CN115677703A - Pyridone compound and use thereof - Google Patents

Pyridone compound and use thereof Download PDF

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CN115677703A
CN115677703A CN202110855224.0A CN202110855224A CN115677703A CN 115677703 A CN115677703 A CN 115677703A CN 202110855224 A CN202110855224 A CN 202110855224A CN 115677703 A CN115677703 A CN 115677703A
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compound
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pyridone derivative
pharmaceutically acceptable
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陈力
曹芹
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Suzhou Yuanzhi Pharmaceutical Technology Co ltd
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Suzhou Yuanzhi Pharmaceutical Technology Co ltd
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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) and a pharmaceutically acceptable salt thereof, and application of the novel pyridone derivative and the pharmaceutically acceptable salt thereof in preparation of medicines for preventing and/or treating influenza A type or/and influenza B type viral infection diseases, in particular application of the novel pyridone derivative and the pharmaceutically acceptable salt thereof as a PA subunit cap-dependent endonuclease inhibitor in prevention and/or treatment of influenza A type or/and influenza B type viral infection diseases.

Description

Pyridone compound and use thereof
Technical Field
The invention relates to a novel pyridone derivative or an optical isomer thereof, a pharmaceutical composition containing the pyridone derivative or the optical isomer thereof and application of the pyridone derivative or the optical isomer thereof as antiviral drugs, in particular to application of the pyridone derivative or the optical isomer thereof as drugs for preparing Cap dependent endonuclease inhibitors (Cap dependent endonucleases inhibitors) for preventing and/or treating influenza virus infection, and particularly application of the pyridone derivative or the optical isomer thereof for preparing drugs for preventing or treating influenza virus A and influenza virus B infection.
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 due to the emergence of new resistant virus strains and mutant virus strains, and there is a need to develop broader-spectrum vaccines and more effective anti-influenza drugs.
Oseltamivir (Oseltamivir) and zanamivir (zanamivir) as neuraminidase inhibitors can suppress virus budding and release, but the curative effect of neuraminidase inhibitors is limited clinically, particularly severe patients may not have the effect, and in addition, the wide spread of drug-resistant strains generated by the neuraminidase inhibitors is also a problem to 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-deprivation' mechanism, PB2 subunit is responsible for recognizing and combining with 'cap structure' of host precursor mRNA, and PA subunit cuts host mRNA as a primer to start a transcription process. The endonuclease active site of the PA subunit, responsible for cleaving the mRNA of the host, serves as a primer in the PB1 subunit for further viral mRNA synthesis. Because the cap-dependent endonuclease of the PA subunit is necessary for the life process of the virus, and the host does not have an enzyme with a structure similar to that of the virus endonuclease, the cap-dependent endonuclease of the PA subunit is an ideal target of an anti-influenza drug and is used for developing a high-activity oral drug.
Disclosure of Invention
The invention aims to provide a novel pyridone derivative suitable for preventing or treating influenza virus A and influenza virus B infection.
In order to achieve the purpose, the invention adopts a technical scheme as follows:
the invention provides a novel pyridone derivative shown in a formula (I) and a medicinal salt thereof,
Figure BDA0003183839160000011
wherein:
(1) R is selected from Cl, br, I, cyano, C 2-6 Alkynyl, amido, sulfonamido, trifluoromethyl, difluoromethyl, -OCF 3 、-OCF 2 H、-R 1 OH、-R 1 CONH 2 、-R 1 NH 2 、C 3-6 Cyclic amino, N-methyl C 3-6 Cycloalkylamino, -X-R 1 OH、-XCONH 2 and-XR 1 CONH 2 X is O, CF 2 、S、NH、SO 2 ；R 1 Selected from the following unsubstituted or substituted with 1,2 or 3 first substituent groups: c 1-6 Hydrocarbyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyl radical C 1-6 A hydrocarbyl group;
(2) A is selected from a phenyl ring, a pyridine ring or a thiophene ring which is unsubstituted or substituted with 1,2 or 3 second substituent groups;
(3) n is selected from 1 or 2;
(4) P is selected from H or a group metabolized into a raw drug by a chemical method or under the action of an enzyme in vivo;
the first substituent group and the second substituent group are independently the following groups:
cyano, fluoro, chloro, bromo, iodo, hydroxy, carboxy, C 1-6 Ester group, sulfone group, sulfonamide group, amide group, amine group, C 1-6 Hydrocarbyl, halogenated C 1-6 Hydrocarbyl, hydroxy-substituted C 1-6 Hydrocarbyl, amide substituted C 1-6 Hydrocarbyl radical, C 1-6 Alkoxy, halo C 1-6 Hydrocarbyloxy, C 1-6 Hydrocarbon oxidationRadical C 1-6 Hydrocarbyl radical, C 1-6 Hydrocarbyloxy group C 1-6 Hydrocarbyloxy, C 1-6 Hydrocarbylamino, C 1-6 Mercapto group of hydrocarbon, C 1-6 Hydrocarbyl carbonyl group, C 1-6 Hydrocarbyl amine acyl, C 1-6 Hydrocarbyl amido, halo C 1-6 Hydrocarbyl amide group, C 1-6 Hydroxyoxyacyl group, C 1-6 Hydrocarbyl amine amido, C 1-6 Hydrocarbyl sulfone group, C 1-6 A hydrocarbyl sulfonamide group.
The pyridone derivative and the pharmaceutically acceptable salt thereof are in a racemic form of a single compound, an optical isomer form of a single compound or a mixture form of a plurality of compounds.
The composition is used for preventing or treating influenza virus A and influenza virus B infection, and can be used for clinically and independently or jointly curing influenza infection patients quickly and effectively.
According to some embodiments of the invention, R is selected from Cl, br, I, ethynyl, propynyl, butynyl, isopropynyl.
According to some embodiments of the invention, R is selected from cyano, amido, sulfonamido, and sulfonamide,
Figure BDA0003183839160000021
According to some embodiments of the invention, R is selected from-R 1 OH、-R 1 CONH 2 、-X-R 1 OH、-XCONH 2 and-XR 1 CONH 2 (ii) a Wherein X is O, CF 2 、S、NH、SO 2 ；R 1 Selected from the following substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl.
According to some embodiments of the invention, R is selected from trifluoromethyl, difluoromethyl, -OCF 3 、-OCF 2 H。
Further, the first substituent group and the second substituent group are independently the following groups: cyano, F, cl, br, hydroxyl, carboxyl, ester, sulfone, sulfonamide, amide, carbonyl, amino, methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, halomethyl, haloethyl, halo-n-propyl, haloisopropyl, halocyclopropyl, halo-n-butyl, haloisobutyl, halo-tert-butyl, halocyclobutyl, hydroxymethyl, hydroxyethyl, hydroxy-n-propyl, hydroxyisopropyl, hydroxycyclopropyl, hydroxy-n-butyl, hydroxyisobutyl, hydroxy-tert-butyl, hydroxycyclobutyl, hydroxy-n-pentyl, hydroxyisopentyl, hydroxyneopentyl, hydroxycyclohexyl, methoxy, ethoxy, propoxy.
Further, the first substituent group and the second substituent group are independently the following groups: cyano, fluorine, chlorine, bromine, iodine, hydroxyl, carboxyl, carbomethoxy, carbethoxy, sulfonyl, sulfamide, amido, amino, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, difluoromethyl, cyclopropylalkyl, cyclobutylalkyl, fluorocyclopropylalkyl.
According to some preferred embodiments of the invention, the structural unit
Figure BDA0003183839160000031
Is selected from
Figure BDA0003183839160000032
Figure BDA0003183839160000033
According to some preferred embodiments of the invention, P is selected from the group consisting of: (1) H; (2) -C (= O) -CH 3 ；(3)-CH 2 -O-C(＝O)-O-CH 3 。
In a preferred embodiment according to the present invention P is acetyl. We have found that when P is acetyl, it is easily metabolized into a hydroxy compound compared to other groups, thereby exhibiting the same activity as the hydroxy compound, and that the isolation and purification of the compound are more convenient.
Further, according to some aspects of the invention, the structural unit
Figure BDA0003183839160000034
Is selected from
Figure BDA0003183839160000035
According to some aspects of the invention, the structural unit
Figure BDA0003183839160000036
Is selected from
Figure BDA0003183839160000037
Figure BDA0003183839160000038
Figure BDA0003183839160000041
According to some embodiments of the invention, the pyridone derivative is in the form of an optical isomer represented by formula (II-1) or formula (II-2):
Figure BDA0003183839160000042
in the formulae (II-1) and (II-2), R, P, A, n is as defined in the corresponding position of the aforementioned pyridone derivative.
According to some embodiments of the present invention, all of the hydrogen atoms, except for the active hydrogen, may each be independently replaced with deuterium.
The invention also provides a pyridone derivative and a pharmaceutically acceptable salt thereof, wherein the pyridone derivative is a compound selected from the following racemes and/or optical isomer forms:
Figure BDA0003183839160000043
Figure BDA0003183839160000051
Figure BDA0003183839160000061
Figure BDA0003183839160000071
Figure BDA0003183839160000081
the invention also provides a pyridone derivative and a pharmaceutically acceptable salt thereof, wherein the pyridone derivative is selected from the following compounds and is in a racemic form or an optical isomer form:
Figure BDA0003183839160000082
Figure BDA0003183839160000091
the invention also provides a pyridone derivative and a pharmaceutically acceptable salt thereof, wherein the pyridone derivative is a compound shown in a formula (III-1), a formula (III-2), a formula (III-3) or a formula (III-4) and a compound in a racemic form and/or an optical isomer form of the formula (III-1) to the formula (III-4):
Figure BDA0003183839160000092
wherein P is as defined for the corresponding position of the pyridone derivative.
At present, although Balaxavir acid and analogues thereof have good in vitro activity, and the prodrug Balaxavir Marboxil can effectively reduce the virus titer and quickly relieve the influenza symptom clinically, the novel pyridone derivative provided by the invention obtains unexpectedly superior in vitro activity, and is beneficial to obviously reducing the clinical dose and inhibiting or relieving the drug resistance generated by Balaxavir Marboxil. The data have shown that the activity of preferred compounds of the invention in MDCK cell lines can be increased 4-6 fold compared to control compounds.
The invention further provides a preparation method of the pyridone derivative, which comprises the following steps:
(1) Preparing a compound C by using a compound A and a compound B as raw materials;
Figure BDA0003183839160000101
(2) Preparing a compound D by taking the compound C as a starting material;
Figure BDA0003183839160000102
(3) Preparing a compound shown as a formula (I) by taking a compound D as a starting material;
Figure BDA0003183839160000103
in compounds A, C and D, Z is a hydroxyl protecting group including, but not limited to Bn and n-hexane;
in compound B, C, D and formula (I), R, A is the same as the group at the corresponding position of the pyridone derivative of the preceding claims;
in compound A, C, D and formula (I),
Figure BDA0003183839160000111
the same as the group at the corresponding position of the pyridone derivative according to the preceding claim;
in the formula (I), P is the same as the group at the corresponding position of the pyridone derivative according to the preceding claim.
