CN110041327B - Pyridone derivative, composition thereof and application of pyridone derivative as anti-influenza virus medicament - Google Patents

Pyridone derivative, composition thereof and application of pyridone derivative as anti-influenza virus medicament Download PDF

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CN110041327B
CN110041327B CN201810044308.4A CN201810044308A CN110041327B CN 110041327 B CN110041327 B CN 110041327B CN 201810044308 A CN201810044308 A CN 201810044308A CN 110041327 B CN110041327 B CN 110041327B
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influenza
hydrocarbyl
compound
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CN110041327A (en
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陈力
邵庆
武进
薛晓剑
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Jiangxi Caishi Pharmaceutical Technology Co., Ltd
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Jiangxi Caishi Pharmaceutical Technology Co Ltd
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Priority to AU2019210414A priority patent/AU2019210414B2/en
Priority to CN202010817434.6A priority patent/CN111848615B/en
Priority to SG11202011447UA priority patent/SG11202011447UA/en
Priority to CN202010817435.0A priority patent/CN111848616B/en
Priority to CA3088926A priority patent/CA3088926A1/en
Priority to JP2020560532A priority patent/JP7352297B2/en
Priority to US16/487,088 priority patent/US11247993B2/en
Priority to PCT/CN2019/071902 priority patent/WO2019141179A1/en
Priority to CN202010817035.XA priority patent/CN111848614B/en
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    • 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
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    • C07D471/12—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 three hetero rings
    • C07D471/14—Ortho-condensed systems
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    • 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
    • C07D471/22—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 systems contains four or more hetero rings
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    • 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
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    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
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    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring
    • C07F7/0816—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring said ring comprising Si as a ring atom

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Abstract

The invention belongs to the field of medicinal chemistry antivirus, and relates to a novel pyridone derivative shown in formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a crystal thereof, and application thereof in preparing a medicament for preventing or treating influenza A type or/and influenza B type and other viral infection diseases, in particular application in preventing or treating influenza A type or/and influenza B type viral infection diseases as a PA subunit cap-dependent endonuclease inhibitor. The compound of the invention has significant activity of inhibiting influenza endonuclease and influenza DNA, and can be used alone or together with neuraminidase inhibitor, nucleoside drug, PB2 inhibitor, PB1 inhibitor, M2 inhibitor or other anti-influenza drugsThe drug combination obviously shortens the time of influenza infection and reduces the death rate, and has good clinical application prospect.

Description

Pyridone derivative, composition thereof and application of pyridone derivative as anti-influenza virus medicament
Technical Field
The invention belongs to the field of medicinal chemistry, and particularly relates to a novel pyridone derivative or a stereoisomer thereof, a pharmaceutical composition containing the pyridone derivative or the stereoisomer thereof and application of the pyridone derivative or the stereoisomer thereof as an antiviral drug, in particular application of the pyridone derivative or the stereoisomer thereof as a drug for preparing a Cap-dependent endonuclease inhibitor (Cap dependent endolyase inhibitor) for preventing and/or treating infection of influenza virus, particularly application of the pyridone derivative or the stereoisomer thereof for preparing a drug for preventing and/or treating infection of influenza virus type A and influenza virus type B.
Background
Influenza is an acute respiratory infectious disease caused by infection with influenza virus. Annual influenza can cause the death of thousands of people, while large-scale influenza outbreaks can cause the death of millions of people worldwide. Although influenza vaccines and adamantane (amantadine) can be used for the prevention and treatment of influenza, their prevention and treatment effects are very limited, and development of a broader spectrum of vaccines and more effective anti-influenza drugs are required.
Neuraminidase inhibitors Oseltamivir (Oseltamivir) and Zanamivir (Zanamivir) can suppress virus budding and release, but the therapeutic effects of neuraminidase inhibitors are questionable in the clinic, and may not be effective particularly for critically ill patients, and in addition, drug resistance is a problem that neuraminidase inhibitors must be considered. For the worry of the pandemic of the novel influenza virus with high lethality, anti-influenza drugs with a brand new mechanism are urgently needed clinically.
Transcription of 8 RNA segments is a critical step in the life span of influenza viruses. This step requires transcription and replication of the viral antisense RNA. RNA polymerase comprises a trimer of three subunits, PA, PB1, and PB2, responsible for the replication and transcription of viral RNA in infected nuclei. Transcription of influenza virus RNA has a special "cap-robbing" mechanism, PB2 subunit is responsible for recognizing and binding the "cap structure" of host precursor mRNA, PA subunit cleaves host mRNA as a primer, initiates the transcription process the endonuclease active site of PA subunit, is responsible for cleaving host mRNA, and is used in PB1 subunit as a primer for further viral mRNA synthesis. Because the cap-dependent endonuclease of the PA subunit is necessary for the virus life process and has virus-specific enzyme activity which is not possessed by a host, the PA subunit is suitable for being used as a target of anti-influenza drugs to develop novel anti-influenza drugs.
CN102803260A discloses substituted polycyclic carbamoylpyridone derivatives having inhibitory activity against cap-dependent endonucleases useful as therapeutic and/or prophylactic agents for influenza infectious diseases.
Disclosure of Invention
The present invention aims to provide a potent novel pyridone derivative antiviral drug having improved activity for preventing or inhibiting influenza virus and/or bioavailability, particularly activity for preventing or inhibiting infection with influenza virus a and influenza virus B by having a cap-dependent endonuclease inhibitor, as compared with the existing polycyclic carbamoylpyridone derivative. The invention further provides a prodrug, which improves the absorption of the drug and improves the bioavailability of the drug, thereby achieving excellent clinical treatment effect. In summary, the present patent provides a drug for treating influenza a and influenza B viruses by PA endonuclease inhibitory activity, which can rapidly cure influenza-infected patients by single or combined administration.
