件为本领域技术人员所公知的，例如可以加热回流或者用微波加热。所述碱为本领域技术人员所公知的，如碳酸铯、碳酸钾、叔丁醇钾、叔丁醇钠等。所述金属催化剂为本领域技术人员所公知的，例如醋酸钯、Pd(PPh3)4、Pd(dppf)2Cl2等。所述配体为本领域技术人员所公知的，例如三苯基膦、DPPP(1,1'-双(二苯基膦)二茂铁)、BINAP(联萘二苯基膦)、Sphos(2-二环己基膦-2′,6′-二甲氧基-联苯)、Davephos(2-二环己膦基-2'-(N,N-二甲胺)-联苯)等。
路线3中所述的格式试剂R1MgBr为本领域技术人员所公知的，如烷基溴化镁、环烷基溴化镁、芳基溴化镁，如甲基溴化镁、乙基溴化镁、异丙基溴化镁、正丁基溴化镁、环丙基溴化镁、环己基溴化镁、苯基溴化镁。
路线3中所述的Michael加成反应条件在溶剂下进行；所述溶剂优选为四氢呋喃、2-甲基四氢呋喃、乙醚、甲苯、苯。
根据本发明的又一方面，本发明提供了通式I所示的哒嗪酮类化合物或其药学上可接受的盐在制备乙型肝炎病毒抑制剂中的用途，以及在制备用于预防和/或治疗乙型肝炎疾病的药物中的用途。
根据本发明的再一方面，本发明还提供了一种包含治疗有效量的通式I所示的哒嗪酮类化合物或其药学上可接受的盐中的一种或多种的药物组合物。所述药物组合物可以作为乙型肝炎病毒抑制剂，用于预防和/或治疗乙型肝炎，进一步地，该药物组合物可以任选包含药学上可接受的载体或赋形剂。
上述药学上可接受的载体是指药学领域常规的药物载体，例如：稀释剂，如水等；填充剂，如淀粉、蔗糖等；粘合剂，如纤维素衍生物、藻酸盐、明胶、聚乙烯吡咯烷酮；湿润剂，如甘油；崩解剂，如琼脂、碳酸钙和碳酸氢钠；吸收促进剂，如季铵化合物；表面活性剂，如十六烷醇；吸附载体，如高岭土和皂粘土；润滑剂，如滑石粉、硬脂酸钙和硬脂酸镁、和聚乙二醇等。另外，还可以在上述药物组合物中加入其它辅剂，如香味剂和甜味剂等。
根据本发明的又一方面，本发明还提供了预防和/或治疗乙型肝炎疾病的方法，所述方法包括施用治疗有效量的通式I所示的哒嗪酮类化合物或其药学上可接受的盐中的一种或多种或者本发明的上述药物组合物给患者。
本发明提供的化合物或组合物可以通过口服、直肠或肠外给药的方式施用于需要这种治疗的患者。用于口服时，可以将其制成常规的固体制剂，如片剂、粉剂、粒剂、胶囊等，或制成液体制剂，如水或油悬浮剂，或其它液体制剂，如糖浆等；用于肠外给药时，可将其制成注射用的溶液、水或油性悬浮剂等。
本发明有如下有益效果：
通过本发明化合物对HepG2.2.15细胞的毒性和抑制HBV DNA的活性的检测，发明人发现：上述通式I表示的化合物中，多个化合物的HBV DNA抑制活性在3μM以下，最好的化合物抑制活性小于0.4μM。因此，通式I表示的化合物是有效的乙型肝炎病毒抑制剂。
具体实施方式
下面的实施例用于具体地说明本发明提供的哒嗪酮类化合物的制备，以及其作为乙型肝炎病毒抑制剂的生物学活性，但本发明并不局限于这些实施例。
在以下实施例中，核磁共振氢谱用BrukerAMX-400型、Gemini-300型或AMX–600型核磁共振仪记录，化学位移δ的单位为ppm。比旋光度由Perkin-Elmer241型自动旋光仪测定，所用微波为CEM-discovery微波反应器。如无特别说明，所有反应溶剂均按照常规方法进行纯化。柱层析用硅胶(200-300目)为青岛海洋化工分厂生产。薄层层析使用GF254高效板，为烟台化工研究所生产。制备型薄层层析板由中国科学院上海药物研究所制备，固定相采用GF254(HG/T2354-92)硅胶和羧甲基纤维素钠(800-1200)制备，分别为青岛海洋化工有限公司和中国医药(集团)上海化学试剂公司生产。如无特别标注，所有溶剂均为分析纯试剂，所用试剂均购自国药集团化学试剂有限公司。采用碘、紫外荧光等方法显色。减压蒸除有机溶剂在旋转蒸发仪中进行。
化合物的制备：
实施例1：
Figure PCTCN2016095869-appb-000023
步骤1：
将5g 4-氟苯乙酮加入到3.76ml丙酮酸中，120℃下搅拌10h后，冷却至室温，在冰浴下，加入氨水调pH至8-9，水层用乙酸乙酯萃取未反应的4-氟苯乙酮。水层加入4ml水合肼(85％)后，100℃回流过夜。次日冷却反应液，此时有固体析出，抽滤得5.2g白色固体(化合物2)(收率72％)。1H NMR(300MHz,CDCl3)δ11.39(s,1H),7.86–7.71(m,2H),7.57(s,1H),7.15(t,J＝8.7Hz,2H),2.32(s,3H).
步骤2：
将100mg中间体化合物2溶于30ml N,N-二甲基甲酰胺(DMF)中，再加入94mg对氯氯苄和190mg碳酸铯，反应液在50℃下反应5-6小时，TLC示底物完全消失，停止反应并将反应液冷却至室温，反应液用乙酸乙酯萃取，有机层水洗3次后用无水硫酸钠干燥，浓缩，柱层析得100mg白色固体(化合物I-1)(收率62％)。1H NMR(300MHz,CDCl3)δ7.75(dd,J＝8.6,5.6Hz,2H),7.49(s,1H),7.44(d,J＝8.2Hz,2H),7.30(d,J＝8.3Hz,2H),7.14(t,J＝8.7Hz,2H),5.34(s,2H),2.27(s,3H).
