CN106467495A - Pyridazinone compound, its preparation method, pharmaceutical composition and purposes - Google Patents

Pyridazinone compound, its preparation method, pharmaceutical composition and purposes Download PDF

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CN106467495A
CN106467495A CN201510512718.3A CN201510512718A CN106467495A CN 106467495 A CN106467495 A CN 106467495A CN 201510512718 A CN201510512718 A CN 201510512718A CN 106467495 A CN106467495 A CN 106467495A
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straight
group
methyl
formula
halogen
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Inventor
胡有洪
左建平
陆栋
唐炜
邢唯强
杨莉
王浪
王亚娟
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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Priority to CN201510512718.3A priority Critical patent/CN106467495A/en
Priority to CN201680040315.6A priority patent/CN107848986A/en
Priority to PCT/CN2016/095869 priority patent/WO2017028798A1/en
Publication of CN106467495A publication Critical patent/CN106467495A/en
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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
    • 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
    • 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
    • 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

Abstract

The present invention relates to the pyridazinone compound shown in a kind of below formula I or its pharmaceutically acceptable salt, its preparation method, pharmaceutical composition and its purposes in the medicine preparing hepatitis B viruss inhibitor and prevention and/or treatment hepatitis B.

Description

Pyridazinone compound, its preparation method, pharmaceutical composition and purposes
Technical field
The invention belongs to medicinal chemistry art.Specifically, the present invention relates to a kind of pyridazinone compound or its pharmaceutically may be used Salt, its preparation method, pharmaceutical composition and the purposes accepting.Such compound or its pharmaceutical composition can be used for preparing B-mode Hepatitis viruss inhibitor, to prevent and/or to treat hepatitis B.
Background technology
According to the statistics of World Health Organization (WHO), the current whole world has had 2,000,000,000 people to infect hepatitis B viruss (HBV), And about 3.5-4.0 hundred million Genus Homo is in chronic infection.It is hard that annual about 1,000,000 people die from liver because of infection hepatitis B virus Change, the liver function energy metabolism complication such as complete, hepatocarcinoma.Therefore, hepatitis b virus infected is still that a kind of serious harm public is good for The worldwide disease of health.
At present, interferon and ucleosides anti-hepatitis virus medicine are two kinds of hepatitis b virus infected Main Means for the treatment of.But Interferon has that poor resistance, untoward reaction be many, somewhat expensive the shortcomings of；And 6 kinds of nucleoside medicines of listing at present (draw Meter Fu Ding, adefovir ester, entecavir grace, Telbivudine, tenofovir and Clevudine) all act on hepatitis B The reverse transcriptase of poison, can produce different degrees of drug resistance and side effect in long-term treatment, greatly limit this kind of medicine Application.
Therefore, more anti-second of non-nucleoside small molecule acting on novel targets, new mechanism and brand new parent nucleus are researched and developed Hepatitis virus medicine is increasingly urgent, is the focus of current medicinal chemistry art research, and has highly important theoretical, warp Ji and social meaning.
Content of the invention
It is an object of the present invention to provide a kind of pyridazinone compound or its pharmaceutically acceptable salt.
It is a further object to provide the preparation method of the compounds of this invention.
A further object of the present invention is to provide the pyridazinone compound of the present invention or its pharmaceutically acceptable salt as second Hepatitis virus inhibitor and the purposes in the medicine of preparation prevention and treatment hepatitis B.
It is also another object of the present invention to provide a kind of method of prevention and/or treatment hepatitis B.
According to an aspect of the present invention, the invention provides the pyridazinone compound shown in a kind of below formula I or its medicine Acceptable salt on：
Wherein,
R1、R2It is each independently H, C1-C7 straight or branched alkyl, C3-C6 cycloalkyl or 6-10 unit aryl, or Person R1And R2Formed together with the carbon atom being connected containing the 1-3 heteroatomic 5-7 unit heteroaryl in N, O and S Ring or non-aromatic heterocyclic rings,
Preferably, R1、R2It is each independently H, C1-C4 straight or branched alkyl, C3-C6 cycloalkyl or phenyl, or Person R1And R2Formed together with the carbon atom being connected containing 1-2 heteroatomic 5-7 unit hetero-aromatic ring in N, O and S Or non-aromatic heterocyclic rings,
It is highly preferred that R1、R2It is each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl or phenyl, or R1And R2Form pyrrole ring, thiphene ring, furan nucleuss, pyrazine ring, nafoxidine ring, tetrahydrochysene together with the carbon atom being connected Thiphene ring or oxolane ring；
A be 6-10 unit's aryl or containing 1-3 the heteroatomic 5-10 unit's heteroaryl in N, O and S,
Preferably, A be phenyl or containing 1-2 the heteroatomic 5-10 unit's heteroaryl in N, O and S,
It is highly preferred that A be phenyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, thienyl, furyl, Pyrazolyl, imidazole radicals, oxazolyl, thiazolyl, indyl, azaindolyl, naphthyridinyl or quinolyl；
It is highly preferred that A is phenyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyrazolyl, pyridazinyl, indyl, azepine Yin Diindyl base, naphthyridinyl or quinolyl；
R3Represent one or more substituent groups, preferably represent 1,2 or 3 substituent groups, described substituent group is selected independently of one another From H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxyl,
Wherein, n be integer selected from 0 to 10 it is preferable that n is the integer selected from 0 to 7, it is highly preferred that n be 0, 1st, 2,3 or 4；
R4For H, halogen, C1-C7 straight or branched alkyl, C3-C6 cycloalkyl, 6-10 unit aryl, contain 1-3 choosing Heteroatomic 5-10 unit's heteroaryl from N, O and S, amino that is unsubstituted or being replaced by 1-2 substituent group；Wherein, Substituent group in described " amino being replaced by 1-2 substituent group " is C1-C7 straight or branched alkyl, preferably methyl, Ethyl, propyl group or butyl；
Preferably, R4For H, halogen, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or be by 1-2 The amino that individual substituent group in methyl, ethyl, propyl group or butyl replaces.
Preferably, the pyridazinone compound shown in formula I is selected from and has the knot shown in one of below formula I-I to I-VIII The compound of structure：
Wherein, R1、R2、R3Definition identical with the definition in formula I.
Preferably, in formula I-I, R1、R2Be each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl or Phenyl, or R1And R2Form pyrrole ring, thiphene ring, furan nucleuss, pyrazine ring, tetrahydrochysene pyrrole together with the carbon atom being connected Cough up ring, Tetramethylene sulfide ring or oxolane ring；R3Represent 1,2 or 3 substituent groups, described substituent group is selected independently of one another From H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxyl, Wherein, n is 0,1,2,3 or 4；R4For H, halogen, Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or be selected from methyl, ethyl, propyl group or fourth by 1-2 The amino that substituent group in base replaces.
