CN115677698A - High-efficiency antiviral compound and application thereof - Google Patents

High-efficiency antiviral compound and application thereof Download PDF

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CN115677698A
CN115677698A CN202211354886.0A CN202211354886A CN115677698A CN 115677698 A CN115677698 A CN 115677698A CN 202211354886 A CN202211354886 A CN 202211354886A CN 115677698 A CN115677698 A CN 115677698A
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李海德
侯雯
姜龙
潘伟
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Nanjing Zhihe Medical Technology Co ltd
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • A61K31/503—Pyridazines; Hydrogenated pyridazines spiro-condensed
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
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Abstract

The invention provides a compound shown as the following formula (I-0) or a hydrate, a solvate, an optical isomer, a polymorphic substance, an isotope derivative, a pharmaceutically acceptable salt and a preparation method thereof. The compound of the present invention can be used for the preparation of a medicament for the prophylaxis/treatment of viral infections including influenza virus.

Description

High-efficiency antiviral compound and application thereof
Technical Field
The invention relates to a compound with anti-influenza virus activity or hydrate, solvate, optical isomer, polymorphic substance, isotopic derivative, pharmaceutically acceptable salt thereof, a preparation method thereof and application thereof in resisting influenza virus.
Background
The influenza viruses mainly include four types of influenza a viruses, influenza b viruses, influenza c viruses and influenza d viruses, wherein the influenza a viruses and the influenza b viruses are the main human influenza viruses, the influenza a viruses are the strongest of them, the number of people infected in influenza-rich seasons is the largest, and severe respiratory infectious diseases can be induced, resulting in death of 30 or more thousand people from influenza every year worldwide. In China, tens of millions of people are infected with influenza viruses every year, particularly, the prevalence rate and the death rate of the influenza viruses are high in infants and old people, and diseases such as pneumonia can be caused.
At present, the main anti-influenza virus drugs on the market are: amantadine (Amantadine), the neuraminidase inhibitor Oseltamivir (Oseltamivir), or Zanamivir (Zanamivir).
The RNA polymerase of influenza virus contains Cap-dependent endonuclease (Cap-dependent endonucleases), and inhibition of the activity of the Cap-dependent endonuclease, which has become a promising target for the development of antiviral drugs, can inhibit the proliferation of viruses, and various heterocyclic compounds have been used as Cap-dependent endonuclease inhibitors.
However, these compounds show poor physicochemical properties, which in turn affect the relevant pharmacokinetic properties, making them less than ideal influenza therapeutics. Therefore, the development of new cap-dependent endonuclease inhibitors for the treatment of influenza is still imminent.
Disclosure of Invention
Unless otherwise specifically indicated herein, the terms used herein have the same basic meaning as commonly understood by one of ordinary skill in the art.
The invention provides a compound with an anti-influenza virus effect. Most of the existing medicines play a role in resisting influenza viruses through targeting neuraminidase, and the compound plays a role in inhibiting virus replication through inhibiting cap-dependent endonuclease in the influenza viruses. Targets the earlier stage of the replication cycle of the virus, thereby having better effects of preventing and treating influenza, shows better anti-influenza virus effects in vitro or in vivo tests, and is expected to treat virus strains resistant to oseltamivir and avian influenza virus strains (H7N 9, H5N 1).
The compound shows better anti-influenza virus effect in-vivo and in-vitro efficacy tests, and also shows better in-vivo exposure in-vivo pharmacokinetic tests of animals. During the optimization of the compounds it was surprisingly found that: (1) After the compound is used for treating, the lung virus titer of a test animal is lower, and the lesion of lung tissues is slight, which shows that the anti-influenza virus activity of the compound is obviously improved; (2) Further, the compound has good lung tissue distribution in animal experiments, and has lower clearing rate and longer half-life in the lung; (3) Although enantiomers of the compounds of the invention have similar antiviral activity in vitro cell assays, only the S-configuration has higher antiviral activity in vivo animal assays, and the R-configuration is essentially absent. Subverts the recognition that human beings generally perceive the difference between pharmacodynamic tests of optical isomers at the cellular level and pharmacodynamic tests in animals; (4) Compared with other esters in various forms, the ester compound provided by the invention has remarkable advantages, and shows better and higher in-vivo exposure, and especially the compound M19 has optimal performance. These characteristics are more advantageous for the treatment of influenza, which is usually transmitted through the respiratory tract, to exert the anti-influenza virus effect of the drug, and are expected to have great clinical value and therapeutic advantages.
The invention provides a compound shown as the following formula (I-0) or a hydrate, a solvate, an optical isomer, a polymorphic substance, an isotope derivative and a pharmaceutically acceptable salt thereof:
Figure BDA0003919695870000021
in the formula (I-0), n is 0, 1, 2, 3 or 4;
R 0 is fluorine, chlorine, bromine, iodine, trifluoromethylA cyano group;
R a 、R b and R c Each independently selected from hydrogen, deuterium or methyl;
q is hydrogen,
Figure BDA0003919695870000031
Wherein the content of the first and second substances,
X 1 is an O atom or an S atom;
n1 is 0, 1, 2, 3,4, 5, 6, 7, 8 or 9; n2 is 0 or 1, and n1 and n2 are not 0 at the same time;
n3 is 0, 1, 2, 3,4, 5, 6, 7, 8 or 9; n4 is 0 or 1, and n3 and n4 are not 0 at the same time;
n5 is 0, 1, 2, 3,4, 5, 6, 7, 8 or 9; n6 is 0 or 1;
each R 1 、R 2 、R 3 Or R 4 Each independently selected from hydrogen or methyl;
R 5 the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio and C1-C8 alkylamino;
the group A is the following group: halogen, cyano, amino, hydroxyl, carboxyl, nitro, trifluoromethyl, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 carbocyclyl, C2-C8 heterocyclyl, and C1-C8 alkylamino.
In some embodiments, the present invention provides a compound, or a hydrate, solvate, optical isomer, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof, represented by formula (I-1):
Figure BDA0003919695870000032
the definition of the substituent in the formula (I-1) is as defined in the formula (I-0).
In some embodiments, the present invention provides a compound, or a hydrate, solvate, optical isomer, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof, represented by formula (I-2):
Figure BDA0003919695870000041
the definition of the substituent in the formula (I-2) is as defined in the formula (I-0).
In some embodiments, the present invention provides a compound, or a hydrate, solvate, optical isomer, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof, represented by formula (I-3):
Figure BDA0003919695870000042
the definition of the substituent in the formula (I-3) is as defined in the formula (I-0).
In some embodiments, the present invention provides a compound, or a hydrate, solvate, optical isomer, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof, represented by formula (I-4):
Figure BDA0003919695870000043
in the formula (I-4), the definition of the other substituents is as defined in the formula (I-0).
In some embodiments, the present invention provides a compound, or a hydrate, solvate, optical isomer, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof, represented by formula (I-5):
Figure BDA0003919695870000051
the definition of the substituent in the formula (I-5) is as defined in the formula (I-0).
In some embodiments, the present invention provides a compound, or a hydrate, solvate, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof:
Figure BDA0003919695870000052
in formula (I), n1 is 0, 1, 2, 3,4, 5, 6, 7, 8 or 9;
n2 is 0 or 1;
X 1 is O or S;
X 2 is S or Se;
each R 1 、R 2 、R 3 Or R 4 Each independently hydrogen or methyl;
R 5 is hydrogen or the following group which is substituted or unsubstituted by one or more groups a: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio and C1-C18 alkylamino;
when X is 1 Is O and X 2 When is S, R 5 Alkoxy other than C1-C8;
the group A is the following group: halogen, cyano, amino, hydroxyl, carboxyl, nitro, trifluoromethyl, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 carbocyclyl, C2-C8 heterocyclyl, and C1-C8 alkylamino.
