CN113880832A - Pyridazinone derivative and application thereof - Google Patents

Pyridazinone derivative and application thereof Download PDF

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CN113880832A
CN113880832A CN202010994695.5A CN202010994695A CN113880832A CN 113880832 A CN113880832 A CN 113880832A CN 202010994695 A CN202010994695 A CN 202010994695A CN 113880832 A CN113880832 A CN 113880832A
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胡双华
林寨伟
崔柏成
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GUANGZHOU NANXIN PHARMACEUTICAL CO Ltd
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    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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Abstract

The invention belongs to the field of medicines, and particularly relates to a pyridazinone derivative and application thereof, wherein a compound and pharmaceutically acceptable salts and solvates thereof comprise hydrates, polycrystals, prodrugs, cocrystals, tautomers and stereoisomers, and more particularly, the pyridazinone derivative can be used as an anti-influenza medicine with a CEN (receptor for N) inhibition effect.

Description

Pyridazinone derivative and application thereof
Technical Field
The invention belongs to the field of medicines, and particularly relates to a pyridazinone derivative and application thereof. More specifically, the compound of the present invention can be used as an anti-influenza drug having a CEN inhibitory effect.
Background
Influenza is a highly contagious respiratory disease caused by influenza virus, wherein influenza A virus has the widest host range, can infect both birds and mammals, and is very easy to cause pandemics worldwide. Influenza viruses have developed 4 major outbreaks of influenza in only a few hundred years (1918, 1957, 1968, 2009). Among them, the outbreak of "spanish influenza" (H1N1) in 1918 directly caused about 5000 thousands of deaths, and is a big outbreak of influenza with the largest number of deaths in human history. Whereas the last outbreak of "Mexico flu" (A/2009/H1N1) in 2009 spread rapidly to 214 countries worldwide, only 12 months of the outbreak led to approximately 20 million deaths. Therefore, it is very important to develop a novel broad-spectrum anti-influenza virus drug for the prevention and early treatment of influenza virus infection. Typically, these new strains result from the transmission of existing influenza viruses from other animal species to humans.
The influenza virus is an RNA virus of Orthomyxoviridae (Orthomyxoviridae) and belongs to the genus influenza virus. Influenza viruses are mainly classified into A, B, C types, also called type A, B and C, according to the antigenic and genetic properties of the viral particle Nucleoprotein (NP) and matrix protein (M). The three types of viruses have similar biochemical and biological characteristics. The virus particles are 80-120nm in diameter and are usually approximately spherical, but filamentous forms may occur. The virus is composed of three layers, the inner layer is the virus nucleocapsid, containing Nucleoprotein (NP), P protein and RNA. NP is a soluble antigen (S antigen), has type specificity, and is antigenically stable. The P protein (P1, P2, P3) may be a polymerase required for RNA transcription and replication. The middle layer is virus envelope composed of one lipoid and one Membrane Protein (MP), and the MP has stable antigenicity and type specificity. The outer layer is a radial protuberance made of two different glycoproteins, hemagglutinin (H) and neuraminidase (N). H can cause erythrocyte agglutination, is a tool for adsorbing viruses on the surfaces of sensitive cells, N can hydrolyze mucin, and N-acetylneuraminic acid at the tail end of a receptor specific glycoprotein on the cell surface is a tool for separating the viruses from the cell surface after the replication of the viruses is finished. H and N both have variation characteristics, so that only the specific antigenicity of the strain exists, and the antibody has a protection effect.
Unusual for viruses, nucleic acids whose genomes are not single fragments; in contrast, the genome contains 7 or 8 segments of negative-sense RNA. The influenza a genome encodes 11 proteins: hemagglutinin (H), neuraminidase (N), Nucleoprotein (NP), M1, M2, NS1, NS2(NEP), PA, PB1, PB1-F2, and PB 2. H and N are macromolecular glycoproteins outside the virion. HA is a lectin that mediates binding of the virus to the target cell and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells by cleaving sugars that bind to mature viral particles. Therefore, these proteins have been targets for antiviral drugs. Moreover, these proteins are antigens of antibodies that can be produced. Influenza a viruses are classified into subtypes based on antibody responses to H and N, forming the basis for the distinction between H and N in, for example, H5N 1.
Because the influenza virus genome is small, the synthesis of its desired proteins is dependent on the translation system of the host cell. Thus, the messenger rna (mrna) of influenza virus needs to have both a 5 'CAP (CAP) structure and a 3' -poly (a) tail structure that can be recognized by the translation system of the host cell. Wherein the 5 'cap is "captured" by cleavage of the PA subunit endonuclease activity of the influenza RNA polymerase complex from the 5' end of the host cell precursor mRNA. This mode, known as "CAP-snatchinging", deprives the CAP CAP of host mRNA for transcription of viral self mRNA, is necessary for transcription initiation of influenza virus.
Because "CAP-snatching" is a key element in the replication cycle of influenza virus, and because similar mechanisms and corresponding proteases do not exist in host cells, inhibitors against "CAP-snatching" endonuclease can selectively block the transcription process of influenza virus, and simultaneously have no influence on host cells, namely, have CAP-dependent endonuclease (CEN) inhibition. This mechanism then becomes a potential anti-influenza drug target.
The existing means for preventing and treating influenza virus infection mainly comprise influenza vaccine inoculation and influenza virus resisting medicine application. Vaccination with influenza is the primary prophylactic method and is highly effective, but it has the major disadvantages of having to be injected once a year and having low efficacy against adults and young children with low immunity and high risk of disease. Furthermore, if the predicted influenza vaccine species are incorrect, the efficacy of the vaccine will be reduced to 25%. Thus, anti-influenza virus drugs are the first line of treatment for influenza.
To date, FDA-approved anti-influenza virus drugs for clinical use fall broadly into two categories: 1) m2 ion channel blockers including amantadine and rimantadine; 2) neuraminidase inhibitors, mainly oseltamivir and zanamivir, and peramivir and ranimivir, which have been approved in several countries. In addition, the anti-influenza drugs currently approved only in japan on the market are the RNA inhibitors faviravir and xoflurza. Because the influenza viruses which are epidemic at present are resistant to amantadine drugs (S31N mutation appears in the NS gene of the virus), the amantadine drugs are no longer the first choice drugs recommended by WHO for preventing and treating influenza. Neuraminidase inhibitor drugs are the main choice for antiviral therapy of influenza patients, however, researchers have successively found drug-resistant strains of H1N1, H5N1, H3N2 and B that are resistant to oseltamivir, indicating that their resistance remains of great concern.
Documents 1 to 5 report the structure and structure-activity relationship of flutamide (flutimide) and 2, 4-dioxobutyric acid derivatives as CEN inhibitors. CN201080036154 discloses synthesis of 3-hydroxy-4-pyridone derivatives as CEN inhibitors, antiviral action, in particular biological activity for inhibiting influenza virus proliferation. CN201680027747 discloses methods of synthesis of aza-pyridone compounds as CEN inhibitors and amelioration and/or treatment of diseases and/or disorders including influenza virus infection. WO2017072341a1 discloses the use of pyrimidinone derivatives as CEN inhibitors in the field of antiviral.
The above compounds still have some defects in terms of drug-forming property, and therefore, research and development of novel anti-influenza drugs having CEN inhibitory effect is still very urgent for scientists.
The literature:
1.Tetrahedron Lett 1995，36（12），2005；
2.Tetrahedron Lett 1995，36（12），2009。
3.Antimicrobial Agents And Chemotherapy，Dec. 1994，p.2827－2837
4.Antimicrobial Agents And Chemotherapy，May 1996，p.1304 － 1307
5.J. Med. Chem. 2003，46，1153 － 1164
disclosure of Invention
The invention provides a novel compound serving as an influenza virus RNA polymerase inhibitor, in particular to a novel compound with a CEN (cancer cell protein) inhibition function and a general formula I, and the compound and a composition thereof can be used for preparing medicines for preventing, treating or relieving virus infection diseases of patients.