Preferably, in formula I-II, R1、R2Be each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl or Phenyl；R3Represent 1 or 2 substituent group, described substituent group is each independently selected from H, halogen, cyano group, nitro, C1-C7 Straight or branched alkyl, C1-C6 straight or branched alkoxyl,Wherein, n be 0,1, 2nd, 3 or 4；R4For H, halogen, methyl, ethyl, propyl group, isopropyl, butyl or isobutyl group.
Preferably, in formula I-III, R1、R2It is each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl Or phenyl；R3Represent 1 or 2 substituent group, described substituent group be each independently selected from H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxyl,Wherein, n For 0,1,2,3 or 4；R4For H, halogen, methyl, ethyl, propyl group, isopropyl, butyl or isobutyl group.
Preferably, in formula I-IV, R1、R2It is each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl Or phenyl；R3Represent 1 or 2 substituent group, described substituent group be each independently selected from H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxyl orWherein, n is 0,1,2,3 Or 4；R4For H, halogen, methyl, ethyl, propyl group, isopropyl, butyl or isobutyl group.
Preferably, in formula I-V, R1、R2It is each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl Or phenyl；R3Represent 1 or 2 substituent group, described substituent group be each independently selected from H, halogen, cyano group, nitro, C1-C6 straight or branched alkyl, C1-C6 straight or branched alkoxyl,Wherein, n For 0,1,2,3 or 4；R4For H, halogen, methyl, ethyl, propyl group, isopropyl, butyl or isobutyl group.
Preferably, in formula I-VI, R1、R2It is each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl Or phenyl；R3Represent 1 or 2 substituent group, described substituent group be each independently selected from H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxyl,Wherein, n For 0,1,2,3 or 4；R4For H, halogen, methyl, ethyl, propyl group, isopropyl, butyl or isobutyl group.
Preferably, in formula I-VII, R1、R2It is each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl Or phenyl；R3Represent 1 or 2 substituent group, described substituent group be each independently selected from H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxyl orWherein, n is 0,1,2,3 Or 4；R4For H, halogen, methyl, ethyl, propyl group, isopropyl, butyl or isobutyl group.
Preferably, in formula I-VIII, R1、R2It is each independently H, methyl, n-pro-pyl, cyclopropyl, hexamethylene Base or phenyl；R3Represent 1 or 2 substituent group, described substituent group be each independently selected from H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl or C1-C6 straight or branched alkoxyl.
In the present invention, unless otherwise specifically indicated, the implication of substituent group is made and being defined as below：
Described halogen atom refers to F, Cl, Br or I.
Described C1-C7 straight or branched alkyl refers to the straight or branched alkyl with 1 to 7 carbon atom, and it is concrete Example include methyl, ethyl, n-pro-pyl, isopropyl, normal-butyl, isobutyl group, the tert-butyl group, sec-butyl, n-pentyl, 1- methyl butyl, 2- methyl butyl, 3- methyl butyl, isopentyl, 1- ethyl propyl, neopentyl, n-hexyl, 1- methyl Amyl group, 2- methyl amyl, 3- methyl amyl, isohesyl, 1,1- dimethylbutyl, 2,2- dimethylbutyl, 3,3- dimethyl Butyl, 1,2- dimethylbutyl, 1,3- dimethylbutyl, 2,3- dimethylbutyl, 2- ethyl-butyl, n-heptyl, 2- methyl Hexyl, 3- methylhexyl, 2,2- dimethyl amyl group, 3,3- dimethyl amyl group, 2,3- dimethyl amyl group, 2,4- dimethyl amyl group, 3- ethyl pentyl group, 2,2,3- trimethyl butyl etc..Term " C1-C4 straight or branched alkyl " has similar implication.
Described C1-C6 straight or branched alkoxyl refers to the straight or branched alkoxyl with 1 to 6 carbon atom, its Specific example include methoxyl group, ethyoxyl, positive propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, Sec-butoxy, n-pentyloxy, isoamoxy, neopentyl oxygen, positive hexyloxy, dissident's epoxide, 3- methyl amoxy etc..
Described C3-C6 cycloalkyl refers to the aliphatic carbon ring group on ring with 3 to 6 carbon atoms, its specific example Including cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl etc..
Described 6-10 unit aryl refers to the armaticity carbocylic radical on ring with 6 to 10 carbon atoms, its specific example bag Include phenyl, naphthyl etc..
The described heteroatomic 5-10 unit's heteroaryl containing 1-3 in N, O and S refer to have on ring 5 to 10 atoms and comprise the 1-3 heteroatomic armaticity ring group in N, O, S, such as pyridine radicals, pyrrole radicals, Pyrimidine radicals, pyrazinyl, pyridazinyl, thienyl, furyl, pyrazolyl, imidazole radicals, oxazolyl, thiazolyl, indyl, Azaindolyl, naphthyridinyl or quinolyl etc..Term is " containing the 1-2 heteroatomic 5-10 in N, O and S Unit's heteroaryl " has similar implication.
The described heteroatomic 5-7 unit hetero-aromatic ring containing 1-3 in N, O and S refers to have 5 to 7 on ring Individual atom and comprise the 1-3 heteroatomic armaticity ring in N, O, S, such as pyridine ring, pyrrole ring, pyrimidine Ring, pyrazine ring, pyridazine ring, thiphene ring, furan nucleuss, pyrazole ring, imidazole ring, azoles ring, thiazole ring etc..Term " contains Have 1-2 selected from N, O and the heteroatomic 5-7 unit hetero-aromatic ring in S " there is similar implication.
The described 1-3 heteroatomic 5-7 unit non-aromatic heterocyclic rings in N, O and S that comprise refer to have on ring 5 to 7 atoms and comprise the 1-3 heteroatomic nonaro-maticity ring group in N, O, S, such as nafoxidine ring, Tetramethylene sulfide ring or oxolane ring etc..Term is " non-aromatic containing the 1-2 heteroatomic 5-7 unit in N, O and S Fragrance heterocycle " has similar implication.
In the present invention, particularly preferred particular compound is one of following compounds：
Described pharmaceutically acceptable salt, for example, can be alkali metal salt (for example, sodium salt, potassium salt, lithium salts, cesium salt etc.)； Alkali salt (such as calcium salt, magnesium salt, strontium salt etc.) etc.；Ammonium salt；With salt formed by organic base, such as with three (rudimentary) Alkylamine (such as trimethylamine, triethylamine, N- ethyl diisopropylamine etc.), pyridine, quinoline, piperidines, imidazoles, methyl pyrrole Pyridine, dimethylamino naphthyridine, dimethylaniline, N- (rudimentary) alkyl morpholine (such as N-methylmorpholine etc.), 1,5- phenodiazine Miscellaneous bicyclic [4.3.0] nonene -5 (DBN), 1,8- diazabicyclo [5.4.0] endecatylene -7 (DBU), 1,4- diazabicyclo The formed salt such as [2.2.2] octane (DABCO)；Inorganic acid salt, such as hydrochlorate, hydrobromate, hydriodate, sulfur Hydrochlorate, nitrate, phosphate, carbonate etc.；Acylate, such as formates, acetate, propionate, oxalates, Malonate, succinate, fumarate, maleate, lactate, malate, citrate, citrate, Tartrate, carbonate, picrate, mesylate, esilate, tosilate, glutamate, Glu, double hydroxyl naphthalene Hydrochlorate etc..