以与实施例1相同的方法制备如下化合物：
Figure PCTCN2016095869-appb-000024
Figure PCTCN2016095869-appb-000025
Figure PCTCN2016095869-appb-000026
Figure PCTCN2016095869-appb-000027
Figure PCTCN2016095869-appb-000028
Figure PCTCN2016095869-appb-000029
实施例2
Figure PCTCN2016095869-appb-000030
步骤1：
将10g 3,6-二氯-4-甲基哒嗪溶于100ml醋酸，120℃回流4h，TLC示底物完全消失，停止反应并将反应液冷却至室温，减压蒸去醋酸得到固体。加入200ml乙酸乙酯，将不溶固过滤，所得白色固体为中间体化合物7(3g，收率33％)。1H NMR(300MHz,DMSO)δ13.02(s,1H),6.89(s,1H),2.16(s,3H).
滤液干燥，浓缩，柱层析得白色固体为中间体化合物6(4g，收率44％)。1H NMR(300MHz,DMSO)δ13.03(s,1H),7.43(d,J＝1.3Hz,1H),2.04(d,J＝1.2Hz,3H).
步骤2：
将500mg中间体化合物7溶于50ml N,N-二甲基甲酰胺(DMF)中，再加入670mg对氯氯苄和1.35g碳酸铯，反应液在50℃下反应5-6小时，TLC示底物完全消失，停止反应并将反应液冷却至室温，反应液用乙酸乙酯萃取，有机层水洗3次后用无水硫酸钠干燥，浓缩，柱层析得700mg白色固体(化合物8a)(收率75％)。1H NMR(300MHz,CDCl3)δ7.41(s,1H),7.38(s,1H),7.30(d,J＝8.5Hz,2H),7.06(d,J＝1.2Hz,1H),5.20(s,2H),2.20(d,J＝1.2Hz,3H).
步骤3：
将100mg化合物8a溶于30ml 1,4-二氧六环(1,4-dioxane)和3ml水，依次加入62mg对氟苯硼酸、30mg Pd(dppf)2Cl2([1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物)和197mg磷酸钾，用氮气置换3次，100℃反应过夜。TLC示底物完全消失，停止反应并将反应液冷却至室温，反应液用乙酸乙酯萃取，有机层水洗3次后用无水硫酸 钠干燥，浓缩，柱层析得72mg白色固体(化合物I-2)(收率60％)。1H NMR(400MHz,CDCl3)δ8.92(s,1H),7.42(ddd,J＝23.2,18.5,8.1Hz,6H),7.23(t,J＝7.9Hz,2H),7.05(d,J＝1.2Hz,1H),6.87(t,J＝7.3Hz,1H),5.14(s,2H),2.10(d,J＝0.9Hz,3H).
实施例3
Figure PCTCN2016095869-appb-000031
步骤1：
将500mg中间体6(实施例2中制备)溶于50ml DMF中，再加入670mg对氯氯苄和1.35g碳酸铯，反应液在50℃下反应5-6小时，TLC示底物完全消失，停止反应并将反应液冷却至室温，反应液用乙酸乙酯萃取，有机层水洗3次后用无水硫酸钠干燥，浓缩，柱层析得700mg白色固体(化合物8b)(收率75％)。1H NMR(300MHz,CDCl3)δ7.41(s,1H),7.38(s,1H),7.30(d,J＝8.5Hz,2H),7.06(d,J＝1.2Hz,1H),5.20(s,2H),2.20(d,J＝1.2Hz,3H).
步骤2：
将100mg化合物8b溶于30ml DMF和3ml水，依次加入93mg 1-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂戊硼烷-2-基)-1H-吡唑、30mg Pd(dppf)2Cl2([1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物)和197mg磷酸钾，用氮气置换3次，100℃反应过夜。TLC示底物完全消失，停止反应并将反应液冷却至室温，反应液用乙酸乙酯萃取，有机层水洗3次后用无水硫酸钠干燥，浓缩，柱层析得68mg白色固体(化合物I-19)(收率58％)。1H NMR(300MHz,CDCl3)δ7.60(s,1H),7.53(d,J＝4.7Hz,1H),7.44(s,1H),7.41(s,2H),7.32–7.23(m,3H),5.32(s,2H),2.26(s,3H).
以与实施例3相同的方法制备如下化合物：
Figure PCTCN2016095869-appb-000032
Figure PCTCN2016095869-appb-000033
Figure PCTCN2016095869-appb-000034
Figure PCTCN2016095869-appb-000035
Figure PCTCN2016095869-appb-000036
Figure PCTCN2016095869-appb-000037
Figure PCTCN2016095869-appb-000038
Figure PCTCN2016095869-appb-000039
Figure PCTCN2016095869-appb-000040
Figure PCTCN2016095869-appb-000041
Figure PCTCN2016095869-appb-000042
Figure PCTCN2016095869-appb-000043
Figure PCTCN2016095869-appb-000044
Figure PCTCN2016095869-appb-000045
Figure PCTCN2016095869-appb-000046
Figure PCTCN2016095869-appb-000047
实施例4：
Figure PCTCN2016095869-appb-000048
将150mg化合物I-18(实施例1中制备)溶于25ml 95％乙醇中，加入94.4mg还原铁粉和1.56ml醋酸，回流4h。TLC示底物完全消失，过滤掉固体，滤液减压蒸馏除去，用乙酸乙酯萃取，有机层水洗3次后用无水硫酸钠干燥，浓缩，柱层析得80mg黄 色固体(化合物I-32)(收率60％)。1H NMR(300MHz,DMSO)δ7.83(s,1H),7.54(d,J＝8.4Hz,2H),7.39–7.29(m,4H),6.59(d,J＝8.2Hz,2H),5.48(s,2H),5.24(s,2H),2.12(s,3H).1H NMR(300MHz,D2O)δ7.59(d,J＝8.7Hz,2H),7.48–7.44(m,2H),7.42(s,1H),7.30(s,1H),7.27(d,J＝1.9Hz,1H),6.73(d,J＝8.8Hz,2H),5.32(s,2H),4.77–4.68(m,1H),3.91–3.83(m,1H),2.25(d,J＝1.2Hz,3H).