In one aspect, the invention relates to a compound shown as a general formula I, and pharmaceutically acceptable salts and solvates thereof, including hydrates, polymorphs, prodrugs, co-crystals, tautomers and stereoisomers,
Figure 211565DEST_PATH_IMAGE001
wherein R is1: is H or-C (═ O) Y1、-C(＝O)-O-Y1、-(CH2)-O-(C＝O)-Y1、-(CH2)-O-(C＝O)-O-Y1、-(CHCH3)-O-(C＝O)-Y1And- (CHCH)3)-O-(C＝O)-O-Y1；
Y1Is optionally substituted C1-10Alkyl, optionally substituted C3-8Cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, mono-substituted amino group, di-substituted amino and-C (R)*)2NHR**(ii) a And each R*And R**Independently is hydrogen or optionally substituted C1-6An alkyl group;
R2and R3Can be independently H, C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN、-COOR*、-OR*、-(CH2)qNR*R**,-C(O)-NR*R**；R2And R3May be linked to form a ring to form an optionally substituted cycloalkyl, an optionally substituted heterocyclyl and an optionally substituted cycloalkenyl; r*And R**Independently H and optionally substituted C1-6An alkyl group; q is 0 to 6;
R4is a structure shown in the following formula
Figure 54756DEST_PATH_IMAGE002
R9 And R10Is optionally substituted aryl, and optionally substituted heteroaryl; wherein the substituents are independent C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN、-COOR*、-OR*、-(CH2)qNR*R**,-C(O)-NR*R**； R*And R**Independently H and optionally substituted C1-6Alkyl, q is 0 to 6;
R9and R10Can be connected to form the structure shown as follows:
Figure 774450DEST_PATH_IMAGE003
wherein n and m may independently be 0-3, Q is CR*R**、 NR*、O、S、SO、SO2；R*And R**Independently H and optionally substituted C1-6An alkyl group;
R5，R6: is H, or is selected from optionally substituted C1-8Alkyl, optionally substituted C2-8Alkenyl, optionally substituted heterocyclic group, optionally substituted C3-8Cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein the substituents may be independent C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN、-COOR*、-OR*、-(CH2)qNR*R**,-C(O)-NR*R**Wherein R is*And R**Independently H and optionally substituted C1-6Alkyl, q is 0 to 6;
R7,R8: is H, C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN、-COOR*、-OR*、-(CH2)qNR*R**,-C(O)-NR*R**；R*And R**Independently H and optionally substituted C1-6An alkyl group; q is 0 to 6.
R5、R7Or R6、R8May be joined to form a 5-8 membered ring, optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally substituted cycloalkenyl; for example, to form a 6-membered ring, which may be carbocyclic, or contain O, N heterocycles.
In another aspect, the present invention provides a pharmaceutical composition, which comprises an effective amount of the compound of the present invention, and the compound is represented by formula I, and pharmaceutically acceptable salts and solvates thereof, including hydrates, polymorphs, prodrugs, co-crystals, tautomers, stereoisomers,
Figure 880946DEST_PATH_IMAGE001
wherein the content of the first and second substances,
R1: is H;
R2and R3Can be independently H, C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN、-COOR*、-OR*；R2And R3Optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally substituted cycloalkenyl can be formed, R*Independently H and optionally substituted C1-6An alkyl group;
R4is a structure shown in the following formula
Figure 545146DEST_PATH_IMAGE002
R9AndR10are optionally substituted aryl, and optionally substituted heteroaryl, which may be joined to form the structure shown below:
Figure 67394DEST_PATH_IMAGE003
wherein n and m may independently be 0-3, Q is CR*R**、 NR*、O、S、SO、SO2；R*And R** Independently H and optionally substituted C1-6An alkyl group;
R5,R6is H or is selected from optionally substituted C1-8Alkyl, optionally substituted C2-8Alkenyl, optionally substituted heterocyclic group, optionally substituted C3-8A cycloalkyl group; wherein the substituents may be independent C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN、-COOR*、-OR*，R*Independently H and optionally substituted C1-6An alkyl group;
R7,R8can be independently H, C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN；
R5、R7Or R6、R8May be joined as a 5-to 8-membered saturated or unsaturated ring, for example a 6-membered ring, which may be carbocyclic or contain an O, N heterocyclic ring.
In another aspect, the present invention provides a pharmaceutical composition, which comprises an effective amount of the compound of the present invention, and the compound is represented by formula I, and pharmaceutically acceptable salts and solvates thereof, including hydrates, polymorphs, prodrugs, co-crystals, tautomers, stereoisomers,
wherein R is1: is H;
R2and R3Can be independently H, C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN；
R4Is a structure shown in the following formula
Figure 766229DEST_PATH_IMAGE002
R9And R10Are optionally substituted aryl, and optionally substituted heteroaryl, which may be joined to form the structure shown below:
Figure 43626DEST_PATH_IMAGE003
wherein n and m may independently be 0-3, Q is O, S, SO2；
R5,R6Is H, or optionally substituted C1-8Alkyl, optionally substituted C2-8Alkenyl, optionally substituted heterocyclic group, optionally substituted C3-8A cycloalkyl group; wherein the substituents may be independent C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN；
R7,R8Can be independently H, C1-6An alkyl group;
R5、R7or R6、R8May be joined to form a 5-to 8-membered ring, for example a 6-membered ring, which may be carbocyclic or contain O, N heterocycles.
In another aspect, the present invention provides a pharmaceutical composition, which comprises an effective amount of the compound of the present invention, and the compound is represented by formula I, and pharmaceutically acceptable salts and solvates thereof, including hydrates, polymorphs, prodrugs, co-crystals, tautomers, stereoisomers,
wherein R is1: is H;
R2and R3Can be independently C1-6Alkyl, halogen, -CF3、-CN；
R4Is a structure shown in the following formula
Figure 601646DEST_PATH_IMAGE002
R9 And R10Are optionally substituted aryl, and optionally substituted heteroaryl, which may be joined to form the structure shown below:
Figure 927586DEST_PATH_IMAGE003
wherein n and m may independently be 0-3, Q is O, S;
R5,R6is H or is selected from optionally substituted C1-8Alkyl, optionally substituted C2-8Alkenyl, optionally substituted heterocyclic group, optionally substituted C3-8A cycloalkyl group; wherein the substituents may be independent C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN；
R7,R8Can be independently H, C1-6An alkyl group;
R5、R7or R6、R8May be linked to form a ring to form an optionally substituted cycloalkyl group.
In some embodiments of the invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle, or combination thereof.
In some embodiments, the pharmaceutical compositions provided herein further comprise one or more additional therapeutic agents.
In still other embodiments, the additional therapeutic agent is selected from an anti-influenza virus agent or a vaccine.
In other embodiments, the pharmaceutical composition may be in a liquid, solid, semi-solid, gel or spray dosage form.
In still other embodiments, the pharmaceutical composition of the present invention may comprise one or more agents that inhibit replication of influenza virus infection selected from the group consisting of neuraminidase inhibitors, M2 protein inhibitors, polymerase inhibitors, PB2Inhibitors, immunomodulators.
In still other embodiments, the pharmaceutical composition of the invention, wherein the additional therapeutic agent is Amantadine (Amantadine), Rimantadine (Rimantadine), Oseltamivir (Oseltamivir), Zanamivir (Zanamivir), Peramivir (Peramivir), Laninamivir (Laninamivir), Laninamivir Octanoate (Laninamivir Octanoate), Favipiravir (Favipiravir), Arbidol (Arbidol), Ribavirin (ribirin), Beraprost (Beraprost), stafurin, Ingavirin (Ingavirin), influenza enzyme (flase), drugs No. 1422050-75-6, JNJ-872, S-033188, influenza vaccines (e.g., FluMist, Quadrivalent), or combinations thereof.
In another aspect, the invention provides the use of the compound or the pharmaceutical composition for the manufacture of a medicament for the prevention, alleviation or treatment of a viral infectious disease in a patient.
In some embodiments, the viral infection is an influenza viral infection.
In some further embodiments, the present invention provides the use of the compound or the pharmaceutical composition for the manufacture of a medicament for inhibiting RNA polymerase of influenza virus.
In some further embodiments, the present invention provides the use of the compound or the pharmaceutical composition in the manufacture of a medicament for the inhibition of cap-dependent endonuclease (CEN).
Unless otherwise indicated, the present invention includes all compounds of the present invention and pharmaceutically acceptable salts, solvates, including hydrates, polymorphs, prodrugs, co-crystals, tautomers, stereoisomers thereof.
In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.
The compounds of the present invention also include the salt forms thereof, which are not necessarily pharmaceutically acceptable salts, but may be used for the preparation and/or purification of the compounds of the present invention and/or intermediates used in the isolation of isomers of the compounds of the present invention.
The compounds of the invention, including salts thereof, may also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present invention may form solvates, either inherently or by design, with pharmaceutically acceptable solvents (including water); thus, the invention also includes solvated and unsolvated forms thereof.
On the other hand, the compounds of the invention may contain several asymmetric centers or their racemic mixtures as generally described. The invention further comprises racemic mixtures, partial racemic mixtures and isolated enantiomers and diastereomers.
The compound of the present invention may exist in one of the possible isomers, rotamers, atropisomers, tautomers or mixtures thereof, and the present invention may further comprise the isomers, rotamers, atropisomers, tautomers or mixtures thereof, or partial mixtures or separated isomers, rotamers, atropisomers, tautomers of the compound of the present invention.
In another aspect, the invention relates to methods of preparation, isolation and purification of compounds encompassed by formula I.
The foregoing merely summarizes certain aspects of the invention and is not intended to be limiting. These and other aspects will be more fully described below.
Detailed description of the invention
Definitions and general 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 and all patent publications cited throughout the disclosure of the present invention are hereby incorporated by reference in their entirety.
The articles "a," "an," and "the" as used herein are intended to include "at least one" or "one or more" unless otherwise indicated or clearly contradicted by context. Thus, as used herein, the articles refer to articles of one or more than one (i.e., at least one) object. For example, "a component" refers to one or more components, i.e., there may be more than one component contemplated for use or use in embodiments of the described embodiments.