In some embodiments, the present invention provides a compound, or a hydrate, solvate, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof, represented by formula (II):
Figure BDA0003919695870000061
the definition of the substituents in formula (II) is as defined for formula (I).
In some embodiments, the present invention provides a compound, or a hydrate, solvate, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof, represented by formula (III):
Figure BDA0003919695870000062
the definition of the substituents in formula (III) is as defined for formula (I).
In some embodiments, the present invention provides a compound, or a hydrate, solvate, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof, represented by formula (iv):
Figure BDA0003919695870000063
the definition of the substituent in the formula (IV) is as defined in the formula (I).
In embodiments herein, the halogen refers to fluorine, chlorine, bromine, or iodine.
In embodiments herein, the heteroatom refers to N, O or S.
In embodiments of the present application, the solvate refers to a complex formed by interaction of a compound with a pharmaceutically acceptable solvent, including ethanol, isopropanol, acetic acid, ethanolamine.
In the embodiments of the present application, the C1-C8 alkyl group refers to a straight or branched chain saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms in the molecule. Including but not limited to methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, and the like.
In the embodiments of the present application, the C1-C8 alkoxy group and the C1-C8 alkylthio group refer to a group in which an oxygen atom or a sulfur atom is inserted into a saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms at any reasonable position in the molecule, and include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, isobutoxy, 2-ethylethoxy, methylthio, ethylthio, propylthio, isopropylthio, isobutylthio, and the like.
In the embodiment of the application, the C1-C8 alkylamino refers to that-NH-or-NH-is inserted into a saturated aliphatic hydrocarbon group containing 1 to 8 carbon atoms in the molecule at any reasonable position 2 The group of the group includes monoalkylamino, dialkylamino and cycloalkylamino, including but not limited to methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, di-n-propylamino, diisopropylamineAnd the like.
In embodiments herein, the C3-C8 carbocyclyl refers to a monocyclic or fused polycyclic saturated or unsaturated cyclic hydrocarbon group containing 3 to 8 carbon atoms and includes, but is not limited to, cyclopropyl, cyclopentyl, bicyclo [3.1.0] hexyl, bicyclo [3.2.0] heptyl, cyclopentadienyl, and the like.
In the embodiments herein, the C2-C8 heterocyclic group means a saturated or unsaturated cyclic group having 2 to 8 carbon atoms and 1 to 4 hetero atoms in the molecule. Including but not limited to, cycloalkoxy, aziridinyl, tetrahydrothienyl, tetrahydropyrrolyl, piperidinyl, hexahydropyridazinyl, dihydropyridinyl, cyclopentylsulfanyl, morpholinyl, and the like.
In some embodiments, in formula (I-0), n is 0; in some embodiments, in formula (I-0), n is 1, 2, 3, or 4; in some specific embodiments, in formula (I-0), n is 1; in some specific embodiments, in formula (I-0), n is 2.
In some embodiments, in formula (I-0), R 0 Is fluorine, chlorine, bromine or iodine, preferably R 0 Is fluorine or chlorine; in some embodiments, in formula (I-0), R 0 Is trifluoromethyl or cyano.
In some embodiments, in formula (I-0), R a Is hydrogen; in some embodiments, in formula (I-0), R a Is deuterium; in some embodiments, in formula (I-0), R a Is methyl.
In some embodiments, R b And R c Are all hydrogen; in some embodiments, R b And R c Are all deuterium; in some embodiments, R b Is hydrogen, R c Is deuterium; in some embodiments, R b And R c Are all methyl; in some embodiments, R b Is hydrogen, R c Is methyl.
In some embodiments, in formula (I-0), Q is hydrogen; in some embodiments, in formula (I-0), Q is
Figure BDA0003919695870000081
Some embodimentsIn the formula (I-0), Q is
Figure BDA0003919695870000082
In some embodiments, in formula (I-0), Q is
Figure BDA0003919695870000083
In an embodiment of the present invention, n1 and n2 are not both 0; wherein the content of the first and second substances,
in some embodiments, n1 is 0; in some embodiments, n1 is 1, 2, 3,4, 5, 6, 7, 8, or 9; in some specific embodiments, n1 is 1; in some specific embodiments, n1 is 2;
in some embodiments, n2 is 0; in some embodiments, n2 is 1.
In an embodiment of the present invention, n3 and n4 are not both 0; wherein, the first and the second end of the pipe are connected with each other,
in some embodiments, n3 is 0; in some embodiments, n3 is 1, 2, 3,4, 5, 6, 7, 8, or 9; in some specific embodiments, n3 is 1; in some specific embodiments, n3 is 2;
in some embodiments, n4 is 0; in some embodiments, n4 is 1.
In some embodiments, n5 is 0; in some embodiments, n5 is 1, 2, 3,4, 5, 6, 7, 8, or 9; in some specific embodiments, n5 is 1; in some specific embodiments, n5 is 2.
In some embodiments, n6 is 0; in some embodiments, n6 is 1.
In some embodiments, X 1 Is an O atom; in some embodiments, X 1 Is an S atom.
In an embodiment of the invention, each R is 1 Or R 2 Each independently hydrogen or methyl, means R 1 And R 2 The carbon to which it is attached will have n1 or n3 or n5, and when n1 or n3 or n5 is greater than 1, the n1 or n3 or n 5R 1 Or R 2 May be the same or different.
In an embodiment of the invention, each R is 3 Or R 4 Each independently of the others being hydrogen or methyl, i.e. with R 1 、R 2 、R 3 Or R 4 The carbon atoms to which they are attached may or may not be substituted by methyl.
In some embodiments, R 5 The following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio and C1-C18 alkylamino; preferably, R 5 The following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C1-C8 alkoxy; more preferably, R 5 Is C1-C8 alkoxy which is unsubstituted or substituted by one or more groups A.
In some embodiments, group a is halogen, trifluoromethyl or cyano; in some embodiments, the group a is amino, hydroxyl, carboxyl, nitro; in some embodiments, the group a is the following group: C1-C8 alkyl, C1-C8 alkoxy, C3-C8 carbocyclyl, C2-C8 heterocyclyl, and C1-C8 alkylamino.
In the embodiment of the present invention, the compound of the present invention or its intermediate can be obtained by chiral separation to a single configuration compound, wherein the formula (I-0) comprises a chiral center (marked by chiral carbon atom).
Figure BDA0003919695870000091
In an embodiment of the invention, the compounds of S-configuration and R-configuration are subjected to absolute configuration determination via electron circular dichroism. In some embodiments, the compounds of the present invention are racemates; in some embodiments, the compounds of the present invention are in the S-configuration.
In an embodiment of the invention, the optical rotation of the S-and R-configured compounds is measured (according to the chinese pharmacopoeia 2020 edition-four part-0621 optical rotation assay using methanol as solvent). In some particular embodiments, the compounds of the invention are racemates; in some specific embodiments, the compound of the invention is the levorotatory form.
In an embodiment of the invention, the compound of the S-configuration is the levorotatory form.
The present invention provides compounds, including but not limited to the following:
Figure BDA0003919695870000101
Figure BDA0003919695870000111
or a hydrate, solvate, optical isomer, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof.
Further, the pharmaceutically acceptable salt comprises inorganic acid salt and organic acid salt thereof.
In some embodiments, pharmaceutically acceptable salts of the compounds include inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulfate, and the like, and organic acid salts include trifluoroacetate, methanesulfonate, tartrate, p-toluenesulfonate, and the like.
In a second aspect, the present invention provides a process for the preparation of a polycyclic compound of formula (I), comprising the steps of:
Figure BDA0003919695870000112
the definition of the radicals in the above scheme is as defined for the radical in formula (I), wherein L 1 And L 2 To activate the leaving group, the group represented by formula (II-3) is synthesized according to the existing literature report method (j.med. Chem.52, (3), 2009,771-778, wo2019/136112), formula (II-1) and formula (II-2) can produce formula (II-3) under basic conditions, and then formula (II-3) and formula compound (II-4) can produce formula (I) under basic conditions.