实施例5：
Figure PCTCN2016095869-appb-000049
将60mg化合物I-20(实施例3中制备)溶于20ml二氯甲烷，加入20μl乙酰氯和30μl吡啶，室温搅拌过夜。TLC示底物完全消失，反应液用水洗3次后用无水硫酸钠干燥，浓缩，柱层析得20mg白色固体(化合物I-33)(收率30％)。1H NMR(400MHz,CDCl3)δ8.66(d,J＝2.3Hz,1H),8.29(d,J＝8.7Hz,1H),8.09(dd,J＝8.8,2.3Hz,1H),8.05(s,1H),7.49(s,1H),7.44(d,J＝8.3Hz,2H),7.30(d,J＝8.4Hz,2H),5.35(s,2H),2.28(s,3H),2.25(s,3H).
以与实施例5相同的方法制备如下化合物：
Figure PCTCN2016095869-appb-000050
Figure PCTCN2016095869-appb-000051
Figure PCTCN2016095869-appb-000052
实施例6：
Figure PCTCN2016095869-appb-000053
将100mg化合物I-15(实施例1中制备)溶于30ml甲苯，依次加入26mg甲胺盐酸盐、48mg Pd2(dba)3(三(双亚苄基丙酮)二钯)，41mg S-Phos(2-二环己基膦-2′,6′-二甲氧基-联苯)和127mg碳酸铯，用氮气置换3次，100℃反应过夜。TLC示底物完全消失，停止反应并将反应液冷却至室温，反应液用乙酸乙酯萃取，有机层水洗3次后用无水硫酸钠干燥，浓缩，柱层析得50mg白色固体(化合物I-36)(收率56％)。1H NMR(300MHz,CDCl3)δ7.62(d,J＝8.7Hz,2H),7.46(d,J＝5.2Hz,1H),7.43(s,1H),7.30(s,1H),7.26(s,2H),6.64(d,J＝8.7Hz,2H),5.33(s,2H),3.97(s,1H),2.89(s,3H),2.25(s,2H).
以与实施例6相同的方法制备如下化合物：
Figure PCTCN2016095869-appb-000054
Figure PCTCN2016095869-appb-000055
实施例7：
Figure PCTCN2016095869-appb-000056
步骤1：
将2g化合物I-15(实施例1中制备)溶于100ml N,N-二甲基亚砜(DMSO)，依次加入24ml甲醇、345mg醋酸钯、433mg dppf([1,1'-双(二苯基膦)二茂铁)和5.9ml三乙胺，用CO置换3次，100℃反应过夜。TLC示底物完全消失，停止反应并将反应液冷却至室温，反应液用乙酸乙酯萃取，有机层水洗3次后用无水硫酸钠干燥，浓缩，柱层析得1.1g白色固体(化合物13)(收率58％)。1H NMR(300MHz,CDCl3)δ8.11(d,J＝6.2Hz,2H),7.85(d,J＝6.1Hz,2H),7.56(s,1H),7.45(d,J＝6.4Hz,2H),7.34–7.28(m,2H),5.37(s,2H),3.95(d,J＝2.6Hz,3H),2.29(s,3H).
步骤2：
将250mg化合物13溶于30ml四氢呋喃(THF)和20ml水，加入70mg氢氧化锂，室温搅拌过夜。TLC示底物完全消失，减压蒸馏除去溶剂，用乙酸乙酯萃取，有机层水洗3次后用无水硫酸钠干燥，浓缩，柱层析得230mg白色固体(化合物I-38)(收率96％)。1H NMR(300MHz,CDCl3)δ8.19(d,J＝8.4Hz,1H),7.89(d,J＝8.0Hz,1H),7.59(s,1H),7.46(d,J＝8.4Hz,1H),7.33(s,1H),5.38(s,1H),2.30(d,J＝2.8Hz,1H).
步骤3：
将50mg化合物I-38溶于20ml二氯甲烷，加入23mg甲胺盐酸盐、32mg EDC(1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐)、23mg HOBT(1-羟基苯并三唑)和100μl三乙胺，室温搅拌过夜。TLC示底物完全消失，反应液用水洗3次后用无水硫酸钠干燥，浓缩，柱层析得30mg白色固体(化合物I-39)(收率58％)。1H NMR(300MHz,CDCl3)δ7.84(s,4H),7.55(s,1H),7.44(d,J＝8.3Hz,2H),7.30(d,J＝8.4Hz,2H),6.23(s,1H),5.36(s,2H),3.05(d,J＝4.9Hz,3H),2.28(s,3H).
以与实施例7相同的方法制备如下化合物：
Figure PCTCN2016095869-appb-000057
Figure PCTCN2016095869-appb-000058
Figure PCTCN2016095869-appb-000059
实施例8：
Figure PCTCN2016095869-appb-000060
步骤1：
将5g 4-氟苯乙酮与13.3g一水合乙醛酸加入250ml圆底烧瓶，120℃下搅拌10h后，冷却至室温，在冰浴下，加入氨水调pH至8-9，水层用乙酸乙酯萃取未反应的4-氟苯乙酮。水层加入4ml水合肼(85％)后，100℃回流过夜。次日冷却反应液，此时有固体析出，抽滤得5g白色固体(化合物10)(收率73％)。
步骤2：
将2.6ml 2M正丙基格式试剂溶于30ml的2-甲基四氢呋喃，再加入200mg化合物10，用氮气置换3次，90℃反应过夜。TLC示底物完全消失，停止反应并将反应液冷却至室温，反应液用乙酸乙酯萃取，有机层水洗3次后用无水硫酸钠干燥，浓缩，柱层析得130mg白色固体(化合物11)(收率55％)。1H NMR(300MHz,CDCl3)δ11.27(s,1H), 7.81–7.74(m,2H),7.50(d,J＝2.6Hz,1H),7.15(t,J＝8.5Hz,2H),2.69–2.60(m,2H),1.73(dd,J＝15.1,7.6Hz,2H),1.03(t,J＝7.3Hz,3H).