The term "subject" as used herein refers to an animal. Typically the animal is a mammal. Subjects also refer to primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, birds, and the like. In certain embodiments, the subject is a primate. In still other embodiments, the subject is a human.
The terms "subject" and "patient" as used herein are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds or mammals such as chickens, quails or turkeys), particularly "mammals" including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), and more particularly humans. In one embodiment, the subject is a non-human animal, such as a farm animal (e.g., a horse, cow, pig, or sheep) or a pet (e.g., a dog, cat, guinea pig, or rabbit). In other embodiments, the "patient" refers to a human.
All stereoisomeric forms of the compounds of the present invention, including but not limited to diastereomers, enantiomers, and atropisomers (atropisomers) and mixtures thereof, such as racemic mixtures, are also included within the scope of the present invention. Many organic compounds exist in an optically active form, i.e., they have the ability to rotate the plane of plane polarized light. When describing optically active compounds, the prefixes D and L or R and S are used to denote the absolute configuration of the molecule with respect to the chiral center (or centers) in the molecule. The prefixes d and l or (+) and (-) are the symbols used to specify the rotation of plane polarized light by the compound, where (-) or l indicates that the compound is left-handed. Compounds prefixed with (+) or d are dextrorotatory. For a given chemical structure, these stereoisomers are identical except that they are mirror images of each other. A particular stereoisomer may also be referred to as an enantiomer, and a mixture of such isomers is often referred to as a mixture of enantiomers. A 50:50 mixture of enantiomers is referred to as a racemic mixture or racemate, which may occur when there is no stereoselectivity or stereospecificity in the chemical reaction or process.
Depending on the choice of starting materials and process, the compounds according to the invention may be present as one of the possible isomers or as a mixture thereof, for example as the pure optical isomer, or as a mixture of isomers, for example as a mixture of racemic and non-corresponding isomers, depending on the number of asymmetric carbon atoms. Optically active (R) -or (S) -isomers can be prepared using chiral synthons or chiral preparations, or resolved using conventional techniques. If the compound contains a double bond, the substituents may be in the E or Z configuration; if the compound contains a disubstituted cycloalkyl group, the substituents of the cycloalkyl group may be in the cis or trans (cis-or trans-) configuration.
The term "stereoisomers" refers to compounds having the same chemical structure, but differing in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis/trans), atropisomers, and the like.
"solvate" of the present invention refers to an association of one or more solvent molecules with a compound of the present invention. Solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, aminoethanol. The term "hydrate" refers to an association of solvent molecules that is water.
As used herein, "pharmaceutically acceptable salts" refer to organic and inorganic salts of the compounds of the present invention. Pharmaceutically acceptable non-toxic acid salts include, but are not limited to, salts of inorganic acids formed by reaction with amino groups such as hydrochlorides, hydrobromides, phosphates, sulfates, perchlorates, and salts of organic acids such as acetates, oxalates, maleates, tartrates, citrates, succinates, malonates, or those obtained by other methods described in the literature above, such as ion exchange. Other pharmaceuticalsThe above-acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, cyclopentylpropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxy-ethanesulfonates, lactobionates, lactates, laurates, malates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, palmitates, pamoates, pectinates, persulfates, 3-phenylpropionates, picrates, pivalates, propionates, stearates, thiocyanate, p-toluenesulfonate, undecanoate, valerate, and the like. Salts obtained with appropriate bases include alkali metals, alkaline earth metals, ammonium and N+(C1-4Alkyl radical)4A salt. The present invention also contemplates quaternary ammonium salts formed from compounds containing groups of N. Water-soluble or oil-soluble or dispersion products can be obtained by quaternization. Alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Pharmaceutically acceptable salts further include suitable, non-toxic ammonium, quaternary ammonium salts and amine cations resistant to formation of counterions, such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, C1-8Sulfonates and aromatic sulfonates.
The term "prodrug", as used herein, represents a compound that is converted in vivo to a compound of formula (I). Such conversion is effected by hydrolysis of the prodrug in the blood or by enzymatic conversion to the parent structure in the blood or tissue. The prodrug compound of the invention can be ester, and in the prior invention, the ester can be used as the prodrug and comprises phenyl ester and aliphatic (C)1-24) Esters, acyloxymethyl esters, carbonates, carbamates and amino acid esters. For example, a compound of the present invention contains a hydroxy group, i.e., it can be acylated to provide the compound in prodrug form. Other prodrug forms include phosphate estersThese phosphate compounds are obtained by phosphorylation of hydroxyl groups on the parent substance.
Any asymmetric atom (e.g., carbon, etc.) of a compound of the invention can exist in racemic or enantiomerically enriched forms, such as the (R) -, (S) -, (R, R) -, (S, S) -, (S, R) -or (R, S) -configurations. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess in the (R) -or (S) -configuration. The substituents on the atoms having an unsaturated double bond may be present in the- (Z) -or- (E) -form, if possible.
As described herein, the compounds of the present invention may be optionally substituted with one or more substituents, such as those of the general formula above, or as specifically exemplified, sub-classes, and classes of compounds encompassed by the present invention, within the examples. It will be appreciated that the terms "optionally substituted" and "unsubstituted or substituted with … … substituents" are used interchangeably. The terms "optionally," "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. In general, the term "optionally" whether preceded by the term "substituted" or not, indicates that one or more hydrogen atoms in a given structure are unsubstituted or substituted with a particular substituent. Unless otherwise indicated, an optional substituent group may be substituted at each substitutable position of the group. When more than one position in a given formula can be substituted with one or more substituents selected from a particular group, the substituents may be substituted at each position, identically or differently. Wherein the substituent can be, but is not limited to, F, Cl, Br, I, CN, N3、OH、NH2、NO2Oxo (═ O), C1-12Alkyl radical, C1-6Haloalkyl, C1-6Alkoxy radical, C1-6Alkylamino radical, C2-6Alkenyl radical, C2-6Alkynyl, C3-12Cycloalkyl radical, C3-12cycloalkyl-C1-4Alkylene radical, C3-12Carbocyclyl, C3-12carbocyclyl-C1-4Alkylene, heterocyclic group consisting of 3 to 12 atoms, (heterocyclic group consisting of 3 to 12 atoms) -C1-4Alkylene radical, C6-10Aryl radical, C6-10aryl-C1-4Alkylene, heteroaryl of 5 to 16 atoms or (heteroaryl of 5 to 16 atoms) -C1-4An alkylene group.
In the various parts of this specification, substituents of the disclosed compounds are disclosed in terms of group type or range. It is specifically intended that the invention includes each and every independent subcombination of the various members of these groups and ranges. For example, the term "C1-6Alkyl "in particular denotes independently disclosed methyl, ethyl, C3Alkyl radical, C4Alkyl radical, C5Alkyl and C6An alkyl group; the term "heteroaryl of 5 to 10 atoms" refers in particular to heteroaryl of 5 atoms, heteroaryl of 6 atoms, heteroaryl of 7 atoms, heteroaryl of 8 atoms, heteroaryl of 9 atoms and heteroaryl of 10 atoms, which are independently disclosed.
The term "alkyl" as used herein, denotes a saturated straight or branched chain monovalent hydrocarbon radical containing from 1 to 20 carbon atoms. Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-1-butyl, 2-methyl-1-butyl, n-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2, 3-dimethyl-2-butyl, 3, 3-dimethyl-2-butyl, n-heptyl, n-octyl, and the like, wherein the alkyl groups can be independently unsubstituted or substituted with one or more substituents described herein.
The term "alkyl" and its prefix "alk", as used herein, are intended to encompass both straight and branched saturated carbon chains.
The term "cycloalkyl" refers to a monocyclic, bicyclic, or tricyclic ring system containing 3-6 ring carbon atoms that is saturated, having one or more points of attachment to the rest of the molecule. In some embodiments, cycloalkyl is a ring system containing 3 to 6 ring carbon atoms, e.g., C3-6A cycloalkyl group; in some embodiments, cycloalkyl is a ring system containing 5 to 6 ring carbon atoms, e.g., C5-6A cycloalkyl group; examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like, and the cycloalkyl groups can independently be unsubstituted or substituted with one or more substituents described herein.