In an embodiment of the invention, the synthesis of the materials or intermediates required for formula (I-0) or for the comparative examples (e.g., such as the references or patents for formula SM1, SM2, SM3-0 and SM 5), the definition of the relevant substituents in formula SM5 is as described for formula (I-0),
Figure BDA0003919695870000113
formula SM1 is synthesized by the synthetic method described in patent CN 110300753A; the formula SM3 and SM5 are synthesized by the synthesis method in patent CN 113226327A. Formula SM2 is synthesized from commercially available product SM2-0 and methanesulfonyl chloride in one step, specifically referring to the synthesis method in patent CN 113226327A.
In a third aspect of the present invention, there is provided a pharmaceutical composition comprising the above compound or a hydrate, solvate, optical isomer, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier comprises one or more of filler, binder, diluent, lubricant, preservative, taste masking agent or cosolvent. The pharmaceutical composition can be used for resisting influenza virus.
Further, the pharmaceutical composition can be prepared into tablets, capsules, powder, granules, pills, suspensions, syrups and injections.
In a fourth aspect of the invention, the compounds of the invention, including hydrates, solvates, optical isomers, polymorphs, isotopic derivatives, pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, are used against influenza virus.
The compounds of the invention have stronger antiviral activity in vivo or in vitro. Research shows that the S configuration product has better anti-influenza virus activity in vivo, while the R configuration product has relatively poor activity.
In the research on the in-animal drug effect of the compound, the virus titer of the animal lung is lower, and the lesion of the lung tissue is slight; in tissue distribution studies, the compounds of the invention exhibited good lung tissue distribution; in pharmacokinetic studies, the ester compounds of the present invention exhibited higher in vivo exposure and shorter peak-to-peak times than other ester compounds.
Stronger antiviral activity, high in-vivo exposure, rapid peak reaching concentration and high lung distribution, and the characteristics are more favorable for playing the role of the medicament in resisting influenza viruses, and are expected to have great clinical value and treatment advantages.
The invention provides application of the compound, the clathrate compound, the hydrate, the solvate, the optical isomer, the polymorphic substance, the isotope derivative, the pharmaceutically acceptable salt or the pharmaceutical composition thereof in preparing a medicament for resisting influenza viruses.
The present invention provides a method for preventing or treating influenza virus infection, which comprises administering a therapeutically effective amount of the above compound, including hydrates, solvates, optical isomers, polymorphs, isotopic derivatives, pharmaceutically acceptable salts thereof, to an individual in need thereof.
Drawings
FIG. 1 is a comparison of quantitative computational prediction of theoretical electron circular dichroism spectra with experimental ECD spectra to determine absolute configurations.
FIG. 2 shows the body weight change of each group of animals in the anti-influenza virus efficacy test.
FIG. 3 shows the survival rate of animals in each group in the anti-influenza virus efficacy test.
FIG. 4 shows the pulmonary viral titers in the anti-influenza virus efficacy test.
Fig. 5 is a lung tissue distribution.
Detailed Description
The following examples will allow one skilled in the art to more fully understand the invention without limiting it in any way, all compounds having the structure of MS or 1 H-NMR confirms that all related optical isomers with single configuration are subjected to configuration confirmation by optical rotation tests or electronic circular dichroism.
In the present example, the solvents and reagents used were all common commercial products unless otherwise specified. The starting materials were all purchased commercially.
The first embodiment is as follows: synthesis of M01 and M11
Figure BDA0003919695870000131
Figure BDA0003919695870000141
Synthesis of Compound 2:
at room temperature, compound 1 (100g, 793mmol, 1eq) is dissolved in DMF (1.5L), potassium carbonate (219g, 1.59mol, 2eq) is added, the temperature is reduced to 0 ℃ in an ice-water bath, benzyl bromide (203g, 1.19mol, 1.5eq) is added dropwise, the temperature is kept at 0 ℃ after the dropwise addition is finished, the reaction is carried out for 30 minutes, and then the mixture is moved to an oil bath kettle and reacted for 5 hours at 80 ℃. TLC (EA/PE =1/2, EA is ethyl acetate, PE is petroleum ether) to detect that only a small amount of raw material remains, after-treatment, the system is cooled to room temperature, poured into water (3L), extracted by ethyl acetate (300 mlx 3), combined with organic phase water washing (100 mlx 3), saturated common salt water washing (200 mlx 1), dried by anhydrous sodium sulfate for 20 minutes, filtered by organic phase, concentrated and purified by column chromatography (EA/PE = 1/5-1/1) to obtain 157g of product. Yellow oil, yield 91.8%.
Synthesis of Compound 3:
compound 2 (100g, 115mmol, 1eq) was dissolved in bromobenzene (1L) at room temperature, seO was added 2 (152g, 347mmol, 3eq) was reacted in an oil bath at 180 ℃ for 16 hours and TLC (EA/PE = 1/2) checked for completion. The system was cooled to room temperature, filtered through celite in a buchner funnel, washed with dichloromethane celite (100 ml x 3), the combined organic phases were pumped to concentrate dichloromethane and bromobenzene by oil pump to give crude product (100 g, red oil).
Synthesis of Compound 4:
dissolving the compound 3 (100g, 434mmol and 1eq) in DMSO (1.5L) at room temperature, adding cyclopropylformaldehyde (91g, 1.3mol and 3eq), cooling to 0 ℃ in an ice-water bath, dropwise adding pyrrolidine (31g, 434mmol and 1eq) under the protection of nitrogen, keeping the temperature below 15 ℃ after dropwise adding, continuing to react for 30 minutes, and moving to an oil bath pan for reacting for 5 hours at 50 ℃. TLC (DCM/MeOH = 20/1) detects the completion of the starting material reaction, the system is cooled to room temperature, poured into water (3L), extracted with ethyl acetate (250 mlx 3), and combined withThe organic phase was washed with water (100 ml x 3), saturated brine (100 ml x 1), dried over anhydrous sodium sulfate for 30 minutes, filtered, concentrated and purified by column chromatography (EA/PE = 1/10-1/1) to give the product (32 g, red oil, yield 24.6%). ESI-MS (+): m/z =301.1; 1 H-NMR(CDCl 3 ,400MHz)：δ8.85(s,1H),7.69-7.67(d,1H),7.28-7.43(m,5H),6.42-6.43(d,1H),5.28(s,2H)，4.93-4.95(d,1H),2.79-2.81(d,1H),1.15-1.27(m,4H)。
synthesis of Compound 5:
compound 4 (32g, 107mmol, 1eq) was dissolved in methanol (300 ml)/water (150 ml) in an ice-water bath, trifluoroacetohydrazide (27.3 g,214mmol, 2eq) was added, the ice-water bath was maintained for 30 minutes after the addition was completed, the reaction was carried out in an oil bath at 50 ℃ for 4 hours, and the completion of the reaction of the starting material was detected by TLC (DCM/MeOH = 20/1). The reaction system was cooled to room temperature, methanol in the system was concentrated, water (150 ml) was added, ethyl acetate was extracted (100 ml x 3), the organic phases were combined and washed with saturated brine (500 ml x 1), dried over anhydrous sodium sulfate for 10 minutes, and the organic phase was filtered and concentrated to purify by column chromatography (EA/PE = 1/10-1/1) to obtain a product (14 g, yellow solid, yield 45%). ESI-MS (+): m/z =297.1; 1 H-NMR(DMSO-D6,400MHz)：δ7.90-7.92(d,1H),7.31-7.43(m,5H),7.14-7.15(s,1H),6.28-6.30(d,1H),5.78-5.79(d,1H)，5.27-5.30(d,1H),5.03-5.06(d,1H),4.09-4.10(m,1H),1.19-1.28(m,2H),0.85-0.90(m,1H),0.61-0.64(m,1H)。
synthesis of Compound 6:
compound 5 (14g, 47.2mmol, 1eq) was dissolved in THF (150 ml) under an ice-water bath, and triethylamine (9.6g, 94.5mmol, 2eq) and DMAP (1.73g, 14.2mmol, 0.3eq) were added. Acetic anhydride (9.6 g,94.5mmol, 2eq) was added dropwise while maintaining the temperature at 0 ℃ and after the addition was complete, the reaction was maintained at 0 ℃ for 30 minutes and then allowed to react at room temperature for 2 hours. TLC (EA/PE = 1/1) detected complete reaction of starting material. The system was poured into water (150 ml), extracted with ethyl acetate (50 ml x 3), the combined organic phases washed with saturated brine (100 ml x 2), dried over anhydrous sodium sulfate for 10min, filtered from the organic phase, concentrated and purified by column chromatography (EA/PE = 1/10-1/1) to give product 6 (15 g, yellow solid, yield 94%).