The pharmaceutically acceptable salt of the pyridazinone compound shown in formula I that the present invention provides can pass through formula I institute The pyridazinone compound showing is dissolved in being reacted in the alcoholic solution of sour saturation accordingly to be prepared, for example：The present invention is carried For pyridazinone compound be dissolved in the methanol solution of HCl saturation, be stirred at room temperature 30 minutes, solvent be evaporated, that is, be obtained Corresponding hydrochlorate.
The pyridazinone compound of the present invention or its pharmaceutically acceptable salt are in the case of not affecting its application effect, permissible Used with forms such as its isomer, prodrug or solvates further, skilled artisan would appreciate that the pyridazine of the present invention The above-mentioned form of ketone compounds is also within protection scope of the present invention.
Described isomer includes geometric isomer, stereoisomer etc..
Described prodrug refers to that the inactive in vitro or activity that medicine obtains after modifying for chemical structure is less, in vivo through enzyme Or the conversion of non-enzymatic discharges active medicine and plays the compound of drug effect.Prodrug forms in the present invention are not specially limited, As long as it is in vivo through the active compound that enzyme or chemical action release are active, thus pharmacological action expected from playing, permissible It is precursor carrier medicine or bioprecursor.
Described solvate, for example, can be hydrate, ethanolates etc., and preferred solvate is hydrate.
According to a further aspect in the invention, the invention provides the preparation method of the pyridazinone compound shown in formula I, it is somebody's turn to do Method is passed through one of formulas below and is realized：
Circuit 1：
Circuit 2：
Wherein A, R1、R2、R3Definition the definition in formula I is identical with it,
Each route is specific as follows：
Route 1：Hydrazine hydrate cyclization after compound shown in formula 1, with acetone acid condensation obtains compound shown in formula 2, Again with nucleophilic substitution carried out to benzyl chloride chlorine obtain the pyridazinone compound shown in formula 4；
Route 2：Compound shown in formula 5, obtains the compound shown in formula 6 and 7, shown in formula 7 after hydrolysis Compound with nucleophilic substitution carried out to benzyl chloride chlorine obtain the compound shown in formula 8, finally in metallic catalyst or alkali In the presence of, by coupling reaction (suzuki reaction), obtain the pyridazinone compound shown in formula 9；
Route 3：Hydrazine hydrate cyclization after compound shown in formula 1, with glyoxalic acid condensation obtains the chemical combination shown in formula 10 Thing, with grignard reagent R1MgBr carries out Michael additive reaction and obtains the compound shown in formula 11, finally and to benzyl chloride Chlorine carries out nucleophilic substitution and obtains the pyridazinone compound shown in formula 12.
Nucleophilic substitution described in route 1, route 2 and route 3 can such as potassium carbonate, cesium carbonate, sodium hydride, In the presence of the alkali such as hydrofining, potassium tert-butoxide, sodium tert-butoxide, sodium hydroxide such as acetonitrile, N,N-dimethylformamide, Carry out in oxolane equal solvent；
Hydrolysis condition described in route 2 is to carry out in a solvent under acidity or alkalescence condition；Described acid is preferably One or more of acetic acid, hydrochloric acid, sulphuric acid, trifluoroacetic acid；Described alkali is preferably potassium hydroxide, sodium hydroxide, acetic acid One or more of potassium, sodium acetate, potassium tert-butoxide, sodium tert-butoxide；Described solvent is preferably ethanol, methanol, water, second One or more of acid.
Coupling reaction condition described in route 2, is the conventional selection of those skilled in the art.In general, selecting such as DMF (DMF), toluene, Isosorbide-5-Nitrae-dioxane are solvent, in the presence of metallic catalyst, alkali and part Carry out in a heated condition.Described heating condition is known to those skilled in the art, for example, can be heated to reflux or use Microwave heating.Described alkali is known to those skilled in the art, such as cesium carbonate, potassium carbonate, potassium tert-butoxide, sodium tert-butoxide Deng.Described metallic catalyst is known to those skilled in the art, for example palladium, Pd (PPh3)4、Pd(dppf)2Cl2 Deng.Described part is known to those skilled in the art, such as triphenylphosphine, DPPP (1,1'- double (diphenylphosphine) two cyclopentadienyl Ferrum), BINAP (dinaphthalene diphenylphosphine), Sphos (2- dicyclohexylphosphontetrafluoroborate -2 ', 6 '-dimethoxy-biphenyl), Davephos (2- bicyclo- Own phosphino- -2'- (N, N dimethylamine)-biphenyl) etc..
Grignard reagent R described in route 31MgBr is known to those skilled in the art, such as alkyl bromination magnesium, cycloalkanes Base magnesium bromide, aryl magnesium bromide, such as methyl-magnesium-bromide, ethylmagnesium bromide, isopropyl magnesium bromide, normal-butyl magnesium bromide, ring Propyl group magnesium bromide, cyclohexyl magnesium bromide, phenyl-magnesium-bromide.
Michael additive reaction condition described in route 3 is carried out under solvent；Described solvent is preferably oxolane, 2- Methyltetrahydrofuran, ether, toluene, benzene.
According to another aspect of the invention, the invention provides the pyridazinone compound shown in formula I or its pharmaceutically can connect Purposes in preparing hepatitis B viruss inhibitor for the salt being subject to, and be used for preventing and/or treat hepatitis B disease in preparation Purposes in the medicine of disease.
In accordance with a further aspect of the present invention, present invention also offers a kind of 2H-Pyridazin-3-one shown in formula I comprising therapeutically effective amount The pharmaceutical composition of one or more of class compound or its pharmaceutically acceptable salt.Described pharmaceutical composition can conduct Hepatitis B viruss inhibitor, for preventing and/or treating hepatitis B, further, this pharmaceutical composition can be optional Comprise pharmaceutically acceptable carrier or excipient.
Above-mentioned pharmaceutically acceptable carrier refers to the conventional pharmaceutical carrier of pharmaceutical field, for example：Diluent, such as water etc.；Fill out Fill agent, such as starch, sucrose etc.；Binding agent, such as cellulose derivative, alginate, gelatin, Polyvinylpyrrolidone；Wet Profit agent, such as glycerol；Disintegrating agent, such as agar, Calcium Carbonate and sodium bicarbonate；Absorption enhancer, such as quaternary ammonium compound；Surface Activating agent, such as hexadecanol；Absorption carrier, such as Kaolin and soap clay；Lubricant, such as Pulvis Talci, calcium stearate and hard Fatty acid magnesium and Polyethylene Glycol etc..Furthermore it is also possible to add other adjuvant in aforementioned pharmaceutical compositions, such as flavouring agent and sweet Taste agent etc..