The term "heterocyclyl" may be used alone or as a majority of "heterocyclylalkyl" or "heterocyclylalkoxy" and refers to a saturated or partially unsaturated, non-aromatic, monocyclic, bicyclic, or tricyclic ring system containing 3 to 12 ring atoms, wherein at least one ring atom is selected from the group consisting of nitrogen, sulfur, and oxygen, wherein the heterocyclyl is non-aromatic and does not contain any aromatic rings, and wherein the ring system has one or more attachment points to the rest of the molecule. The terms "heterocyclyl" and "heterocycle" are used interchangeably herein. The term "heterocyclyl" includes monocyclic, bicyclic or polycyclic fused, spiro or bridged heterocyclic ring systems. Bicyclic heterocyclic groups include bridged bicyclic heterocyclic groups, fused bicyclic heterocyclic groups, and spiro bicyclic heterocyclic groups. In some embodiments, heterocyclyl is a ring system of 3-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 3-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-7 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 6-8 ring atoms; in other embodiments, heterocyclyl is a ring system of 5-6 ring atoms; in other embodiments, heterocyclyl is a ring system of 4 ring atoms; in other embodiments, heterocyclyl is a ring system of 5 ring atoms; in other embodiments, heterocyclyl is a ring system of 6 ring atoms; in other embodiments, heterocyclyl is a ring system of 7 ring atoms; in other embodiments, heterocyclyl is a ring system of 8 ring atoms.
Examples of heterocyclyl groups include, but are not limited to: oxirane, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, dihydrothienyl, 1, 3-dioxolanyl, dithiocyclopentyl, tetrahydropyranyl, dihydropyranyl, 2H-pyranyl, 4H-pyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, dioxanyl, dithianyl, thiaoxanyl, homopiperazinyl, homopiperidinyl, oxepanyl, thietanyl. In heterocyclic radicals of-CH2Examples of-groups substituted by-C (═ O) -include, but are not limited to, 2-oxopyrrolidinyl, oxo-1, 3-thiazolidinyl, 2-piperidinonyl, 3, 5-dioxopiperidinyl, pyrimidinedione. Examples of heterocyclic sulfur atoms that are oxidized include, but are not limited to, sulfolane and 1, 1-dioxothiomorpholinyl. Bridging heterocyclyl groups include, but are not limited to, 2-oxabicyclo [2.2.2]Octyl, 1-azabicyclo [2.2.2]Octyl, 3-azabicyclo [3.2.1]Octyl, and the like. The heterocyclyl group may be optionally substituted with one or more substituents as described herein.
The term "aryl" may be used alone or as a majority of "arylalkyl" or "arylalkoxy" and refers to monocyclic, bicyclic, and tricyclic aromatic carbocyclic ring systems containing 6 to 14 ring atoms, or 6 to 12 ring atoms, or 6 to 10 ring atoms, wherein at least one ring system is aromatic, each ring contains 3 to 7 ring atoms, and one or more attachment points are attached to the rest of the molecule. The term "aryl" may be used interchangeably with the terms "aromatic ring" or "aromatic ring", e.g., aryl may include phenyl, naphthyl and anthracenyl. The aryl group can be independently unsubstituted or substituted with one or more substituents described herein.
The term "heteroaryl" may be used alone or as"Heteroarylalkyls" or a majority of "heteroarylalkoxys" refer to monocyclic, bicyclic, and tricyclic aromatic systems containing 5 to 16 ring atoms, or 5 to 14 ring atoms, or 5 to 12 ring atoms, or 5 to 10 ring atoms, or 5 to 8 ring atoms, or 5 to 7 ring atoms, or 5 to 6 ring atoms, wherein at least one ring system is aromatic and at least one ring contains one or more heteroatoms, wherein each ring contains 5 to 7 ring atoms, and wherein the heteroaryl group has one or more attachment points to the rest of the molecule. when-CH is present in the heteroaryl group2When it is a group, -CH2-the group may optionally be replaced by-C (═ O) -. Unless otherwise indicated, the heteroaryl group may be attached to the rest of the molecule (e.g., the main structure in the general formula) via any reasonable site (which may be C in CH, or N in NH). The term "heteroaryl" may be used interchangeably with the terms "heteroaromatic ring" or "heteroaromatic compound". In some embodiments, heteroaryl is 5-14 atom composed of 1,2,3, or 4 heteroatoms independently selected from O, S, and N. In other embodiments, heteroaryl is a heteroaryl consisting of 5 to 12 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a heteroaryl consisting of 5 to 10 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a heteroaryl consisting of 5 to 8 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a heteroaryl consisting of 5 to 7 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a heteroaryl consisting of 5 to 6 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a heteroaryl consisting of 5 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N; in other embodiments, heteroaryl is a heteroaryl consisting of 6 atoms containing 1,2,3, or 4 heteroatoms independently selected from O, S, and N.
In other embodiments, heteroaryl includes, but is not limited to, the following monocyclic groups: 2-furyl group, 3-furyl group, N-imidazolyl group, 2-imidazolyl group, 4-imidazolyl group, 5-imidazolyl group, 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, 2-oxazolyl group, 4-oxazolyl group, 5-oxazolyl group, N-pyrrolyl group, 2-pyrrolyl group, 3-pyrrolyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-pyrimidinyl group, 4-pyrimidinyl group, 5-pyrimidinyl group, pyridazinyl group (e.g., 3-pyridazinyl group), 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, tetrazolyl group (e.g., 5H-tetrazolyl group, 2H-tetrazolyl group), triazolyl group (e.g., 2-triazolyl group, 5-triazolyl group, 4H-1,2, 4-triazolyl, 1H-1,2, 4-triazolyl, 1,2, 3-triazolyl), 2-thienyl, 3-thienyl, pyrazolyl (e.g. 2-pyrazolyl and 3-pyrazolyl), isothiazolyl, 1,2, 3-oxadiazolyl, 1,2, 5-oxadiazolyl, 1,2, 4-oxadiazolyl, 1,3, 4-oxadiazolyl, 1,2, 3-thiadiazolyl, 1,3, 4-thiadiazolyl, 1,2, 5-thiadiazolyl, pyrazinyl, 1,3, 5-triazinyl; the following bi-or tricyclic groups are also included, but are in no way limited to these groups: indolinyl, 1,2,3, 4-tetrahydroisoquinolinyl, 4,5,6, 7-tetrahydrobenzofuranyl, benzimidazolyl, benzofuranyl, benzothienyl, indolyl (e.g., 2-indolyl), purinyl, quinolinyl (e.g., 2-quinolinyl, 3-quinolinyl, 4-quinolinyl), isoquinolinyl (e.g., 1-isoquinolinyl, 3-isoquinolinyl, or 4-isoquinolinyl), phenoxathiyl, dibenzoimidazolyl, dibenzofuranyl, dibenzothienyl, said heteroaryl group optionally being substituted with one or more substituents as described herein.
As used herein, the term "pharmaceutically acceptable carrier" includes any solvent, dispersion medium, coating, surfactant, antioxidant, preservative (e.g., antibacterial, antifungal), isotonic agent, salt, pharmaceutical stabilizer, binder, excipient, dispersant, lubricant, sweetener, flavoring agent, coloring agent, or combination thereof, which are known to those skilled in the art. Except insofar as any conventional carrier is incompatible with the active ingredient, its use in therapeutic or pharmaceutical compositions is contemplated.
The term "effective amount" of a compound of the invention refers to an amount that elicits the desired biological response. In the present invention, the biological response is expected to be inhibition of influenza virus replication, reduction in the amount of influenza virus or reduction or amelioration of the severity, duration, progression or onset of influenza virus infection, prevention of spread of influenza virus infection, prevention of recurrence, evolution, onset or progression of symptoms associated with influenza virus infection, or enhancement of the prophylactic or therapeutic effect of another anti-influenza infection therapy used. The exact amount of the compound to be administered to a subject will depend on the mode of administration, the type and severity of the infection and the characteristics of the subject, such as health, age, sex, weight and tolerance to drugs. The skilled artisan will be able to determine the appropriate dosage based on these and other factors. When administered in combination with other antiviral agents, such as anti-influenza drugs, the "effective amount" of the second agent will depend on the type of drug used. Suitable dosages of approved agents are known and can be adjusted by the skilled artisan according to the condition of the subject, the type of condition being treated and the amount of the compound of the invention being used. In the case where amounts are not explicitly specified, an effective amount should be taken. For example, a compound of the invention may be administered to a subject at a dosage in the range of about 0.01-100 mg/body weight/day for therapeutic or prophylactic treatment.
The term "treatment" as used herein refers to both therapeutic and prophylactic treatment. For example, therapeutic treatment includes reducing or ameliorating the progression, severity, and/or duration of an influenza virus-mediated condition, or ameliorating one or more symptoms (particularly, one or more discernible symptoms) of an influenza virus-mediated condition as a result of administration of one or more therapies (e.g., one or more therapeutic agents (e.g., compounds and compositions of the invention)) The days they were ill.
In other embodiments, the present invention relates to a compound, but is in no way limited to, one of the following, or a stereoisomer, tautomer, nitrogen oxide, solvate, metabolite, pharmaceutically acceptable salt or prodrug thereof: (specific Compound)
In another aspect, the invention provides a pharmaceutical composition comprising an effective amount of a compound of the invention.
In some embodiments of the invention, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier, adjuvant, vehicle, or combination thereof.
In some embodiments, the pharmaceutical compositions provided herein further comprise a second agent.