Synthesis of Compound 7:
compound 6 (15g, 44.3mmol, 1eq) was dissolved in THF (150 ml) and methanol (50 ml) in an ice-water bath, and sodium borohydride (3.35g, 133mmol, 3eq) was added in portions while maintaining the temperature at 0 deg.C, and after the addition, the reaction was maintained at 0 deg.C for 30 minutes, and then the mixture was allowed to react at room temperature for 2 hours. TLC (EA/PE = 1/1) detects disappearance of starting material, pours the system into an aqueous ammonium chloride solution (150 ml), extracts with ethyl acetate (50 ml x 3), combines the organic phases, washes with saturated brine (50 ml x 3), dries over anhydrous sodium sulfate for 10 minutes, filters the organic phase and concentrates to give the crude product (15 g, yellow solid) which is directly fed to the next step without purification.
Synthesis of Compound 8:
under ice-water bath, compound 7 (15g, 44mmol, 1eq) was dissolved in THF (150 ml), DMAP (0.54g, 4.4mmol, 0.1eq) and triethylamine (8.92g, 88mmol, 2eq) were added, and Boc was added dropwise while maintaining the temperature at 0 deg.C 2 O (19.2 g,88mmol, 2eq), after the addition, the reaction was maintained at 0 ℃ for 30 minutes and then the reaction was allowed to proceed at room temperature for 2 hours. TLC (DCM/MeOH = 20/1) detects disappearance of starting material, pours the system into water (150 ml), extracts with ethyl acetate (50 ml x 3), combines organic phases, washes with brine (50 ml x 3), dries over anhydrous sodium sulfate for 10min, filters the organic phases, concentrates and purifies by column chromatography (EA/PE = 1/10-1/1) to obtain the product (15 g, yellow solid, yield 78%).
Synthesis of Compound 9:
compound 8 (15g, 34mmol, 1eq) was dissolved in methanol (150 ml) in an ice-water bath, and potassium carbonate (4.7g, 34mmol, 1eq) was added in portions, and after the addition was completed, the reaction was carried out at 0 ℃ for 30 minutes and at room temperature for 6 hours. TLC (DCM/MeOH = 20/1) detects the completion of the starting material reaction, the system is poured into water (150 ml), extracted with ethyl acetate (50 ml x 3), the organic phases are combined and washed with saturated brine (30 ml x 3), dried over anhydrous sodium sulfate for 10min, and the organic phase is filtered and concentrated to give the crude product (10 g, yellow solid).
Compound 10 synthesis:
compound 9 (10g, 25mmol, 1eq) was dissolved in DCM (100 ml) in an ice-water bath, dess-Martin oxidant (1696 g,37.6mmol, 1.5eq) was added in portions while keeping the temperature at 0 ℃ and the reaction was carried out for 30 minutes while keeping the temperature at 0 ℃ and at room temperature for 5 hours. TLC (DCM/MeOH = 15/1) detects the completion of the starting material reaction, the system is poured into aqueous sodium bicarbonate (100 ml), DCM extracted (30 mlx 3), and the combined organic phases are washed with brine (30 mlx 1).Drying with anhydrous sodium sulfate for 10min, filtering, concentrating, purifying by column chromatography (EA/PE = 1/10-1/0) to obtain crude product 10g, pulping with ethyl acetate to obtain pure product 5.4g, and concentrating the mother liquor to obtain crude product 4.6g. ESI-MS (+): m/z =397.3; 1 H-NMR(DMSO-D6,400MHz)：δ7.84-7.86(d,1H),7.28-7.46(m,5H),6.30-6.32(d,1H),5.07-5.20(m,2H)，3.85-4.20(dd,2H),1.43(s,9H),1.35-1.37(m,1H),1.18-1.28(m,2H),1.08-1.12(m,1H)。
synthesis of Compound 12
After nitrogen is replaced in a three-neck flask, 226ml of phenyl magnesium bromide (2.8 mol/L) is added, the temperature is reduced to below 10 ℃ in ice water bath, 49.9g of selenium powder is added in batches, the reaction temperature is controlled not to exceed 30 ℃, and the selenium powder reacts for 2 hours after the addition. Adding 2mol/L hydrochloric acid in ice water bath, reacting to release heat obviously, adding EA for extraction, separating liquid, and spin-drying an organic phase to obtain a product 12 which is brown oily matter and has strong odor. Directly carrying out the next reaction.
Synthesis of Compound 14
After nitrogen is replaced in a three-neck flask, 81.18g of LDA (lithium diisopropylamide) is added, the temperature of a dry ice-ethanol solution is reduced to-30 ℃,50 g of THF (tetrahydrofuran) solution of a compound 3, 4-difluorobenzoic acid is dropwise added, the heat release is obvious in the dropwise adding process, the temperature of a reaction system is controlled to be lower than-20 ℃, the reaction is carried out for 2 hours, DMF is added, the heat release is obvious, the temperature of the reaction system is controlled to be lower than-20 ℃, the temperature is not required to be controlled, the reaction is gradually shifted to the room temperature, the reaction is carried out overnight, and the sampling detection reaction is finished. Adding HCl into a reaction system, obviously releasing heat, adding EA for extraction, separating liquid, and spin-drying an organic phase to obtain 72g of a crude product of the compound 14, wherein the obtained product is directly used for the next reaction, and the obtained crude product is a yellow solid with the yield of 122% (DMF in the material is not spin-dried).
Synthesis of Compound 15
After replacing nitrogen gas in a three-necked flask, 58.81g of Compound 12, 49.6g of Compound 14, 300ml of toluene and 17.6g of camphorsulfonic acid were added thereto, and the mixture was allowed to warm to 70 ℃ to react overnight. Cooling the reaction system to room temperature, adding NaOH solution, separating liquid, adding EA into the water phase for extraction, combining organic phases, washing the organic phases by saturated NaCl, and then spin-drying to obtain a crude product: 123.08g, pulping the obtained crude product by using PE, and then carrying out suction filtration to obtain 34.4g of a product, and recovering 14.83g of the product from pulping filtrate. Compound 15 was an orange solid in 47.9% yield.
Synthesis of Compound 16
16.9g of AlCl is added into a three-mouth bottle 3 250ml of toluene, cooling the system in ice-water bath, adding 17.1g of tetramethyldisiloxane, stirring uniformly, adding 150ml of toluene solution of compound 15 (34.4), reacting slightly with heat, and adding AlCl 3 Gradually dissolving, heating to 80 ℃, and reacting for 1 hour; stopping the reaction, adding a sulfuric acid solution (16.2mL +240mL water), separating, extracting the water phase with EA, spin-drying the organic phase, pulping the crude product with PE, and performing suction filtration to obtain 22g of a solid, wherein the obtained solid is a yellow powdery solid, and the theoretical amount of the product is as follows: 34.68g, to obtain 22g of the solid product compound 16, yield: and (4) percent. Directly used for the next reaction.