Further, according to some aspects of the invention, step (1): dissolving the compounds A and B in a first organic solvent, adding alkali, reacting at 10-80 ℃, continuing the reaction after selectively replenishing DMF, and carrying out aftertreatment purification to obtain an intermediate compound C; wherein the first organic solvent comprises acetonitrile and/or dichloromethane, and the base comprises but is not limited to triethylamine;
step (2): dissolving the compound C in a second organic solvent, adding Dess-Martin periodate (Dess-Martin reagent) at room temperature, reacting at 10-40 ℃, quenching, purifying to obtain a compound, detecting by using a chiral column (the column model is UniChiral CMZ-5H,50mm I.D. multiplied by 250mm L), and carrying out mobile phase: n-Hexane/Ethanol =50/50 (v/v), flow rate: 120ml/min, temperature: 25 ℃, wavelength: 254nm to obtain a compound D (which can be selectively resolved to obtain optical isomers); the second organic solvent includes, but is not limited to, dichloromethane; the quenching reaction can be carried out by adding water, adding saturated sodium bicarbonate and sodium thiosulfate solution, and the like;
and (3): dissolving the compound D in a third organic solvent containing lithium chloride, reacting the reaction solution at 80-120 ℃ for 3-12 hours, cooling, adding water, and extracting with ethyl acetate to obtain a hydroxyl compound (in the structure of the general formula (I), P is H); wherein the third organic solvent includes, but is not limited to, N-dimethylacetamide, and the like;
starting from the resulting hydroxy compound (in the structure of general formula (I), P is H), compounds in which the hydroxy group is protected (also referred to as prodrugs in the present application) can be further obtained. According to some aspects of the present application, the resulting hydroxy compound may be reacted with a compound providing a protecting group in the presence of a base to obtain a prodrug of the corresponding compound. Wherein the base comprises organic base and inorganic base, and the organic base can be selected from triethylamine, DIPEA, DBU, pyridine, etc.; the inorganic base may be selected from sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride, potassium hydride, sodium bicarbonate, and the like. The aforementioned compounds providing protecting groups include, but are not limited to, acid chlorides or halides, etc., such as acetyl chloride, chloromethyl methyl carbonate, acetic anhydride, etc. According to some aspects of the present invention, the process for preparing the compound of formula (III-1) follows the following route:
(1) Preparing a compound C1 by using a compound A1 and a compound B1 as raw materials;
Figure BDA0003183839160000112
(2) Preparing a compound D1 by taking the compound C1 as a starting material;
Figure BDA0003183839160000121
(3) Preparing a compound shown as a formula (III-1) by taking the compound D1 as a starting material;
Figure BDA0003183839160000122
according to some aspects of the present invention, the process for preparing the compound of formula (III-2) follows the following route:
(1) Preparing a compound C2 by using a compound A2 and a compound B2 as raw materials;
Figure BDA0003183839160000123
(2) Preparing a compound D2 by taking the compound C2 as a starting material;
Figure BDA0003183839160000124
(3) Preparing a compound shown as a formula (III-2) by taking the compound D2 as a starting material;
Figure BDA0003183839160000131
according to some aspects of the present invention, the process for preparing the compound of formula (III-3) follows the following route:
(1) Preparing a compound C3 by using a compound A3 and a compound B3 as raw materials;
Figure BDA0003183839160000132
(2) Preparing a compound D3 by taking the compound C3 as a starting material;
Figure BDA0003183839160000133
(3) Preparing a compound shown as a formula (III-3) by taking the compound D3 as a starting material;
Figure BDA0003183839160000134
according to some aspects of the present invention, the process for preparing the compound of formula (III-4) follows the following route:
(1) Preparing a compound C4 by using a compound A4 and a compound B4 as raw materials;
Figure BDA0003183839160000141
(2) Preparing a compound D4 by taking the compound C4 as a starting material;
Figure BDA0003183839160000142
(3) Preparing a compound shown as a formula (III-4) by taking the compound D4 as a starting material;
Figure BDA0003183839160000143
the invention also provides an intermediate for preparing the pyridinone derivative and the pharmaceutically acceptable salt thereof, wherein the intermediate is a compound represented by the general formula B, the general formula C or the general formula D:
Figure BDA0003183839160000144
in the general formula B, the general formula C or the general formula D, Z is a hydroxyl protecting group, and R, A, n is defined as the corresponding position of the pyridone derivative.
Further, the intermediate is a compound selected from the group consisting of:
Figure BDA0003183839160000151
Figure BDA0003183839160000161
preferably, a is a benzene ring, a pyridine ring or a thiophene ring, and n is 1 or 2.
The invention also provides a pharmaceutical composition, which contains the pyridone derivative, the pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. Preferably, the pharmaceutical composition is an antiviral pharmaceutical composition, optionally further comprising one or more therapeutic agents selected from the group consisting of: neuraminidase inhibitors, nucleosides, PB2 inhibitors, PB1 inhibitors, M2 inhibitors or other anti-influenza drugs.
According to some schemes of the invention, the pharmaceutical composition comprises the following components in parts by mass:
Figure BDA0003183839160000162
according to some schemes, the invention provides an application of the pyridone derivative and the pharmaceutically acceptable salt thereof or a pharmaceutical composition containing the pyridone derivative and the pharmaceutically acceptable salt thereof in preparing a medicament for preventing and/or treating viral infection diseases. In particular, the viral infectious disease is an infectious disease caused by influenza type a and/or influenza type B.
According to some embodiments of the present invention, the use of the pyridone derivative and pharmaceutically acceptable salts, hydrates, solvates, crystals thereof or pharmaceutical compositions containing the pyridone derivative for the preparation of a medicament for treating influenza virus; in particular, the antiviral drug is a drug or agent that inhibits influenza cap-dependent endonuclease activity.
The pyridone derivatives and pharmaceutically acceptable salts thereof of the present invention are in the form of racemates of single compounds, optical isomers of single compounds or mixtures of a plurality of compounds. In some preferred embodiments, it is in the form of an optical isomer of a single compound.
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 as an active ingredient can be various forms such as tablets, powder, capsules, granules, oral liquid, injection, suppository, pills, cream, paste, gel, powder, inhalant, suspension, dry suspension, patch, lotion, nano preparation and the like. The dosage form of the pharmaceutical composition is preferably tablets, capsules, injections and the like.
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 type a and influenza type B.
Due to the implementation of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention provides a novel pyridone derivative, and a compound synthesized through electrostatic interaction with a side chain carboxyl of glutamic acid (E80) in a PA endonuclease combined cavity has activity of strongly inhibiting influenza virus A and influenza virus B, and has unexpectedly higher activity compared with the existing reported compound.
Furthermore, the compound has high activity of inhibiting influenza virus, can be used for clinical treatment alone or/and combined with other anti-influenza drugs such as neuraminidase inhibitors, nucleoside drugs and PB2 inhibitors, and can cure patients infected with influenza virus rapidly 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 C 1-6 Alkyl 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 1,2,3 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.
The term "stereoisomer" refers to an isomer resulting from the different arrangement of atoms in a molecule. Including cis-trans isomers, enantiomers, and conformers. 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 is specifically selected 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 saturated alkyl, alkenyl alkyl, and alkynyl alkyl groups.
The term "saturated alkyl" refers to a straight, branched, or cyclic, saturated or unsaturated substituent consisting essentially of carbon and hydrogen. Preferably 1 to 20 carbon atoms, more preferably 1 to 12 carbon atoms. The term "alkyl" refers to a straight, branched, or cyclic saturated hydrocarbon group. Alkyl specifically includes methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl, tert-butyl, cyclobutyl, n-pentyl, isopentyl, neopentyl, cyclohexyl, n-hexyl, isohexyl, 2,2, -methylbutyl and 2,3-dimethylbutyl, 16-alkyl, 18-alkyl. The term "C 1-20 Alkyl "refers to a straight, branched or cyclic saturated hydrocarbon group containing 1 to 20 carbon atoms. Alkyl groups include substituted and unsubstituted alkyl groups. When the alkyl group is substituted, the substituent may be substituted at any available point of attachment, and the substituent may be mono-or polysubstituted. The substituents are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxy, nitro, carboxy, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, oxo, the substituents usually being placed before the alkyl group when named, e.g. C 1-3 Alkoxy radical C 3-8 Cycloalkyl radical C 1-6 Alkyl refers to C 1-6 Alkyl radical, which is substituted by C 3-8 Cycloalkyl is substituted and the C is 3-8 Cycloalkyl radicals being further C 1-3 Alkoxy substitution, examples being: the structural formula of the methoxycyclobutylmethyl group is as follows:
Figure BDA0003183839160000181
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. Alkenyl, alkynyl includes substituted and unsubstituted alkenyl, alkynyl groups. When substituted, the substituents may be substituted at any available point of attachment, and the substituents may be mono-or polysubstituted. The substituents are independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, deuterium, halogen, thiol, hydroxy, nitro, carboxy, ester, cyano, cycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, oxo, the substituents usually preceded by alkenyl, alkynyl when named.
The term "ring" refers to both carbocyclic and heterocyclic rings. "carbocyclyl" or "carbocycle" refers to a carbocyclyl group having 3 to 20 carbon atoms, preferably 3 to 16 carbon atoms, more preferably 4 to 12 carbon atoms, and includes cycloalkyl, cycloalkenyl, aryl, bicyclic carbocycles, polycyclic carbocycles, and the like. "Heterocyclyl" or "heterocycle" includes heteroaryl, non-aromatic heterocyclyl, bicyclic heterocyclyl, polycyclic heterocyclyl, and the like having 1 or more than 1 identical or different heteroatoms, optionally selected from O, s and N, within the ring. The term "ring" includes monocyclic, bridged, spiro, fused and polycyclic rings.
The term "cycloalkyl" refers to a saturated and/or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon group. A single ring may comprise 3-10 carbon atoms. Non-limiting examples of monocyclocycloalkane groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl and the like. Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups. Cycloalkyl includes unsubstituted and substituted. The substituent is selected from one or more substituent groups, including but not limited to, independently selected from alkyl, cycloalkyl, alkoxy, halogen, carboxyl, ester, amino, amido, hydroxyl, cyano, nitro, aryl, heteroaryl.
The term "aryl" refers to both carbocyclic aryl and heteroaryl groups.
The term "carbocyclic aryl" refers to 6-10 membered all carbon monocyclic or polycyclic aromatic groups including phenyl, naphthyl, biphenyl and the like. Aryl groups may be substituted and unsubstituted. The substituents are independently selected from alkyl, cycloalkyl (cyclopropane, cyclobutane, cyclopentane, etc.), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halogen, thiol, hydroxy, nitro, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, alkylsilyl, etc.
The term "heteroaryl" refers to a group of a heteroaromatic system comprising 1-10 heteroatoms. Heteroatoms include oxygen, sulfur, nitrogen, phosphorus, and the like. Wherein the mono-heterocyclic group includes, but is 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 heterocyclic 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 substituents are independently selected from alkyl, cycloalkyl (cyclopropyl, cyclobutyl, cyclopentyl, etc.), alkenyl, alkynyl, azide, amino, deuterium, alkoxy, alkylthio, alkylamino, halo, thiol, hydroxy, nitro, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, alkylsilyl, etc.
The term "halogen" refers to fluorine, chlorine, bromine, iodine.
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. Deuteration "and" deuterium "mean 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, wherein the heteroatom is 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 structure 1 H NMR or MS.
The compound names used in the examples are abbreviated as follows:
DCM: dichloromethane; etOAc: ethyl acetate; THF: tetrahydrofuran; DME: ethylene glycol dimethyl ether; 1,4-Dioxane:1,4-dioxane; TEA: triethylamine; T3P: 1-propyl phosphoric 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:
synthesis of intermediate compound 8:
Figure BDA0003183839160000201
synthesis of Compound 2:
compound 1 (19.6 g,137.9 mmol) was added to concentrated sulfuric acid (160 ml), warmed to 65 ℃, bromosuccinimide (30.0 g,165.5 mmol) was added in three portions, and stirred at 65 ℃ for 10h. The reaction solution was cooled to room temperature, quenched with ice water, extracted twice with petroleum ether (200 ml), the organic layers were combined, washed with saturated brine, concentrated, and the crude product was subjected to column chromatography (100% PE) twice to give 15.4g of a liquid.
Synthesis of Compound 3:
compound 2 (15.4 g,69.3 mmol) was dissolved in methanol (75 ml), cooled to 0-5 deg.C, added sodium borohydride (3.2 g,83.2 mmol) in four portions, and stirred at room temperature for 1h. Cooling to 0-5 ℃, adding water for quenching, extracting twice by dichloromethane (150 ml), combining organic layers, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, decompressing and concentrating to obtain liquid 15.0g.
Synthesis of Compound 4:
compound 3 (15.0g, 67.3mmol) and triethylamine (13.6g, 134.5mmol) were dissolved in dichloromethane (150 ml), cooled to 0 to 5 ℃, and a solution of methanesulfonyl chloride (93g, 80.7mmol) in dichloromethane (20 ml) was added dropwise, and the mixture was stirred at room temperature for 1 hour. After quenching with water, the layers were separated, and the aqueous layer was extracted with methylene chloride (150 ml), and the organic layers were combined, washed with saturated brine, and concentrated under reduced pressure to dryness to give 16.5g of a liquid.
Synthesis of Compound 5:
sodium hydroxide (2.6g, 65.8mmol) was dissolved in water (70 ml) and ethanol (75 ml), thiosalicylic acid (93g, 60.3mmol) was added with stirring, and with stirring, 30min, compound 4 (16.5g, 54.8mmol) was added and with stirring at room temperature for 2h. Adjusting pH to 2 with 4N hydrochloric acid, concentrating under reduced pressure, adding water (165 ml), stirring for 30min, filtering, and air drying at 50 deg.C to obtain solid 17.7g.