In order to achieve the purpose, the invention adopts the following technical scheme:
a pyridone derivative represented by formula (I) or a stereoisomer, a pharmaceutically acceptable salt, a solvate or a crystal thereof,
Figure BDA0001550400590000011
wherein:
(1) a is selected from N or CR1，R1Selected from H, deuterium, cyano, hydroxyl, halogen, carboxyl, ester group, amide group, sulfonamide; alternatively, R1 is selected from the group consisting of unsubstituted or substituted: c1-6Hydrocarbyl radical, C1-6Hydrocarbyloxy, C1-6Hydrocarbylamino, C1-6Hydrocarbon mercapto, hydrazinoacyl, C1-6Hydrocarbyl carbonyl group, C1-6Hydrocarbyl aminocarbonyl group, C1-6Hydrocarbyl carbonylamino group, C1-6Hydrocarbyloxycarbonyl radical, C1-6Alkyl sulfinyl, C1-6Hydrocarbyl aminocarbonylamino group, C3-6Cycloalkyl radical, C3-6Cycloalkoxy, C3-6Cycloalkylamino radical, C3-6Cycloalkanemercapto group, C3-6Cycloalkanecarbonyl group, C3-6Cycloalkylamino carbonyl group, C3-6Cycloalkanecarbonylamino group, C3-6Cycloalkylamino carbonylamino group, C4-8Heterocycloalkyl radical, C4-8Heterocyclic alkoxy radical, C4-8Heterocyclic alkylamino radical, C4-8Heterocycloalkylmercapto group, C4-8Heterocycloalkylcarbonyl radical, C4-8Heterocycloalkylaminocarbonyl radical, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Aryloxy hydrocarbyl group, C5-10Arylamine group, C5-10Aromatic mercapto group, C5-10Aryl carbonyl, C1-6Hydrocarbyl sulfone group, C1-6Alkyl sulfonylamino group, C3-6Cycloalkyl sulfone group, C3-6Cycloalkylsulfonylamino, C5-10Aryl sulfone group, C5-10Arylsulfonylamino, aminooxalylamino, aminooxalyl, C5-10Arylaminocarbonyl radicals or C5-10Arylaminocarbonylamino;
(2) m is selected from N or CR2，R2Selected from H, deuterium, cyano, hydroxyl, halogen, carboxyl, ester group, amido and sulfonamide; or, R2Selected from the group consisting of unsubstituted or substituted: c1-6Hydrocarbyl radical, C1-6Hydrocarbyloxy, C1-6Hydrocarbylamino, C1-6Hydrocarbon mercapto, hydrazinoacyl, C1-6Hydrocarbyl carbonyl group, C1-6Hydrocarbyl aminocarbonyl group, C1-6Hydrocarbyl carbonylamino group, C1-6Hydrocarbyloxycarbonyl radical, C1-6Alkyl sulfinyl, C1-6Hydrocarbyl aminocarbonylamino group, C3-6Cycloalkyl radical, C3-6Cycloalkoxy, C3-6Cycloalkylamino radical, C3-6Cycloalkanemercapto group, C3-6Cycloalkanecarbonyl group, C3-6Cycloalkylamino carbonyl group, C3-6Cycloalkanecarbonylamino group, C3-6Cycloalkylamino carbonylamino group, C4-8Heterocycloalkyl radical, C4-8Heterocyclic alkoxy radical, C4-8Heterocyclic alkylamino radical, C4-8Heterocycloalkylmercapto group, C4-8Heterocycloalkylcarbonyl radical, C4-8Heterocycloalkylaminocarbonyl radical, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Aryloxy hydrocarbyl group, C5-10Arylamine group, C5-10Aromatic mercapto group, C5-10Aryl carbonyl group, C1-6Hydrocarbyl sulfone group, C1-6Alkyl sulfonylamino group, C3-6Cycloalkyl sulfone group, C3-6Cycloalkylsulfonylamino, C5-10Aryl sulfone group, C5-10Arylsulfonylamino, aminooxalylamino, aminooxalyl, C5-10Arylaminocarbonyl radicals or C5-10Arylaminocarbonylamino; or, R1And R2Joined to form a first ring or R2And R7Linked to form a second ring, said first and second rings being uninterrupted or selected from the group consisting of heteroatom, silicon, C-O, S-O, SO2And the first ring, the second ring, and the third ring are each monocyclic, spiro, fused, bridged, or polycyclic;
(3) q is selected from N or CR3，R3Selected from H, deuterium, cyano, carboxyl, ester group, amide; or, R3Selected from the group consisting of unsubstituted or substituted: c1-6Hydrocarbyl radical, C3-6Cycloalkyl radical, C4-8Heterocycloalkyl radical, C5-10Aryl, spiro, bridged, cycloalkylmercapto C1-6Alkyl, cycloalkyl C1-6Hydrocarbyl thio radical C1-6Alkyl, cycloalkyl C1-6Hydrocarbyl mercapto cycloalkyl, cyclohydrocarbyloxy cycloalkyl, cyclic amido C1-6Alkyl, cyclic amido cyclic alkyl, cyclic sulphonyl C1-6Hydrocarbyl, cyclic sulfone cycloalkyl; or, R3And R4Linked to form a third ring, said third ring being uninterrupted or selected from the group consisting of hetero atoms, Si-based, C-O, S-O, SO2Is interrupted and unsubstituted or substituted carbocycle, and the third ring is monocyclic, spiro, fused, bridged or polycyclic;
(4) r is selected from NH, carbonyl or CR4R5，R4、R5Independently selected from H, deuterium, cyano, carboxyl, ester group and amido; or, R4、R5Independently selected from the group consisting of unsubstituted or substituted: c1-6Hydrocarbyl radical, C1-6Hydrocarbyloxy, C1-6Hydrocarbylamino, C1-6Mercapto group of hydrocarbon, C1-6Hydrocarbyl carbonyl group, C1-6Hydrocarbyl aminocarbonyl group, C1-6Hydrocarbyl carbonylamino group, C1-6Hydrocarbyloxycarbonyl radical, C1-6Hydrocarbyl amine amido, C3-6Cycloalkyl radical, C3-6Cycloalkoxy, C3-6Cycloalkylamino radical, C3-6Cycloalkanemercapto group, C3-6Cycloalkanecarbonyl group, C3-6Cycloalkylaminocarbonyl group, C3-6Cycloalkylamino carbonylamino group, C3-6Cycloalkyl carbonylamino group, C4-8Heterocycloalkyl radical, C4-8Heterocyclic alkoxy radical, C4-8Heterocyclic alkylamino radical, C4-8Heterocycloalkylmercapto group, C4-8Heterocycloalkylcarbonyl radical, C4-8Heterocycloalkylaminocarbonyl radical, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Aryloxy group C1-6Hydrocarbyl radical, C5-10Arylamine group, C5-10Aromatic mercapto group, C5-10Aryl carbonyl group, C5-10Arylaminocarbonyl radicals or C5-10Arylaminocarbonylamino; or, R4And R5Linked to form a fourth ring, said fourth ring being uninterrupted or selected from the group consisting of heteroatom, silyl, C-O, S-O, SO2Is interrupted and unsubstituted or substituted carbocycle, and the fourth ring is monocyclic, spirocyclic, fused, bridged or polycyclic;