Synthesis of compound 17:
adding 429g of polyphosphoric acid into a three-necked bottle, heating to 80 ℃, adding 42g of compound 16, heating to 120 ℃, reacting for 1 hour, taking a sample, adding water, and treating with EA; reducing the reaction temperature to be below 100 ℃, adding water, stirring uniformly, adding EA for extraction, separating an organic phase, carrying out spin drying, pulping a crude product by using PE, filtering to obtain a product 3.4g, carrying out column chromatography separation on a filtrate to obtain a product 10g, wherein a compound 17 is colorless to light yellow flocculent solid, and has theoretical yield: 39.69g, actual yield: 13.4g, yield: 33.76 percent.
Synthesis of compound 18:
to a three-necked flask were added 2.12g of compound 17 and 20ml of ethanol, and the system was stirred. Dropwise adding an ethanol solution of sodium borohydride (0.26 g) in an ice water bath, slightly heating a reaction system, transferring to room temperature for reaction after dropwise adding is finished, gradually dissolving materials, sampling and detecting after reaction liquid is clear, and treating after the reaction is finished; adding 2mol/L hydrochloric acid until no bubbles are generated, and the pH is = 4-6, separating out a large amount of solid, performing suction filtration to obtain solid, extracting the filtrate with EA, separating an organic phase, and spin-drying the organic phase to obtain a product 18 which is brown solid and is directly used for the next reaction.
Synthesis of Compound 19
Adding 2.5g of compound 10, 2.13g of compound 18, 5.44g of compound T3P (propylphosphoric anhydride), 1.1g of methanesulfonic acid and 30ml of EA (ethylene-vinyl acetate) into a single-mouth bottle, heating to reflux, reacting overnight, sampling, detecting, and treating after the reaction is finished; and (3) post-treatment: adding saturated sodium bicarbonate water solution until no bubble is discharged, separating liquid, extracting water phase with EA, combining organic phases, spin-drying, pulping crude product with PE to obtain product 19 which is light brown powdery solid with theoretical yield: 3.36g, actual yield: 2.2g, yield: 65.48 percent.
Synthesis of compound M01:
adding 2.6g of compound 19, 0.94g of compound LiCl and 20ml of DMA (N, N-dimethylacetamide) into a single-mouth bottle, heating to 100 ℃, reacting for 2 hours, sampling and detecting, and treating after the reaction is finished, wherein the reaction solution is yellow and turbid; adding saturated sodium bicarbonate water solution, separating out solids, performing suction filtration, extracting filtrate by using EA, performing spin drying on an organic phase, pulping a crude product by using PE to obtain 2.28g of a compound M01, wherein the product is brown solid powder, and the yield is as follows: 104% (yield slightly higher than theoretical yield, judged because of residual solvent DMA). Directly used for the next reaction. ESI-MS (+): m/z =501.1.
Synthesis of compound M11:
to a single-neck flask were added 1.1g of Compound M01 and 0.61g of K 2 CO 3 0.55g of KI and 0.55g of chloromethyl dimethyl carbonate. Adding 20mL of DMA into the system, heating to 60 ℃, reacting overnight, sampling, detecting, and processing after the reaction is finished. Cooling the reaction system to room temperature, adding 2N HCl, adding water, separating out solids, performing suction filtration, extracting the filtrate by using EA, separating an organic phase, dissolving a filter cake by using EA, mixing the filter cake with the organic phase, drying the organic phase by using anhydrous sodium sulfate, performing spin drying, and performing column chromatography separation to obtain 0.766g of brown solid powder of a compound M11, wherein the yield is as follows: 58.9 percent. ESI-MS (+): m/z =589.5; 1 H-NMR(DMSO-D6,400MHz)：δ7.26-7.41(m,5H),7.10-7.13(m,1H),6.92-6.98(m,2H),5.90-5.92(d,1H),5.74-5.86(d,1H),5.56-5.58(d,1H),5.38-5.42(m,2H),4.12-4.16(m,2H)，4.01-4.07(m,1H),3.74(s,3H),2.79(s,1H),1.73-1.75(m,1H),1.16-1.24(m,2H),0.87-0.90(m,1H),0.72-0.74(m,1H)。
the second embodiment: resolution of M19
Figure BDA0003919695870000191
Compound M11 was isolated as a white solid to yield M19 and enantiomer M19-1. The preparation conditions are as follows: using a supercritical liquid chromatograph; and (3) chromatographic column: CHIRALPAK IB-N4.6 x 100mm,3 μm; the solvent is methanol, and the carrier is liquid CO 2 (ii) a The pressure was 1500psi, the flow rate was set at 2.0ml/min, the column temperature was 25 ℃ and the elution was carried out in a gradient. Wherein the retention time of M19 is 2.86min, and the optical rotation measurement is carried out by taking methanol as a solvent, and the result shows that the levorotatory isomer is obtained. The retention time of M19-1 was 2.55min, and the optical rotation was measured using methanol as a solvent, and the result was shown to be a dextrorotatory form. M19 and M19-1 adopt a method which is widely adopted internationally at present to determine the absolute configuration of the chiral compound, quantitatively calculate and predict a theoretical electronic circular dichroism (ECD, namely the commonly-referred circular dichroism) spectrum, and compare the spectrum with an experimental ECD spectrum (the comparison result is shown in figure 1), wherein the experimental ECD signal conforms to the theoretical calculation result, so that the absolute configuration is finally determined, M19 is S configuration, and M19-1 is R configuration.
Example three: synthesis of PX90-02
Figure BDA0003919695870000201
Synthesis of compound 25:
2g of the compound SM1, 2.54g of the compound SM2, 0.6g of pyridine and 30ml of 1, 4-dioxane were charged into a reaction flask, and the system was heated at 60 ℃ for reaction for 6 hours. After the reaction was completed, the system was concentrated to dryness, extracted with dichloromethane and water, the organic phase was concentrated to dryness, and purified by silica gel column to obtain 2.16g of compound 25 with a yield of 59%. ESI-MS (+): m/z =542.48.
Synthesis of compound N01:
2g of Compound 25, 20ml of ethyl acetate and 0.88g of 5% palladium on charcoal are charged into a reaction flask, and the reaction mixture is charged with a hydrogen balloon and replaced with hydrogen (1 atm), followed by stirring at room temperature for 2 hours. The system was concentrated to dryness under reduced pressure after celite filtration and purified through a fast silica gel column to give 1.48g of Compound N01 in 89% yield, ESI-MS (+): m/z =452.78.