Synthesis of Compound 6:
compound 5 (17.7g, 49.3mmol) was added to polyphosphoric acid (189.21 g), heated to 170 ℃ and stirred for 8h. Cooling to room temperature, quenching with ice water, extracting twice with ethyl acetate (150 ml), combining organic layers, washing with water, washing with saturated sodium bicarbonate solution, washing with saturated salt water, concentrating under reduced pressure to dryness, and purifying the crude product by column chromatography (PE: EA = 50: 1) to obtain 2.5g of the product. 1 HNMR(400MHz，CDCl 3 )δ7.96～7.94(m，1H)，7.48-7.41(m，2H)，7.35-7.29(m，2H)，4.16(s，2H).
Synthesis of compound 7:
compound 6 (2.5g, 7.3mmol) was dissolved in methanol (2.5 ml) and tetrahydrofuran (25 ml), cooled to 0 to 5 ℃ and sodium borohydride (0.7g, 17.6 mmol) was added in portions and stirred at room temperature for 2h. Cooling to 0-5 ℃, adding water for quenching, extracting twice by dichloromethane (50 ml), combining organic layers, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, decompressing and concentrating to obtain 2.4g of product.
Synthesis of compound 8:
compound 7 (0.50g, 1.44mmol) was dissolved in methylene chloride (5 ml), and thionyl chloride (1.71g, 14.36mmol) was added thereto, followed by stirring at room temperature overnight. The mixture is decompressed, concentrated and dried, and then is replaced and concentrated by toluene (20 ml) to be dried to obtain a chloro-compound, namely the compound 8, which is directly used for the subsequent reaction.
Synthesis of intermediate compound 16:
Figure BDA0003183839160000211
synthesis of compound 9:
2,3-difluorobenzaldehyde 1 (15.00g, 0.11mol) was added to concentrated sulfuric acid (120 ml), warmed to 65 ℃, iodosuccinimide (28.50g, 0.13mol) was added in three portions, and stirred at 65 ℃ for 7h. The reaction mixture was cooled to room temperature, quenched with ice water, extracted twice with petroleum ether (200 ml), the organic layers were combined, washed with saturated sodium thiosulfate and saturated brine, concentrated, and the crude product was subjected to column chromatography (100% PE) to obtain 10.60g of a solid.
Synthesis of compound 10:
compound 9 (10.60g, 39.60mmol) was dissolved in methanol (55 ml), cooled to 0-5 deg.C, added sodium borohydride (1.60g, 41.50mmol) in three portions and stirred at room temperature for 1.5h. Cooling to 0-5 ℃, adding water for quenching, extracting twice by dichloromethane (150 ml), combining organic layers, washing by saturated saline solution, drying by anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain white solid 9.30g.
Synthesis of compound 11:
compound 10 (9.30g, 34.40mmol) and triethylamine (7.15g, 68.80mmol) were dissolved in dichloromethane (100 ml), cooled to 0 to 5 ℃ and a solution of methanesulfonyl chloride (4.92g, 41.30mmol) in dichloromethane (15 ml) was added dropwise and stirred at room temperature for 1 hour. After quenching with water, the layers were separated, and the aqueous layer was extracted with methylene chloride (150 ml), and the organic layers were combined, washed with saturated brine, and concentrated under reduced pressure to dryness to give 11.20g of a liquid.
Synthesis of compound 12:
sodium hydroxide (2.62g, 64.40mmol) was dissolved in water (55 ml) and ethanol (60 ml), thiosalicylic acid (5.70g, 35.40mmol) was added with stirring, stirring was carried out for 30min, compound 11 (11.20g, 32.20mmol) was added, and stirring was carried out at room temperature for 3 hours. Adjusting the pH value to 2-3 with 4N hydrochloric acid, decompressing and concentrating, adding water (150 ml), stirring for 30min, filtering, and drying by blowing at 50 ℃ to obtain 13.00g of solid.
Synthesis of compound 13:
compound 12 (11.57g, 0.03mol) was added to polyphosphoric acid (180.21 g), heated to 170 ℃ and stirred for 7h. Cooling to room temperature, quenching with ice water, extracting twice with ethyl acetate (150 ml), combining organic layers, washing with water, washing with saturated sodium bicarbonate solution, washing with saturated saline solution, concentrating under reduced pressure to dryness, and purifying the crude product by column chromatography (PE/EA = 50/1) to obtain 1.80g of the product.
1 HNMR(400MHz，CDCl 3 )δ8.00(dd，J＝1.2Hz，J＝7.6Hz，1H)，7.69-7.65(m，1H)，7.49-7.45(m，1H)，7.37-7.30(m，2H)，4.18(s，2H).
Synthesis of compound 14:
a mixture of compound 13 (2.50g, 6.44mmol), alkynyltrimethylsilane (3.95g, 38.70mmol), pd (PPh) 3 ) 2 Cl 2 (0.90g, 1.29mmol), cuprous iodide (0.55g, 2.58mmol) and triethylamine (50 ml) were added to a reaction flask containing 1,4-dioxane (30 ml), replaced with nitrogen five times in vacuo, heated to 90 ℃ and stirred for 2h. Cooling to room temperature, adding water (25 ml) and ethyl acetate (50 ml), stirring, standing, layering, extracting the water layer with ethyl acetate (50 ml), combining the organic layers, washing with saturated brine, concentrating under reduced pressure to dryness, and purifying the crude product by column chromatography (PE/EA = 100/1) to obtain 1.60g of product. 1 HNMR(400MHz，CDCl 3 )δ 7.95-7.92(m，1H)，7.46-7.42(m，1H)，7.33-7.26(m，3H)，4.13(s，2H)，0.28(s，9H).
Synthesis of compound 15:
compound 14 (1.60g, 4.47mmol) was dissolved in methanol (16 ml) and tetrahydrofuran (16 ml), cooled to 0-5 deg.C, and sodium borohydride (0.21g, 5.36mmol) was added in portions and stirred at room temperature for 1h. Cooling to 0-5 ℃, adding water (20 ml) for quenching, extracting twice by ethyl acetate (50 ml), combining organic layers, washing by saturated salt solution, drying by anhydrous sodium sulfate, filtering, decompressing, concentrating and drying to obtain 1.60g of the product.
Synthesis of compound 16:
compound 15 (0.62g, 1.67mmol) was dissolved in methylene chloride (10 ml), and thionyl chloride (2.20g, 16.70mmol) was added thereto, and the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness under reduced pressure, and then toluene (30 ml) was used for displacement concentration until dryness to obtain the chloride 16, which was used directly in the subsequent reaction.
Synthesis of intermediate compound 18:
Figure BDA0003183839160000221
for the synthesis of compound 17, reference is made to the patent polycystic pyridine derivative, crystal and preparation method therof, jpn. Tokkyo Koho.2017, 38pp. JP6212678.
Synthesis of compound 18:
compound 17 (0.37g, 1.33mmol) was dissolved in dichloromethane (5 ml), and thionyl chloride (0.80g, 6.64mmol) was added and stirred at room temperature for 8h. The mixture was concentrated to dryness under reduced pressure, and then toluene (20 ml) was used for displacement concentration until dryness to obtain chloride 18 which was used directly in the subsequent reaction.
Synthesis of target Compound
Example 1: preparation of Compounds 1-13
1″-(7，8-difluoro-6，11-dihydrodibenzo[b，e]thiepin-11-y1)-4″，6″-dioxo-1″，2″，4″，6″-tetrahydrodispiro[cyclopropane-l，1′-cyclobutane-3′，3-pyrido[1，2-b]pyridazin]-5″-yl acetate(1-13)
Figure BDA0003183839160000231
The reaction scheme is as follows:
Figure BDA0003183839160000232
synthesis of Compounds 1-2:
dissolving compound 1-1 (5.00g, 53.70mmol) and potassium hydroxide (12.75g, 225.50mmol) in ethanol (20 ml) and water (20 ml), stirring at room temperature for 10min, heating to 90-95 deg.C, and stirring for 3h. Concentrating under reduced pressure to remove ethanol, cooling to 0-5 ℃, adjusting the pH value to 1 with concentrated hydrochloric acid, extracting with dichloromethane (50 ml) twice, combining organic layers, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain the product 5.65g.
Synthesis of Compounds 1-3:
compound 1-2 (5.02g, 44.60mmol) was dissolved in dichloromethane (25 ml) and methanol (5 ml), cooled to 0-5 deg.C, and trimethylsilylated diazomethane (25 ml) was added dropwise and stirred at room temperature for 2h. Quench with acetic acid (1 ml), concentrate to dryness under reduced pressure and purify the crude product by column chromatography (PE: EA = 10: 1) to give 1.70g of a colourless liquid.
Synthesis of Compounds 1-4:
diethyl zinc (1M, 23.80ml, 23.80mmol) was dissolved in dichloromethane (20 ml), cooled to 0-5 ℃, added with a solution of trifluoroacetic acid (2.72g, 23.80mmol) in dichloromethane (8 ml), stirred for 1h, then added dropwise with a solution of diiodomethane (6.38g, 23.80mmol) in dichloromethane (8 ml), stirred for 40min, added dropwise with a solution of compound 1-3 (1.20g, 9.52mmol) in dichloromethane (6 ml), stirred for 1h, warmed to room temperature and stirred for 30min. Adding saturated ammonium chloride solution (50 ml), quenching, demixing, extracting water layer with dichloromethane (50 ml), combining organic layers, washing with saturated salt solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure, and directly carrying out the next reaction on the crude product.
Synthesis of Compounds 1-5:
compound 1-4 (0.96g, 6.85mmol) was dissolved in tetrahydrofuran (20 ml), cooled to 0-5 ℃ and lithium aluminum hydride (1M, 13.80ml, 13.80mmol) was slowly added dropwise. Adding 1N hydrochloric acid solution to quench the reaction to alkalescence, adding water (50 ml) and ethyl acetate (50 ml), stirring, standing for layering, extracting the water layer with ethyl acetate (50 ml) twice, combining the organic layers, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain oil 0.96g.
Synthesis of Compounds 1-6:
oxalyl chloride (1.21g, 9.41mmol) was dissolved in dichloromethane (20 ml), cooled to-70 ℃, a solution of dimethyl sulfoxide (1.05 g) in dichloromethane (10 ml) was slowly added dropwise, stirred for 20min, a solution of compound 1-5 (0.96g, 8.56mmol) in dichloromethane (10 ml) was added dropwise, stirred for 15min, triethylamine (6.20 ml) was added, warmed to room temperature and stirred for 1.5h. Adding water (50 ml) to quench, layering, washing the organic layer with 1N hydrochloric acid solution, water, saturated sodium carbonate solution and saturated salt solution in sequence, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 1.20g.
Synthesis of Compounds 1-7:
compound 1-6 (1.20g, 10.91mmol), 3- (benzyloxy) -4-oxo-4H-pyran-2-carbaldehyde (1.68g, 7.27mmol) was dissolved in tetrahydrofuran (20 ml), and pyrrolidine (0.21g, 2.91mmol) and glacial acetic acid (0.99g, 16.43mmol) were added and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and dried, and purified by column chromatography (PE: EA = 1: 1) to obtain 1.10g of a product. LCMS ESI m/z:3413 (M + H) + 。
Synthesis of Compounds 1-8:
compound 1-7 (1.22g, 3.58mmol), hydrazine hydrochloride (3.78g, 35.80mmol) was dissolved in N, N-dimethylformamide (20 ml), heated to 80 ℃ and stirred for 2h. The reaction mixture was poured into water (60 ml), extracted with ethyl acetate (60 ml) three times, the organic layers were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a brown solid (0.90 g).
Synthesis of Compounds 1-9:
dissolving the compound 1-8 (0.90g, 2.66mmol) in tetrahydrofuran (20 ml), cooling to 0-5 ℃, adding sodium borohydride (0.30g, 7.98mmol) in batches, stirring for 1h at room temperature, adding sodium borohydride (0.15g, 3.99mmol), and continuing to stir for 1h. Adding saturated ammonium chloride solution (20 ml), quenching, extracting with ethyl acetate (50 ml) for three times, mixing organic layers, washing with saturated saline, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 0.68g.
Synthesis of Compounds 1-10:
compound 17 (0.37g, 1.33mmol) was dissolved in dichloromethane (5 ml), and thionyl chloride (0.80g, 6.64mmol) was added and stirred at room temperature for 8h. The mixture was concentrated to dryness under reduced pressure, and the resulting mixture was subjected to displacement concentration with toluene (20 ml) to dryness to obtain chloride 18 which was used directly in the subsequent reaction.