According to another aspect of the invention, present invention also offers the method for prevention and/or treatment hepatitis B disease, described Method includes applying the pyridazinone compound shown in formula I of therapeutically effective amount or in its pharmaceutically acceptable salt Kind or the multiple or present invention aforementioned pharmaceutical compositions to patient.
It is this that compound that the present invention provides or compositionss can be applied to needs by way of oral, rectum or parenteral administration The patient for the treatment of.The solid preparation of routine, such as tablet, powder, granule, capsule etc. during for being administered orally, can be made into, Or make liquid preparation, and such as water or oil-suspending agent, or other liquid preparation, such as syrup etc.；For during parenteral administration, can be by It makes the solution of injection, water or oleaginous suspension etc..
The method have the advantages that：
By the detection to the toxicity of HepG2.2.15 cell and the activity of suppression HBV DNA for the compounds of this invention, invention People finds：In the compound that above-mentioned formula I represents, the HBV DNA inhibitory activity of multiple compounds below 3 μM, Best compound inhibitory activity is less than 0.4 μM.Therefore, the compound that formula I represents is effective hepatitis B viruss suppression Preparation.
Specific embodiment
The following examples are used for specifically describing the preparation of the pyridazinone compound of present invention offer, and it is as B-mode The biologic activity of hepatitis viruss inhibitor, but the invention is not limited in these embodiments.
In the examples below, proton nmr spectra BrukerAMX-400 type, Gemini-300 type or AMX 600 Type nuclear magnetic resonance analyser record, the unit of chemical shift δ is ppm.Specific rotatory power is by the automatic optically-active of Perkin-Elmer241 type Instrument measures, and microwave used is CEM-discovery microwave reactor.If no special instructions, all reaction dissolvents are all according to normal Rule method carries out purification.Column chromatography silica gel (200-300 mesh) is that Qingdao Haiyang chemical industry subsidiary factory produces.Thin layer chromatography uses The efficient plate of GF254, is that Yantai chemical institute produces.Preparative thin-layer chromatography plate is by Chinese Academy of Sciences's Shanghai drug research Prepared, fixing phase adopts GF254 (HG/T2354-92) silica gel and sodium carboxymethyl cellulose (800-1200) preparation, respectively Qingdao Marine Chemical Co., Ltd. and China Medicine (Group) Shanghai Chemical Reagent Co., produce.As no especially marked, Suo Yourong Agent is analytical reagent, and agents useful for same is purchased from Chemical Reagent Co., Ltd., Sinopharm Group.Using the side such as iodine, Ultraluminescence Method develops the color.Remove organic solvent under reduced pressure to carry out in Rotary Evaporators.
The preparation of compound：
Embodiment 1：
Step 1：
5g 4- fluoro acetophenone is added in 3.76ml acetone acid, after stirring 10h at 120 DEG C, is cooled to room temperature, in ice Under bath, ammonia is added to adjust pH to 8-9, aqueous layer with ethyl acetate extracts unreacted 4- fluoro acetophenone.Water layer adds 4ml After hydrazine hydrate (85%), 100 DEG C of backflows are overnight.Next day cools down reactant liquor, now has solid to separate out, it is white that sucking filtration obtains 5.2g Color solid (compound 2) (yield 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).
Step 2：
100mg midbody compound 2 is dissolved in 30ml DMF (DMF), adds 94mg P-chlorobenzylchloride and 190mg cesium carbonate, reactant liquor reacts 5-6 hour at 50 DEG C, and TLC shows that substrate is wholly absent, and stops Reactant liquor is simultaneously cooled to room temperature by reaction, and reactant liquor is extracted with ethyl acetate, and organic layer is done with anhydrous sodium sulfate after washing 3 times Dry, concentrate, column chromatography obtains 100mg white solid (compound I-1) (yield 62%).1H NMR(300MHz,CDCl3) δ 7.75 (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).
Prepare following compound in the same manner as in Example 1：
Embodiment 2
Step 1：
By 10g 3, the chloro- 4- methyl pyridazine of 6- bis- is dissolved in 100ml acetic acid, and 120 DEG C of backflow 4h, TLC show that substrate is wholly absent, Reactant liquor is simultaneously cooled to room temperature by stopped reaction, and decompression boils off acetic acid and obtains solid.Add 200ml ethyl acetate, will not Molten solid filtration, gained white solid is midbody compound 7 (3g, yield 33%).1H NMR(300MHz,DMSO) δ13.02(s,1H),6.89(s,1H),2.16(s,3H).
Filtrate is dried, and concentrates, and it is midbody compound 6 (4g, yield 44%) that column chromatography obtains white solid.1H NMR(300 MHz, DMSO) δ 13.03 (s, 1H), 7.43 (d, J=1.3Hz, 1H), 2.04 (d, J=1.2Hz, 3H).
Step 2：
500mg midbody compound 7 is dissolved in 50ml DMF (DMF), adds 670mg to chlorine Benzyl chloride and 1.35g cesium carbonate, reactant liquor reacts 5-6 hour at 50 DEG C, and TLC shows that substrate is wholly absent, and stopped reaction is simultaneously Reactant liquor is cooled to room temperature, reactant liquor is extracted with ethyl acetate, organic layer uses anhydrous sodium sulfate drying after washing 3 times, dense Contracting, column chromatography obtains 700mg white solid (compound 8a) (yield 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).
Step 3：
100mg compound 8a is dissolved in 30ml Isosorbide-5-Nitrae-dioxane (Isosorbide-5-Nitrae-dioxane) and 3ml water, sequentially adds 62mg To fluorobenzoic boric acid, 30mg Pd (dppf)2Cl2([1,1'- double (diphenylphosphine) ferrocene] palladium chloride dichloromethane complex) and 197mg potassium phosphate, with nitrogen displacement 3 times, 100 DEG C of reactions are overnight.TLC shows that substrate is wholly absent, and stopped reaction simultaneously will Reactant liquor is cooled to room temperature, and reactant liquor is extracted with ethyl acetate, and organic layer uses anhydrous sodium sulfate drying after washing 3 times, concentrates, Column chromatography obtains 72mg white solid (compound I-2) (yield 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).
Embodiment 3
Step 1：
500mg intermediate 6 (preparing in embodiment 2) is dissolved in 50ml DMF, adds 670mg p-chlorobenzylchloride With 1.35g cesium carbonate, reactant liquor reacts 5-6 hour at 50 DEG C, and TLC shows that substrate is wholly absent, and stopped reaction simultaneously will be anti- Answer liquid to be cooled to room temperature, reactant liquor is extracted with ethyl acetate, organic layer uses anhydrous sodium sulfate drying after washing 3 times, concentrate, Column chromatography obtains 700mg white solid (compound 8b) (yield 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).