In still other embodiments, the second agent is one or more agents that inhibit replication of influenza virus infection selected from the group consisting of neuraminidase inhibitors, M2 protein inhibitors, polymerase inhibitors, PB2 inhibitors, zanamivir, oseltamivir, peramivir, laninamivir octanoate, faviravir, immunomodulators, beraprost, ribavirin.
In another aspect, the invention provides the use of the compound or the pharmaceutical composition for the manufacture of a medicament for the prevention, treatment or alleviation of a viral infectious disease in a patient.
In some embodiments, the viral infection is an influenza viral infection.
In some further embodiments, the present invention provides the use of the compound or the pharmaceutical composition for the manufacture of a medicament for inhibiting RNA polymerase of influenza virus.
In some further embodiments, the present invention provides the use of the compound or the pharmaceutical composition in the manufacture of a medicament for the inhibition of cap-dependent endonuclease (CEN).
In some embodiments, the salt refers to a pharmaceutically acceptable salt. The term "pharmaceutically acceptable" means that the substance or composition must be chemically and/or toxicologically compatible with the other ingredients comprising the formulation and/or the mammal being treated therewith.
The compounds of the present invention also include other salts of such compounds, which are not necessarily pharmaceutically acceptable salts, and which may be useful as intermediates for the preparation and/or purification of the compounds of the present invention and/or for the isolation of enantiomers of the compounds of the present invention.
Pharmaceutically acceptable acid addition salts may be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlorotheophylline, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, methanesulfonate, methylsulfate, naphthoate, naphthalenesulfonate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate/biphosphate/dihydrogen phosphate, dihydrogenphosphate, and the like, Polysilonolactates, propionates, stearates, succinates, sulfosalicylates, tartrates, tosylates and trifluoroacetates.
Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, sulfosalicylic acid, and the like.
Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
Inorganic bases from which salts can be derived include, for example, ammonium salts and metals of groups I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts.
Organic bases from which salts can be derived include primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include, for example, isopropylamine, benzathine, choline salts, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound, basic or acidic moiety, by conventional chemical methods. In general, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of the appropriate base (e.g., Na, Ca, Mg, or K hydroxide, carbonate, bicarbonate, etc.), or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are usually carried out in water or an organic solvent or a mixture of both. Generally, where appropriate, it is desirable to use a non-aqueous medium such as diethyl ether, ethyl acetate, ethanol, isopropanol or acetonitrile.
Furthermore, the compounds of the present invention, including salts thereof, may also be obtained in the form of their hydrates or include other solvents used for their crystallization. The compounds of the present invention may form solvates, either inherently or by design, with pharmaceutically acceptable solvents (including water); thus, the present invention is intended to include both solvated and unsolvated forms.
Compositions, formulations and administration of the compounds of the invention
The invention provides a pharmaceutical composition which comprises a compound shown as a formula (I), a formula (I-a) or a formula (I-b) or a stereoisomer, a racemic or non-racemic mixture of isomers or a pharmaceutically acceptable salt or solvate thereof. The pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier, diluent, adjuvant or vehicle, and optionally, other therapeutic and/or prophylactic ingredients. In some embodiments, the pharmaceutical composition comprises an effective amount of at least one pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle.
Pharmaceutically acceptable carriers may contain inert ingredients that do not unduly inhibit the biological activity of the compound. The pharmaceutically acceptable carrier should be biocompatible, e.g., non-toxic, non-inflammatory, non-immunogenic, or free of other adverse or side effects once administered to a patient. Standard pharmaceutical techniques may be employed.
The pharmaceutical composition or pharmaceutically acceptable composition of the present invention further comprises a pharmaceutically acceptable carrier, adjuvant or excipient, as described herein, including any solvent, diluent, liquid excipient, dispersant, suspending agent, surfactant, isotonic agent, thickener, emulsifier, preservative, solid binder or lubricant, and the like, as appropriate for the particular intended dosage form, as used herein. In addition to conventional carrier vehicles which are incompatible with the compounds of the present invention, e.g., may produce undesirable biological effects or may deleteriously interact with any other component of the pharmaceutically acceptable composition, any other conventional carrier vehicle and its use are contemplated by the present invention.
Some examples of substances that may be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., tween 80, phosphate, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (e.g., protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, or zinc salts), silica gel, magnesium trisilicate, polyvinyl pyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block copolymers, methylcellulose, hydroxypropylmethylcellulose, lanolin, sugars (e.g., lactose, glucose, and sucrose), starches (e.g., corn starch and potato starch), celluloses and derivatives thereof (e.g., sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate), Powdered tragacanth, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol or polyethylene glycol), esters (such as ethyl oleate and ethyl dodecanoate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol and phosphate buffers, as well as other non-toxic compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), as well as coloring agents, detackifiers, coating agents, sweetening and flavoring agents, preservatives and antioxidants, according to the judgment of the formulator, may also be present in the composition.
The compounds or compositions of the present invention may be administered by any suitable means, and the above-described compounds and pharmaceutically acceptable compositions may be administered to humans or other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally as an oral or nasal spray, and the like, depending on the severity of the infection being treated.
Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Injectable preparations may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents, for example sterile injectable aqueous or oily suspensions. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution, u.s.p. and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids, such as octadecenoic acid, are used in the preparation of injections.
For example, injectable formulations can be sterilized by filtration through a bacteria retaining filter or by the addition of a sterilizing agent in the form of a sterile solid composition which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
To prolong the effect of the compounds or compositions of the present invention, it is often desirable to slow the absorption of the compounds from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of the compound then depends on its rate of dissolution, which in turn depends on crystal size and crystal form. Alternatively, delayed absorption of the parenterally administered compound is achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming a microcapsule matrix of the compound in a biodegradable polymer such as polylactide-polyglycolic acid. Depending on the ratio of compound to polymer and the nature of the particular polymer employed, the rate of release of the compound can be controlled. Examples of other biodegradable polymers include polyorthoesters and polyanhydrides. Depot injectable formulations can also be prepared by entrapping the compound in liposomes or microemulsions which are compatible with body tissues.
Oral solid dosage forms include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders, such as carboxymethylcellulose, alginates, gels, polyvinylpyrrolidone, sucrose, and acacia, c) humectants, such as glycerol, d) disintegrating agents, such as agar- -agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents, such as paraffin, f) absorption accelerators, such as quaternary ammonium compounds, g) wetting agents, such as cetyl alcohol and glycerol monostearate, h) absorbents, such as kaolin and bentonite, and i) lubricants, such as talc, calcium stearate, sodium stearate, and sodium stearate, magnesium, Magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical art. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard gelatin capsules using excipients such as lactose or milk sugar as well as high molecular weight polyethylene glycols.
The active compound may also be in the form of a microencapsulated form with one or more of the above-mentioned excipients. Solid dosage forms of tablets, dragees, capsules, pills and granules can be prepared with coatings and shells such as enteric coatings, controlled release coatings and other coatings well known in the pharmaceutical art. In such solid dosage forms, the active compound may be mixed with at least one inert diluent, for example sucrose, lactose or starch. In general, such dosage forms may also contain additional substances in addition to the inert diluents, such as tableting lubricants and other tableting aids, for example magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and may also have the properties of a composition such that the active ingredient is released only, optionally in a delayed manner, or preferably, in a certain part of the intestinal tract. Examples of embedding compositions that can be used include polymers and waxes.
Formulations for topical or transdermal administration of the compounds of the present invention include ointments, salves, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. Under sterile conditions, the active compound is combined with a pharmaceutically acceptable carrier and any required preservatives or buffers that may be required. Ophthalmic formulations, ear drops and eye drops are also contemplated within the scope of the present invention. In addition, the present invention contemplates the use of a dermal patch that has the added advantage of providing controlled delivery of the compound to the body. Such dosage forms may be made by dissolving or dispersing the compound in the appropriate medium. Absorption enhancers may also be used to increase the flux of the compound through the skin. The rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
The compositions of the present invention may also be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted kit. The term "parenteral" as used herein includes, but is not limited to, subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. In particular, the compositions are administered orally, intraperitoneally, or intravenously.
The sterile injectable form of the composition of the invention may be an aqueous or oily suspension. These suspensions may be prepared using suitable dispersing or wetting agents and suspending agents following techniques known in the art. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, as natural pharmaceutically acceptable oils, such as olive oil or castor oil, especially in polyoxyethylated form, fatty acids, such as octadecenoic acid and its glyceride derivatives are used for the preparation of injections. These oil solutions or suspensions may also contain a long chain alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents commonly used in formulating pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants such as Tweens, Spans, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for formulation purposes.
The pharmaceutical compositions of the present invention may be administered orally in any orally acceptable dosage form, including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In the case of tablets for oral administration, carriers that are commonly used include, but are not limited to, lactose and starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are required for oral administration, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening, flavoring or coloring agents may also be added.
For topical application, the pharmaceutical compositions may be formulated as a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers. Suitable carriers for topical application of the compounds of the present invention include, but are not limited to, mineral oil, petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, the pharmaceutical compositions may be formulated as a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
For ophthalmic use, the pharmaceutical compositions may be formulated as micronized suspensions in isotonic pH adjusted sterile saline, or solutions in isotonic pH adjusted sterile saline in particular, with or without preservatives such as benzalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutical composition may be formulated as an ointment, such as petrolatum.