步骤3：
将100mg化合物11溶于30ml DMF中，再加入84mg对氯氯苄和168mg碳酸铯，反应液在50℃下反应5-6小时，TLC示底物完全消失，停止反应并将反应液冷却至室温，反应液用乙酸乙酯萃取，有机层水洗3次后用无水硫酸钠干燥，浓缩，柱层析得90mg白色固体(化合物I-45)(收率59％)。1H NMR(300MHz,Acetone)δ8.03–7.92(m,2H),7.80(s,1H),7.49(d,J＝8.3Hz,2H),7.37(d,J＝8.4Hz,2H),7.24(t,J＝8.8Hz,2H),5.38(d,J＝6.9Hz,2H),2.59(t,J＝7.5Hz,2H),1.68(dd,J＝15.0,7.6Hz,2H),0.97(t,J＝7.3Hz,3H).
以与实施例8相同的方法制备如下化合物：
Figure PCTCN2016095869-appb-000061
Figure PCTCN2016095869-appb-000062
实施例9：
Figure PCTCN2016095869-appb-000063
步骤1：
将5g 3,4-噻吩二羧酸溶解于50ml无水乙醇中，加入0.5ml水合肼(85％)，回流4小时后冷却至室温，抽滤得4.5g白色固体(化合物14)(收率97％)。
步骤2：
将4.5g化合物14溶解于50ml二氯亚砜中，回流7小时后冷却至室温，减压蒸馏除去二氯亚砜后，向残渣中加入冰水，然后用乙酸乙酯萃取(2x50mL)，有机层水洗3次后用无水硫酸钠干燥，浓缩，柱层析得1g白色固体(化合物15)(收率19％)。
步骤3：
将1g化合物15溶解于20mL冰醋酸中，回流4小时后冷却至室温，减压除去溶剂后得到白色固体(化合物16)约1g(收率>100％)。
步骤4：
将260mg化合物16溶于20mL DMF中，加入225mg对氯苄率和455mg碳酸铯，50℃反应5小时，TLC示底物完全消失，停止反应并将反应液冷却至室温，反应液用乙酸乙酯萃取，有机层水洗3次后用无水硫酸钠干燥，浓缩，柱层析得120mg白色固体(化合物17)(收率28％)。
步骤5：
将100mg化合物17溶于30ml 1,4-二氧六环和3ml水，依次加入62mg对氟苯硼酸、30mg Pd(dppf)2Cl2([1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物)和137mg磷酸钾，用氮气置换3次，100℃反应过夜。TLC示底物完全消失，停止反应并将反应液冷却至室温，反应液用乙酸乙酯萃取，有机层水洗3次后用无水硫酸钠干燥，浓缩，柱层析得80mg白色固体(化合物I-49)(收率67％)。1H NMR(300MHz,CDCl3)δ8.46(s,1H),7.81(s,1H),7.75–7.66(m,2H),7.44(d,J＝8.4Hz,2H),7.29(d,J＝8.4Hz,2H),7.21(t,J＝8.5Hz,2H),5.35(s,2H).
以与实施例9相同的方法制备如下化合物：
Figure PCTCN2016095869-appb-000064
Figure PCTCN2016095869-appb-000065
测试实施例1：本发明实施例中制得的化合物对乙型肝炎病毒DNA复制能力的影响
1、实验材料
1.1 筛选体系
稳定转染全长HBV的人肝癌细胞HepG2.2.15细胞株(中科院药物研究所提供)
1.2 实验仪器
培养箱(ThermoForma3111)；酶标仪(Molecular Devices Spectra Max 190)；电子天平；显微镜；生物安全柜(Heal Force safe15)；离心机(Eppendorf Centrifuge 5810R)；Real-Time PCR(FASTA GEN-DNA fast2000)
1.3 实验药物和试剂
阳性药及配置：拉米夫定(3TC)，由中科院上海药物研究所药物化学组合成，用DMEM/High Glucose培养液(Dulbecco’s modified Eagle’s medium，Hyclone公司)配置成40mM储液待用。
其他溶液及配置：
DMEM/High Glucose培养液：Dulbecco’s modified Eagle’s medium 1×(Hyclone 公司)磷酸盐缓冲液(PBS，pH7.3，1L)：NaCl，8.0g；Na2HPO4，1.16g；KH2PO4，0.2g；KCl：0.2g；
MTT溶液：MTT(Sigma公司)，用PBS配制成5mg/ml；
DNA抽提试剂盒：
Figure PCTCN2016095869-appb-000066
Blood&Tissue(Qiagen公司)
2、实验方法
2.1 细胞培养
HepG2.2.15细胞按常规方法培养传代。利用的培养基为DMEM，内含有10％(v/v)牛血清及选择抗生素G418，在37℃，5％CO2的培养箱中培养8天(第4天换液)。
2.2 待测化合物及阳性药的配制
待测化合物用DMSO配置成40mM的储备液，含10％HycloneTMFetal Bovine Serum的DMEM培养液配成指定最高浓度的溶液并稀释；阳性药为拉米夫定，同样以含10％HycloneTMFetal Bovine Serum的DMEM培养液配成指定浓度。
2.3 MTT测定细胞毒性
HepG2.2.15细胞以5×103细胞/孔接种于96孔板，按上述方法在药物作用下培养八天，取出上清200μl后加入MTT溶液，培养4h后加入裂解液，培养12h后用酶标仪测定OD570，与对照孔的吸光度进行比较，计算存活细胞百分比，并计算出致半数细胞毒性所需浓度CC50。
2.4 细胞培养上清中HBV DNA含量的测定
HepG2.2.15细胞经不同浓度的化合物作用8天(第4天换液)后，吸取培养上清，采用实时PCR(Real-time PCR)法定量检测上清中成熟病毒粒子内含有的HBV DNA。
柱提HepG2.2.15细胞上清DNA(Qiagen，
Figure PCTCN2016095869-appb-000067
Blood&Tissue Handbook)
1)收96孔板上清DNA，200μl每孔，将复孔均收集至同一个EP管中，4000rcf*5min离心，取上清；
2)取200上清，加入1.5ml EP管中，加入20μl蛋白酶K和200μl Buffer AL(Qiagen，
Figure PCTCN2016095869-appb-000068
Blood&Tissue Kit),涡旋使其完全混匀，56℃孵育10min；
3)加入200乙醇，涡旋使其完全混匀；
4)将第3)步的液体全部加入置于2ml废液收集管中的DNeasy Mini spin column(Qiagen，
Figure PCTCN2016095869-appb-000069
Blood&Tissue Kit)，6000rcf*1min离心，弃去上清；