Compound 1-9 (0.25g, 0.74mmol), the chloro compound 18 prepared above, and triethylamine (0.17g, 1.65mmol) were dissolved in dichloromethane (10 ml) and stirred at room temperatureStirring overnight. The reaction mixture was concentrated to dryness under reduced pressure and purified by column chromatography (DCM: meOH = 10: 1) to obtain 0.25g of a product. LCMS ESI m/z:585.1 (M + H) + 。
Synthesis of Compounds 1-11:
compound 1-10 (0.25g, 0.42mmol) was dissolved in dichloromethane (10 ml), cooled to 0-5 deg.C, and dess-Martin reagent (0.41g, 0.97mmol) was added and stirred at room temperature for 1.5h. Quenched by addition of saturated sodium bicarbonate and sodium thiosulfate solution, extracted with dichloromethane (20 ml), combined organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product purified by column chromatography (DCM: meOH = 100: 1) to give 55mg of product.
Synthesis of Compounds 1-12:
compound 1-11 (55mg, 0.09mmol), lithium chloride (80mg, 1.89mmol) was dissolved in N, N-dimethylacetamide (5 ml), heated to 100 ℃ and stirred for 3h. Cooling to room temperature, adding water (20 ml) and ethyl acetate (20 ml), stirring, standing, layering, extracting the water layer with ethyl acetate (20 ml), combining the organic layers, washing twice, washing with saturated salt solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 53mg.
Synthesis of Compounds 1-13:
compounds 1-12 (53mg, 0.11mmol), triethylamine (22mg, 0.22mmol), acetyl chloride (13mg, 0.11mmol) were dissolved in dichloromethane (10 ml) and stirred at room temperature for 2h. Water (10 ml) and dichloromethane (20 ml) were added, stirred, allowed to stand, the layers were separated, the aqueous layer was extracted with dichloromethane (20 ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was purified by thin layer chromatography preparation plate (DCM: meOH = 10: 1) to give 16mg of product. LCMS ESI m/z:535.2 (M + H) + ； 1 HNMR(400MHz，CDCl 3 )：δ7.38(d，J＝7.2Hz，1H)，7.11(s，2H)，7.07-7.05(m，1H)，6.94-6.92(m，1H)，6.82-6.80(m，1H)，6.74(d，J＝6.4Hz，1H)，6.07(d，J＝7.2Hz，1H)，5.59(d，J＝14.0Hz，1H)，4.69(s，1H)，4.14(d，J＝13.2Hz，1H)，4.00(d，J＝14.8Hz，1H)，3.92(d，J＝15.2Hz，1H)，3.13(d，J＝10.4Hz，1H)，2.57-2.54(m，1H)，2.48(s，3H)，2.15-2.12(m，1H)，2.01-1.99(m，1H)，0.71-0.69(m，1H)，0.61-0.58(m，1H)，0.47-0.41(m，2H)。
Example 2: preparation of Compounds 2-4
1″-(10-bromo-7，8-difluoro-6，11-dihydrodibenzo[b，e]thiepin-11-yl)-4″，6″-dioxo-1″，2″，4″，6″-tetrahydrodispiro[cyclopropane-1，1′-cyclobutane-3′，3″-pyrido[1，2-b]pyridazin]-5″-yl acetate(2-4)
Figure BDA0003183839160000261
The reaction scheme is as follows:
Figure BDA0003183839160000262
synthesis of Compound 2-1:
compound 7 (0.50g, 1.44mmol) was dissolved in methylene chloride (5 ml), and thionyl chloride (1.71g, 14.36mmol) was added thereto, followed by stirring at room temperature overnight. The mixture was concentrated to dryness under reduced pressure, and the resulting mixture was subjected to displacement concentration with toluene (20 ml) to dryness to obtain chloride 8 which was used directly in the subsequent reaction.
Compounds 1-9 (0.27g, 0.80mmol), chloride 8 prepared above, and triethylamine (0.19g, 1.79mmol) were dissolved in dichloromethane (5 ml), heated to 50 ℃ and stirred for 7h. The reaction solution was concentrated to dryness under reduced pressure and purified by column chromatography (PE: EA = 1: 2) to obtain 0.12g of a product. LCMS ESI m/z:663.1 665.1 (M + H) + 。
Synthesis of Compound 2-2:
compound 2-1 (0.12g, 0.18mmol) was dissolved in methylene chloride (10 ml), and dess-martin reagent (0.09g, 0.21mmol) was added in portions at room temperature, followed by stirring at room temperature for 1.5h. Quenched by addition of saturated sodium bicarbonate and sodium thiosulfate solution, extracted with dichloromethane (10 ml), combined organic layers, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product purified by column chromatography (DCM: meOH = 50: 1) to give 0.15g of a tan solid.
Synthesis of Compounds 2-3:
compound 2-2 (0.15g, 0.23mmol), lithium chloride (0.20g, 4.54mmol) was dissolved in N, N-dimethylacetamide (5 ml), and the mixture was heated to 100 ℃ and stirred for 6 hours. Cooled to room temperature, added with water (20 ml) and ethyl acetate (20 ml), stirred, stood, layered, the aqueous layer was extracted with ethyl acetate (20 ml), the organic layers were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 0.14g of an oil.
Synthesis of Compounds 2-4:
compound 2-3 (0.14g, 0.24mmol), triethylamine (0.12g, 1.22mmol), acetyl chloride (0.06g, 0.73mmol) were dissolved in dichloromethane (5 ml) and stirred at room temperature for 2h. Water (10 ml) and dichloromethane (20 ml) were added, stirred, allowed to stand, the layers were separated, the aqueous layer was extracted with dichloromethane (20 ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was purified by thin layer chromatography preparation plate (DCM: meOH = 15: 1) to give 24mg of product. LCMSISI m/z:613.0 615.1 (M + H) + ； 1 HNMR(400MHz，CDCl 3 )：δ7.41-7.36(m，2H)，7.16-7.12(m，2H)，6.96-6.90(m，2H)，6.06(d，J＝7.2Hz，1H)，5.72(d，J＝13.2Hz，1H)，5.45(s，1H)，4.15(d，J＝13.2Hz，1H)，4.11(d，J＝12.0Hz，1H)，3.85(d，J＝14.8Hz，1H)，3.45(d，J＝11.6Hz，1H)，2.60-2.57(m，1H)，2.48(s，3H)，2.15-2.12(m，1H)，1.93-1.89(m，1H)，0.69-0.63(m，1H)，0.56-0.51(m，1H)，0.46-0.42(m，2H)。
Example 3: preparation of Compound A-2rac
1′-(10-bromo-7，8-difluoro-6，11-dihydrodibenzo[b，e]thiepin-11-yl)-4′，6′-dioxo-1′，2′，4′，6′-tetrahydrospiro[cyclopropane-1，3′-pyrido[1，2-b]pyridazin]-5′-yl acetate(A-2-rac)
Figure BDA0003183839160000271
The reaction scheme is as follows:
Figure BDA0003183839160000272
Figure BDA0003183839160000281
synthesis of Compound 3-1:
cyclopropanecarboxaldehyde (2.26g, 31.30mmol), 3- (benzyloxy) -4-oxo-4H-pyran-2-carbaldehyde (2.40g, 10.40mmol) and pyrrolidine (0.75g, 10.40mmol) were dissolved in dimethyl sulfoxide (12 ml), heated to 50 ℃ and stirred for 3 hours. Ethyl acetate (30 ml) was added thereto, and the mixture was stirred, allowed to stand, separated, washed with saturated brine, concentrated to dryness under reduced pressure, and purified by column chromatography (PE: EA = 1: 1) to give 1.47g of a light brown oil.
Synthesis of Compound 3-2:
compound 3-1 (1.51g, 5.03mmol), trifluoroacetohydrazide (1.31g, 10.23mmol) was dissolved in methanol (25 ml) and water (13 ml), heated to 50-55 deg.C and stirred for 6h. The mixture was concentrated to dryness under reduced pressure, dissolved in dichloromethane (30 ml), washed twice with saturated brine, concentrated to dryness under reduced pressure, and the crude product was subjected to column chromatography (DCM: meOH = 20: 1) to give 1.02g of a foamy solid, followed by further pulping with methyl t-butyl ether (30 ml) to give 0.78g of a pale yellow solid.
Synthesis of Compounds 3-3:
dissolving the compound 3-2 (0.80g, 2.69mmol) in methanol (5 ml), cooling to 0-5 deg.C, adding sodium borohydride (0.21g, 5.39mmol) in batches, and stirring at room temperature for 1h. After quenching with water (20 ml), dichloromethane (50 ml) was extracted three times, the organic layers were combined, washed with brine and concentrated to dryness under reduced pressure to give a brown solid (0.78 g).
Synthesis of Compounds 3-4:
compound 7 (0.75g, 2.19mmol) was dissolved in dichloromethane (20 ml), and thionyl chloride (0.5ml, 4.37mmol) was added thereto, followed by stirring at room temperature overnight. The mixture was concentrated to dryness under reduced pressure, and the residue was subjected to displacement concentration with toluene (20 ml) twice to dryness to obtain chloride 8, which was used directly in the subsequent reaction.
3-3 (0.42g, 1.41mmol), the chloride 8 prepared above, and triethylamine (031g, 3.10 mmol) were dissolved in dichloromethane (5 ml) and acetonitrile (5 ml), heated to 50-55 deg.C, stirred for 4h, supplemented with N, N-dimethylformamide (5 ml), and stirred for 2h at 50-55 deg.C. Reaction solutionAdding water (20 ml) and ethyl acetate (50 ml), filtering, separating the filtrate into layers, extracting the water layer twice with ethyl acetate (50 ml), combining the organic layers, washing with water, washing with saturated salt solution, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying by column chromatography (EA: PE = 3: 1) to obtain 0.23g of the product. LCMS ESI m/z:623.1 625.1 (M + H) + 。
Synthesis of Compounds 3-5:
compound 3-4 (0.20g, 0.32mmol) was dissolved in methylene chloride (20 ml), and dess-Martin reagent (0.14g, 0.32mmol) was added thereto at room temperature, and the mixture was heated to 35 to 40 ℃ and stirred for 5 hours. After quenching with a saturated sodium bicarbonate and sodium thiosulfate solution, dichloromethane (20 ml) was used for extraction, the organic layers were combined, washed with a saturated common salt solution, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by column chromatography (EA: PE = 3: 1) to obtain 0.13g of a pale yellow foamy solid. . LCMS ESI m/z:621.4 623.4 (M + H) + 。
Synthesis of Compounds 3-6:
compound 3-5 (0.12g, 0.20mmol), lithium chloride (0.17g, 3.96mmol) was dissolved in N, N-dimethylacetamide (4 ml), heated to 100 ℃ and stirred for 2 hours. Cooling to 0-10 deg.c, adding 2 drops of 1N hydrochloric acid and water (12 ml), separating out solid, filtering, washing filter cake with petroleum ether, dissolving dichloromethane (20 ml), washing twice with water, drying with anhydrous sodium sulfate, filtering, vacuum concentrating to dryness, and pulping dichloromethane/ether to obtain 52mg solid.
Synthesis of Compound A-2-rac:
compound 3-6 (45mg, 0.08mmol), triethylamine (43mg, 0.42mmol) and acetyl chloride (20mg, 0.25mmol) were dissolved in methylene chloride (2 ml), and stirred at room temperature for 30min. Water (10 ml) and dichloromethane (20 ml) were added, stirred, allowed to stand, the layers separated, the aqueous layer was extracted with dichloromethane (20 ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was purified by thin layer chromatography preparation plate (DCM: meOH = 15: 1) to give 26mg of product. LCMS ESI m/z:573.1 575.0 (M + H) + )； 1 HNMR(400MHz，CDCl 3 )：δ 7.46-7.43(m，1H)，7.38(d，J＝7.6Hz，1H)，7.17-7.15(m，2H)，6.96(s，2H)，6.06(d，J＝7.6Hz，1H)，5.90(s，1H)，5.68(d，J＝12.8Hz，1H)，4.26(d，J＝14.4Hz，1H)，4.13(d，J＝13.6Hz，1H)，2.98(d，J＝14.8Hz，1H)，2.45(s，3H)，2.21-2.11(m，1H)，1.63-1.51(m，1H)，1.41-1.35(m，1H)，0.97-0.92(m，1H)。
Example 4: preparation of Compound B-4
(R)-1′-(10-bromo-7，8-difluoro-6，11-dihydrodibenzo[b，e]thiepin-11-yl)-4′，6′-dioxo-1′，2′，4′，6′-tetrahydrospiro[cyclopropane-1，3′-pyrido[1，2-b]pyridazin]-5′-yl acetate(B-4)
Figure BDA0003183839160000291
The reaction scheme is as follows:
Figure BDA0003183839160000292
Figure BDA0003183839160000301
synthesis of Compound 3-1:
cyclopropanecarbaldehyde (13.7g, 195.47mmol), 3- (benzyloxy) -4-oxo-4H-pyran-2-carbaldehyde (15.00g, 65.16mmol) and pyrrolidine (4.63g, 65.16mmol) were dissolved in dimethyl sulfoxide (75 ml), heated to 50 ℃ and stirred for 3H. Ethyl acetate (200 ml) was added thereto, and the mixture was stirred, allowed to stand, separated, washed with saturated brine, concentrated to dryness under reduced pressure, and purified by column chromatography (PE: EA = 1: 1) to give 8.66g of a light brown oil.