The pharmaceutical compositions may also be administered by nasal aerosol spray or inhalation. Such compositions are prepared according to techniques well known in the pharmaceutical art and are prepared as solutions in saline using benzyl alcohol and other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons and/or other conventional solubilizing or dispersing agents.
The compounds for use in the methods of the invention may be formulated in unit dosage form. The term "unit dosage form" refers to physically discrete units suitable as unitary dosages for subjects, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, optionally in association with a suitable pharmaceutical carrier. The unit dosage form can be administered in a single daily dose or in multiple daily doses (e.g., about 1-4 or more times per day). When multiple daily doses are used, the unit dosage form for each dose may be the same or different.
In summary, the present invention provides the use of said compound or said pharmaceutical composition for the manufacture of a medicament for the inhibition of cap-dependent endonuclease (CEN). The compound of the invention is suitable for being prepared into medicines with various dosage forms, and can be widely used for treating seasonal influenza, avian influenza, swine influenza and influenza virus mutant strains with drug resistance to tamiflu.
In addition to being beneficial for human therapy, the compounds and pharmaceutical compositions of the present invention may also find application in veterinary therapy for pets, animals of the introduced species and mammals in farm animals. Examples of other animals include horses, dogs, and cats. Herein, the compound of the present invention includes pharmaceutically acceptable derivatives thereof.
Advantages of the compounds of the invention: compared with the existing similar compounds, the compound of the invention has larger difference in structure, not only can well inhibit influenza virus, but also has lower cytotoxicity, and more excellent in vivo pharmacokinetic property and in vivo pharmacodynamic property. In addition, compared with the existing similar compounds, the compound provided by the invention has better drugability.
Detailed Description
To illustrate the invention, the following examples are set forth. It is to be understood that the invention is not limited to these embodiments, but is provided as a means of practicing the invention.
In this specification, a structure is dominant if there is any difference between the chemical name and the chemical structure.
In general, the compounds of the present invention may be prepared by the methods described herein, wherein the substituents are as defined in formula I, unless otherwise specified. The following reaction schemes and examples serve to further illustrate the context of the invention.
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention.
Preparation examples
In the following preparation examples, the inventors described in detail the preparation of the compounds of the present invention by taking some of the compounds of the present invention as examples.
Synthesis of intermediates
Synthesis of substituted-dibenzothiazepine:
1.4-chloro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-one (Compound 1)
Figure 215347DEST_PATH_IMAGE004
Compound 1a (1.34 g, 10 mmol) was dissolved in DMF (20 mL), 2-chlorothiophenol (1.44 g, 10 mmol) and potassium carbonate (2.76 g, 20 mmol) were added, and the mixture was stirred in an oil bath at 150 ℃ for 4 hours. After cooling to room temperature, 200mL of ice-water was added, and the mixture was washed with ethyl acetate (100 mL. times.2). And adjusting the pH of the water phase to 7 by using a 2N HCl solution, and adjusting the pH to 3-4 by using a 2N HCl solution. Extraction with ethyl acetate (70 mL. times.3), combination of the organic phases, washing with saturated brine (100 mL. times.2), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave a yellow solid. Ethyl acetate-petroleum ether recrystallization and drying gave the compound 1b 2.14 g as a white solid, yield: 76.8 percent.
Compound 1b (500 mg, 1.79 mmol) and polyphosphoric acid (12 g) were mixed well and heated in an oil bath at 120 ℃ for 3 hours. After cooling to room temperature, 100mL of ice-water was added, and the mixture was stirred to completely dissolve the viscous substance, followed by extraction with ethyl acetate (30 mL. times.3). The organic phases were combined, washed successively with a saturated sodium carbonate solution (50 mL. times.2) and a saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 20/1) to obtain a white solid compound 1 (b = c)Nuclear magnetic confirmed structure) 280 mg, yield: 60.0 percent.1H NMR (500 MHz, CDCl3) δ(ppm) 8.13 (dd, J = 8.5, 1.0 Hz, 1 H), 7.51-7.46 (m, 3 H), 7.35 (td, J = 7.5, 1.0 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 1 H), 7.21 (t, J = 8.0 Hz, 1 H), 4.08 (s, 2 H)。
2.4-chloro-8-fluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-one (Compound 2)
Figure 666576DEST_PATH_IMAGE005
Compound 2a (6.17 g, 40 mmol) was dissolved in DMF (30 mL), potassium carbonate (16.58 g, 0.12 mol) was added and stirred at room temperature for 45 min. Iodothane (4.8 mL, 60 mmol) was added dropwise, stirring was continued and the reaction was allowed to proceed overnight. Adding 150 mL of ethyl acetate and 150 mL of water, shaking uniformly, and separating an organic layer; the aqueous layer was extracted with ethyl acetate (75 mL. times.2). The organic phases were combined, washed with saturated brine (150 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow liquid. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 50/1) gave 6.26g of the colorless liquid compound 2b, yield: 85.8 percent.
Compound 2b (1.82 g, 10 mmol) was dissolved in dichloromethane (15 mL), water (15 mL) was added, and the mixture was stirred at room temperature. Adding bromine (513) dropwise in sequenceμL, 10 mmol) and 30% hydrogen peroxide (1 mL), and the mixture is stirred continuously and reacted for 24 hours. Adding 15 mL of dichloromethane, shaking uniformly, and separating an organic layer; the aqueous layer was extracted with dichloromethane (15 mL. times.2). The organic phases were combined, washed with saturated brine (30 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow liquid. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 40/1) gave 2.32g of the colorless liquid compound 2c, yield: 90.0 percent.
Compound 2c (2.32 g, 8.89 mmol) was dissolved in DMF (20 mL), potassium carbonate (2.46 g, 17.77 mmol) was added, 2-chlorothiophenol (1.01 mL, 8.89 mmol) was added dropwise, and the mixture was stirred at room temperature for 45 min. Then heating and stirring the mixture in an oil bath at the temperature of 60 ℃,the reaction was allowed to proceed overnight. Cooling to room temperature, adding 120 mL of ethyl acetate and 120 mL of water, shaking uniformly, and separating an organic layer; the aqueous layer was extracted with ethyl acetate (60 mL. times.2). The organic phases were combined, washed with saturated brine (120 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow liquid. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 40/1) gave 1.94 g of compound 2d (nuclear magnetic confirmed structure) as a colorless liquid, yield: 67.2 percent.1H NMR (500 MHz, CDCl3) δ(ppm) 7.98 (dd, J = 8.5, 6.0 Hz, 1 H), 7.39-7.37 (m, 1 H), 7.22-7.20 (m, 1 H), 7.15-7.12 (m, 2 H), 7.00-6.95 (m, 2 H), 4.56 (s, 2 H), 4.36 (q, J = 7.0 Hz, 2 H), 1.39 (t, J = 7.0 Hz, 3 H)。
Compound 2d (552 mg, 1.7 mmol) was dissolved in methanol (3 mL), tetrahydrofuran (6 mL) was added, and a sodium hydroxide solution (prepared by dissolving sodium hydroxide (703 mg, 17.56 mmol) in water (6 mL)) was added dropwise and stirred at room temperature for 4 hours. And (3) evaporating the organic solvent under reduced pressure, adjusting the pH to 7 by using a 2N HCl solution, and adjusting the pH to 3-4 by using the 2N HCl solution. Extraction with ethyl acetate (15 mL × 3), combination of organic phases, washing with saturated brine (20mL × 2), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave the compound 2e 430 mg as a yellow solid, yield: 85.3 percent.
Compound 2e (500 mg, 1.68 mmol) and polyphosphoric acid (12 g) were mixed well and heated in an oil bath at 120 ℃ for 4 hours. After cooling to room temperature, 100mL of ice-water was added, and the mixture was stirred to completely dissolve the viscous substance, followed by extraction with ethyl acetate (30 mL. times.3). The organic phases were combined, washed successively with a saturated sodium carbonate solution (50 mL. times.2) and a saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 20/1) to obtain 300 mg of compound 2 (nuclear magnetic confirmed structure) as a white solid, yield: and (3.9).1H NMR (500 MHz, CDCl3) δ(ppm) 8.16 (d, J = 8.0 Hz, 1 H), 7.57-7.54 (m, 1 H), 7.51 (d, J = 7.5 Hz, 1 H), 7.23 (td, J = 8.0, 1.0 Hz, 1 H), 7.04 (td, J = 8.0, 1.5 Hz, 1 H), 6.95 (dd, J = 9.0, 2.0 Hz, 1 H), 4.04 (s, 2 H)。
3.4-chloro-7-fluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-one (Compound 3)
Figure 180734DEST_PATH_IMAGE006
Compound 3a (6.17 g, 40 mmol) was dissolved in DMF (30 mL), potassium carbonate (16.58 g, 0.12 mol) was added and stirred at room temperature for 45 min. Iodothane (4.8 mL, 60 mmol) was added dropwise, stirring was continued and the reaction was allowed to proceed overnight. Adding 150 mL of ethyl acetate and 150 mL of water, shaking uniformly, and separating an organic layer; the aqueous layer was extracted with ethyl acetate (75 mL. times.2). The organic phases were combined, washed with saturated brine (150 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow liquid. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 20/1) gave 6.65g of the colorless liquid compound 3b, yield: 91.2 percent.