Synthesis of compound PX 90-02-01:
1.2g of compound N01 are dissolved in acetonitrile (15 mL), 0.6mL of diisopropylethylamine are added, and 0.4 g of 2-bromoethanol are added. Then heated to 90 ℃ and the reaction was completed by TLC. After cooling to room temperature, evaporation to dryness under reduced pressure, addition of water and dichloromethane, shaking, collection of the organic phase, washing with 10% NaOH (10 ml), water (10 ml) and brine (10 ml), drying over sodium sulfate, filtration, evaporation to dryness under reduced pressure, purification through silica gel column to obtain 0.95 g of compound PX90-02-01 with a yield of 72%. [ M + H ]] + ＝496.13。
Synthesis of compound PX 90-02:
0.5 g of the compound PX90-02-01,0.66 g of cesium carbonate, 33 mg of potassium iodide, 8ml of N, N-dimethylacetamide and 20ml of water were charged into a reaction flask, the system was stirred and heated to 60 ℃ and 5ml of a solution of 0.2 g of chloromethyl methyl carbonate in N, N-dimethylacetamide was added. Reacting the mixture for 8 hours at the temperature of 55 ℃, cooling to room temperature, adding ethyl acetate, washing with saturated ammonium chloride, water and saturated salt solution in sequence, separating the solution, and drying the organic phase with anhydrous sodium sulfate; the organic phase is concentrated and evaporated to dryness, and the residue is purified by a silica gel column to obtain 0.46 g of a compound PX90-02 with a yield of 46%. [ M + H ]] + ＝584.73。
Example four: synthesis of M10
Figure BDA0003919695870000211
Synthesis of compound 22:
synthesis of Compound 22 reference (Pharmaceutical Research,2005, vol.22, #3, p.390-396) method. 2.9g of Compound 21 in dichloromethane solution 10ml cooled to 0 ℃, slowly dropping dimethylamine tetrahydrofuran solution 12ml, the system at room temperature reaction for 24 hours. Concentrating to dryness, adding dichloromethane and water, separating organic phase, and separating organic phase with 5% NaHCO 3 The solution was washed 3 times. The organic phase was concentrated to dryness to give 1.31g of compound 22 in 43% yield. [ M + H ]] + ＝137.92。
Synthesis of compound M10:
a reaction flask was charged with 0.5 g of Compound M01,0.65 g of cesium carbonate, 33 mg of potassium iodide, 8ml of N, N-dimethylacetamide and 20ml of water, the system was stirred and warmed to 60 ℃ and 5ml of a solution of 0.15 g of Compound 22 in N, N-dimethylacetamide was added. Reacting the system at 55 ℃ for 8 hours, cooling to room temperature, adding ethyl acetate, washing with saturated ammonium chloride, water and saturated salt solution in sequence, separating liquid, and drying an organic phase with anhydrous sodium sulfate; the organic phase was concentrated to dryness and the residue was purified on silica gel column to give 0.32g of compound M10 in 53% yield. [ M + H ]] + ＝600.73。
Example five: synthesis of M03 and M14
Figure BDA0003919695870000221
Synthesis of Compound 23
1g of Compound 17 was dissolved in 15ml of THF under nitrogen, 140mg of lithium aluminum hydride-D4 was slowly added thereto at 0 ℃ and the system was heated to 25 ℃ for 8 hours. The temperature of the system is reduced to 0 ℃, and water is added to quench the reaction. The system was extracted with 2N hydrochloric acid and EA. The organic phase was concentrated to dryness. Column chromatography gave a total of 0.58g of compound 23, 57% yield, ESI-MS (+): m/z =314.0.
Synthesis of Compound 24
Referring to the synthesis of compound 19, compound 24 was synthesized to give a total of 0.94g, ESI-MS (+): m/z =592.1.
Synthesis of Compound M03
Referring to the synthesis of compound M01, compound M03 was synthesized at 0.51g total, ESI-MS (+): M/z =502.1.
Synthesis of Compound M14
Referring to the synthesis of compound M11, compound M14 was synthesized to give 0.32g, ESI-MS (+): M/z =590.1.
Example six: synthesis of M07 and M08
Figure BDA0003919695870000231
Synthesis of Compound M08-1:
1g of Compound 17 was dissolved in 15ml of THF under nitrogen protection, 4ml of methyllithium reagent (1.6M in ether) was slowly added dropwise at-20 ℃ and the system was naturally warmed to 25 ℃ for 8 hours. The temperature of the system is reduced to 0 ℃, and water is added to quench the reaction. Concentrated to dryness, EA and water extracted. The organic phase was separated off and concentrated to dryness. Column chromatography gave a total of 0.77g of compound M08-1 in 73% yield and ESI-MS (+): M/z =327.1.
Synthesis of Compound M08-2
Referring to the synthesis of compound 19, compound M08-2 was synthesized at 0.94g total, ESI-MS (+): M/z =605.2.
Synthesis of Compound M07
Referring to the synthesis of compound M01, compound M07 was synthesized at 0.51g total, ESI-MS (+): M/z =515.1.
Synthesis of Compound M08
Referring to the isolation method for the preparation of compound M01, compound M08 was obtained, and it was confirmed that M08 is levorotatory and the absolute configuration is S configuration.
Example seven: synthesis of M24
Figure BDA0003919695870000232
Synthesis of Compound M04
The compound M01 is prepared and separated to obtain M04 and an enantiomer which are both white solids. The preparation conditions are as follows: using a supercritical liquid chromatograph; a chromatographic column: CHIRALPAK IB-N4.6 x 100mm,3 μm; the solvent is methanol, and the carrier is liquid CO 2 (ii) a The pressure was 1500psi, the flow rate was set at 2.0ml/min, the column temperature was 25 ℃ and the elution was carried out in a gradient. When the optical rotation was measured using methanol as a solvent, M04 showed a levorotatory form, and the enantiomer of M04 showed a dextrorotatory form. The absolute configuration of M04 is S configuration, as seen by comparison with M19 and M19-1.
Synthesis of Compound M24
In an ice-water bath, 100mg of compound M04 was dissolved in 3ml of DMF, 16mg of sodium hydride (60%) was added, and after stirring for 30 minutes, 60mg of chloromethyl tert-butyrate was added, the reaction was slowly warmed to room temperature for half an hour, and after further reaction for 12 hours, the reaction mixture was quenched with water, extracted 3 times with EA and water, the organic phases were combined, dried over anhydrous sodium sulfate, and the product was separated by chromatography, and concentrated to give 41.8mg of compound M24 with a yield of 34%, ESI-MS (+): M/z =615.1.
Example eight: synthesis of Compound M26
Figure BDA0003919695870000241
Synthesis of Compound M26-3
4.7ml of compound M26-1 and 3ml of pyridine are dissolved in 30ml of dichloromethane and the system is cooled to 0 ℃.3ml of the compound M26-2 was slowly dropped into the above system, and the internal temperature was controlled to be not higher than 10 ℃. The system reacts for 16 hours at room temperature, saturated sodium carbonate solution is added into the system for extraction, and the organic phase is concentrated under reduced pressure to be dry to obtain oily matter which is directly used for the next step.
Synthesis of Compound M26
Referring to the synthesis method of the compound M11, the compound M04 and the compound M26-3 were reacted to obtain a total of 48mg of the compound M26, a yield of 42%, ESI-MS (+): M/z =633.1.
Comparative example one: synthesis of N02
Figure BDA0003919695870000242
Referring to the preparation and separation method of the compound M19, the compound N02 is obtained by preparation and separation of the compound N01, and NO2 is levorotatory after optical rotation test and comparison with the optical rotation of M19.
Comparative example two: synthesis of N11 and N12
Figure BDA0003919695870000251
Referring to the synthesis method of the compound M19, N01 is taken as a material to synthesize N11 in one step, and then the compound N12 is obtained by a preparation separation method similar to that of M19. And after optical rotation test and optical rotation comparison with M19, N12 is in a levorotatory form and an S configuration.