5)将DNeasy Mini spin column置于新的2ml废液收集管，加入500μl Buffer AW1(Qiagen，
Figure PCTCN2016095869-appb-000070
Blood&Tissue Kit)，6000rcf*1min离心，弃去上清；
6)将DNeasy Mini spin column置于新的2ml废液收集管，加入500μl Buffer AW2，(Qiagen，
Figure PCTCN2016095869-appb-000071
Blood&Tissue Kit)20000rcf*3min离心，弃去上清；
7)将DNeasy Mini spin column置于新的1.5ml EP管内，吸取50μl Buffer AE(Qiagen，
Figure PCTCN2016095869-appb-000072
Blood&Tissue Kit)直接加入DNeasy Mini spin column的膜上，在室温放置5min，6000rcf*1min离心洗脱膜上的DNA，弃去DNeasy Mini spin column，收集DNA样品至-20℃。
实时PCR检测上清HBV DNA(异性肝炎病毒核酸定量检测试剂盒，达安基因)
1)标准曲线：1e7-1e4IU/ml，1μl上样，设置一个空白孔，以检测反应体系是否污染；
2)按顺序加DNA样品1μl；
3)加入酶及反应缓冲液：先将两管反应液加入酶中，混匀之后稍微离心置于冰上，在上样后加入酶反应液19μl，加入时确保不触碰到DNA样品造成污染；
4)贴上封膜，离心；
5)PCR反应：
第一阶段:93℃，2min
第二阶段:10个循环
第一步：93℃，45s
第二步：55℃，1min
第三阶段：45个循环
第一步：93℃，30s
第二步：55℃，45s
样品：20μl
检测：在完成第三阶段的第二步(55℃，45s)后收集数据。
2.8 数据处理
采用Origin软件对实验数据进行统计，计算IC50
实验结果：
实验结果如表1所示。
表1：本发明实施例的部分化合物对HepG2.2.15细胞的毒性和抑制HBV DNA的活性
化合物 CC50(μM) IC50(μM)
I-1 >100 3.3
I-2 >100 6.5
I-3 >100 7.0
I-4 >100 26.7
I-5 >100 45.4
I-6 >100 6.32
I-7 >100 4.26
I-8 >100 7.27
I-9 70.5 11.8
I-10 55.6 6.24
I-11 52.4 6.8
I-12 24.7 4.4
I-13 50.9 13.8
I-14 66.5 17.6
I-15 42.2 4.3
I-16 51.8 15.0
I-17 82.5 15.6
I-18 50.9 2.6
I-19 >100 10.1
I-20 33.8 1.2
I-21 >100 2.9
I-22 41.3 6.6
I-23 33.3 3.2
I-24 70.5 11.8
I-25 >100 2.6
I-26 23.3 1.5
I-27 82.2 11.8
I-28 32.5 3.9
I-29 11.1 7.1
I-30 47.6 6.8
I-31 38.2 31.7
I-32 31.4 5.8
I-33 62.4 11.1
I-34 >100 1.1
I-35 >100 33
I-36 35.7 6.1
I-37 10.0 2.8
I-38 >100 19.8
I-39 84.7 3.6
I-40 51.9 4.5
I-41 78.6 2.6
I-42 70.4 4.2
I-43 10.7 3.7
I-44 10.0 1.2
I-45 77 22.1
I-46 33.6 18.8
I-47 88.6 28.7
I-48 >100 43.4
I-49 >100 20.2
I-50 >100 10.4
I-51 >100 7.7
I-52 >100 4.6
I-53 >100 24.6
I-54 >100 25.7
I-55 >100 13.6
I-56 67.7 7.8
I-57 >100 15.8
I-58 50.6 16.8
I-59 46.9 11.3
I-60 77.9 3.2
I-61 33.5 1.6
I-62 >100 6.9
I-63 >100 4.7
I-64 >100 22.4
I-65 >100 20.1
I-66 44.9 4.4
I-67 34.4 1.6
I-68 >100 0.5
I-69 >100 2.9
I-70 >100 0.05
I-71 >100 10.8
I-72 38.8 4.6
I-73 >100 5.1
I-74 >100 1.3
I-75 37.3 4.9
I-76 33.3 30
I-77 >100 1.1
I-78 8.1 1.6
I-79 34.4 0.2
I-80 6.7 0.26
I-81 42 3.6
I-82 25.7 0.9
I-83 30.3 0.22
I-84 24.3 0.9
I-85 33.3 1.2
I-86 >100 2.5
I-87 19.7 2.0
I-88 27.6 0.3
I-89 48.8 0.1
I-90 >100 4.56
I-91 93.2 5.1
I-92 32.1 3.6
I-93 22.7 2.1
I-94 27.9 0.4
注：CC50为样品药物对HepG2.2.15细胞的生长的影响，半数(50％)致死浓度。
IC50为样品药物对乙肝病毒DNA复制的抑制达半数(50％)时的浓度。
从测试结果可以看出该类化合物大部分在细胞水平上都具有中等到优良的抑制HBV DNA复制的活性，其中57个化合物的IC50小于10μM。
上述实施例仅作为说明的目的，本发明的范围并不受此限制。对本领域的技术人员来说进行修改是显而易见的，本发明仅受所附权利要求范围的限制。

Claims (10)

  1. 如下通式I所示的哒嗪酮类化合物或其药学上可接受的盐：
    Figure PCTCN2016095869-appb-100001
    其中，
    R1、R2各自独立地为H、C1-C7直链或支链烷基、C3-C6环烷基或6-10元芳基，或者R1和R2与相连的碳原子一起形成含有1-3个选自N、O和S中的杂原子的5-7元杂芳环或者非芳香性杂环，
    A为6-10元芳环或含有1-3个选自N、O和S中的杂原子的5-10元杂芳环，
    R3表示一个或多个取代基，优选表示1、2或3个取代基，所述取代基各自独立地选自H，卤素，氰基，硝基，C1-C7直链或支链烷基，C1-C6直链或支链烷氧基，被两个C1-C7直链或支链烷基取代的氨基，含有1-3个选自N、O和S中的杂原子的3-8元饱和杂环基，
    Figure PCTCN2016095869-appb-100002
    其中，n为选自0至10的整数；