Compound 3b (1.82 g, 10 mmol) was dissolved in 1, 2-dichloroethane (25 mL). N-bromosuccinimide (1.96 g, 11 mmol) and azobisisobutyronitrile (164.2 mg, 1 mmol) were added in this order, and the mixture was heated and stirred in an oil bath at 90 ℃ for 6 hours. Cooling to room temperature, filtering, and evaporating the filtrate under reduced pressure. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 20/1) gave 2.13g of the colorless liquid compound 3c, yield: 81.7 percent.
Compound 3c (2.32 g, 8.89 mmol) was dissolved in DMF (20 mL), potassium carbonate (2.46 g, 17.77 mmol) was added, 2-chlorothiophenol (1.01 mL, 8.89 mmol) was added dropwise, and the mixture was stirred at room temperature for 45 min. Then, the mixture was heated and stirred in an oil bath at 60 ℃ to react overnight. Cooling to room temperature, adding 120 mL of ethyl acetate and 120 mL of water, shaking uniformly, and separating an organic layer; the aqueous layer was extracted with ethyl acetate (60 mL. times.2). The organic phases were combined, washed with saturated brine (120 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow liquid. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 40/1) gave 1.94 g of the colorless liquid compound 3d, yield: 67.2 percent.
Compound 3d (1.32 g, 4.06 mmol) was dissolved in methanol (8 mL), tetrahydrofuran (16 mL) was added, and sodium hydroxide solution (prepared by dissolving sodium hydroxide (1.69 g, 42.27 mmol) in water (16 mL) was added dropwise and stirred at room temperature for 4 hours. And (3) evaporating the organic solvent under reduced pressure, adjusting the pH to 7 by using a 2N HCl solution, and adjusting the pH to 3-4 by using the 2N HCl solution. Extraction with ethyl acetate (30 mL × 3), combination of organic phases, washing with saturated brine (50 mL × 2), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave 1.12 g of compound 3e as a yellow solid, yield: 92.9 percent.
Compound 3e (600 mg, 2.02 mmol) and polyphosphoric acid (18 g) were mixed well and heated in an oil bath at 120 ℃ for 4 hours. After cooling to room temperature, 120 mL of ice-water was added, and the mixture was stirred to completely dissolve the viscous substance, followed by extraction with ethyl acetate (40 mL. times.3). The organic phases were combined, washed successively with a saturated sodium carbonate solution (60 mL. times.2) and a saturated brine (60 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 20/1) to obtain 305 mg of compound 3 (nuclear magnetic confirmed structure) as a white solid, yield: 54.1 percent.1H NMR (500 MHz, CDCl3) δ(ppm) 8.08 (dd, J = 8.0, 1.5 Hz, 1 H), 7.51 (dd, J = 7.5, 1.5 Hz, 1 H), 7.32-7.28 (m, 2 H), 7.25-7.20 (m, 2 H), 4.14 (s, 2 H)。
4.4-fluoro-8-fluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-one (Compound 4)
Figure 434998DEST_PATH_IMAGE007
Compound 4a (2.08 g, 8.0 mmol) was dissolved in DMF (20 mL), potassium carbonate (2.36 g, 16.0 mmol) was added, and 2-fluorobenzothiophenol (900) was added dropwiseμL, 4.2 mmol), stirred at room temperature for 45 min. Then, the mixture was heated and stirred in an oil bath at 60 ℃ to react overnight. Cooling to room temperature, adding 120 mL of ethyl acetate and 120 mL of water, shaking uniformly, and separating an organic layer; the aqueous layer was extracted with ethyl acetate (60 mL. times.2). The organic phases were combined, washed with saturated brine (120 mL. times.2),drying with anhydrous sodium sulfate, filtering, and concentrating the filtrate under reduced pressure to obtain yellow liquid. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 40/1) gave 1.34 g of colorless liquid compound 4b (nuclear magnetic confirmed structure), yield: 54.6.%.1H NMR (500 MHz, CDCl3) δ(ppm) 7.95 (dd, J = 8.5, 6.0 Hz, 1 H), 7.26-7.21 (m, 2 H), 7.05 (t, J = 8.5 Hz, 1 H), 7.00 (td, J = 7.5, 1.0 Hz, 1 H), 6.95-6.92 (m, 1 H), 6.84 (dd, J = 9.5, 2.5 Hz, 1 H), 4.48 (s, 2 H), 4.36 (q, J = 7.0 Hz, 2 H), 1.39 (t, J = 7.0 Hz, 3 H).
Compound 4b (1.34 g, 4.35 mmol) was dissolved in methanol (8 mL), tetrahydrofuran (16 mL) was added, and sodium hydroxide solution (prepared by dissolving sodium hydroxide (1.81 g, 45.2 mmol) in water (16 mL)) was added dropwise and stirred at room temperature for 4 hours. And (3) evaporating the organic solvent under reduced pressure, adjusting the pH to 7 by using a 2N HCl solution, and adjusting the pH to 3-4 by using the 2N HCl solution. Extraction with ethyl acetate (20mL × 3), combination of organic phases, washing with saturated brine (30 mL × 2), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave yellow solid compound 4c 1.10 g, yield: 90.3 percent.
Compound 4c (600 mg, 2.14 mmol) and polyphosphoric acid (18 g) were mixed well and heated in an oil bath at 120 ℃ for 4 hours. After cooling to room temperature, 100mL of ice-water was added, and the mixture was stirred to completely dissolve the viscous substance, followed by extraction with ethyl acetate (30 mL. times.3). The organic phases were combined, washed successively with a saturated sodium carbonate solution (50 mL. times.2) and a saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 20/1) to obtain 410 mg of compound 4 (nuclear magnetic confirmed structure) as a white solid, yield: 73.0 percent.1H NMR (500 MHz, CDCl3) δ(ppm) 8.05 (d, J = 8.0 Hz, 1 H), 7.62 (dd, J = 8.5, 6.0 Hz, 1 H), 7.28-7.24 (m, 1 H), 7.19 (dd, J = 8.5, 1.0 Hz, 1 H), 7.05 (td, J = 8.5, 1.5 Hz, 1 H), 6.95 (dd, J = 8.5, 2.0 Hz, 1 H), 4.08 (s, 2 H).
5.8-chloro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-one (Compound 5)
Figure 452632DEST_PATH_IMAGE008
Compound 5a (3.42 g, 20 mmol) was dissolved in DMF (25 mL), potassium carbonate (8.30 g, 60 mmol) was added, and the mixture was stirred at room temperature for 30 min. Iodothane (2.4 mL, 30 mmol) was added dropwise, stirring was continued and the reaction was allowed to proceed overnight. Adding 100mL of ethyl acetate and 100mL of water, shaking uniformly, and separating an organic layer; the aqueous layer was extracted with ethyl acetate (50 mL. times.2). The organic phases were combined, washed with saturated brine (100 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow liquid. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 40/1). To obtain 3.32g of the colorless liquid compound 5b, yield: 83.4 percent.
Compound 5b (1.99 g, 10 mmol) was dissolved in dichloromethane (25 mL), water (25 mL) was added, and the mixture was stirred at room temperature. Adding bromine (520) dropwise in sequenceμL, 10 mmol) and 30% hydrogen peroxide (1 mL), and the mixture is stirred continuously and reacted for 24 hours. Adding 25mL of dichloromethane, shaking uniformly, and separating an organic layer; the aqueous layer was extracted with dichloromethane (25 mL. times.2). The organic phases were combined, washed with saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow liquid. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 40/1). To obtain colorless liquid compound 5c 2.75g, yield: 98.9 percent.
Compound 5c (1.56 g, 5.62 mmol) was dissolved in DMF (12 mL), and sodium thiophenolate (817 mg, 6.18 mmol) and potassium carbonate (1.55 g, 11.24 mmol) were added, followed by stirring at room temperature and reaction overnight. Adding 50mL of ethyl acetate and 50mL of water, shaking uniformly, and separating an organic layer; the aqueous layer was extracted with ethyl acetate (25 mL. times.2). The organic phases were combined, washed with saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow liquid. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 40/1) gave 1.04g of compound 5d (nuclear magnetic confirmed structure) as a colorless liquid, yield: 60.3 percent.1H NMR (500 MHz, CDCl3) δ(ppm) 7.86 (d, J = 8.5 Hz, 1 H), 7.30-7.28 (m, 2 H), 7.26-7.20 (m, 4 H), 7.16 (d, J = 2.0 Hz, 1 H), 4.46 (s, 2 H), 4.34 (q, J = 7.0 Hz, 2 H), 1.38 (t, J = 7.0 Hz, 3 H).