Comparative example three: synthesis of Compound N13
Figure BDA0003919695870000252
Synthesis of Compound N13-2
1g of the compound N13-1 and 60ml of dichloromethane were charged into a reaction flask, and 1g of imidazole and 1.55g of t-butyldimethylsilyl chloride (TBSCl) were added to the system at room temperature, and the system was reacted at room temperature for 3 hours. Concentrated to dryness, and purified by a silica gel column to obtain 0.968g of Compound N13-2. 1 H-NMR(CDCl 3 ，300MHz)σ:0.08(s,6H),0.42-0.58(m,4H),0.93(s,9H),2.76(brs,1H),3.44-3.60(s,2H),3.62-3.65(s,2H)。
Synthesis of Compound N13-3
0.91g of the compound N13-2 and 40ml of methylene chloride were charged into a reaction flask, and 1.96g of dess-martin reagent (DMP) was added to the system at 0 ℃ to conduct a reaction at 0 ℃ for 30 minutes. The system was purified by means of a silica gel column to obtain 0.72g of a compound N13-3. 1 H-NMR(CDCl 3 ，300MHz)σ:0.05(s,6H),0.87(s,9H),1.12(s,4H),3.87-3.95(s,2H),8.97-9.04(s,1H)。
Synthesis of Compound N13-4
Under nitrogen protection, a reaction flask was charged with 1.2g of triphenylphosphine bromomethane and 20ml of anhydrous tetrahydrofuran. The system was cooled to 0 ℃ and 1.5ml (2.5M) of n-butyllithium was added and reacted for 10min. 10ml of an anhydrous tetrahydrofuran solution of the compound N13-3 (0.66 g) was added thereto, and the mixture was reacted at room temperature for 2 hours. Water was added to quench the reaction, the system was concentrated to dryness, extracted with dichloromethane and water, the organic phase was concentrated to dryness and purified by silica gel column to give 0.53g of Compound N13-4. 1 H-NMR(CDCl 3 ，300MHz)σ:0.05(s,6H),0.50-0.75(m,4H),0.85-0.92(s,9H),3.62-3.66(s,2H),4.90-5.05(m,2H),5.65-5.75(m,1H)。
Synthesis of Compound N13-5
To the reaction flask was added 0.52g of Compound N13-4, followed by 7.5ml of tetrabutylammonium fluoride (TBAF) in tetrahydrofuran mixture (1M TBAF in THF). The system was reacted at room temperature. The system is concentrated to dryness in dichloromethaneExtracting, and purifying with silica gel column to obtain 25mg of compound N13-5. 1 H-NMR(CDCl 3 ，300MHz)σ:0.50-0.77(m,4H),3.60-3.66(s,2H),5.01-5.20(m,2H),5.61-5.75(m,1H)。
Synthesis of Compound N13-6
22mg of chloromethyl chloroformate were dissolved in anhydrous dichloromethane under nitrogen protection, and 24mg of pyridine was added at 0 ℃ followed by dropwise addition of a solution of 15mg of compound N13-5 in dichloromethane. Then the system is transferred to room temperature for reaction for 3 hours, and the system is concentrated to be dry to obtain a crude product of the compound N13-6, which is directly used for the next step without treatment.
Synthesis of Compound N13
At room temperature, 30mg of compound M04 was added to 1ml of DMA (N, N-dimethylacetamide), followed by 2mg of potassium iodide and 16.6mg of potassium carbonate. A DMA solution of the compound N13-6 was added to the system and reacted at 50 ℃ for 5 hours. Reverse phase column chromatography gave 18.45mg of Compound N13 in 47% yield and ESI-MS (+): M/z655.1[ M + H ].
The following compounds of examples were synthesized in the same manner as in the above examples, using commercially available compounds or intermediate compounds appropriately synthesized from commercially available compounds:
Figure BDA0003919695870000271
Figure BDA0003919695870000281
or a hydrate, solvate, optical isomer, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof.
Example nine: cytopathic extent (CPE) assay
Inoculation of MDCK cells into 96-well culture plates, setting up to 5% CO 2 And cultured at 37 ℃. During the exponential growth phase of cells, a maintenance solution containing samples with different dilutions and a positive control drug is added, and each concentration is provided with 3 multiple wells and a normal cell control well. After adding the sample, the sample was cultured for 72 hours, and the cytotoxicity test of the sample was performed by the CPE method. In addition willInoculation of MDCK cells into 96-well culture plates, setting up to 5% CO 2 And cultured at 37 ℃. Infecting influenza virus 24 hours later (A/Hanfang/359/95 (H3N 2)), adsorbing for 2 hours, discarding virus solution, adding maintenance solution containing samples with different dilutions and positive control drug, setting 3 multiple wells for each concentration, setting cell control well and virus control well, 5% CO 2 And cultured at 37 ℃. The antiviral test of the test sample is carried out by the CPE method, and the cytopathic degree (CPE) of each group is observed when the pathological change degree (CPE) of the virus control group reaches 4 +. Respectively calculating the half Toxic Concentration (TC) of the sample to the cells by a Reed-Muench method 50 ) And effective concentration of drug (EC) that inhibits 50% of cytopathic effects 50 ) As shown in table 1:
table 1: cytotoxicity of the compound and inhibitory activity against influenza virus
Figure BDA0003919695870000291
Description of the samples: in the experiment, N01, N02, N11 and N12 are compounds disclosed in the prior art and are used as comparative examples in the invention.
Experiments show that the compound has better anti-influenza virus activity. Wherein, compared with the comparative compounds N01 and N02 and the Barosavir, the cell activities of M01 to M08 (all of which have non-esterified structures) in the compound of the invention are obviously better; compared with the comparative compounds N11 and N12 and the Barosavir ester, the compound also has better anti-influenza virus activity; and all compounds showed no significant cytotoxicity.
Example ten: in vivo anti-influenza virus activity
BALB/c mice 30, female, 6-8 weeks old. Randomized into 6 groups: a solvent group, a positive control group and a test article group. Mice were inoculated nasally with the virus (A/PR/8/34 (H1N 1)) at 1500p.f.u./mouse on day 0. Continuously treating with solvent or positive control or test sample for 7 days from day 1 to day 7, 2 times daily, and administering by intragastric administration with a volume of 10mL/kg, and the first administration time is 24 hr after virus inoculation. Animals were observed continuously from day 0 to day 14 and body weight, health and survival were recorded.
As can be seen from fig. 2: the vehicle, 3 rd (M19-1 low dose) and 4 th (M19-1 high dose) mice showed a significant body weight drop starting at day 3 and then continued to drop until death or euthanasia; mice in the baloxavir (5 mpk) group experienced a significant weight loss from day 3, a weight loss to the lowest point on day 3 with a maximum drop of 9.59%, followed by recovery from day 4 to normal levels; mice in group 5 (M19 low dose group) showed a significant weight loss from day 3, with weight loss to the lowest point on day 6 with a maximum drop of 15.51% and recovery to normal levels starting on day 7. The mice in group 6 (M19 high dose group) showed a significant weight loss from day 3, with a maximum 5% loss by day 3 and recovery to normal levels starting on day 5.
As can be seen from fig. 3: the mice in the vehicle group died from day 6 and all died at day 9, with a final survival rate of 0%; mice in group 3 (M19-1 low dose group) died from day 6 and all died at day 8, with a final survival rate of 0%; mice in group 4 (M19-1 high dose group) died from day 7 and all died at day 8 with a final survival rate of 0%; mice in both the baloxavir group and the M19 high/low dose group did not die, and survival rates were 100%.
The results show that: the mice in the solvent group have infection symptoms after virus inoculation and die completely at last, the median survival time is 7.5 days, and the final survival rate is 0 percent; the baloxavir can relieve the weight loss of mice caused by virus infection under the set experimental conditions, protect the mice from death, and show the expected in-vivo anti-influenza virus drug effect. The results reach the selection standard, the model should be expected, the experimental science is proved to be credible, and a reference and a window are provided for the drug effect evaluation of the tested compound. Surprisingly, the test compound M19-1 which shows better in the cell activity test can not relieve the weight loss of mice caused by infection under the set experimental conditions, and shows that no in-vivo anti-influenza virus efficacy exists. And another test compound M19 which is slightly poor in cell activity test is administrated after virus inoculation for 24 hours, so that the weight loss of a mouse caused by virus infection can be relieved, the mouse is protected from death, and the in-vivo anti-influenza A virus drug effect is good.
Example eleven: viral titer test and histopathological examination
C57BL/6J mice 20 (female, 8 weeks, 18-20 g), divided into 4 groups, each group of 5. Test drugs were administered by gavage twice daily after nasal drip inoculation with a semi-lethal dose of A/PR/8/34 (H1N 1) virus. Lung tissue samples were harvested 5 days after infection, left lung pathologically examined, right lung homogenate for TCID 50 And (4) measuring. Results for viral titers are shown in figure 4.
The lung virus titer test result shows that compared with the solvent group, the lung tissue virus titer of the compounds M19 and M20 of the invention and the comparative compound N12 is lower; compared with the comparative compound N12, the compound M19 and the compound M20 of the invention have lower virus titer and show better anti-influenza virus effect under the same dosage. At the same time, the results of lung pathology examination also showed that lung pathology was more mild in mice treated with compounds M19 and M20 of the invention compared to comparative compound N12.