    R4为H，卤素，C1-C7直链或支链烷基，C3-C6环烷基，6-10元芳基，含有1-3个选自N、O和S中的杂原子的5-10元杂芳基，含有1-3个选自N、O和S中的杂原子的3-8元饱和杂环基，未取代或被1-2个取代基取代的氨基；其中，所述“被1-2个取代基取代的氨基”中的取代基为C1-C7直链或支链烷基。
  2. 根据权利要求1所述的哒嗪酮类化合物或其药学上可接受的盐，其特征在于，
    R1、R2各自独立地为H、C1-C4直链或支链烷基、C3-C6环烷基或苯基，或者R1和R2与相连的碳原子一起形成含有1-2个选自N、O和S中杂原子的5-7元杂芳环或者非芳香性杂环，
    A为苯环或含有1-2个选自N、O和S中的杂原子的5-10元杂芳环，
    R3表示一个或多个取代基，优选表示1、2或3个取代基，所述取代基各自独立地选自H，卤素，氰基，硝基，C1-C7直链或支链烷基，C1-C6直链或支链烷氧基，被两个C1-C4直链或支链烷基取代的氨基，含有1-3个选自N、O或S中的杂原子的3-5元 饱和杂环基，
    Figure PCTCN2016095869-appb-100003
    其中，n为选自0至7的整数；
    R4为H，卤素，C1-C7直链或支链烷基，C3-C6环烷基，6-10元芳基，含有1-3个选自N、O和S中的杂原子的5-10元杂芳基，含有1-3个选自N、O和S中的杂原子的3-8元饱和杂环基，未取代或被1-2个取代基取代的氨基；其中，所述“被1-2个取代基取代的氨基”中的取代基为甲基、乙基、丙基或丁基。
  3. 根据权利要求1所述的哒嗪酮类化合物或其药学上可接受的盐，其特征在于，
    R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基，或者R1和R2与相连的碳原子一起形成吡咯环、噻吩环、呋喃环、吡嗪环、四氢吡咯环、四氢噻吩环或四氢呋喃环；
    A为苯环、吡啶环、吡咯环、嘧啶环、吡嗪环、哒嗪环、噻吩环、呋喃环、吡唑环、咪唑环、噁唑环、噻唑环、吲哚环、氮杂吲哚环、萘啶环、喹啉环、苯并咪唑环、咪唑并吡啶环或咪唑并嘧啶环；
    R3表示一个或多个取代基，优选表示1、2或3个取代基，所述取代基各自独立地选自H、卤素、氰基、硝基、C1-C7直链或支链烷基、C1-C6直链或支链烷氧基、被两个C1-C2直链或支链烷基取代的氨基、含有1-3个选自N、O或S中的杂原子的3-5元饱和杂环基，
    Figure PCTCN2016095869-appb-100004
    其中，n为0、1、2、3或4；
    R4为H、卤素、甲基、乙基、丙基、异丙基、正丁基、异丁基、叔丁基、环丙基、氧杂环丁烷基、氮杂环丁烷基或者为被1-2个选自甲基、乙基、丙基或丁基中的取代基取代的氨基。
  4. 根据权利要求1所述的哒嗪酮类化合物或其药学上可接受的盐，其特征在于，
    R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基，或者R1和R2与相连的碳原子一起形成吡咯环、噻吩环、呋喃环、吡嗪环、四氢吡咯环、四氢噻吩环或四氢呋喃环；
    A为苯环、吡啶环、嘧啶环、吡嗪环、吡唑环、哒嗪环、吲哚环、氮杂吲哚环、萘啶环、喹啉环、咪唑并[1,2-a]吡啶环或咪唑并[1,2-a]嘧啶环；
    R3表示一个或多个取代基，优选表示1、2或3个取代基，所述取代基各自独立地 选自H、卤素、氰基、硝基、C1-C7直链或支链烷基、C1-C6直链或支链烷氧基、二甲氨基、氧杂环丁烷基、氮杂环丁烷基、
    Figure PCTCN2016095869-appb-100005
    Figure PCTCN2016095869-appb-100006
    其中，n为0、1、2、3或4；
    R4为H、卤素、甲基、乙基、丙基、异丙基、正丁基、异丁基、环丙基、叔丁基、氧杂环丁烷基、氮杂环丁烷基或者为被1-2个选自甲基、乙基、丙基或丁基中的取代基取代的氨基。
  5. 根据权利要求1-4中任一项所述的哒嗪酮类化合物或其药学上可接受的盐，其特征在于，所述化合物选自如下通式I-I至I-VIII之一所示的结构的化合物：
    Figure PCTCN2016095869-appb-100007
    其中，R1、R2、R3的定义与相应权利要求中通式I中的定义相同；
    优选地，在通式I-I中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基，或者R1和R2与相连的碳原子一起形成吡咯环、噻吩环、呋喃环、吡嗪环、四氢吡咯环、四氢噻吩环或四氢呋喃环；R3表示1、2或3个取代基，所述取代基各自独立地选自H、卤素、氰基、硝基、C1-C7直链或支链烷基、C1-C6直链或支链烷氧基、
    Figure PCTCN2016095869-appb-100008
    其中，n为0、1、2、3或4； R4为H、卤素、甲基、乙基、丙基、异丙基、丁基、异丁基、或者为被1-2个选自甲基、乙基、丙基或丁基中的取代基取代的氨基；
    优选地，在通式I-II中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基；R3表示1或2个取代基，所述取代基各自独立地选自H，卤素，氰基，硝基，C1-C7直链或支链烷基，C1-C6直链或支链烷氧基，被两个C1-C7直链或支链烷基取代的氨基，含有1-3个选自N、O或S中的杂原子的3-8元饱和杂环基，
    Figure PCTCN2016095869-appb-100009
    Figure PCTCN2016095869-appb-100010
    其中，n为0、1、2、3或4；R4为H、卤素、甲基、乙基、丙基、异丙基、正丁基、叔丁基、环丙基、氧杂环丁烷基、氮杂环丁烷基或异丁基；
    优选地，在通式I-III中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基；R3表示1或2个取代基，所述取代基各自独立地选自H、卤素、氰基、硝基、C1-C7直链或支链烷基、C1-C6直链或支链烷氧基、
    Figure PCTCN2016095869-appb-100011
    其中，n为0、1、2、3或4；R4为H、卤素、甲基、乙基、丙基、异丙基、丁基或异丁基；
    优选地，在通式I-IV中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基；R3表示1或2个取代基，所述取代基各自独立地选自H、卤素、氰基、硝基、C1-C7直链或支链烷基、C1-C6直链或支链烷氧基或
    Figure PCTCN2016095869-appb-100012
    其中，n为0、1、2、3或4；R4为H、卤素、甲基、乙基、丙基、异丙基、丁基或异丁基；
    优选地，在通式I-V中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基；R3表示1或2个取代基，所述取代基各自独立地选自H、卤素、氰基、硝基、C1-C6直链或支链烷基、C1-C6直链或支链烷氧基、