Synthesis of Compound 3-2:
compound 3-1 (8.66g, 28.86mmol), trifluoroacetohydrazide (7.41g, 57.71mmol) was dissolved in methanol (400 ml) and water (200 ml), heated to 50-55 deg.C, and stirred for 12h. Concentrate to dryness under reduced pressure, dissolve in dichloromethane (200 ml), wash twice with saturated brine, concentrate to dryness under reduced pressure, and column chromatographe the crude product (DCM: meOH = 15: 1) to give 6.06g of a foamy solid.
Synthesis of Compounds 3-3:
compound 3-2 (6.06g, 20.45mmol) was dissolved in methanol (60 ml), cooled to 0-5 deg.C, and sodium borohydride (1.54g, 40.90mmol) was added in portions and stirred at room temperature for 1h. Quenched by addition of water (180 ml), stirred for 30min, filtered, washed with water and dried by forced air at 50 ℃ for 4h to give a solid (4.78 g). LCMS ESI m/z:299.4 (M + H) +.
Synthesis of Compounds 3-4:
compound 7 (5.20g, 15.15mmol) was dissolved in methylene chloride (40 ml), and thionyl chloride (9.03g, 75.75mmol) was added thereto, and the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness under reduced pressure, and the resulting mixture was subjected to displacement concentration with toluene (40 ml) twice to dryness to obtain chloride 8, which was used directly in the subsequent reaction.
Compound 3-3 (2.97g, 10.06mmol), previously prepared compound 8, triethylamine (2.28g, 22.53mmol) were dissolved in dichloromethane (30 ml), acetonitrile (30 ml) and N, N-dimethylformamide (100 ml), heated to 50-55 deg.C and stirred for 6h. The reaction mixture was concentrated, water (50 ml) and ethyl acetate (200 ml) were added, the mixture was stirred and allowed to stand for layer separation, the aqueous layer was extracted twice with ethyl acetate (200 ml), the organic layers were combined, washed with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by column chromatography (DCM: meOH = 50: 1) to give 4.37g of a product. LCMS ESI m/z:623.4 625.4 (M + H) + 。
Synthesis of Compounds 4-5:
compound 3-4 (4.25g, 6.82mmol) was dissolved in methylene chloride (100 ml), and dess-Martin reagent (2.89g, 6.82mmol) was added thereto at room temperature, followed by stirring at room temperature for 1 hour. After quenching with saturated sodium bicarbonate and sodium thiosulfate solution, dichloromethane (150 ml) was added for extraction, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by column chromatography (DCM: meOH = 20: 1) to obtain 3.38g of a pale yellow foamy solid. The purified compound was purified using a chiral column (column model: uniChiral CMZ-5H,50mm I.D.. Times.250 mm L), mobile phase: n-Hexane/Ethanol =50/50 (v/v), flow rate: 120ml/min, temperature: 25 ℃, wavelength: 254nm, resolving the compound to obtain 4-5,1.39g of compound; 5-5, 131g. LCMS ESI m/z:621.4 623.4 (M + H) + 。
Synthesis of Compound C-2:
the compound 4-5 (1.30g, 2.0)9 mmol), lithium chloride (0.80g, 18.83mmol) was dissolved in N, N-dimethylacetamide (13 ml), heated to 100 ℃ and stirred for 4h. Cooling to 0-10 deg.c, adding 1N hydrochloric acid (4 ml), dropping water (26 ml) slowly, separating out solid, filtering, washing filter cake with water, dissolving dichloromethane (30 ml), washing twice, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude product, purifying part of the crude product with thin layer chromatography plate (DCM: meOH = 10: 1) to obtain 73mg product. 1 HNMR(400MHz，CDCl 3 )：δ7.47(t，J＝8.0Hz，1H)，7.33(d，J＝8.0Hz，1H)，7.19-7.13(m，2H)，6.95-6.84(m，2H)，5.95(s，1H)，5.89(d，J＝7.6Hz，1H)，，5.68(d，J＝13.6Hz，1H)，4.25(d，J＝14.0Hz，1H)，4.13(d，J＝13.6Hz，1H)，2.95(d，J＝14.8Hz，1H)，2.14-2.11(m，1H)，1.77-1.73(m，1H)，0.96-0.90(m，2H)。
Synthesis of Compound B-4:
compound C-2 (100mg, 0.19mmol), triethylamine (96mg, 0.94mmol) and acetyl chloride (44mg, 0.57mmol) were dissolved in dichloromethane (5 ml) and stirred at room temperature for 1h. Water (10 ml) and dichloromethane (20 ml) were added, stirred, allowed to stand, the layers were separated, the aqueous layer was extracted with dichloromethane (20 ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was purified by thin layer chromatography preparation plate (DCM: meOH = 15: 1) to give 32mg of product. LCMSISI m/z:573.3 575.3 (M + H) + ； 1 HNMR(400MHz，CDCl 3 )：δ7.46(t，J＝8.0Hz，1H)，7.38(d，J＝8.0Hz，1H)，7.20-7.13(m，2H)，6.96(s，2H)，6.07(d，J＝8.0Hz，1H)，5.90(s，1H)，5.68(d，J＝13.6Hz，1H)，4.25(d，J＝14.4Hz，1H)，4.13(d，J＝14.0Hz，1H)，2.98(d，J＝14.8Hz，1H)，2.44(s，3H)，2.18-2.12(m，1H)，1.59-1.55(m，1H)，1.38-1.33(m，1H)，0.85-0.80(m，1H)。
Synthesis of prodrug (Compound D-2):
Figure BDA0003183839160000311
compound B-4 (0.40g, 0.75mmol), chloromethyl methyl carbonate (0.14 g,1.13 mmol), potassium carbonate (0.21g, 1.51mmol), potassium iodide (0.13g, 0.75mmol) were dissolved in N, N-dimethylacetamide (5 ml), heated to 50 ℃ and stirred for 5h. Cooling to-10-0 ℃, adding 1N hydrochloric acid (2 ml), adding water (20 ml) and ethyl acetate (30 ml), stirring, standing, layering, extracting the water layer twice with ethyl acetate (30 ml), combining the organic layers, washing twice with water, washing with saturated common salt water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying the crude product by a thin layer chromatography preparation plate (DCM: meOH = 25: 1) to obtain a light yellow solid 55mg. LCMS ESI m/z:619.4 621.4 (M + H) + ； 1 HNMR(400MHz，CDCl 3 )：δ 7.47(t，J＝8.4Hz，1H)，7.36(d，J＝7.6Hz，1H)，7.20-7.13(m，2H)，6.99-6.93(m，2H)，6.04-6.01(m，2H)，5.88(s，1H)，5.85(d，J＝6.4Hz，1H)，5.67(d，J＝12.8Hz，1H)，4.21(d，J＝14.8Hz，1H)，4.12(d，J＝14.0Hz，1H)，3.90(s，3H)，2.97(d，J＝14.4Hz，1H)，2.20-2.15(m，1H)，1.56-1.51(m，1H)，0.89-0.85(m，1H)，0.78-0.73(m，1H)。
Example 5: preparation of Compound B-3
(S)-１′-(10-bromo-7，8-difluoro-6，11-dihydrodibenzo[b，e]thiepin-11-y1)-4′，6′-dioxo-1′，2′，4′，6′-tetrahydrospiro[cyclopropane-1，3′-pyrido[1，2-b]pyridazin]-5′-yl acetate(B-3)
Figure BDA0003183839160000321
The reaction scheme is as follows:
Figure BDA0003183839160000322
synthesis of Compound C-1:
compound 5-5 (1.31g, 2.11mmol), lithium chloride (0.83g, 19.00mmol) was dissolved in N, N-dimethylacetamide (15 ml), heated to 100 ℃ and stirred for 4h. Cooling to 0-10 deg.C, adding 1N hydrochloric acid (4.5 ml), slowly dripping water (30 ml), stirring for 1 hr to precipitate solid, filtering, washing filter cake with water, and collecting dichloromethaneDissolving (30 ml), washing twice, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude product, pulping and purifying with dichloromethane (2 ml) and diethyl ether (7 ml), and drying to obtain solid 0.58g. 1 HNMR(400MHz，CDCl 3 )：δ 7.47(t，J＝8.4Hz，1H)，7.33(d，J＝8.0Hz，1H)，7.20-7.14(m，2H)，6.92-6.85(m，2H)，5.95(s，1H)，5.89(d，J＝8.0Hz，1H)，，5.68(d，J＝12.0Hz，1H)，4.25(d，J＝14.8Hz，1H)，4.13(d，J＝13.6Hz，1H)，2.95(d，J＝15.2Hz，1H)，2.14-2.11(m，1H)，1.77-1.73(m，1H)，0.99-0.89(m，2H)。
Synthesis of Compound B-3:
compound C-1 (80mg, 0.15mmol), triethylamine (90mg, 0.75mmol), acetyl chloride (41mg, 0.45mmol) was dissolved in dichloromethane (5 ml) and stirred at room temperature for 3h. Water (10 ml) and dichloromethane (20 ml) were added, stirred, allowed to stand, the layers were separated, the aqueous layer was extracted with dichloromethane (20 ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was purified by thin layer chromatography preparation plate (DCM: meOH = 18: 1) to give 19mg of product. LCMS ESI m/z:573.5 575.5 (M + H) + ； 1 HNMR(400MHz，CDCl 3 )：δ7.46(t，J＝8.4Hz，1H)，7.37(d，J＝7.6Hz，1H)，7.20-7.12(m，2H)，6.96(s，2H)，6.06(d，J＝8.0Hz，1H)，5.90(s，1H)，5.68(d，J＝14.8Hz，1H)，4.25(d，J＝14.4Hz，1H)，4.12(d，J＝13.6Hz，1H)，2.98(d，J＝15.2Hz，1H)，2.44(s，3H)，2.17-2.12(m，1H)，1.58-1.54(m，1H)，1.37-1.34(m，1H)，0.85-0.80(m，1H)。
Synthesis of the prodrug:
Figure BDA0003183839160000331
compound C-1 (0.43g, 0.81mmol), chloromethyl methyl carbonate (0.18g, 1.21mmol), potassium carbonate (0.22g, 1.61mmol), potassium iodide (0.13g, 0.81mmol) were dissolved in N, N-dimethylacetamide (5 ml), heated to 50 ℃ and stirred for 5 hours. Cooling to-10-0 deg.C, adding 1N hydrochloric acid (2 ml), adding water (20 ml) and ethyl acetate (30 ml), stirring, standing, layering,the aqueous layer was extracted twice with ethyl acetate (30 ml), the organic layers were combined, washed twice with water, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (PE: EA = 1: 2) and thin layer chromatography preparation plate (DCM: meOH = 25: 1) to give 65mg of a pale yellow solid. LCMS EsI m/z:619.4 6213 (M + H) + ； 1 HNMR(400MHz，CDCl 3 )：δ7.47(t，J＝8.0Hz，1H)，7.35(d，J＝7.6Hz，1H)，7.19-7.13(m，2H)，6.99-6.92(m，2H)，6.04-6.01(m，2H)，5.88(s，1H)，5.84(d，J＝6.0Hz，1H)，5.67(d，J＝12.8Hz，1H)，4.21(d，J＝14.8Hz，1H)，4.12(d，J＝12.8Hz，1H)，3.90(s，3H)，2.97(d，J＝14.8Hz，1H)，2.20-2.15(m，1H)，1.57-1.49(m，1H)，0.89-0.84(m，1H)，0.77-0.72(m，1H)。
Example 6: preparation of Compound A-5rac
1′-(10-bromo-7，8-difluoro-6，1１-dihydrodibenzo[b，e]thiepin-１１-y1)-4′，6′-dioxo-l′，2′，4′，6′-tetrahydrospiro[cyclobutane-1，3′-pyrido[1，2-b]pyridazin]-5′-yl acetate(A-5-rac)
Figure BDA0003183839160000332
The reaction scheme is as follows:
Figure BDA0003183839160000333
Figure BDA0003183839160000341
synthesis of Compound 6-1:
ring Ding Jiaquan (1.65g, 19.55mmol), 3- (benzyloxy) -4-oxo-4H-pyran-2-carbaldehyde (3.00g, 13.03mmol) was dissolved in tetrahydrofuran (30 ml), pyrrolidine (0.37g, 5.21mmol) and glacial acetic acid (1.77g, 29.45mmol) were added and stirred at room temperature for 2H. The reaction solution was concentrated under reduced pressure and dried, and purified by column chromatography (PE: EA = 1: 1) to obtain 2.40g of a product.