(5)R6selected from H, deuterium, cyano, hydroxyl, ester group, amide group, sulfonamide group; or, R6Selected from the group consisting of unsubstituted or substituted: c1-6Hydrocarbyl radical, C1-6Hydrocarbyloxy, C1-6Hydrocarbylamino, C1-6Hydrocarbon mercapto, hydrazinoacyl, C1-6Hydrocarbyl carbonyl group, C1-6Hydrocarbyl aminocarbonyl group, C1-6Hydrocarbyl carbonylamino group, C1-6Hydrocarbyloxycarbonyl radical, C1-6Alkyl sulfinyl, C1-6Hydrocarbyl aminocarbonylamino group, C3-6Cycloalkyl radical, C3-6Cycloalkoxy, C3-6Cycloalkylamino radical, C3-6Cycloalkanemercapto group, C3-6Cycloalkanecarbonyl group, C3-6Cycloalkylamino carbonyl group, C3-6Cycloalkanecarbonylamino group, C3-6Cycloalkylamino carbonylamino group, C4-8Heterocycloalkyl radical, C4-8Heterocyclic alkoxy radical, C4-8Heterocyclic alkylamino radical, C4-8Heterocycloalkylmercapto group, C4-8Heterocycloalkylcarbonyl radical, C4-8Heterocycloalkylaminocarbonyl radical, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Aryloxy hydrocarbyl group, C5-10Arylamine group, C5-10Aromatic mercapto group, C5-10Aryl carbonyl, C1-6Hydrocarbyl sulfone group, C1-6Alkyl sulfonylamino group, C3-6Cycloalkyl sulfone group, C3-6Cycloalkylsulfonylamino, C5-10Aryl sulfone group, C5-10Arylsulfonylamino, aminooxalylamino, aminooxalyl, C5-10Arylaminocarbonyl radicals or C5-10Arylaminocarbonylamino; or, R6Is a fifth ring which is uninterrupted or selected from the group consisting of heteroatom, silicon, C-O, S-O or-SO2Is interrupted and is an unsubstituted or substituted carbocyclic ring, said fifth ring being spiro, fused, bridged or polycyclic; or, R6And R are linked to form a sixth ring which is monocyclic, spiro, fused, bridged or polycyclic and which contains at least one N and optionally S, O, silyl, C O, S ═ O or-SO2One or more of;
(6) m is 0, 1,2,3, 4 or 5, R7Independently selected from H, deuterium, hydroxyl, cyano, halogen, carboxyl, ester group, sulfonamide group and amido group; or, R7Selected from the group consisting of unsubstituted or substituted: c1-6Hydrocarbyl radical, C1-6Hydrocarbyloxy, C1-6Hydrocarbylamino, C1-6Hydrocarbon mercapto, hydrazinoacyl, C1-6Hydrocarbyl carbonyl group, C1-6Hydrocarbyl aminocarbonyl group, C1-6Hydrocarbyl carbonylamino group, C1-6Hydrocarbyloxycarbonyl radical, C1-6Alkyl sulfinyl, C1-6Hydrocarbyl aminocarbonylamino group, C3-6Cycloalkyl radical, C3-6Cycloalkoxy, C3-6Cycloalkylamino radical, C3-6Cycloalkanemercapto group, C3-6Cycloalkanecarbonyl group, C3-6Cycloalkylamino carbonyl group, C3-6Cycloalkanecarbonylamino group, C3-6Cycloalkylamino carbonylamino group, C4-8Heterocycloalkyl radical, C4-8Heterocyclic alkoxy radical, C4-8Heterocyclic alkylamino radical, C4-8Heterocycloalkylmercapto group, C4-8Heterocycloalkylcarbonyl radical, C4-8Heterocycloalkylaminocarbonyl radical, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Aryloxy hydrocarbyl group, C5-10Arylamine group, C5-10Aromatic mercapto group, C5-10Aryl carbonyl, C1-6Hydrocarbyl sulfone group, C1-6Alkyl sulfonylamino group, C3-6Cycloalkyl sulfone group, C3-6Cycloalkylsulfonylamino, C5-10Aryl sulfone group, C5-10Arylsulfonylamino, aminooxalylamino, aminooxalyl, C5-10Arylaminocarbonyl radicals or C5-10Arylaminocarbonylamino, or m is 2,3, 4 or 5, one or more groups of two adjacent R7Linked to form a seventh ring, said seventh ring being uninterrupted or selected from the group consisting of heteroatom, silicon, C-O, S-O or-SO2Is interrupted and is unsubstituted or substituted carbocycle, said seventh ring is monocyclic, spiro, fused, bridged or polycyclic; or, R2And R7Linked to form an eighth ring, said eighth ring being uninterrupted or selected from the group consisting of heteroatom, silicon, C-O, S-O, SO2Is interrupted and unsubstituted or substituted carbocycle, and the eighth ring is monocyclic, spiro, fused, bridged or polycyclic;
(7) x is selected from Y (CH)2)n、-CH(OCH3)、-CH(SCH3) N, O or S, Y is a bond, NH, O or S, n is 0, 1,2 or 3;
(8) w is H or a group which is metabolized into the parent drug by a chemical method or under the action of an enzyme in vivo;
(9) ar1 and Ar2 are independently selected from benzene rings, aromatic heterocyclic rings containing one or more heteroatoms.
According to a particular aspect of the invention, Ar1 and Ar2 are both phenyl rings and the pyridone derivative is represented by the following formula (II):
Figure BDA0001550400590000031
according to yet another aspect of the invention at least one of Ar1 and Ar2 is an aromatic heterocycle.
According to the invention, the heteroatoms of said heterocyclic or heteroaromatic ring are preferably independently selected from N, O, S.
In some embodiments according to the invention, A is CR1M is CR2，R1And R2Forming the first ring.
In some embodiments according to the invention, Q is CR3R is CR4R5，R3And R4Forming the second ring.
In certain embodiments according to the invention, R is CR4R5，R4And R6Joined to form the sixth loop.
According to the present invention, W as depicted in formula (I) includes, but is not limited to, the following groups:
(a)-C(＝O)-R8；(b)-C(＝O)-(CH2)k-R8k is selected from 1 to 3; (c) -C (═ O) -O- (CH)2)k-R8K is selected from 1 to 3; (d) -CH2-O-R8；(e)-CH2-O-C(＝O)-R8；(f)-CH2-O-C(＝O)-O-R8；(g)-CH(-CH3)-O-C(＝O)-R8；(h)-CH(-CH3)--O-C(C＝O)-O-(CH2)k-R8K is selected from 0 to 3; (i) -CH2O-P(＝O)(OH)8；(j)-CH2-O-P(＝O)(OPh)(NHR8)；(k)-CH2-O-P(＝O)(OCH2OC(＝O)OR8)2(ii) a The R is8The following unsubstituted or substituted groups: c1-6Hydrocarbyl radical, C1-6Hydrocarbyloxy, C1-6Hydrocarbylamino, C1-6Hydrocarbon mercapto, hydrazinoacyl, C1-6Hydrocarbyl carbonyl group, C1-6Hydrocarbyl aminocarbonyl group, C1-6Hydrocarbyl carbonylamino group, C1-6Hydrocarbyloxycarbonyl radical, C1-6Alkyl sulfinyl, C1-6Hydrocarbyl aminocarbonylamino group, C3-6Cycloalkyl radical, C3-6Cycloalkoxy, C3-6Cycloalkylamino radical, C3-6Cycloalkanemercapto group, C3-6Cycloalkanecarbonyl group, C3-6Cycloalkylamino carbonyl group, C3-6Cycloalkanecarbonylamino group, C3-6Cycloalkylamino carbonylamino group, C4-8Heterocycloalkyl radical, C4-8Heterocyclic alkoxy radical, C4-8Heterocyclic alkylamino radical, C4-8Heterocycloalkylmercapto group, C4-8Heterocycloalkylcarbonyl radical, C4-8Heterocycloalkylaminocarbonyl radical, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Aryloxy hydrocarbyl group, C5-10Arylamine group, C5-10Aromatic mercapto group, C5-10Aryl carbonyl, C1-6Hydrocarbyl sulfone group, C1-6Alkyl sulfonylamino group, C3-6Cycloalkyl sulfone group, C3-6Cycloalkylsulfonylamino, C5-10Aryl sulfone group, C5-10Arylsulfonylamino, aminooxalylamino, aminooxalyl, C5-10Arylaminocarbonyl radicals or C5-10Arylaminocarbonylamino.