Step 2：
100mg compound 8b is dissolved in 30ml DMF and 3ml water, sequentially adds 93mg 1- methyl -4- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolan -2- base) -1H- pyrazoles, 30mg Pd (dppf)2Cl2([double (diphenylphosphine) ferrocene of 1,1'-] dichloro Change palladium dichloromethane complex) and 197mg potassium phosphate, with nitrogen displacement 3 times, 100 DEG C are reacted overnight.TLC shows substrate It is wholly absent, reactant liquor is simultaneously cooled to room temperature by stopped reaction, and reactant liquor is extracted with ethyl acetate, after organic layer washes 3 times With anhydrous sodium sulfate drying, concentrate, column chromatography obtains 68mg white solid (compound I-19) (yield 58%).1H NMR (300MHz,CDCl3) δ 7.60 (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).
Following compound is prepared with method same as Example 3：
Embodiment 4：
150mg compound I-18 (preparing in embodiment 1) is dissolved in 25ml 95% ethanol, adds 94.4mg reduction Iron powder and 1.56ml acetic acid, flow back 4h.TLC shows that substrate is wholly absent, and filters out solid, and filtrate decompression is distilled off, It is extracted with ethyl acetate, organic layer uses anhydrous sodium sulfate drying after washing 3 times, concentrates, column chromatography obtains 80mg yellow solid (compound I-32) (yield 60%).1H NMR (300MHz, DMSO) δ 7.83 (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) δ 7.59 (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).
Embodiment 5：
60mg compound I-20 (preparing in embodiment 3) is dissolved in 20ml dichloromethane, adds 20 μ l chloroacetic chlorides and 30 μ l pyridine, is stirred overnight at room temperature.TLC shows that substrate is wholly absent, and reactant liquor uses anhydrous sodium sulfate drying after washing 3 times with water, Concentrate, column chromatography obtains 20mg white solid (compound I-33) (yield 30%).1H NMR(400MHz,CDCl3)δ 8.66 (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).
Following compound is prepared with method same as Example 5：
Embodiment 6：
100mg compound I-15 (preparing in embodiment 1) is dissolved in 30ml toluene, sequentially adds 26mg methylamine salt Hydrochlorate, 48mg Pd2(dba)3(three (double BENZYLIDENE ACETONE) two palladiums), 41mg S-Phos (2- dicyclohexylphosphontetrafluoroborate -2 ', 6 '-diformazan Epoxide-biphenyl) and 127mg cesium carbonate, with nitrogen displacement 3 times, 100 DEG C of reactions are overnight.TLC shows that substrate is wholly absent, Reactant liquor is simultaneously cooled to room temperature by stopped reaction, and reactant liquor is extracted with ethyl acetate, and organic layer uses anhydrous slufuric acid after washing 3 times Sodium is dried, and concentrates, and column chromatography obtains 50mg white solid (compound I-36) (yield 56%).1H NMR(300MHz, CDCl3) δ 7.62 (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).
Prepare following compound to the same method as example 6：
Embodiment 7：
Step 1：
2g compound I-15 (in embodiment 1 prepare) is dissolved in 100ml N, N- dimethyl sulfoxide (DMSO), successively Add 24ml methanol, 345mg palladium, 433mg dppf ([1,1'- double (diphenylphosphine) ferrocene) and 5.9ml tri- second Amine, is replaced 3 times with CO, 100 DEG C of reactions are overnight.TLC shows that substrate is wholly absent, and reactant liquor is simultaneously cooled down by stopped reaction To room temperature, reactant liquor is extracted with ethyl acetate, and organic layer uses anhydrous sodium sulfate drying after washing 3 times, concentrates, and column chromatography obtains 1.1g white solid (compound 13) (yield 58%).1H NMR(300MHz,CDCl3) δ 8.11 (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).
Step 2：
250mg compound 13 is dissolved in 30ml oxolane (THF) and 20ml water, adds 70mg Lithium hydrate, It is stirred overnight at room temperature.TLC shows that substrate is wholly absent, and vacuum distillation removes solvent, is extracted with ethyl acetate, organic layer water Use anhydrous sodium sulfate drying after washing 3 times, concentrate, column chromatography obtains 230mg white solid (compound I-38) (yield 96%).1H NMR (300MHz, CDCl3) δ 8.19 (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).
Step 3：
50mg compound I-38 is dissolved in 20ml dichloromethane, adds 23mg methylamine hydrochloride, 32mg EDC (1- Ethyl-(3- dimethylaminopropyl) phosphinylidyne diimmonium salt hydrochlorate), 23mg HOBT (I-hydroxybenzotriazole) and 100 μ l Triethylamine, is stirred overnight at room temperature.TLC shows that substrate is wholly absent, and reactant liquor uses anhydrous sodium sulfate drying after washing 3 times with water, Concentrate, column chromatography obtains 30mg white solid (compound I-39) (yield 58%).1H NMR(300MHz,CDCl3)δ 7.84 (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).
Following compound is prepared with method same as Example 7：
Embodiment 8：
Step 1：
5g 4- fluoro acetophenone is added 250ml round-bottomed flask with 13.3g mono- glyoxylic acid, after stirring 10h at 120 DEG C, It is cooled to room temperature, under ice bath, add ammonia to adjust pH to 8-9, aqueous layer with ethyl acetate extracts unreacted 4- fluorophenethyl Ketone.After water layer adds 4ml hydrazine hydrate (85%), 100 DEG C of backflows are overnight.Next day cools down reactant liquor, now has solid to analyse Go out, sucking filtration obtains 5g white solid (compound 10) (yield 73%).
Step 2：
2.6ml 2M n-pro-pyl grignard reagent is dissolved in the 2- methyltetrahydrofuran of 30ml, adds 200mg compound 10, With nitrogen displacement 3 times, 90 DEG C of reactions are overnight.TLC shows that substrate is wholly absent, and reactant liquor is simultaneously cooled to room by stopped reaction Temperature, reactant liquor is extracted with ethyl acetate, and organic layer uses anhydrous sodium sulfate drying after washing 3 times, concentrates, and column chromatography obtains 130mg White solid (compound 11) (yield 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).
Step 3：
100mg compound 11 is dissolved in 30ml DMF, adds 84mg p-chlorobenzylchloride and 168mg cesium carbonate, instead Liquid is answered to react 5-6 hour at 50 DEG C, TLC shows that substrate is wholly absent, reactant liquor is simultaneously cooled to room temperature by stopped reaction, Reactant liquor is extracted with ethyl acetate, and organic layer uses anhydrous sodium sulfate drying after washing 3 times, concentrates, it is white that column chromatography obtains 90mg Color solid (compound I-45) (yield 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).