Synthesis of Compound 6-2:
compound 6-1 (2.29g, 7.32mmol) and hydrazine hydrochloride (7.67g, 73.20mmol) were dissolved in N, N-dimethylformamide (40 ml), and the mixture was heated to 85 ℃ and stirred for 3 hours. The reaction mixture was poured into water (60 ml), extracted with ethyl acetate (100 ml) three times, the organic layers were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give 1.46g of a product.
Synthesis of Compounds 6-3:
compound 6-2 (1.46g, 4.72mmol) was dissolved in tetrahydrofuran (20 ml), cooled to 0-5 deg.C, and sodium borohydride (0.54g, 14.15mmol) was added in portions and stirred at room temperature for 1h. Adding saturated ammonium chloride solution (20 ml), quenching, extracting with ethyl acetate (50 ml) for three times, mixing organic layers, washing with saturated saline, drying over anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain brown solid 1.25g. LCMS ESI m/z:313.3 (M + H) + 。
Synthesis of Compounds 6-4:
compound 7 (0.59g, 1.73mmol) was dissolved in dichloromethane (5 ml), thionyl chloride (1.03g, 8.64mmol) was added, and stirred at room temperature for 6h. The mixture was concentrated to dryness under reduced pressure, and the resulting mixture was subjected to displacement concentration with toluene (20 ml) to dryness to obtain chloride 8 which was used directly in the subsequent reaction.
Compound 6-3 (0.30g, 0.96mmol), the chloro compound 8 prepared above, triethylamine (0.22g, 2.15mmol) were dissolved in dichloromethane (5 ml), stirred at room temperature overnight, heated to 50 ℃ and stirred for 7h. The reaction mixture was extracted three times with water (20 ml) and dichloromethane (20 ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by column chromatography (DCM: meOH = 50: 1) to give 0.19g of a product. LCMS ESI m/z:637.2 639.1 (M + H) +.
Synthesis of Compounds 6-5:
compound 6-4 (0.19g, 0.30mmol) was dissolved in dichloromethane (5 ml), and dess-Martin reagent (0.13g, 0.30mmol) was added thereto at room temperature, followed by stirring at room temperature for 1.5h. Adding saturated sodium bicarbonate and sodium thiosulfate solution for quenching, extracting with dichloromethane (20 ml), combining organic layers, washing with saturated common salt water, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 0.33g of product. . LCMS ESI m/z:635.1，637.0(M+H) + 。
synthesis of Compounds 6-6:
compound 6-5 (0.32g, 0.50mmol), lithium chloride (0.42g, 9.92mmol) was dissolved in N, N-dimethylacetamide (5 ml), heated to 100 ℃ and stirred for 3h. Cooling to room temperature, adding water (20 ml) and ethyl acetate (20 ml), stirring, standing, layering, extracting the water layer with ethyl acetate (20 ml), combining the organic layers, washing twice, washing with saturated salt solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain 0.20g of product.
Synthesis of Compound A-5-rac:
compound 6-6 (0.24g, 0.43mmol), triethylamine (0.22g, 2.11mmol), acetyl chloride (0.10g, 1.29mmol) were dissolved in dichloromethane (10 ml), and stirred at room temperature for 2 hours. Water (10 ml) and dichloromethane (20 ml) were added, stirred, allowed to stand, the layers separated, the aqueous layer was extracted with dichloromethane (20 ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was purified by thin layer chromatography preparation plate (DCM: meOH = 15: 1) to give 42mg of product. LCMS ESI m/z:587.2 589.2 (M + H) + ； 1 HNMR(400MHz，CDCl 3 )：δ7.41-7.34(m，2H)，7.15-7.11(m，2H)，6.95-6.88(m，2H)，6.05(d，J＝6.0Hz，1H)，5.69(d，J＝13.2Hz，1H)，5.41(s，1H)，4.13(d，J＝13.6Hz，1H)，3.98(d，J＝16.8Hz，1H)，3.70(d，J＝14.8Hz，1H)，3.27(s，1H)，2.48(s，3H)，2.30-2.04(m，5H)。
Example 7: preparation of Compound B-10
(R)-1′-(10-bromo-7，8-difluoro-6，11-dihydrodibenzo[b，e]thiepin-11-yl)-4′，6′-dioxo-1′，2′，4′，6′-tetrahydrospiro[cyclobutane-1，3′-pyrido[1，2-b]pyridazin]-5′-yl acetate(B-10)
Figure BDA0003183839160000351
The reaction scheme is as follows:
Figure BDA0003183839160000352
synthesis of Compound 6-1:
ring Ding Jiaquan (8.23g, 97.74mmol), 3- (benzyloxy) -4-oxo-4H-pyran-2-carbaldehyde (15.00g, 65.16mmol) was dissolved in tetrahydrofuran (150 ml), pyrrolidine (1.86g, 26.06mmol) and glacial acetic acid (8.85g, 147.26mmol) were added and stirred at room temperature for 3H. The reaction solution was concentrated under reduced pressure and dried, and purified by column chromatography (PE: EA = 1: 2) to obtain 12.10g of a product.
Synthesis of Compound 6-2:
compound 6-1 (13.96g, 44.41mmol), hydrazine hydrochloride (46.65g, 444.10 mmol) were dissolved in N, N-dimethylformamide (210 ml), and the mixture was heated to 85 ℃ and stirred for 5 hours. The reaction mixture was poured into water (200 ml), extracted with ethyl acetate (300 ml) three times, the organic layers were combined, washed successively with water and saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by column chromatography (DCM: meOH = 15: 1) to give 6.94g of a product. LCMS ESI m/z:311.4 (M + H) +.
Synthesis of Compounds 6-3:
compound 6-2 (6.94g, 22.36mmol) was dissolved in tetrahydrofuran (100 ml), cooled to 0-5 deg.C, and sodium borohydride (2.58g, 67.09mmol) was added in portions and stirred at room temperature for 2h. Adding saturated ammonium chloride solution (100 ml) to quench, extracting with ethyl acetate (200 ml) for three times, combining organic layers, washing with saturated common salt water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, pulping with ethyl acetate/petroleum ether (50 ml/50 ml) and purifying to obtain 6.10g of reddish brown solid. LCMS ESI m/z:313.4 (M + H) + 。
Synthesis of Compounds 6-4:
compound 7 (4.20g, 12.24mmol) was dissolved in methylene chloride (40 ml), and thionyl chloride (7.25g, 60.95mmol) was added thereto, and the mixture was stirred at room temperature for 6 hours. The mixture was concentrated to dryness under reduced pressure, and then toluene (50 ml) was used for displacement concentration until dryness to obtain chloride 8, which was used directly in the subsequent reaction.
Compound 6-3 (3.00g, 9.60mmol), the chloro compound 8 prepared above, and triethylamine (2.19g, 21.50mmol) were dissolved in dichloromethane (100 ml), heated to 50 ℃ and stirred for 6h. The reaction mixture was extracted three times with water (200 ml) and methylene chloride (200 ml), the organic layers were combined, washed with saturated brine and driedDried over sodium sulfate, filtered, concentrated to dryness under reduced pressure and purified by column chromatography (DCM: meOH = 50: 1) to give 5.01g of product. LCMS ESI m/z:637.2 639.1 (M + H) + 。
Synthesis of Compounds 7-5:
compound 6-4 (4.90g, 7.69mmol) was dissolved in dichloromethane (50 ml), and dess-Martin reagent (3.26g, 7.69mmol) was added thereto at room temperature, followed by stirring at room temperature for 1h. After quenching with saturated sodium bicarbonate and sodium thiosulfate solution, dichloromethane (150 ml) was used for extraction, the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by column chromatography (DCM: meOH = 20: 1) to obtain 4.87g of a product. The resulting compound was purified using a chiral column (column model: uniChiral CMZ-5H,50mm I.D.. Times.250 mm L), mobile phase: n-Hexane/Ethanol =50/50 (v/v), flow rate: 120ml/min, temperature: 25 ℃, wavelength: 254nm, resolving racemic compound to obtain 7-5,1.39g; 8-5,1.96g of compound. LCMS ESI m/z:635.1 637.0 (M + H) + 。
Synthesis of Compound C-8:
compound 7-5 (1.31g, 2.06mmol), lithium chloride (0.85g, 18.55mmol) was dissolved in N, N-dimethylacetamide (15 ml), heated to 100 ℃ and stirred for 8 hours. Cooling to-5-0 deg.c, adding 1N hydrochloric acid (4 ml), dropping water (30 ml) slowly, filtering, washing the filter cake with water, dissolving dichloromethane (30 ml), washing twice, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude product, and purifying part of the crude product twice with thin layer chromatography plate (DCM: meOH = 10: 1) to obtain 8mg of product. 1 HNMR(400MHz，CDCl 3 )：δ 7.42-7.34(m，2H)，7.17-7.09(m，2H)，6.97-6.87(m，2H)，6.06(d，J＝7.6Hz，1H)，5.69(d，J＝13.6Hz，1H)，5.42(s，1H)，4.13(d，J＝13.6Hz，1H)，3.98(d，J＝15.2Hz，1H)，3.70(d，J＝14.8Hz，1H)，3.27(s，1H)，2.30-2.07(m，3H)，1.95-1.73(m，2H)。
Synthesis of Compound B-10:
compound C-8 (0.15g, 0.28mmol), triethylamine (0.07g, 0.55mmol), acetic anhydride (0.06g, 0.55mmol), and a catalytic amount of dimethylaminopyridine were dissolved in dichloromethane (6 ml) and stirred at room temperature for 1 hour. Water (10 ml) and methylene chloride (20 ml) were added thereto, and the mixture was stirredAfter standing and separation, the aqueous layer was extracted with dichloromethane (20 ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was purified by thin layer chromatography preparation plate (DCM: meOH = 20: 1) to give 70mg of product. LCMS ESI m/z:587.4 589.4 (M + H) + ； 1 HNMR(400MHz，CDCl 3 )：δ 7.42-7.34(m，2H)，7.17-7.09(m，2H)，6.97-6.87(m，2H)，6.06(d，J＝7.6Hz，1H)，5.69(d，J＝13.6Hz，1H)，5.42(s，1H)，4.13(d，J＝13.6Hz，1H)，3.98(d，J＝15.2Hz，1H)，3.70(d，J＝14.8Hz，1H)，3.27(s，1H)，2.46(s，3H)，2.30-2.07(m，3H)，1.95-1.73(m，2H)。
Synthesis of prodrug (Compound D-14 (R)):
Figure BDA0003183839160000371
compound C-8 (0.25g, 0.46mmol), chloromethyl methyl carbonate (0.10g, 0.69mmol), potassium carbonate (0.13g, 0.92mmol), potassium iodide (0.08g, 0.46mmol) were dissolved in N, N-dimethylacetamide (5 ml), heated to 50 ℃ and stirred for 5 hours. Cooling to-10-0 ℃, adding 1N hydrochloric acid (2 ml), adding water (20 ml) and ethyl acetate (30 ml), stirring, standing, layering, extracting the water layer twice with ethyl acetate (30 ml), combining the organic layers, washing twice with water, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying the crude product with a thin layer chromatography preparation plate (DCM: meOH = 25: 1) to obtain 0.10g of a light yellow solid. LCMS ESI m/z:633.5 635.5 (M + H) + ； 1 HNMR(400MHz，CDCl 3 )：δ7.42(t，J＝8.0Hz，1H)，7.34(d，J＝7.2Hz，1H)，7.15-7.09(m，2H)，6.93(s，2H)，6.05-6.01(m，2H)，5.92(d，J＝6.0Hz，1H)，5.70(d，J＝13.6Hz，1H)，5.44(s，1H)，4.12(d，J＝13.6Hz，1H)，3.95(s，3H)，3.95(d，J＝14.8Hz，1H)，3.64(d，J＝14.8Hz，1H)，3.31(s，1H)，2.47(s，1H)，2.16-2.05(m，2H)，1.93-1.86(m，1H)，1.74-1.70(m，1H)。