According to certain preferred embodiments of the invention, R6Selected from the group consisting of:
Figure BDA0001550400590000041
according to the invention, said pyridone derivatives may be and are preferably, for example, the following compounds:
Figure BDA0001550400590000042
Figure BDA0001550400590000051
Figure BDA0001550400590000061
Figure BDA0001550400590000071
Figure BDA0001550400590000081
Figure BDA0001550400590000091
Figure BDA0001550400590000101
according to the invention, all of the hydrogen atoms, except the active hydrogen, may each independently be replaced by deuterium.
The invention further provides a pharmaceutical composition containing the pyridone derivative shown in the formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate or a crystal thereof.
Further, the pharmaceutical composition is an antiviral pharmaceutical composition, optionally further comprising one or more therapeutic agents selected from the group consisting of: neuraminidase inhibitors, nucleoside drugs, PB2 inhibitors, PB1 inhibitors, M2 inhibitors or other anti-influenza drugs. Preferably, the antiviral pharmaceutical composition comprises at least one therapeutic agent.
The invention also relates to application of the pyridone derivative shown in the formula (I), a stereoisomer, a pharmaceutically acceptable salt, a solvate or a crystal or a pharmaceutical composition thereof in preparing a medicament for preventing and/or treating viral infectious diseases, wherein the viral infectious diseases are preferably infectious diseases caused by influenza A or influenza B.
The invention also relates to the application of the pyridone derivative shown in the formula (I), the stereoisomer, the pharmaceutically acceptable salt, the solvate or the crystal or the pharmaceutical composition thereof in preparing an antiviral medicament, wherein the antiviral medicament is preferably a medicament or an agent for inhibiting the activity of influenza cap-dependent endonuclease. The present invention further provides a process for the preparation of the pyridone derivatives of the present invention, which comprises the following route:
Figure BDA0001550400590000102
according to one embodiment of the present invention, the above reaction can be carried out as follows:
step-1: a and B are dissolved in, for example, 50% T3P in ethyl acetate, in a sealed tube at, for example, 100 ℃ for 1 hour to give intermediate C.
Step-2: the intermediate C is dissolved in a DMA solution of, for example, lithium chloride, and the reaction solution is reacted at, for example, 100 ℃ for, for example, 12 hours, followed by purification to obtain a compound D.
Step-3: the obtained compound D and acyl chloride or halide are subjected to hydroxyl protection in the presence of a base to obtain a prodrug (I), wherein the base comprises an organic base and an inorganic base, and the organic base is selected from triethylamine, DIPEA, DBU, pyridine and the like; the inorganic base is selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium bicarbonate, etc.
In the present invention, for convenience of description, the pyridone derivative represented by formula (I), a stereoisomer, a pharmaceutically acceptable salt, and a solvate thereof of the present invention are collectively referred to as the present compound in some places.
The pharmaceutical composition according to the invention, wherein the compound according to the invention is preferably present in a therapeutically effective amount.
The pharmaceutically acceptable carrier in the pharmaceutical composition can be pharmaceutically acceptable diluent, excipient, filler, binder, disintegrant, absorption enhancer, surfactant, lubricant, flavoring agent, sweetener, etc.
The medicine prepared by taking the compound of the invention as an active ingredient can be various forms such as tablets, powder, capsules, granules, oral liquid, injection preparations and the like. The dosage form of the pharmaceutical composition is preferably tablets, capsules or injections.
The medicaments in various dosage forms can be prepared by the conventional method in the pharmaceutical field.
The invention also provides the use of a compound of the invention in the preparation of a medicament for the prophylaxis or treatment of a viral infectious disease, preferably wherein the viral infectious disease is a viral infection of influenza a and influenza B.
The pharmaceutical composition of the invention can be prepared from the following components in proportion:
Figure BDA0001550400590000111
due to the implementation of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention provides novel pyridone derivatives which have extremely strong activity of inhibiting influenza virus A and influenza virus B. In order to further improve the bioavailability of the drug, the synthesized prodrug compound has excellent pharmacokinetic properties.
Furthermore, the compound has high activity of inhibiting influenza viruses, can be used for clinical treatment alone or combined with other anti-influenza drugs such as neuraminidase inhibitors, nucleoside drugs and PB2 inhibitors, and can cure influenza patients quickly in clinic.
Definition of terms
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
The term "unsubstituted" when used to define a group means that the defined group is not substituted with other groups than a hydrogen atom, when the group has the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. E.g. unsubstituted C1-6Alkyl groups are methyl, ethyl, and the like as is commonly understood by those skilled in the art.
The term "substituted" when used to define a group means that one or more hydrogen atoms of the defined group are replaced with a substituent, in which case the meaning of the group is to be understood in conjunction with the substituent. In the present invention, unless otherwise specified, "substituted" when referring to a group defined thereby means that the hydrogen atom in the group is substituted by one or more substituents selected from the group consisting of:
deuterium, cyano, halogen, hydroxyl, carboxyl, ester group, sulfone group, sulfonamide group, amide group, carbonyl group (-C (═ O) -), C1-6Hydrocarbyl S (═ O) (═ NH) -, amino, hydrazinoacyl, C1-6Hydrocarbyl, halogenated C1-6Hydrocarbyl, hydroxy-substituted C1-6Hydrocarbyl, amide substituted C1-6Hydrocarbyl radical, C1-6Alkoxy, halo C1-6Hydrocarbyloxy, C1-6Hydrocarbyloxy group C1-6Hydrocarbyl radical, C1-6Hydrocarbyloxy group C1-6Hydrocarbyloxy, C1-6Hydrocarbylamino, C1-6Mercapto group of hydrocarbon, C1-6Hydrocarbyl carbonyl group, C1-6Hydrocarbyl amine acyl, C1-6Hydrocarbyl amido, halo C1-6Hydrocarbyl amide group, C1-6Hydroxyoxyacyl group, C1-6Hydrocarbyl amine amido, C1-6Hydrocarbyl sulfone group, C1-6Hydrocarbyl sulfonamide, C3-6Cycloalkyl, halo C3-6Cycloalkyl radical, C3-6Cycloalkoxy, halo C3-6Cycloalkoxy, C3-6Cycloalkyl radical C1-6Hydrocarbyl radical, C3-6Cycloalkanoxy C1-6Hydrocarbyl radical, C3-6Cycloalkyl radical C1-6Hydrocarbyloxy, C3-6Cycloalkyl radical C1-6Hydrocarbyloxy group C1-6Hydrocarbyloxy, C3-6Cycloalkylamino radical, C3-6Cycloalkyl radical C1-6Hydrocarbylamino, C3-6Cycloalkanemercapto, halogeno C3-6Cycloalkanemercapto group, C3-6Cycloalkyl radical C1-6Mercapto group of hydrocarbon, C3-6Cycloalkyl sulfone group, C3-6Cycloalkyl radical C1-6Hydrocarbon sulfone group, C3-6Cycloalkylsulfonamide, C3-6Cycloalkyl radical C1-6Hydrocarbyl sulfonamide, C3-6Cycloalkanecarbonyl group, C3-6Cycloalkyl radical C1-6Hydrocarbyl carbonyl group, C3-6Cycloalkaneaminoacyl radical, C3-6Cycloalkyl radical C1-6Hydrocarbyl amine acyl, C3-6Cycloalkaneamide group, C3-6Cycloalkyl radical C1-6Hydrocarbyl amide group, C3-6Cycloalkane amidesAmino group, C4-8Heterocycloalkyl radical, C4-8Heterocycloalkyloxy, halo C4-8Heterocycloalkyloxy, C4-8Heterocycloalkyloxy C1-6Hydrocarbyl, halo C4-8Heterocycloalkyloxy C1-6Hydrocarbyl radical, C4-8Heterocycloalkyl radical C1-6Alkoxy, halo C4-8Heterocycloalkyl radical C1-6Hydrocarbyloxy, C4-8Heterocycloalkyl radical C1-6Hydrocarbyl radical, C4-8Heterocycloalkyl radical C1-6Hydrocarbyloxy group C1-6Hydrocarbyl radical, C4-8Heterocyclic alkylamino radical, C4-8Heterocycloalkylmercapto group, C4-8Heterocycloalkyl radical C1-6Hydrocarbyl mercapto group, C4-8Heterocyclylalkylsulfone radical, C4-8Heterocycloalkyl radical C1-6Hydrocarbon sulfone group, C4-8Heterocyclylalkylsulfonamide group, C4-8Heterocycloalkyl radical C1-6Hydrocarbyl sulfonamide, C4-8Heterocycloalkylcarbonyl radical, C4-8Heterocycloalkyl radical C1-6Hydrocarbyl carbonyl group, C4-8Heterocycloalkyl substituted by carbonyl groups, C4-8Heterocyclic alkylamine acyl, C4-8Heterocyclylalkylamide radical, C4-8Heterocycloalkyl radical C1-6Hydrocarbyl amide group, C5-10Aryl radical, C5-10Aryloxy radical, C5-10Aryloxy radical C1-6Hydrocarbyl radical, C5-10Aryl radical C1-6Hydrocarbyl radical, C5-10Aryl radical C1-6 oxyl, C5-10 arylamine, C5-10 arylsulfydryl, C5-10 aryl C1-6 hydrocarbon sulfydryl, C5-10 aryl sulfone, C5-10 aryl C1-6 hydrocarbon sulfone, C5-10 arylsulfonamide, C5-10 aryl C1-6 alkyl sulfonamide, C5-10 arylcarbonyl, C5-10 aryl C1-6 alkyl carbonyl, C5-10 arylamine acyl, C5-10 arylamine or C5-10 arylamine.