Following compound is prepared with method same as Example 8：
Embodiment 9：
Step 1：
By 5g 3,4- thiophene dicarboxylic acid is dissolved in 50ml dehydrated alcohol, adds 0.5ml hydrazine hydrate (85%), backflow 4 It is cooled to room temperature, sucking filtration obtains 4.5g white solid (compound 14) (yield 97%) after hour.
Step 2：
4.5g compound 14 is dissolved in 50ml thionyl chloride, backflow was cooled to room temperature after 7 hours, and vacuum distillation is removed After removing thionyl chloride, add frozen water in residue, be then extracted with ethyl acetate (2x50mL), organic layer is washed 3 times Use anhydrous sodium sulfate drying afterwards, concentrate, column chromatography obtains 1g white solid (compound 15) (yield 19%).
Step 3：
1g compound 15 is dissolved in 20mL glacial acetic acid, backflow was cooled to room temperature, removal of solvent under reduced pressure after 4 hours After obtain white solid (compound 16) about 1g (yield>100%).
Step 4：
260mg compound 16 is dissolved in 20mL DMF, adds 225mg to benzyl chloride rate and 455mg cesium carbonate, 50 DEG C are reacted 5 hours, and TLC shows that substrate is wholly absent, and reactant liquor is simultaneously cooled to room temperature, reactant liquor second by stopped reaction Acetoacetic ester extracts, and organic layer uses anhydrous sodium sulfate drying after washing 3 times, concentrates, and column chromatography obtains 120mg white solid and (changes Compound 17) (yield 28%).
Step 5：
100mg compound 17 is dissolved in 30ml Isosorbide-5-Nitrae-dioxane and 3ml water, sequentially add 62mg to fluorobenzoic boric acid, 30mg Pd(dppf)2Cl2([double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex) and 137mg phosphoric acid Potassium, with nitrogen displacement 3 times, 100 DEG C of reactions are overnight.TLC shows that substrate is wholly absent, and reactant liquor is simultaneously cooled down by stopped reaction To room temperature, reactant liquor is extracted with ethyl acetate, and organic layer uses anhydrous sodium sulfate drying after washing 3 times, concentrates, and column chromatography obtains 80mg white solid (compound I-49) (yield 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=8.5 Hz,2H),5.35(s,2H).
Following compound is prepared with method same as Example 9：
Testing example 1：The impact of the Compounds on Hepatitis B viral dna replication ability being obtained in the embodiment of the present invention
1st, experiment material
1.1 screening systems
The human liver cancer cell HepG2.2.15 cell strain (offer of institute of materia medica of the Chinese Academy of Sciences) of stable transfection total length HBV
1.2 experimental apparatus
Incubator (ThermoForma3111)；Microplate reader (Molecular Devices Spectra Max 190)；Electronics sky Flat；Microscope；Biohazard Safety Equipment (Heal Force safe15)；Centrifuge (Eppendorf Centrifuge 5810R)； Real-Time PCR(FASTA GEN-DNA fast2000)
1.3 Experimental agents and reagent
Positive drug and configuration：Lamivudine (3TC), is combined into by Chinese Academy of Sciences's Shanghai institute of materia medica pharmaceutical chemistry, uses DMEM/High Glucose culture fluid (Dulbecco ' s modified Eagle ' s medium, Hyclone company) configures Become 40mM liquid storage stand-by.
Other solution and configuration：
DMEM/High Glucose culture fluid：Dulbecco’s modified Eagle’s medium 1×(Hyclone Company) phosphate buffer (PBS, pH7.3,1L)：NaCl, 8.0g；Na2HPO4, 1.16g；KH2PO4, 0.2g； KCl：0.2g；
MTT solution：MTT (Sigma company), is configured to 5mg/ml with PBS；
DNA extraction agent box：Blood＆Tissue (Qiagen company)
2nd, experimental technique
2.1 cell culture
HepG2.2.15 cell subculture according to a conventional method.Using culture medium be DMEM, be contained within 10% (v/v) Ox blood serum and selection antibiotic G418, at 37 DEG C, 5%CO2Incubator in cultivate 8 days (changing liquid on the 4th day).
2.2 testing compounds and the preparation of positive drug
Testing compound DMSO is configured to the storing solution of 40mM, containing 10%HycloneTMFetal Bovine Serum DMEM culture fluid be made into the solution of specified maximum concentration and dilute；Positive drug is Lamivudine, equally to contain 10%HycloneTMThe DMEM culture fluid of Fetal Bovine Serum is made into prescribed concentration.
2.3 MTT measure cytotoxicity
HepG2.2.15 cell is with 5 × 103Cells/well is inoculated in 96 orifice plates, cultivates eight days as stated above under medicine effect, Add MTT solution after taking out supernatant 200 μ l, add lysate after culture 4h, after culture 12h, measure OD with microplate reader570, It is compared with the absorbance of control wells, calculating survivaling cell percentage ratio, and calculate cause half cytotoxicity desired concn CC50.
The mensure of HBV DNA content in 2.4 cells and supernatant
HepG2.2.15 cell, after the compound effects 8 days (changing liquid on the 4th day) of variable concentrations, draws culture supernatant, adopts PCR (Real-time PCR) standard measure detects the HBV DNA that in supernatant, mature virion is contained within real time.
Post carry HepG2.2.15 cell conditioned medium DNA (Qiagen,Blood&Tissue Handbook)
1) receive 96 orifice plate supernatant DNA, the every hole of 200 μ l, multiple holes are all collected to same EP pipe, 4000rcf*5min from The heart, takes supernatant；
2) take 200 supernatants, add in 1.5ml EP pipe, add 20 μ l E.C. 3.4.21.64s and 200 μ l Buffer AL (Qiagen,Blood＆Tissue Kit), being vortexed makes it mix completely, 56 DEG C of incubation 10min；
3) 200 ethanol are added, being vortexed makes it mix completely；
4) by the 3rd) liquid of step all adds the DNeasy Mini spin column being placed in 2ml waste collection pipe (Qiagen,Blood＆Tissue Kit), 6000rcf*1min is centrifuged, supernatant discarded；
5) DNeasy Mini spin column is placed in new 2ml waste collection pipe, adds 500 μ l Buffer AW1 (Qiagen,Blood＆Tissue Kit), 6000rcf*1min is centrifuged, supernatant discarded；
6) DNeasy Mini spin column is placed in new 2ml waste collection pipe, adds 500 μ l Buffer AW2, (Qiagen,Blood＆Tissue Kit) 20000rcf*3min centrifugation, supernatant discarded；
7) DNeasy Mini spin column is placed in new 1.5ml EP pipe, absorption 50 μ l Buffer AE (Qiagen,Blood＆Tissue Kit) it is directly added on the film of DNeasy Mini spin column, place 5min in room temperature, 6000rcf*1min is centrifuged the DNA on eluting film, discards DNeasy Mini spin column, collects DNA sample to -20 DEG C.