Example 8: preparation of Compound B-9
(S)-1′-(10-bromo-7，8-difluoro-6，11-dihydrodibenzo[b，e]thiepin-11-y1)-4′，6′-dioxo-1′，2′，4′，6′-tetrahydrospiro[cyclobutane-1，3′-pyrido[1，2-b]pyridazin]-5′-yl acetate(B-9)
Figure BDA0003183839160000381
The reaction scheme is as follows:
Figure BDA0003183839160000382
synthesis of Compound C-7:
compound 8-5 (1.90g, 2.99mmol), lithium chloride (1.14g, 26.91mmol) was dissolved in N, N-dimethylacetamide (19 ml), heated to 100 ℃ and stirred for 4h. Cooling to-5-0 deg.c, adding 1N hydrochloric acid (5.7 ml), dropping water (38 ml) slowly, filtering, washing the filter cake with water, dissolving dichloromethane (30 ml), washing twice, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to obtain crude product, and purifying part of the crude product with thin layer chromatography plate (DCM: meOH = 10: 1) to obtain 21mg of product. 1 HNMR(400MHz，CDCl 3 )：δ7.42-7.34(m，2H)，7.17-7.09(m，2H)，6.98-6.87(m，2H)，6.06(d，J＝7.6Hz，1H)，5.69(d，J＝13.6Hz，1H)，5.42(s，1H)，4.13(d，J＝14.0Hz，1H)，3.98(d，J＝15.6Hz，1H)，3.71(d，J＝15.6Hz，1H)，2.37-2.26(m，2H)，2.17-2.07(m，2H)，1.95-1.65(m，2H)。
Synthesis of Compound B-9:
compound C-7 (0.30g, 0.55mmol), triethylamine (0.11g, 1.10mmol), acetic anhydride (0.11g, 1.10mmol), and a catalytic amount of dimethylaminopyridine were dissolved in dichloromethane (10 ml), and the mixture was stirred at room temperature for 1 hour. Water (10 ml) and dichloromethane (20 ml) were added, stirred, allowed to stand, the layers were separated, the aqueous layer was extracted with dichloromethane (20 ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was purified by thin layer chromatography preparation plate (DCM: meOH = 15: 1) to give 0.11g of product. LCMS ESI m/z:587.3 589.4 (M + H) + ； 1 HNMR(400MHz，CDCl 3 )：δ 7.42-7.34(m，2H)，7.17-7.09(m，2H)，6.98-6.87(m，2H)，6.06(d，J＝7.6Hz，1H)，5.69(d，J＝13.6Hz，1H)，5.42(s，1H)，4.13(d，J＝14.0Hz，1H)，3.98(d，J＝15.6Hz，1H)，3.71(d，J＝15.6Hz，1H)，2.46(s，3H)，2.37-2.26(m，2H)，2.17-2.07(m，2H)，1.95-1.65(m，2H)。
Synthesis of prodrug (Compound D-14 (s)):
Figure BDA0003183839160000391
compound C-7 (0.50g, 0.92mmol), chloromethyl methyl carbonate (0.17g, 1.38mmol), potassium carbonate (0.25g, 1.83mmol), potassium iodide (0.15g, 0.92mmol) were dissolved in N, N-dimethylacetamide (5 ml), heated to 50 ℃ and stirred for 5h. Cooling to-10-0 ℃, adding 1N hydrochloric acid (2 ml), adding water (20 ml) and ethyl acetate (30 ml), stirring, standing, layering, extracting the water layer twice with ethyl acetate (30 ml), combining the organic layers, washing twice with water, washing with saturated common salt water, drying with anhydrous sodium sulfate, filtering, concentrating under reduced pressure to dryness, and purifying the crude product by a thin layer chromatography preparation plate (DCM: meOH = 25: 1) to obtain a light yellow solid 42mg. LCMS ESI m/z:633.4 635.5 (M + H) + ； 1 HNMR(400MHz，CDCl 3 )：δ 7.42(t，J＝8.0Hz，1H)，7.34(d，J＝6.8Hz，1H)，7.15-7.08(m，2H)，6.93(s，2H)，6.05-6.00(m，2H)，5.91(d，J＝6.0Hz，1H)，5.70(d，J＝13.2Hz，1H)，5.43(s，1H)，4.11(d，J＝13.6Hz，1H)，3.94(s，3H)，3.94(d，J＝14.4Hz，1H)，3.64(d，J＝15.2Hz，1H)，3.31(s，1H)，2.47(s，1H)，2.17-2.04(m，2H)，1.93-1.86(m，1H)，1.74-1.69(m，1H)。
Example 9: preparation of Compound B-40
(S)-1′-(10-ethynyl-7，8-difluoro-6，11-dihydrodibenzo[b，e]thiepin-11-yl)-4′，6′-dioxo-1′，2′，4′，6′-tetrahydrospiro[cyclopropane-1，3′-pyrido[1，2-b]pyridazin]-5′-yl acetate(B-40)
Figure BDA0003183839160000392
The reaction scheme is as follows:
Figure BDA0003183839160000401
synthesis of Compound 9-1:
compound 14 (0.15g, 0.42mmol) and potassium carbonate (0.23g, 1.66mmol) were dissolved in methanol (5 ml), and the mixture was stirred at room temperature for 30min. Water (10 ml) and ethyl acetate (20 ml) were added thereto, and the mixture was stirred, allowed to stand, and then the layers were separated, and the aqueous layer was extracted with ethyl acetate (20 ml), and the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 0.13g of a product.
Synthesis of Compounds 9-3:
compound 9-1 (0.53g, 1.84mmol) was dissolved in methylene chloride (5 ml), and thionyl chloride (1.10g, 9.19mmol) was added thereto, and the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness under reduced pressure, and then replaced with toluene (30 ml) and concentrated to dryness to obtain chloride 9-2, which was used directly in the subsequent reaction.
Compound 3-3 (0.40g, 1.34mmol), the chloro compound 9-2 prepared previously, triethylamine (0.39g, 3.85mmol) were dissolved in dichloromethane (10 ml) and N, N-dimethylformamide (10 ml), heated to 50 ℃ and stirred for 5 hours. Cooled to room temperature, quenched with water (10 ml), extracted twice with dichloromethane (30 ml), the combined organic layers washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product purified by column chromatography (DCM: meOH = 10: 1) to give 0.25g of product.
Synthesis of Compounds 9-4:
compound 9-3 (0.75g, 1.29mmol) was dissolved in dichloromethane (15 ml), dess-martin reagent (0.57g, 1.29mmol) was added at room temperature, heated to 50 ℃ and stirred for 2h. Quenched with water (20 ml), extracted twice with dichloromethane (40 ml), the organic layers were combined, washed with brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (DCM: meOH = 100: 1) to give 0.60g of product. The purified compound was purified using a chiral column (column model: uniChiral CMZ-5H,50mm I.D.. Times.250 mm L), mobile phase: n-Hexane/Ethanol =50/50 (v/v), flow rate: 120ml/min, temperature: 25 ℃, wavelength: 254nm, and resolving racemic compound to obtain 9-4,0.27g compound. LCMS ESI m/z:567.2 (M + H)
Synthesis of Compounds 9-5:
compound 9-4 (0.20g, 0.35mmol) and lithium chloride (0.30g, 7.06mmol) were dissolved in N, N-dimethylacetamide (5 ml), and the mixture was heated to 100 ℃ and stirred for 3 hours. Cooling to room temperature, adding water (10 ml) and ethyl acetate (20 ml), stirring, standing, layering, extracting the water layer with ethyl acetate (20 ml), combining the organic layers, washing twice, washing with saturated salt solution, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain crude oil 0.20g.
Synthesis of Compound B-40:
compound 9-5 (0.20g, 0.43mmol), triethylamine (0.22g, 2.13mmol) and acetyl chloride (0.11g, 1.28mmol) were dissolved in methylene chloride (5 ml), and the mixture was stirred at room temperature for 30min. Water (10 ml) and dichloromethane (20 ml) were added, stirred, allowed to stand, the layers separated, the aqueous layer was extracted with dichloromethane (20 ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was purified twice by thin layer chromatography preparation plate (DCM: meOH = 15: 1) to give 26mg of product. LCMS ESI m/z:519.2 (M + H) + ； 1 HNMR(400MHz，CDCl 3 )：δ7.38(d，J＝7.6Hz，1H)，7.33-7.29(m，1H)，7.18-7.12(m，2H)，6.94-6.92(m，2H)，6.07(s，1H)，6.07(d，J＝11.2Hz，1H)，5.59(d，J＝13.2Hz，1H)，4.25(d，J＝14.8Hz，1H)，4.11(d，J＝13.6Hz，1H)，3.51(s，1H)，2.98(d，J＝14.8Hz，1H)，2.44(s，3H)，2.11-2.04(m，1H)，1.57-1.53(m，1H)，1.37-1.32(m，1H)，0.92-0.85(m，1H)。
Example 10: preparation of Compound B-46
(S)-1′-(10-ethynyl-7，8-difluoro-6，11-dihydrodibenzo[b，e]thiepin-11-y1)-4′，6′-dioxo-1′，2′，4′，6′-tetrahydrospiro[cyclobutane-1，3′-pyrido[1，2-b]pyridazin]-5′-yl acetate(B-46)
Figure BDA0003183839160000411
The reaction scheme is as follows:
Figure BDA0003183839160000412
Figure BDA0003183839160000421
synthesis of Compound 10-1:
compound 15 (0.62g, 1.67mmol) was dissolved in methylene chloride (10 ml), and thionyl chloride (2.20g, 16.70mmol) was added thereto and stirred at room temperature overnight. The mixture was concentrated to dryness under reduced pressure, and the resulting mixture was subjected to displacement concentration with toluene (30 ml) to dryness to obtain chloride 16, which was used in the subsequent reaction.
Compound 6-3 (0.35g, 1.12mmol), the chloro compound 16 prepared above, and triethylamine (0.39g, 3.85mmol) were dissolved in dichloromethane (10 ml), heated to 50 ℃ and stirred for 4h. Cooled to room temperature, quenched with water (20 ml), extracted twice with ethyl acetate (30 ml), the combined organic layers washed with saturated brine, concentrated to dryness under reduced pressure, and the crude product purified by column chromatography (PE: EA = 1: 2) to give 0.10g of product. LCMS ESI m/z:655.3 (M + H) + 。
Synthesis of Compound 10-2:
compound 10-1 (0.10g, 0.15mmol) was dissolved in methylene chloride (2 ml), and dess-Martin reagent (0.07g, 0.15mmol) was added thereto at room temperature, followed by stirring at room temperature for 2 hours. Quenching with water, extracting with ethyl acetate (20 ml) twice, mixing organic layers, washing with saturated salt water, and concentrating under reduced pressure to obtain 0.10g. LCMS ESI m/z:6533 (M + H) + 。
Synthesis of Compound 10-3:
compound 10-2 (0.45g, 0.67mmol), potassium carbonate (0.40g, 2.74mmol) were dissolved in methanol (18 ml), and stirred at room temperature for 3 hours. Water (20 ml) and ethyl acetate (40 ml) were added, stirred, allowed to stand, the layers were separated, the aqueous layer was extracted with ethyl acetate (30 ml), the organic layers were combined, washed with saturated brine, concentrated to dryness under reduced pressure, and the crude product was purified by column chromatography (DCM: meOH = 100: 1) to give 0.38g of the product. The obtained pure product was purified by using a chiral column (column model: uniChiral CMZ)-5h,50mm i.d. × 250mm L), mobile phase: n-Hexane/Ethanol =50/50 (v/v), flow rate: 120ml/min, temperature: 25 ℃, wavelength: 254nm, and resolving racemic compound to obtain 10-3,0.17g. LCMS ESI m/z:581.2 (M + H) + 。
Synthesis of Compound 10-4:
compound 10-3 (0.13g, 0.22mmol), lithium chloride (0.35g, 7.65mmol) was dissolved in N, N-dimethylacetamide (2 ml), heated to 100 ℃ and stirred for 3 hours. Cooling to room temperature, adding water (10 ml) and ethyl acetate (20 ml), stirring, standing, layering, extracting water layer with ethyl acetate (20 ml), combining organic layers, washing with water twice, washing with saturated salt water, drying with anhydrous sodium sulfate, filtering, and concentrating under reduced pressure to obtain crude oil.