Preferably, the substituent is selected from deuterium, cyano, halogen (preferably F, Cl, Br), hydroxyl, carboxyl, ester, sulfone, sulfonylamino, carbonylamino, carbonyl, C1-6Alkyl sulfinyl amino, hydrazinoacyl, C1-6Hydrocarbyl, halogenated C1-6Hydrocarbyl, hydroxy-substituted C1-6Hydrocarbyl, amide substituted C1-6Hydrocarbyl radical, C1-6Alkoxy, halo C1-6Hydrocarbyloxy, C1-6Hydrocarbyloxy group C1-6Hydrocarbyl radical, C1-6Hydrocarbyloxy group C1-6A hydrocarbyloxy group.
More preferably, the substituent is selected from deuterium, cyano, F, Cl, Br, hydroxyl, carboxyl, ester group, sulfone group, sulfonamide group, amide group, carbonyl group, methylsulfinylamino, ethylsulfinylamino, isopropylsulfinylamino, tert-butylsulfinylamino, amino group, hydrazoyl group, methyl group, ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, isobutyl group, tert-butyl group, cyclobutyl group, n-pentyl group, isopentyl group, neopentyl group, cyclohexyl group, halomethyl group (specifically, trifluoromethyl group), haloethyl group, halo-n-propyl group, haloisopropyl group, halocyclopropyl group, halo-n-butyl group, haloisobutyl group, halo-tert-butyl group, halocyclobutyl group, hydroxymethyl group, hydroxyethyl group, hydroxy-n-propyl group, hydroxyisopropyl group, hydroxycyclopropyl group, hydroxy-n-butyl group, hydroxyisobutyl group, hydroxy-tert-butyl group, hydroxycyclobutyl group, hydroxyisopropyl group, hydroxyisopropylbutyl group, hydroxyisopropyl group, hydroxyb, Hydroxy-n-pentyl, hydroxy-isopentyl, hydroxy-neopentyl, hydroxy-cyclohexyl, methoxy, ethoxy, propoxy.
When referring to a specific nomenclature, the substituent is typically placed before the group being substituted, e.g. "C1-3Alkoxy radical C3-8Cycloalkyl radical C1-6Alkyl "means C1-6Alkyl radical, which is substituted by C3-8Cycloalkyl is substituted, and the C3-8Cycloalkyl radicals being further C1-3Alkoxy substitution, examples being: the structural formula of the methoxycyclobutylmethyl group is as follows:
Figure BDA0001550400590000121
the term "uninterrupted" when used to define a group means that the covalent bond of the defined group is not interrupted by other groups, when the group has the same meaning as commonly understood by one of ordinary skill in the art to which the invention belongs. Such as uninterrupted cycloalkyl groups, i.e., cyclobutyl, cyclopentyl, and the like, as is commonly understood by those skilled in the art.
The term "interrupted" or "interrupted", when used to define a group, means that one or more covalent bonds to the defined group are interrupted by an atom orWhere a group is interrupted, the meaning of that certain group should be understood in conjunction with the interrupting atom or group. In the present invention, unless otherwise specified, when referring to "interrupted" it is intended that the covalent bond in the group defined thereby consists of a group selected from the group consisting of heteroatom (O, N, S), silicon group, C O, S ═ O or-SO2Is interrupted by one or more of them. The position of the discontinuity may be any chemically available position, and when there are plural discontinuous atoms or groups, the relative positions between the plural discontinuous atoms or groups are not limited as long as they are chemically available.
The term "stereoisomer" refers to isomers resulting from differences in the spatial arrangement of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers. All stereoisomers are within the scope of the present invention. The compounds of the invention may be individual stereoisomers or mixtures of other isomers, such as racemates, or mixtures of all other stereoisomers.
The term "salt" refers to a pharmaceutically acceptable salt of a compound of the invention with an acid, which may be an organic or inorganic acid, and may be selected, for example, from: phosphoric acid, sulfuric acid, hydrochloric acid, hydrobromic acid, citric acid, maleic acid, malonic acid, mandelic acid, succinic acid, fumaric acid, acetic acid, lactic acid, nitric acid, sulfonic acid, p-toluenesulfonic acid, malic acid, methanesulfonic acid, or the like.
The term "solvate" refers to a form of a compound of the present invention that forms a solid or liquid complex by coordination with a solvent molecule. Hydrates are a special form of solvates in which coordination occurs with water. Within the scope of the present invention, the solvate is preferably a hydrate.
The term "crystalline" refers to the various solid forms formed by the compounds of the present invention, including crystalline forms, amorphous forms.
The term "hydrocarbyl" refers to alkyl, alkenylalkyl, and alkynylalkyl groups.
The term "alkyl" refers to a straight, branched, or cyclic saturated substituent consisting of carbon and hydrogen. Preferably 1 to 20 carbon atoms, more preferably 1 to 12 carbon atoms. The term "alkyl" refers to straight chainA chain, branched or cyclic saturated hydrocarbon group. Alkyl includes in particular, for example, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl, isohexyl, 2, -methylbutyl and 2, 3-dimethylbutyl, 16-alkyl, 18-alkyl. The term "C1-20Alkyl "refers to a straight, branched or cyclic saturated hydrocarbon group containing 1 to 20 carbon atoms. When the alkyl group is substituted, the substituent may be substituted at any available point of attachment, and the substituent may be mono-or poly-substituted. For example, the substituent may be alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxyl, nitro, carboxyl, ester group, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, oxo.