The supernatant HBV DNA of PCR detection in real time (different in nature HBV nucleic acid immue quantitative detection reagent box reaches peace gene)
1) standard curve：1e7-1e4IU/ml, 1 μ l loading, a blank well is set, to detect whether reaction system pollutes；
2) add DNA sample 1 μ l in order；
3) enzyme and reaction buffer are added：First two tube reaction liquid are added in enzyme, after mixing, somewhat centrifugation is placed on ice, Add enzyme reaction solution 19 μ l after introduction of the sample, during addition, guarantee that not touching DNA sample pollutes；
4) stick sealer, centrifugation；
5) PCR reaction：
First stage:93 DEG C, 2min
Second stage:10 circulations
The first step：93 DEG C, 45s
Second step：55 DEG C, 1min
Phase III：45 circulations
The first step：93 DEG C, 30s
Second step：55 DEG C, 45s
Sample：20μl
Detection：Collect data in the second step (55 DEG C, 45s) completing the phase III afterwards.
2.8 data processing
Using Origin software, experimental data is counted, calculate IC50
Experimental result：
Experimental result is as shown in table 1.
Table 1：The activity to the toxicity of HepG2.2.15 cell and suppression HBV DNA for the part of compounds of the embodiment of the present invention
Compound 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
Note：CC50For the impact of the growth to HepG2.2.15 cell for the example pharmaceuticals, half (50%) lethasl concentration.
IC50The suppression that position example pharmaceuticals replicate to hepatitis B virus DNA reaches concentration during half (50%).
From test result it can be seen that such compounds main waits until excellent suppression HBV all having on a cellular level The activity of DNA replication dna, the wherein IC of 35 compounds50Less than 10 μM.
Above-described embodiment is only used as descriptive purpose, and the scope of the present invention is not limited thereto.Those skilled in the art is come Saying modifies is it will be apparent that the present invention is only limited by scope.

Claims (10)

1. the pyridazinone compound shown in below formula I or its pharmaceutically acceptable salt：
Wherein,
R1、R2It is each independently H, C1-C7 straight or branched alkyl, C3-C6 cycloalkyl or 6-10 unit aryl, or Person R1And R2Formed together with the carbon atom being connected containing the 1-3 heteroatomic 5-7 unit heteroaryl in N, O and S Ring or non-aromatic heterocyclic rings,
A be 6-10 unit's aryl or containing 1-3 the heteroatomic 5-10 unit's heteroaryl in N, O and S,
R3Represent one or more substituent groups, preferably represent 1,2 or 3 substituent groups, described substituent group is selected independently of one another From H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxyl,
Wherein, n is the integer selected from 0 to 10；
R4For H, halogen, C1-C7 straight or branched alkyl, C3-C6 cycloalkyl, 6-10 unit aryl, contain 1-3 choosing Heteroatomic 5-10 unit's heteroaryl from N, O and S, amino that is unsubstituted or being replaced by 1-2 substituent group；Wherein, Substituent group in described " amino being replaced by 1-2 substituent group " is C1-C7 straight or branched alkyl.
2. pyridazinone compound according to claim 1 or its pharmaceutically acceptable salt it is characterised in that
R1、R2It is each independently H, C1-C4 straight or branched alkyl, C3-C6 cycloalkyl or phenyl, or R1With R2Form containing 1-2 heteroatomic 5-7 unit's hetero-aromatic ring or non-aromatic in N, O and S together with the carbon atom being connected Fragrance heterocycle,
A be phenyl or containing 1-2 the heteroatomic 5-10 unit's heteroaryl in N, O and S,
R3Represent one or more substituent groups, preferably represent 1,2 or 3 substituent groups, described substituent group is selected independently of one another From H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxyl,
Wherein, n is the integer selected from 0 to 7；
R4For H, halogen, C1-C7 straight or branched alkyl, C3-C6 cycloalkyl, 6-10 unit aryl, contain 1-3 choosing Heteroatomic 5-10 unit's heteroaryl from N, O and S, amino that is unsubstituted or being replaced by 1-2 substituent group；Wherein, Substituent group in described " amino being replaced by 1-2 substituent group " is methyl, ethyl, propyl group or butyl.
3. pyridazinone compound according to claim 1 or its pharmaceutically acceptable salt it is characterised in that
R1、R2It is each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl or phenyl, or R1And R2With phase With carbon atom together with form pyrrole ring, thiphene ring, furan nucleuss, pyrazine ring, nafoxidine ring, Tetramethylene sulfide ring or tetrahydrochysene Furan nucleuss；
A be phenyl, pyridine radicals, pyrrole radicals, pyrimidine radicals, pyrazinyl, pyridazinyl, thienyl, furyl, pyrazolyl, Imidazole radicals, oxazolyl, thiazolyl, indyl, azaindolyl, naphthyridinyl or quinolyl；
R3Represent one or more substituent groups, preferably represent 1,2 or 3 substituent groups, described substituent group is selected independently of one another From H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxyl,
Wherein, n is 0,1,2,3 or 4；
R4For H, halogen, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or be that first is selected from by 1-2 The amino that substituent group in base, ethyl, propyl group or butyl replaces.
4. pyridazinone compound according to claim 1 or its pharmaceutically acceptable salt it is characterised in that
R1、R2It is each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl or phenyl, or R1And R2With phase With carbon atom together with form pyrrole ring, thiphene ring, furan nucleuss, pyrazine ring, nafoxidine ring, Tetramethylene sulfide ring or tetrahydrochysene Furan nucleuss；
A is phenyl, pyridine radicals, pyrimidine radicals, pyrazinyl, pyrazolyl, pyridazinyl, indyl, azaindolyl, naphthyridines Base or quinolyl；
R3Represent one or more substituent groups, preferably represent 1,2 or 3 substituent groups, described substituent group is selected independently of one another From H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxyl,
Wherein, n is 0,1,2,3 or 4；
R4For H, halogen, methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or be that first is selected from by 1-2 The amino that substituent group in base, ethyl, propyl group or butyl replaces.