Example twelve: pharmacokinetic experiment of oral drug in rat
The experiment was started after 20 SD rats, male, 180-220 g, had been cannulated for jugular vein before the start of the experiment, adapted for three days (free access to drinking water, room temperature: 20-26 ℃; humidity: 40-70%; light illumination: dark = 12h). The experimental animals were divided into 6 groups of A/B/C/D/E/F, 3 animals per group. Each group was orally administered with gavage to give a suspension of the test article (test articles M04, M19, M24, M25, M26, N13, all suspended with 0.5% sodium carboxymethylcellulose), with an administration dose of 2.25mg/kg in terms of M19, each group was administered at equimolar. Fasting was started at 5 pm before the day before administration but not water, and fasting was 16-17h. The animals are fed after 4h of administration, and water is not forbidden in the whole process.
Before administration and 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h and 24h after administration. Approximately 0.25mL of whole blood was taken separately through the jugular vein into a heparin sodium anticoagulation tube. After blood sampling, the anticoagulation tube containing the blood sample is immediately reversed for 5-10 times and temporarily stored in ice bath. Blood samples were centrifuged at 3000rpm for 5 minutes at 4 ℃ within 1 hour after collection. Transferring the centrifugally collected plasma to a new centrifugal tube with a label, temporarily storing the plasma in a refrigerator at the temperature of-20 ℃, and handing the plasma to a biological sample manager for storing the plasma in the refrigerator at the temperature of-80 ℃ after all samples are collected. The biological sample is processed and then an analyte (M04 as the analyte) is detected by LC-MS/MS. The main pharmacokinetic parameters were calculated according to the non-compartmental model method using WinNonlin 7.0. The main pharmacokinetic parameters after intragastric administration for each group of samples are shown in table 2:
table 2: main pharmacokinetic parameters of test sample in rat body after equimolar gavage administration
M04 M19 M24 M25 M26 N13
T1/2(h) 5.41 4.33 4.27 5.15 4.22 4.53
Tmax(h) 2 1 1 1 1 2
Cmax(ng/ml) 4.39 34.5 22.9 5.36 19.7 2.89
AUC(h*ng/ml) 66.974 289.914 147.285 81.360 145.629 40.970
In the pharmacokinetics research of rat gavage administration, the inventor selects several compounds with different ester structures which are relatively close and have patent drug precedent for research, and the result shows that: compared with M04, after oral gavage administration of rats, the peak time (Tmax) of the compound is shorter, which shows that the compound can take effect quickly; in addition, compared with M04, the plasma exposure (AUC) of the compound M19 group is obviously increased, the exposure of the M24 and M26 groups is also increased to different degrees, but the exposure of the M25 and M13 groups is even reduced, which shows that in the pharmacokinetics experiment of rats, different ester forming modes influence the in vivo exposure of intragastric administration, and the different ester forming compounds are presumed to be caused by different absorption or metabolism degrees.
Example thirteen: mouse tissue distribution test
45 DBA/1J mice (6-8 weeks old, female) were weighed one day before dosing to calculate the dose. The groups were randomly divided into 3 groups of 15, and 1mg/kg of M19, M20 and N12 (N12 in this experiment was used as a comparative compound) was administered by oral gavage. Mice were sampled at the following 5 time points: 1 hour, 2 hours, 4 hours, 8 hours and 24 hours (3 mice per time point). Passage of CO at each time point 2 Mice were euthanized. Organs (lung, liver, kidney, spleen and heart) were collected from euthanized mice, blood was washed clean on the surface with normal saline, then water was blotted with filter paper, weighed, placed in a glass homogenate tube, and ground and homogenized with 3 times of normal saline to obtain homogenate of each tissue. Storing the homogenate at-80 ℃. The biological samples were processed and analyzed by LC-MS/MS. The results are shown in FIG. 5.
As can be seen from fig. 5: the highest concentrations of all three compounds were achieved in the above tissues within 1-4 hours after administration, with the highest concentrations in lung tissue being achieved around 2 hours. The tissue concentration of compound N12 then decreased rapidly, whereas the concentration of compounds M19 and M20 of the invention decreased more slowly and remained detectable in lung tissue 24 hours after administration, but compound N12 was below the limit of detection 24 hours after administration, indicating a low elimination rate and a long half-life of compounds M19 and M20 of the invention in lung tissue.
The description herein describes embodiments, but is intended to be exemplary, rather than limiting and that many more embodiments and implementations are possible within the scope of the embodiments described herein.

Claims (12)

1. A compound represented by formula (I-0), or a hydrate, solvate, optical isomer, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof:
Figure FDA0003919695860000011
in the formula (I-0), n is 0, 1, 2, 3 or 4;
R 0 is fluorine, chlorine, bromine, iodine, trifluoromethyl or cyano;
R a 、R b and R c Each independently selected from hydrogen, deuterium or methyl;
q is hydrogen,
Figure FDA0003919695860000012
Wherein, the first and the second end of the pipe are connected with each other,
X 1 is an O atom or an S atom;
n1 is 0, 1, 2, 3,4, 5, 6, 7, 8 or 9; n2 is 0 or 1, and n1 and n2 are not 0 at the same time;
n3 is 0, 1, 2, 3,4, 5, 6, 7, 8 or 9; n4 is 0 or 1, and n3 and n4 are not 0 at the same time;
n5 is 0, 1, 2, 3,4, 5, 6, 7, 8 or 9; n6 is 0 or 1;
each R 1 、R 2 、R 3 Or R 4 Each independently selected from hydrogen or methyl;
R 5 the following groups, substituted or unsubstituted with one or more groups a: C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkylthio and C1-C8 alkylamino;
the group A is the following group: halogen, cyano, amino, hydroxyl, carboxyl, nitro, trifluoromethyl, C1-C8 alkyl, C1-C8 alkoxy, C3-C8 carbocyclyl, C2-C8 heterocyclyl and C1-C8 alkylamino.
2. A compound represented by the formula (I-1) or a hydrate, solvate, optical isomer, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof:
Figure FDA0003919695860000021
in the formula (I-1), the substituents are as defined in claim 1.
3. A compound according to claim 1 or 2, of formula (I-2):
Figure FDA0003919695860000022
the substituents of formula (I-2) are as defined in any one of claims 1 to 2.
4. A compound according to any one of claims 1 to 3, represented by formula (I-3):
Figure FDA0003919695860000023
the substituents of formula (I-3) are as defined in any one of claims 1 to 3.
5. The compound of claim 1, represented by formula (I-4):
Figure FDA0003919695860000031
in the formula (I-4), the substituents are as defined in claim 1.
6. The compound of claim 1, having formula (IV):
Figure FDA0003919695860000032
in formula (IV), the substituents are as defined in claim 1.
7. The compound of any one of claims 1-5, having formula (I-5):
Figure FDA0003919695860000033
the substituents in formula (I-5) are as defined in any one of claims 1 to 5.
8. The compound of any one of claims 1-7, selected from the structures:
Figure FDA0003919695860000041
Figure FDA0003919695860000051
or a hydrate, solvate, optical isomer, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound of any one of claims 1-8 or a hydrate, solvate, optical isomer, polymorph, isotopic derivative, pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
10. The pharmaceutical composition according to claim 9, in the form of tablets, capsules, powders, granules, pills, suspensions, syrups, injections.
11. The compound of any one of claims 1-8, including hydrates, solvates, optical isomers, polymorphs, isotopic derivatives, pharmaceutically acceptable salts thereof, or the pharmaceutical composition of claim 9, for use against influenza virus.
12. Use of a compound as claimed in any one of claims 1 to 8, including hydrates, solvates, optical isomers, polymorphs, isotopic derivatives, pharmaceutically acceptable salts thereof, or a pharmaceutical composition as claimed in claim 9, in the manufacture of a medicament for the treatment of influenza.
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