The terms "alkenyl" and "alkynyl" refer to straight, branched or cyclic unsaturated hydrocarbon groups containing double and triple bonds, preferably 2 to 20 carbon atoms, more preferably 2 to 12 carbon atoms, respectively. When substituted, the substituents may be substituted at any available point of attachment, and the substituents may be mono-or polysubstituted. For example, the substituent may be selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxy, nitro, carboxy, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, oxo.
The term "cycloalkyl" refers to a saturated monocyclic cycloalkyl group. Monocyclic rings typically comprise 3 to 10 carbon atoms. Non-limiting examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, and the like. In the present invention, cyclic alkyl groups of spiro ring, fused ring and bridged ring are also collectively referred to as polycyclic cyclic alkyl groups.
The term "ring", when not specifically limited, refers to any cyclic structure, unlimited in form and composition, and can be any of monocyclic, bridged, spiro, fused, and polycyclic, can be carbocyclic or heterocyclic or other forms of rings, such as carbocyclic interrupted by a carbonyl group, and can be unsubstituted or substituted.
The term "carbocyclyl" or "carbocycle" refers to carbocyclyl having 3 to 20 carbon atoms, preferably 3 to 16 carbon atoms, more preferably 4 to 12 carbon atoms, including cycloalkyl, cycloalkenyl, aryl, bicyclic carbocycles, polycyclic carbocycles, and the like. The term "heterocyclic group" or "heterocyclic ring" means a heteroaryl group, a non-aromatic heterocyclic group, a bicyclic heterocyclic group, a polycyclic heterocyclic group and the like which structurally contain at least one heteroatom, specifically, for example, 1 or more heteroatoms which may be the same or different and are arbitrarily selected from O, S and N.
The term "aryl" is to be understood in a broad sense and includes not only carbocyclic aryl but also heteroaryl.
The term "carbocyclic aryl" refers to 6-10 membered all carbon monocyclic or polycyclic aromatic groups including phenyl, naphthyl, biphenyl and the like. Carbocyclic aryl groups may be substituted or unsubstituted. The substituents are independently selected from, for example, alkyl, cycloalkyl (e.g., cyclopropylalkyl, cyclobutylalkyl, cyclopentylalkyl and the like), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, alkylsilyl and the like.
The term "heteroaryl" refers to a group of heteroaromatic systems containing 1-10 heteroatoms, including monocyclic heteroaryl and fused ring heteroaryl. Heteroatoms include oxygen, sulfur, nitrogen, phosphorus, and the like. Wherein monocyclic heteroaryl groups include, but are not limited to, furan, thiophene, pyrrole, thiazole, imidazole, 1,2, 3-triazole, 1,2, 4-triazole, 1,2, 3-thiadiazole, oxazole, 1,2, 4-oxadiazole, 1,3, 4-oxadiazole, pyridine, pyrimidine, pyridazine, pyrazine, tetrahydrofuran, tetrahydropyrrole, piperidine, piperazine, morpholine, isoxazoline, and the like. Fused ring heteroaryl groups include, but are not limited to, quinoline, isoquinoline, indole, benzofuran, benzothiophene, purine, acridine, carbazole, fluorene, chromene, fluorenone, quinoxaline, 3, 4-dihydronaphthalenone, dibenzofuran, hydrogenated dibenzofuran, benzoxazolyl, and the like. Heteroaryl groups may be substituted and unsubstituted. The substituent is, for example, selected from alkyl, cycloalkyl (e.g., cyclopropylalkyl, cyclobutylalkyl, cyclopentylalkyl and the like), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxyl, nitro, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, alkylsilyl and the like.
The term "halogen" means fluorine, chlorine, bromine, iodine, preferably fluorine, chlorine, bromine.
The term "deuterium" is an isotope of hydrogen with an atomic mass 2 times that of the latter and is more strongly bound to carbon. Deuterated "and" deuterium "indicate that hydrogen is replaced with deuterium at the indicated position. One "deuterated substituent" is a substituent wherein at least one hydrogen is replaced with deuterium enriched in the specified percentage.
The term "haloalkyl" refers to an alkyl group substituted with at least one halogen atom.
The term "heterocyclyl" refers to a cyclic group containing at least one heteroatom, which may be nitrogen, oxygen, sulfur, and the like. The heterocyclic group includes a mono-heterocyclic group and a poly-heterocyclic group.
Detailed Description
The following examples are presented to enable one of ordinary skill in the art to more fully understand the present invention and are not intended to limit the invention in any way. All compounds have the structure1H NMR or MS.
The compound names used in the examples are abbreviated as follows:
DCM: methylene dichloride
EtOAc: ethyl acetate
THF tetrahydrofuran
DME: ethylene glycol dimethyl ether
1, 4-Dioxane: 1,4-dioxane
TEA: triethylamine
T3P: 1-Propylphosphoric acid anhydride
PPA-polyphosphoric acid
TBAF: tetrabutylammonium fluoride
NBS: n-bromosuccinimide
AIBN: azobisisobutyronitrile
HATU: 2- (7-benzotriazole oxide) -N, N, N ', N' -tetramethyluronium hexafluorophosphate
TFA: trifluoroacetic acid
The invention will be further described with reference to specific examples:
example 1: preparation (I-1)
Figure BDA0001550400590000141
Preparation of compound 1 b: compound 1a (2.0g, 8.1mmol), DBU (1.85g, 12.2mmol) and iodoethane (2.28g, 14.6mmol) were reacted in 20mL DMF at room temperature for 16 h. Then 100mL of water was added for dilution and EA extraction. The organic phases were combined, washed successively with sodium thiosulfate, 0.5N HCl and saturated brine, then dried over anhydrous sodium sulfate and spin-dried to give 2.1g of oily product.
Preparation of compound 1 c: compound 1b (2.1g,7.7mmol), Boc hydrazine (1.53g, 11.6mmol) and pyridine p-toluenesulfonate (5.78g, 23.1mmol) were reacted in N, N-dimethylacetamide (20mL) at 60 ℃ for 16 h. After completion of the reaction, 100mL of water was added to the reaction mixture, followed by extraction with ethyl acetate (50 mL. times.3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate and concentrated, and the crude product was isolated by column chromatography to give 1.9g of a yellow oil. ESI-MS M/z 389.2(M + H)+
Preparation of compound 1 d: compound 1c (1.9g,4.9mmol) was dissolved in 10mL of ethanol, and 1N aq. NaOH solution (14.7mL, 14.7mmol) was added, followed by reaction at 60 ℃ for 24 hours. Acidified with 3N HCl and extracted with DCM. The organic phases were combined, washed with saturated brine, dried and concentrated. The crude product was slurried with methylene chloride/petroleum ether (5mL/50mL) to give 1.1g of a white solid. ESI-MS M/z 361.2(M + H)+
Preparation of compound 1 f: compound 1d (360mg,1mmol), 1e (133mg, 1.2mmol), TEA (303mg, 3.0mmol) and HATU (570mg, 1.5mmol) were stirred in DCM at room temperature overnight, then diluted with water and extracted with DCM. The organic phases were combined, washed with saturated brine, dried, concentrated and separated by column chromatography to give 350mg of a white solid. ESI-MS M/z 454.2(M + H)+
Preparation of compound 1 g: compound 1f (350mg,0.77mmol) was dissolved in 4mL of EDCM, 1mL of TFA was added and reacted at 0 ℃ for 6 hours. Spin-dry, add 1N NaOH to make alkaline, DCM/iPrOH extract. The organic phases were combined, washed with brine, dried and concentrated to give 210mg of oil which was used directly in the next step.