5. the pyridazinone compound according to any one of claim 1-4 or its pharmaceutically acceptable salt, it is special Levy and be, described compound is selected from the compound of the structure shown in one of below formula I-I to I-VIII：
Wherein, R1、R2、R3Definition and respective right require the definition in formula of I identical；
Preferably, in formula I-I, R1、R2Be each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl or Phenyl, or R1And R2Form pyrrole ring, thiphene ring, furan nucleuss, pyrazine ring, tetrahydrochysene pyrrole together with the carbon atom being connected Cough up ring, Tetramethylene sulfide ring or oxolane ring；R3Represent 1,2 or 3 substituent groups, described substituent group is selected independently of one another From H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxyl, Wherein, n is 0,1,2,3 or 4；R4For H, halogen, Methyl, ethyl, propyl group, isopropyl, butyl, isobutyl group or be selected from methyl, ethyl, propyl group or fourth by 1-2 The amino that substituent group in base replaces；
Preferably, in formula I-II, R1、R2Be each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl or Phenyl；R3Represent 1 or 2 substituent group, described substituent group is each independently selected from H, halogen, cyano group, nitro, C1-C7 Straight or branched alkyl, C1-C6 straight or branched alkoxyl,Wherein, n be 0,1, 2nd, 3 or 4；R4For H, halogen, methyl, ethyl, propyl group, isopropyl, butyl or isobutyl group；
Preferably, in formula I-III, R1、R2It is each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl Or phenyl；R3Represent 1 or 2 substituent group, described substituent group be each independently selected from H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxyl,Wherein, n For 0,1,2,3 or 4；R4For H, halogen, methyl, ethyl, propyl group, isopropyl, butyl or isobutyl group；
Preferably, in formula I-IV, R1、R2It is each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl Or phenyl；R3Represent 1 or 2 substituent group, described substituent group be each independently selected from H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxyl orWherein, n is 0,1,2,3 Or 4；R4For H, halogen, methyl, ethyl, propyl group, isopropyl, butyl or isobutyl group；
Preferably, in formula I-V, R1、R2It is each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl Or phenyl；R3Represent 1 or 2 substituent group, described substituent group be each independently selected from H, halogen, cyano group, nitro, C1-C6 straight or branched alkyl, C1-C6 straight or branched alkoxyl,Wherein, n For 0,1,2,3 or 4；R4For H, halogen, methyl, ethyl, propyl group, isopropyl, butyl or isobutyl group；
Preferably, in formula I-VI, R1、R2It is each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl Or phenyl；R3Represent 1 or 2 substituent group, described substituent group be each independently selected from H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxyl,Wherein, n For 0,1,2,3 or 4；R4For H, halogen, methyl, ethyl, propyl group, isopropyl, butyl or isobutyl group；
Preferably, in formula I-VII, R1、R2It is each independently H, methyl, n-pro-pyl, cyclopropyl, cyclohexyl Or phenyl；R3Represent 1 or 2 substituent group, described substituent group be each independently selected from H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl, C1-C6 straight or branched alkoxyl orWherein, n is 0,1,2,3 Or 4；R4For H, halogen, methyl, ethyl, propyl group, isopropyl, butyl or isobutyl group；
Preferably, in formula I-VIII, R1、R2It is each independently H, methyl, n-pro-pyl, cyclopropyl, hexamethylene Base or phenyl；R3Represent 1 or 2 substituent group, described substituent group be each independently selected from H, halogen, cyano group, nitro, C1-C7 straight or branched alkyl or C1-C6 straight or branched alkoxyl.
6. pyridazinone compound according to claim 1 or its pharmaceutically acceptable salt are it is characterised in that institute Stating compound is one of following compounds：
7. a kind of method of the pyridazinone compound prepared any one of claim 1-6, methods described pass through with One of lower reaction equation is realized：
Circuit 1：
Circuit 2：
Circuit 3：
Wherein A, R1、R2、R3Definition with quote respective right requirement in definition identical,
Wherein：
Route 1：Hydrazine hydrate cyclization after compound shown in formula 1, with acetone acid condensation obtains compound shown in formula 2, Again with nucleophilic substitution carried out to benzyl chloride chlorine obtain the pyridazinone compound shown in formula 4；
Route 2：Compound shown in formula 5, obtains the compound shown in formula 6 and 7, shown in formula 7 after hydrolysis Compound with nucleophilic substitution carried out to benzyl chloride chlorine obtain the compound shown in formula 8, finally in metallic catalyst or alkali In the presence of, by coupling reaction, obtain the pyridazinone compound shown in formula 9；
Route 3：Hydrazine hydrate cyclization after compound shown in formula 1, with glyoxalic acid condensation obtains the chemical combination shown in formula 10 Thing, with grignard reagent R1MgBr carries out Michael additive reaction and obtains the compound shown in formula 11, finally and to benzyl chloride Chlorine carries out nucleophilic substitution and obtains the pyridazinone compound shown in formula 12；
Preferably, the nucleophilic substitution described in route 1, route 2 and route 3 is carried out in the presence of a base in a solvent； Described alkali is preferably in potassium carbonate, cesium carbonate, sodium hydride, hydrofining, potassium tert-butoxide, sodium tert-butoxide or sodium hydroxide Plant or multiple；Described solvent is preferably one or more of acetonitrile, N,N-dimethylformamide or oxolane；
Preferably, the hydrolysis described in route 2 are carried out under acidity or alkalescence condition in a solvent；Described acid is choosing From one or more of acetic acid, hydrochloric acid, sulphuric acid, trifluoroacetic acid；Described alkali is selected from potassium hydroxide, sodium hydroxide, second One or more of sour potassium, sodium acetate, potassium tert-butoxide, sodium tert-butoxide；Described solvent be selected from ethanol, methanol, water, One or more of acetic acid；
Preferably, the coupling reaction described in route 2 in a solvent, is heating in the presence of metallic catalyst, alkali and part Under the conditions of carry out；Described solvent is preferably DMF, toluene or Isosorbide-5-Nitrae-dioxane, described heating condition For being heated to reflux or using microwave heating；Described alkali is preferably in cesium carbonate, potassium carbonate, potassium tert-butoxide and sodium tert-butoxide Plant or multiple；Described metallic catalyst is preferably palladium, Pd (PPh3)4Or Pd (dppf)2Cl2One or more of；Institute State part be preferably triphenylphosphine, double (diphenylphosphine) ferrocene of 1,1'-, dinaphthalene diphenylphosphine, 2- dicyclohexylphosphontetrafluoroborate -2 ', 6 '-two One or more of Methoxy-biphenyl and 2- dicyclohexylphosphino -2'- (N, N dimethylamine)-biphenyl；
Preferably, the grignard reagent R described in route 31MgBr is selected from alkyl bromination magnesium, cycloalkyl magnesium bromide or aryl bromide Change magnesium, more preferably methyl-magnesium-bromide, ethylmagnesium bromide, isopropyl magnesium bromide, normal-butyl magnesium bromide, cyclopropyl bromination Magnesium, cyclohexyl magnesium bromide or phenyl-magnesium-bromide；
Preferably, the Michael additive reaction condition described in route 3 is carried out under solvent；Described solvent is selected from tetrahydrochysene One or more of furan, 2- methyltetrahydrofuran, ether, toluene or benzene.
8. pyridazinone compound according to any one of claim 1 to 6 or its pharmaceutically acceptable salt are in system It is ready for use on the purposes in prevention and/or the medicine for the treatment of hepatitis B disease.
9. a kind of pharmaceutical composition, it comprises the pyridazine according to any one of claim 1 to 6 of therapeutically effective amount One or more of ketone compounds or its pharmaceutically acceptable salt.
10. a kind of hepatitis B viruss inhibitor, its comprise therapeutically effective amount according to any one of claim 1 to 6 institute One or more of the pyridazinone compound stated or its pharmaceutically acceptable salt.
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