    Figure PCTCN2016095869-appb-100013
    其中，n为0、1、2、3或4；R4为H、卤素、甲基、乙基、丙基、异丙基、丁基或异丁基；
    优选地，在通式I-VI中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己 基或苯基；R3表示1或2个取代基，所述取代基各自独立地选自H、卤素、氰基、硝基、C1-C7直链或支链烷基、C1-C6直链或支链烷氧基、
    Figure PCTCN2016095869-appb-100014
    其中，n为0、1、2、3或4；R4为H、卤素、甲基、乙基、丙基、异丙基、丁基或异丁基；
    优选地，在通式I-VII中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基；R3表示1或2个取代基，所述取代基各自独立地选自H、卤素、氰基、硝基、C1-C7直链或支链烷基、C1-C6直链或支链烷氧基或
    Figure PCTCN2016095869-appb-100015
    其中，n为0、1、2、3或4；R4为H、卤素、甲基、乙基、丙基、异丙基、丁基或异丁基；
    优选地，在通式I-VIII中，R1、R2各自独立地为H、甲基、正丙基、环丙基、环己基或苯基；R3表示1或2个取代基，所述取代基各自独立地选自H、卤素、氰基、硝基、C1-C7直链或支链烷基或C1-C6直链或支链烷氧基。
  6. 根据权利要求1所述的哒嗪酮类化合物或其药学上可接受的盐，其特征在于，所述化合物为下列化合物之一：
    Figure PCTCN2016095869-appb-100016
    Figure PCTCN2016095869-appb-100017
    Figure PCTCN2016095869-appb-100018
    Figure PCTCN2016095869-appb-100019
    Figure PCTCN2016095869-appb-100020
    Figure PCTCN2016095869-appb-100021
    Figure PCTCN2016095869-appb-100023
  7. 一种制备权利要求1-6中任一项所述的哒嗪酮类化合物的方法，所述方法通过以下反应式之一实现：
    线路1：
    Figure PCTCN2016095869-appb-100024
    线路2：
    Figure PCTCN2016095869-appb-100025
    线路3：
    Figure PCTCN2016095869-appb-100026
    其中A、R1、R2、R3的定义与引用的相应权利要求中的定义相同，
    其中：
    路线1：通式1所示的化合物，与丙酮酸缩合后水合肼关环得到通式2所示化合物，再与对氯苄氯进行亲核取代反应得到通式4所示的哒嗪酮类化合物；
    路线2：通式5所示的化合物，水解后得到通式6和7所示的化合物，通式7所示的化合物与对氯苄氯进行亲核取代反应得到通式8所示的化合物，最后在金属催化剂或者碱的作用下，通过偶联反应，得到通式9所示的哒嗪酮类化合物；
    路线3：通式1所示的化合物，与乙醛酸缩合后水合肼关环得到通式10所示的化合物，与格式试剂R1MgBr进行Michael加成反应得通式11所示的化合物，最后与对氯苄氯进行亲核取代反应得到通式12所示的哒嗪酮类化合物；
    优选地，路线1、路线2和路线3中所述的亲核取代反应在碱存在下在溶剂中进行；所述碱优选为碳酸钾、碳酸铯、氢化钠、氢化钾、叔丁醇钾、叔丁醇钠或氢氧化钠中的一种或多种；所述溶剂优选为乙腈、N,N-二甲基甲酰胺或四氢呋喃中的一种或多种；
    优选地，路线2中所述的水解反应在酸性或者碱性条件下在溶剂中进行；所述酸为选自醋酸、盐酸、硫酸、三氟乙酸中的一种或多种；所述碱为选自氢氧化钾、氢氧化钠、乙酸钾、乙酸钠、叔丁醇钾、叔丁醇钠中的一种或多种；所述溶剂为选自乙醇、甲醇、水、乙酸中的一种或多种；
    优选地，路线2中所述的偶联反应在溶剂中，在金属催化剂、碱及配体存在下在加热条件下进行；所述溶剂优选为N,N-二甲基甲酰胺、甲苯或1,4-二氧六环，所述加热条件为加热回流或者用微波加热；所述碱优选为碳酸铯、碳酸钾、叔丁醇钾和叔丁醇钠中的一种或多种；所述金属催化剂优选为醋酸钯、Pd(PPh3)4或Pd(dppf)2Cl2中的一种或多种；所述配体优选为三苯基膦、1,1'-双(二苯基膦)二茂铁、联萘二苯基膦、2-二环己基膦-2′,6′-二甲氧基-联苯和2-二环己膦基-2'-(N,N-二甲胺)-联苯中的一种或多种；
    优选地，路线3中所述的格式试剂R1MgBr选自烷基溴化镁、环烷基溴化镁或芳基溴化镁，更优选地为甲基溴化镁、乙基溴化镁、异丙基溴化镁、正丁基溴化镁、环丙基溴化镁、环己基溴化镁或苯基溴化镁；
    优选地，路线3中所述的Michael加成反应条件在溶剂下进行；所述溶剂为选自四氢呋喃、2-甲基四氢呋喃、乙醚、甲苯或苯中的一种或多种。
  8. 根据权利要求1至6中任一项所述的哒嗪酮类化合物或其药学上可接受的盐在制备用于预防和/或治疗乙型肝炎疾病的药物中的用途。
  9. 一种药物组合物，其包含治疗有效量的根据权利要求1至6中任一项所述的哒嗪酮类化合物或其药学上可接受的盐中的一种或多种。
  10. 一种乙型肝炎病毒抑制剂，其包含治疗有效量的根据权利要求1至6中任一项所述的哒嗪酮类化合物或其药学上可接受的盐中的一种或多种。
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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020097258A1 (en) * 2018-11-06 2020-05-14 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
WO2020259539A1 (zh) * 2019-06-25 2020-12-30 中国科学院上海药物研究所 4-吡啶取代酞嗪酮类化合物、其制备方法、药物组合物及用途
US11091464B2 (en) 2018-11-06 2021-08-17 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
US11236065B2 (en) 2018-11-06 2022-02-01 Edgewise Therapecutics, Inc. Pyridazinone compounds and uses thereof