Preparation of compound 1 h: compound 1g (210mg,0.59mmol) was dissolved in 5mL of toluene, and 30mg of paraformaldehyde and 100mg of acetic acid were added to react at 100 ℃ for 3 hours. Concentrating, and performing thin-plate chromatography to obtain 145mg of product. ESI-MS M/z 366.2(M + H)+
Preparation of compound 1 j: compound 1h (140mg,0.38mmol) and 1i (114mg,0.5mmol) were reacted in a solution of T3P in ethyl acetate at 100 ℃ for 3 hours under sealed conditions. Cooled, diluted with saturated NaHCO3, and extracted with ethyl acetate. The organic phases were combined, dried and concentrated, and the 170mg product was isolated from the preparative plate. ESI-MS M/z 576.2(M + H)+。
Preparation of Compound I-1: compound 1j (170mg, 0.29mmol) was dissolved in 5mL of methanol, palladium on carbon was added, and catalytic hydrogenation was carried out. After 6 hours filtration was carried out, the filtrate was concentrated and separated by plate to obtain 40mg of product. ESI-MS M/z 486.2(M + H)+。
Example 2: preparation (I-26)
Figure BDA0001550400590000151
Preparation of compound 26 b: compound 1d (360mg,1mmol), 26a (116mg, 1.2mmol), TEA (303mg, 3.0mmol) and HATU (570mg, 1.5mmol) were stirred in DCM at room temperature overnight, then diluted with water and extracted with DCM. The organic phases were combined, washed with saturated brine, dried, concentrated and separated by column chromatography to give 320mg of a white solid. ESI-MS M/z 440.2(M + H)+
Preparation of compound 26 c: compound 26b (320mg,0.73mmol) was dissolved in 4mL of EDCM, 1mL of TFA was added and reacted at 0 ℃ for 6 hours. Spin-dry, add 1N NaOH to make alkaline, DCM/iPrOH extract. The organic phases were combined, washed with brine, dried and concentrated to give 195mg of oil which was used directly in the next step.
Preparation of compound 26 d: compound 26c (195mg,0.57mmol) was dissolved in 5mL of toluene, and 30mg of paraformaldehyde and 100mg of acetic acid were added to react at 100 ℃ for 3 hours. ConcentratingAnd carrying out thin plate chromatography to obtain 130mg of product. ESI-MS M/z 352.2(M + H)+
Preparation of compound 26 e: compound 26d (130mg,0.37mmol) and 1i (114mg,0.5mmol) were reacted in a solution of T3P in ethyl acetate at 100 ℃ for 3 hours under sealed conditions. Cooled, diluted with saturated NaHCO3, and extracted with ethyl acetate. The organic phases were combined, dried and concentrated, and prepared plates were separated to yield 130mg of product. ESI-MS M/z 562.2(M + H)+。
Preparation of Compound I-26: compound 26e (130mg, 0.23mmol) was dissolved in 5mL of methanol, palladium on carbon was added, and catalytic hydrogenation was carried out. After 6 hours filtration was carried out, the filtrate was concentrated and separated on a plate to obtain 35mg of product. ESI-MS M/z 472.2(M + H)+。
Example 3: preparation (I-27)
Figure BDA0001550400590000152
Preparation of compound 27 b: compound 1d (360mg,1mmol), 27a (136mg, 1.2mmol), TEA (303mg, 3.0mmol) and HATU (570mg, 1.5mmol) were stirred in DCM at room temperature overnight, then diluted with water and extracted with DCM. The organic phases were combined, washed with saturated brine, dried, concentrated and separated by column chromatography to give 345mg of a yellow solid. ESI-MS M/z 456.2(M + H)+
Preparation of compound 27 c: compound 27b (345mg,0.76mmol) was dissolved in 4mL of EDCM, 1mL of TFA was added and reacted at 0 ℃ for 6 hours. Spin-dry, add 1N NaOH to make alkaline, DCM/iPrOH extract. The organic phases were combined, washed with brine, dried and concentrated to give 170mg of oil which was used directly in the next step.
Preparation of compound 27 d: compound 27c (170mg,0.48mmol) was dissolved in 5mL of toluene, and 30mg of paraformaldehyde and 100mg of acetic acid were added to react at 100 ℃ for 3 hours. Concentrating, and performing thin-plate chromatography to obtain 80mg of product. ESI-MS M/z 368.2(M + H)+
Preparation of compound 27 e: compound 27d (80mg,0.22mmol) and 1i (68mg,0.3mmol) were reacted in a solution of T3P in ethyl acetate at 100 ℃ for 3 hours under sealed conditions. Cooled, diluted with saturated NaHCO3, and extracted with ethyl acetate. The organic phases are combined, dried and concentrated to prepare a plateAnd separating to obtain 55mg of product. ESI-MS M/z 578.2(M + H)+。
Preparation of Compound I-27: compound 27e (55mg, 0.09mmol) was dissolved in 2mL of methanol, palladium on carbon was added, and catalytic hydrogenation was carried out. After 6 hours filtration was carried out, the filtrate was concentrated and separated on a plate to give 15mg of product. ESI-MS M/z 488.2(M + H)+。
Example 4: preparation (I-33)
Figure BDA0001550400590000161
Preparation of compound 33 b: compound 33a (2.0g,12.8mmol) was dissolved in 20mL of methanol and the nitrogen was replaced 3 times at 0 ℃ under nitrogen. Slowly dropwise adding thionyl chloride (2.35mL,0.032mol), transferring to an oil bath after dropwise adding, carrying out reflux reaction for 3h until the raw materials react completely, spin-drying the reaction solvent, carrying out toluene for 2-3 times, and carrying out silica gel column chromatography with PE: EA being 100:1 to obtain 1.00g of a yellow oily product with the yield of 45.8%.
Preparation of compound 33 c: compound 33b (0.500g,2.97mmol) was dissolved in 10mL of carbon tetrachloride, NBS (1.16g,6.54mmol), and AIBN (0.06g,0.36mmol) were added and reacted at 80 ℃ overnight, the completion of the reaction of the starting materials was monitored by TLC, and the filtrate was filtered and subjected to silica gel column chromatography PE: EA: 50:1 to obtain 600mg of a reddish brown oil. 1H-NMR (CDCl3,400MHz) 7.41-7.36(m,1H),7.22-7.20(m,1H),7.11-7.06(m,1H),4.66(s,2H),3.99(s, 3H).