Synthesis of Compound B-46:
compound 10-4 (0.12g, 0.24mmol), triethylamine (0.25g, 2.45mmol), acetyl chloride (0.10g, 1.22mmol) were dissolved in dichloromethane (2 ml), and the mixture was stirred at room temperature for 2 hours. Water (10 ml) and dichloromethane (20 ml) were added, stirred, allowed to stand, the layers separated, the aqueous layer was extracted with dichloromethane (20 ml), the organic layers were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and the crude product was purified by thin layer chromatography preparation plate (DCM: meOH = 15: 1) to give 15mg of product. LCMS ESI m/z:533.3 (M + H) + ； 1 HNMR(400MHz，CDCl 3 )：δ7.39-7.35(m，1H)，7.26-7.24(m，1H)，7.14-7.10(m，2H)，6.93-6.74(m，2H)，6.09(d，J＝6.8Hz，1H)，5.59(d，J＝10.8Hz，1H)，5.60(s，1H)，4.13(d，J＝13.6Hz，1H)，3.96(d，J＝15.2Hz，1H)，3.73(d，J＝14.8Hz，1H)，3.52(s，1H)，3.24(s，1H)，2.46(s，3H)，2.23-1.88(m，5H)。
The compounds corresponding to examples 11-14 were prepared according to the above synthetic procedure, as follows:
Figure BDA0003183839160000431
example 15 in vitro bioactivity study
Test compound: the compounds of the invention: compound 1-13, compound 2-4, compound A-2-rac, compound B-4, compound C-2, compound B-3, compound C-1, compound A-5-rac, compound B-10, compound C-8, compound B-9, compound C-7, compound B-40, compound B-46, compound B-22, compound B-28, compound B-54, compound B-56; control compound: baloxivir acid, compound a and compound c.
Figure BDA0003183839160000441
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 resting at 37 ℃,5% CO 2 The 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 (H1N 1) strains were 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. Cell plates were incubated at 37 ℃ 5% CO 2 Culturing in an incubator for 5 days. After 5 days of culture, cell activity was measured using cell viability assay kit CCK 8. The inhibition rate and cytotoxicity of the compound are subjected to nonlinear fitting analysis by GraphPad Prism software on the raw data to obtain EC 50 Values (results see table 1).
TABLE 1 inhibitory Activity of Compounds against influenza A/PR/8/34 (H1N 1)
Compound ID EC 50 (nM) Compound ID EC 50 (nM)
1-13(racemic) 65.05 B-40 0.32
2-4(racemic) 14.65 B-46 0.56
A-2-rac 0.66 B-22 0.45
B-4 0.38 B-28 0.72
C-2 0.41 B-54 0.36
A-5-rac 1.09 B-56 0.63
B-10 0.61 Compound c 3.9
C-8 0.67 Baloxivir acid 2.2
Compound a 2.0
And (4) conclusion: the compound 2-4, the compound A-2-rac, the compound B-4, the compound C-2, the compound A-5-rac, the compound B-10, the compound C-8, the compound B-40, the compound B-46, the compound B-22, the compound B-28, the compound B-54 and the compound B-56 have excellent activity of inhibiting H1N1, and the inhibitory activity of part of compounds is lower than 1nM.
From the foregoing, it can be seen that the antiviral pyridone derivatives provided herein have unexpectedly potent activity in preventing or inhibiting influenza virus infection, particularly by having cap-dependent endonuclease inhibitors. Our studies have confirmed that at the para position of the difluorophenyl ring, suitable local electropositive substituents and other functional groups which generate electrostatic interaction with the electronegative carboxyl group of glutamic acid can significantly improve the affinity of the compound and endonuclease and the activity of the compound in inhibiting influenza a and influenza B viruses under the condition of suitable spatial configuration and spatial size. Groups para to the phenyl ring of the difluoride are two main groups of suitable functional groups, according to the mode of action that can interact with the side chain carboxyl of glutamic acid: (a) Halogens and their analogous functional groups form so-called halogen bonds or chalcogen bonds. The electrical distribution around the halogen (excluding F atoms) is not uniform, is anisotropic, and at the para position of the C-halogen bond, a positive surface potential (para position of the delta bond, etc.) can interact with the carboxyl group of the negatively charged group of glutamic acid (E80) based on electrical or induced electrostatic interactions. Because of the long distance, the interaction generated by the isolated halogen is very weak and hardly appears on the activity, but under the action of the strong electron-withdrawing group of the para-difluoro, the electropositivity of the halogen is greatly enhanced to form very strong interaction, thereby obviously improving the activity of the compound. (b) amides and hydroxy substituents. These substituents, when appropriately sterically arranged, can form hydrogen bonds or close electrical interactions with the carboxyl groups of glutamic acid. The carboxyl of the glutamic acid 80 is far away from a catalytic center and exists in electronegativity, and a proper space configuration group is designed and synthesized at the para position of benzene ring difluoride, so that a hydrogen bond donor (HB donor) is provided to form a hydrogen bond with the electronegative carboxyl of the glutamic acid, and the activity of the medicament is remarkably improved.
The invention provides a way for improving the activity of a compound by utilizing electrostatic interaction, the participation effect of a medicament and incision enzyme is obviously enhanced and the activity of the medicament is improved by the electrostatic interaction with electronegative glutamic acid carboxyl, and the obviously improved activity can be converted into a threshold for reducing clinical dosage or improving medicament resistance. Such a way of increasing the activity of the drug is not readily available to any skilled person. The prepared high-activity medicament is suitable for preventing or treating influenza virus A and influenza virus B infection, and can quickly and effectively cure influenza infection patients by clinically using the medicament alone or in combination.
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 (15)

1. A pyridone derivative shown as a formula (I) and a pharmaceutically acceptable salt thereof,
Figure FDA0003183839150000011
wherein:
(1) R is selected from Cl, br, I, cyano, C 2-6 Alkynyl, amido, sulfonamido, trifluoromethyl, difluoromethyl, -OCF 3 、-OCF 2 H、-R 1 OH、-R 1 CONH 2 、-R 1 NH 2 、C 3-6 Cyclic amino, N-methyl C 3-6 Cycloalkylamino, -X-R 1 OH、-XCONH 2 and-XR 1 CONH 2 Wherein X is O, CF 2 、S、NH、SO 2 ；R 1 Selected from the following unsubstituted or substituted with 1,2 or 3 first substituent groups: c 1-6 Hydrocarbyl radical, C 3-6 Cycloalkyl radical, C 3-6 Cycloalkyl radical C 1-6 A hydrocarbyl group;
(2) A is selected from a benzene, pyridine or thiophene ring which is unsubstituted or substituted with 1,2 or 3 second substituent groups;
(3) n is selected from 1 or 2;
(4) P is selected from H or a group metabolized into a raw drug by a chemical method or under the action of an enzyme in vivo;
the first substituent group and the second substituent group are independently the following groups:
cyano, fluoro, chloro, bromo, iodo, hydroxy, carboxy, C 1-6 Ester group, sulfone group, sulfonamide group, amide group, amine group, C 1-6 Hydrocarbyl, halogenated C 1-6 Hydrocarbyl, hydroxy-substituted C 1-6 Hydrocarbyl, amide substituted C 1-6 Hydrocarbyl radical, C 1-6 Alkoxy, halo C 1-6 Hydrocarbyloxy, C 1-6 Hydrocarbyloxy group C 1-6 Hydrocarbyl radical, C 1-6 Hydrocarbyloxy group C 1-6 Hydrocarbyloxy, C 1-6 Alkylamino radical, C 1-6 Mercapto group of hydrocarbon, C 1-6 Hydrocarbyl carbonyl group, C 1-6 Hydrocarbyl amine acyl, C 1-6 Hydrocarbyl amido, halo C 1-6 Hydrocarbyl amide group, C 1-6 Hydroxyoxyacyl group, C 1-6 Hydrocarbyl amine amido, C 1-6 A hydrocarbon sulfone group, C 1-6 A hydrocarbyl sulfonamide group.
The pyridone derivative and the pharmaceutically acceptable salt thereof are in the form of racemate of a single compound, optical isomer of a single compound or mixture of a plurality of compounds.
2. The pyridone derivative and the pharmaceutically acceptable salt thereof according to claim 1, wherein R is selected from the group consisting of Cl, br, I, ethynyl, propynyl, butynyl, isopropynyl;
or R is selected from cyano, amido, sulfonamido, or the like,
Figure FDA0003183839150000012
Or, R is selected from-R 1 OH、-R 1 CONH 2 、-X-R 1 OH、-XCONH 2 and-XR 1 CONH 2 (ii) a Wherein X is O, CF 2 、S、NH、SO 2 ，R 1 Selected from the following substituted or unsubstituted groups: methyl, ethyl, propyl, isopropyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl;
or, R is selected from trifluoromethyl, difluoromethyl, -OCF 3 、-OCF 2 H。
3. The pyridone derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein the first substituent group and the second substituent group are independently selected from the group consisting of:
cyanogen, fluorine, chlorine, bromine, iodine, hydroxyl cyanide, carboxyl cyanide, methyl ester cyanide, ethyl ester cyanide, sulfone cyanide, sulfonamide cyanide, amide cyanide, sulfone cyanide, methyl, ethyl, propyl, isopropyl, methoxy, ethoxy, propoxy, isopropoxy, trifluoromethyl, difluoromethyl, cyclopropyl, cyclobutyl, and fluorocyclopropyl.
4. The pyridone derivative and pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit thereof
Figure FDA0003183839150000021
Is selected from
Figure FDA0003183839150000022
Figure FDA0003183839150000023
5. The pyridone derivative and pharmaceutically acceptable salt thereof according to claim 1, wherein P is selected from the group consisting of: (1) H; (2) -C (= O) -CH 3 ；(3)-CH 2 -O-C(＝O)-O-CH 3 。
6. The pyridone derivative and pharmaceutically acceptable salt thereof according to claim 1, wherein the structural unit thereof
Figure FDA0003183839150000024
Is selected from
Figure FDA0003183839150000025
Figure FDA0003183839150000026
Figure FDA0003183839150000031
7. A pyridone derivative and a pharmaceutically acceptable salt thereof, wherein the pyridone derivative is in the form of an optical isomer represented by formula (ii-1) or formula (ii-2):
Figure FDA0003183839150000032
in the formulae (II-1) and (II-2), R, P, A, n is as defined in any one of claims 1 to 6.
8. A pyridone derivative and a pharmaceutically acceptable salt thereof, wherein the pyridone derivative is a compound selected from the following racemic forms and/or optical isomer forms:
Figure FDA0003183839150000033
Figure FDA0003183839150000041
Figure FDA0003183839150000051
Figure FDA0003183839150000061
Figure FDA0003183839150000071
9. a pyridone derivative and a pharmaceutically acceptable salt thereof, wherein the pyridone derivative is selected from the following compounds and is in a racemic form or an optical isomer form:
Figure FDA0003183839150000072
Figure FDA0003183839150000081
Figure FDA0003183839150000091
10. a pyridone derivative represented by the formula (iii-1), the formula (iii-2), the formula (iii-3) or the formula (iii-4), which is racemic or in the form of an optical isomer:
Figure FDA0003183839150000092
wherein P is as defined for the group at the corresponding position of the pyridone derivative of any one of the preceding claims 1 to 9.
11. A pharmaceutical composition comprising a pyridone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10.
12. Use of the pyridone derivative or pharmaceutically acceptable salt thereof according to any one of claims 1 to 10 and the pharmaceutical composition according to claim 11 for the preparation of a medicament for the prophylaxis and/or treatment of a viral infectious disease which is an infectious disease caused by influenza a and/or influenza B.
13. A process for preparing a pyridone derivative according to any one of claims 1 to 10, and pharmaceutically acceptable salts thereof, comprising the steps of:
(1) Preparing a compound C by using a compound A and a compound B as raw materials;
Figure FDA0003183839150000093
(2) Preparing a compound D by taking the compound C as a starting material;
Figure FDA0003183839150000101
(3) Preparing a compound shown as a formula (I) by taking a compound D as a starting material;
Figure FDA0003183839150000102
in compounds A, C and D, Z is a hydroxy protecting group;
in compound B, C, D and formula (i), R, A is the same as the group at the corresponding position of the pyridone derivative of the preceding claims;
in compound A, C, D and formula (i),
Figure FDA0003183839150000103
the same as the group at the corresponding position of the pyridone derivative according to the preceding claim;
in the formula (I), P is the same as the group at the corresponding position of the pyridone derivative according to the preceding claims.
14. An intermediate suitable for use in the preparation of a pyridone derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein the intermediate is a compound represented by formula B, formula C or formula D:
Figure FDA0003183839150000111
in formula B, formula C or formula D, Z is a hydroxy protecting group, R, A, n is as defined in any one of claims 1 to 10 in the corresponding position.
15. The intermediate of claim 14, wherein the intermediate is selected from the group consisting of:
Figure FDA0003183839150000112
Figure FDA0003183839150000121
in the formula, A is a benzene ring, a pyridine ring or a thiophene ring, and n is 1 or 2.
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