US20230138663A1 (en) * 2018-06-04 2023-05-04 Ohio State Innovation Foundation Eaat2 activators and methods of using thereof

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107334767B (zh) * 2017-06-08 2019-03-05 中国医学科学院医药生物技术研究所 一种哒嗪酮类化合物在肿瘤治疗中的应用
CN109384727B (zh) * 2017-08-10 2023-07-28 中国科学院上海药物研究所 酞嗪酮类化合物、其制备方法、药物组合物及用途
EP3666767B1 (en) * 2017-08-10 2021-12-01 Shanghai Institute of Materia Medica, Chinese Academy of Sciences Phthalazinone derivatives, method for their preparation thereof, pharmaceutical composition comprising them, and their use
CN113912622B (zh) * 2020-07-10 2023-12-01 上海纽思克生物科技有限公司 三环嘧啶酮类化合物、其制备方法、其组合物和用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070021418A1 (en) * 2003-07-30 2007-01-25 Kowa Co., Ltd. Method of inhibiting production of osteopontin
WO2009023411A1 (en) * 2007-08-09 2009-02-19 Bausch & Lomb Incorporated Compositions and methods for treating or controlling anterior- and posterior-segment ophthalmic diseases
TW201127823A (en) * 2009-11-04 2011-08-16 Wyeth Llc Indole based receptor CRTH2 antagonists
CN102731409A (zh) * 2011-04-08 2012-10-17 中国科学院上海药物研究所 一类哒嗪酮类化合物，其药物组合物、制备方法及用途
WO2014096965A2 (en) * 2012-12-21 2014-06-26 Rvx Therapeutics Inc. Novel heterocyclic compounds as bromodomain inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070021418A1 (en) * 2003-07-30 2007-01-25 Kowa Co., Ltd. Method of inhibiting production of osteopontin
WO2009023411A1 (en) * 2007-08-09 2009-02-19 Bausch & Lomb Incorporated Compositions and methods for treating or controlling anterior- and posterior-segment ophthalmic diseases
TW201127823A (en) * 2009-11-04 2011-08-16 Wyeth Llc Indole based receptor CRTH2 antagonists
CN102731409A (zh) * 2011-04-08 2012-10-17 中国科学院上海药物研究所 一类哒嗪酮类化合物，其药物组合物、制备方法及用途
WO2014096965A2 (en) * 2012-12-21 2014-06-26 Rvx Therapeutics Inc. Novel heterocyclic compounds as bromodomain inhibitors

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20230138663A1 (en) * 2018-06-04 2023-05-04 Ohio State Innovation Foundation Eaat2 activators and methods of using thereof
WO2020097258A1 (en) * 2018-11-06 2020-05-14 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
US11091464B2 (en) 2018-11-06 2021-08-17 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
JP2022506687A (ja) * 2018-11-06 2022-01-17 エッジワイズ セラピューティクス， インコーポレイテッド ピリダジノン化合物およびその使用
US11236065B2 (en) 2018-11-06 2022-02-01 Edgewise Therapecutics, Inc. Pyridazinone compounds and uses thereof
US20220106291A1 (en) 2018-11-06 2022-04-07 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
US11390606B2 (en) 2018-11-06 2022-07-19 Edgewise Therapecutics, Inc. Pyridazinone compounds and uses thereof
JP7162132B2 (ja) 2018-11-06 2022-10-27 エッジワイズ セラピューティクス， インコーポレイテッド ピリダジノン化合物およびその使用
US12012395B2 (en) 2018-11-06 2024-06-18 Edgewise Therapeutics, Inc. Pyridazinone compounds and uses thereof
WO2020259539A1 (zh) * 2019-06-25 2020-12-30 中国科学院上海药物研究所 4-吡啶取代酞嗪酮类化合物、其制备方法、药物组合物及用途

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