Preparation of compound 33 e: compound 33c (0.52g,2.1mmol) was dissolved in 5mL of anhydrous tetrahydrofuran, and a solution of compound 33d (0.52mL,2.5mmol) and TBAF (2.5mL,1.0M) was added under ice-bath conditions, and the reaction was stirred for 10min after the addition. Potassium carbonate (0.581g,4.2 mmol) and 2mL DMF were then added, stirred at room temperature overnight, TLC monitored for completion of the reaction, quenched with 30mL of water, extracted with dichloromethane (30 mL. times.3), the organic phases combined, washed with saturated NaCl, dried and concentrated, and the crude product was chromatographed on preparative plates to give 400mg of an oil. 1H-NMR (CDCl3,400MHz) 7.39-7.36(m,1H),7.33-7.22(m,5H),7.03-6.97(m,2H),4.27(s,2H),3.95(s, 3H).
Preparation of compound 33 f: dissolving compound 33e (0.2g,0.72mmol) in 5mL of methanol, adding 32% sodium hydroxide 0.718mL, heating to 65 ℃ for reaction for 2h, monitoring by TLC that the reaction of the raw materials is completed, adjusting pH to 1-2 with 7N hydrochloric acid, extracting with dichloromethane (30 mL. about.3), washing the organic phase with saturated saline, drying over anhydrous sodium sulfate and concentrating to obtain 180mg of product.
Preparation of compound 33 g: dissolving compound 33f (180mg, 0.69mmol) in 1mL of sulfolane, adding 5mL of PPA to react at 170 ℃ for 1.5h, monitoring the completion of the raw material reaction by TLC, pouring the reaction solution into ice water, extracting with dichloromethane (30mL by 3), washing the organic phase with saturated sodium bicarbonate, washing with saturated saline, drying and concentrating to obtain 130mg of product.
Preparation of compound 33 h: compound 33g (130mg, 0.53mmol) was dissolved in 5mL of methanol, and sodium borohydride (42mg, 1.1mmol) was added to the solution to react at room temperature for 3 hours. The reaction mixture was poured into water, extracted with dichloromethane (20mL x 3), the organic phases were combined, washed with saturated brine, dried and concentrated to give 110mg of product.
Preparation of compound 33 i: compound 33h (110mg, 0.4mmol) and compound 1h (146mg,0.4mmol) were reacted in a solution of 3mL T3P in ethyl acetate at 100 ℃ for 3 hours under sealed conditions. Cooled, diluted with saturated NaHCO3, and extracted with ethyl acetate. The organic phases were combined, dried and concentrated, and the plates were prepared and separated to yield 83mg of product. ESI-MS M/z 594.2(M + H)+。
Preparation of Compound I-33: compound 33i (80mg, 0.13mmol) was dissolved in 1mL of methanol, palladium on carbon was added, and catalytic hydrogenation was carried out. After 1 hour filtration, the filtrate was concentrated and separated on a plate to give 20mg of product. ESI-MS M/z 504.2(M + H)+。
Example 5 in vitro bioactivity and cytotoxicity Studies
Test compounds: the compounds of the invention: compound I-1, compound I-26, compound I-27, compound I-33; control compound: VX-787.
Test methods for in vitro bioactivity studies: MDCK cells were seeded into 384-well cell culture plates at a density of 2,000 cells per well, followed by incubation at 37 ℃ with 5% CO2The culture was carried out overnight in an incubator. The next day the compounds were diluted and added to the wells individually (3 fold-rate dilution, 8 concentration points tested), and influenza a/PR/8/34(H1N1) strain was subsequently added to the cell culture wells at 2 x TCID90 per well, with a final DMSO concentration of 0.5% in the culture medium.The cell plates were incubated at 37 ℃ with 5% CO2Culturing in an incubator for 5 days. After 5 days of culture, cell viability was measured using CCK8 cell viability assay kit. Carrying out nonlinear fitting analysis on the inhibition rate and cytotoxicity of the compound by using GraphPad Prism software on the raw data to obtain EC50Values (see table 1 for results).
Study methods for cytotoxicity study: the cytotoxicity test and the antiviral activity test of the compound are carried out in parallel, and other test conditions are consistent with the antiviral activity test except that no virus is added. After 5 days of culture, cell viability was measured using CCK8 cell viability assay kit. Raw data for Compound Cytotoxicity (CC)50) Calculation (see table 1 for results).
TABLE 1 inhibitory Activity and toxicity of Compounds against influenza A/PR/8/34(H1N1)
Figure BDA0001550400590000171
And (4) conclusion: the compounds I-1, I-26, I-27 and I-33 have excellent activity of inhibiting H1N1, the activity is lower than 10nM, and the cytotoxicity is very low.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.

Claims (9)

1. A pyridone derivative represented by formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof,
Figure FDA0003299231380000011
wherein:
(1) a is CR1，R1Selected from H, deuterium;
(2) m is CR2，R2Selected from H, deuterium;
(3) q is N;
(4) r is CR4R5，R4、R5Independently selected from H, deuterium;
(5)R6is spirocyclic and R6Selected from the following groups:
Figure FDA0003299231380000012
(6) m is 0, 1,2,3, 4 or 5, R7Selected from H, deuterium, hydroxy, cyano, halogen, carboxy, C1-6Hydrocarbyl radical, C1-6A hydrocarbyloxy group;
(7) x is S;
(8) w is H or W is selected from the following groups: (d) -CH2-O-R8；(e)-CH2-O-C(＝O)-R8；(f)-CH2-O-C(＝O)-O-R8；(g)-CH(-CH3)-O-C(＝O)-R8；(h)-CH(-CH3)-O-C(C＝O)-O-(CH2)k-R8K is selected from 0 to 3; (j) -CH2-O-P(＝O)(OPh)(NHR8)；(k)-CH2-O-P(＝O)(OCH2OC(＝O)OR8)2(ii) a The R is8Is selected from C1-6Hydrocarbyl radical, C1-6A hydrocarbyloxy group.
2. The pyridone derivative, a stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is7Selected from H, deuterium, hydroxy, cyano, halogen, C1-6Hydrocarbyl radical, C1-6A hydrocarbyloxy group.
3. The pyridone derivative, a stereoisomer, or pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein R is7Selected from H, cyano, halogen; and/or m is 0 or 1 or 2.
4. The pyridone derivative, a stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 1, wherein R is7Selected from H, cyano, fluorine, chlorine, bromine; and/or, R8Is C1-6Alkyl radical, C1-6An alkoxy group.
5. A pharmaceutical composition comprising a pyridone derivative of formula (II), a stereoisomer, or a pharmaceutically acceptable salt thereof, according to any one of claims 1 to 4, wherein the pharmaceutical composition is an antiviral pharmaceutical composition.
6. The pharmaceutical composition of claim 5, further optionally comprising one or more therapeutic agents selected from the group consisting of: neuraminidase inhibitors, nucleoside drugs, PB2 inhibitors, PB1 inhibitors, M2 inhibitors or other anti-influenza drugs.
7. Use of a pyridone derivative of formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, or a pharmaceutical composition according to claim 5 or 6 for the preparation of a medicament for the prophylaxis and/or treatment of a viral infectious disease.
8. Use according to claim 7, characterized in that: the viral infectious disease is an infectious disease caused by influenza type A or influenza type B.
9. Use of a pyridone derivative of formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof as defined in any one of claims 1 to 4, or a pharmaceutical composition according to claim 5 or 6 for the preparation of an antiviral medicament for inhibiting the activity of influenza cap-dependent endonuclease.
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