Compound 5d (1.16 g, 4.35 mmol) was dissolved in methanol (8 mL), tetrahydrofuran (16 mL) was added, and sodium hydroxide solution (prepared by dissolving sodium hydroxide (1.81 g, 45.2 mmol) in water (16 mL)) was added dropwise and stirred at room temperature for 4 hours. And (3) evaporating the organic solvent under reduced pressure, adjusting the pH to 7 by using a 2N HCl solution, and adjusting the pH to 3-4 by using the 2N HCl solution. Extraction with ethyl acetate (20mL × 3), combination of organic phases, washing with saturated brine (30 mL × 2), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave 0.99 g of compound 5e as a yellow solid, yield: 93.9 percent.
5e (750 mg, 2.14 mmol) and polyphosphoric acid (22 g) were mixed well and heated in an oil bath at 120 ℃ for 4 hours. After cooling to room temperature, 120 mL of ice-water was added, and the mixture was stirred to completely dissolve the viscous substance, followed by extraction with ethyl acetate (40 mL. times.3). The organic phases were combined, washed successively with a saturated sodium carbonate solution (60 mL. times.2) and a saturated brine (60 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 20/1) to obtain 450 mg of compound 5 (nuclear magnetic confirmed structure) as a white solid, yield: 64.2 percent.1H NMR (500 MHz, CDCl3) δ(ppm) 8.22 (dd, J = 8.0, 2.0 Hz, 1 H), 7.58 (d, J = 8. 0 Hz, 1 H), 7.38-7.27 (m, 4 H), 7.23 (d, J = 2.0 Hz, 1 H), 4.01 (s, 2 H).
6.8-fluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-one (Compound 6)
Figure 337412DEST_PATH_IMAGE009
Compound 6a (1.35 g, 5.17 mmol) was dissolved in DMF (10mL), and sodium thiophenolate (820 mg, 6.20 mmol) and potassium carbonate (1.43 g, 10.34 mmol) were added, and the mixture was stirred at room temperature and reacted overnight. Adding 60 mL of ethyl acetate and 60 mL of water, shaking uniformly, and separating an organic layer; the aqueous layer was extracted with ethyl acetate (30 mL. times.2). The organic phases were combined, washed with saturated brine (60 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow liquid. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 40/1) gave 1.13 g of the colorless liquid compound 6b, yield: 75.3 percent.
Compound 6b (1.13 g, 3.89 mmol) was dissolved in methanol (8 mL), tetrahydrofuran (16 mL) was added, and sodium hydroxide solution (prepared by dissolving sodium hydroxide (1.62 g, 40.44 mmol) in water (16 mL) was added dropwise and stirred at room temperature for 4 hours. And (3) evaporating the organic solvent under reduced pressure, adjusting the pH to 7 by using a 2N HCl solution, and adjusting the pH to 3-4 by using the 2N HCl solution. Extraction with ethyl acetate (30 mL × 3), combination of organic phases, washing with saturated brine (50 mL × 2), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave yellow solid compound 6c 1.0g, yield: 97.9 percent.
Compound 6c (600 mg, 2.14 mmol) and polyphosphoric acid (18 g) were mixed well and heated in an oil bath at 120 ℃ for 4 hours. After cooling to room temperature, 100mL of ice-water was added, and the mixture was stirred to completely dissolve the viscous substance, followed by extraction with ethyl acetate (30 mL. times.3). The organic phases were combined, washed successively with a saturated sodium carbonate solution (50 mL. times.2) and a saturated brine (50 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 20/1) to obtain 462 mg of compound 6 (nuclear magnetic confirmed structure) as a white solid, yield: 82.7 percent.1H NMR (500 MHz, CDCl3) δ(ppm) 8.24 (dd, J = 8.0, 1.0 Hz, 1 H), 7.67 (dd, J = 8.0, 6.0 Hz, 1 H), 7.40-7.34 (m, 2 H), 7.30-7.27 (m, 1 H), 7.04 (td, J = 8.5, 2.5 Hz, 1 H), 6.92 (dd, J = 9.0, 2.5 Hz, 1 H), 4.02 (s, 2 H).
7.7-fluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-one (Compound 7)
Figure 463500DEST_PATH_IMAGE010
Compound 7a (1.01 g, 3.87 mmol) was dissolved in DMF (6 mL), and sodium thiophenolate (614 mg, 4.64 mmol) and potassium carbonate (1.07 g, 7.74 mmol) were added, and the mixture was stirred at room temperature and reacted overnight. Adding 60 mL of ethyl acetate and 60 mL of water, shaking uniformly, and separating an organic layer; the aqueous layer was extracted with ethyl acetate (30 mL. times.2). The organic phases were combined, washed with saturated brine (60 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow liquid. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 40/1) gave 0.99 g of the colorless liquid compound 7b, yield: 88.1 percent.
Compound 7b (0.99 g, 3.41 mmol) was dissolved in methanol (8 mL), tetrahydrofuran (16 mL) was added, and sodium hydroxide solution (prepared by dissolving sodium hydroxide (1.42 g, 35.46 mmol) in water (16 mL) was added dropwise and stirred at room temperature for 4 hours. And (3) evaporating the organic solvent under reduced pressure, adjusting the pH to 7 by using a 2N HCl solution, and adjusting the pH to 3-4 by using the 2N HCl solution. Extraction with ethyl acetate (30 mL × 3), combination of organic phases, washing with saturated brine (50 mL × 2), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave 7c 824 mg as a yellow solid, yield: 92.1 percent.
Compound 7c (600 mg, 2.14 mmol) and polyphosphoric acid (18 g) were mixed well and heated in an oil bath at 120 ℃ for 4 hours. After cooling to room temperature, 100mL of ice-water was added, and the mixture was stirred to completely dissolve the viscous substance, followed by extraction with ethyl acetate (40 mL. times.3). The organic phases were combined, washed successively with a saturated sodium carbonate solution (60 mL. times.2) and a saturated brine (60 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 20/1) to obtain 426 mg of a white solid compound 7 (nuclear magnetic confirmed structure), yield: 76.2 percent.1H NMR (500 MHz, CDCl3) δ(ppm) 8.17 (dd, J = 8.0, 1.0 Hz, 1 H), 7.40-7.33 (m, 3 H), 7.32-7.28 (m, 2 H), 7.24-7.20 (m, 1 H), 4.13 (s, 2 H).
8.2-fluoro-7-trifluoromethyl-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-one (Compound 8)
Figure 131241DEST_PATH_IMAGE011
Compound 8a (2.45 g, 12 mmol) was dissolved in DMF (20 mL), potassium carbonate (4.98 g, 36 mmol) was added, and the mixture was stirred at room temperature for 30 min. Methyl iodide (1.13 mL, 18 mmol) was added dropwise, stirring was continued and the reaction was allowed to proceed overnight. Adding 100mL of ethyl acetate and 100mL of water, shaking uniformly, and separating an organic layer; the aqueous layer was extracted with ethyl acetate (50 mL. times.2). The organic phases were combined, washed with saturated brine (100 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow liquid. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 20/1). To obtain 2.32g of colorless liquid compound 8b, yield: 88.6 percent.
Compound 8b (1.31 g, 6 mmol) was dissolved in 1, 2-dichloroethane (15 mL). N-bromosuccinimide (1.17 g, 6.6 mmol) and azobisisobutyronitrile (98.5 mg, 0.6 mmol) were added in this order, and the mixture was heated in an oil bath at 90 ℃ with stirring for 6 hours. Cooling to room temperature, filtering, and evaporating the filtrate under reduced pressure. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 20/1) gave 1.70 g of the colorless liquid compound 8c, yield: 95.3 percent.
Compound 8c (1.70 g, 5.72 mmol) was dissolved in DMF (15 mL), potassium carbonate (1.58 g, 11.44 mmol) was added, and 4-fluorophenylthiol (675)μL, 6.29 mmol), stirred at room temperature for 45 min. Then, the mixture was heated and stirred in an oil bath at 60 ℃ to react overnight. Cooling to room temperature, adding 60 mL of ethyl acetate and 60 mL of water, shaking uniformly, and separating an organic layer; the aqueous layer was extracted with ethyl acetate (30 mL. times.2). The organic phases were combined, washed with saturated brine (60 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow liquid. Purification by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 20/1) gave 1.87 g of compound 8d (nuclear magnetic confirmed structure) as a colorless liquid, yield: 94.9 percent.1H NMR (500 MHz, CDCl3) δ(ppm) 7.93 (d, J = 8.0 Hz, 1 H), 7.72 (d, J = 7.5 Hz, 1 H), 7.05 (t, J = 8.0 Hz, 1 H), 7.29-7.27 (m, 2 H), 6.92 (t, J = 8.5 Hz, 2 H), 4.60 (s, 2 H), 3.87 (s, 3 H).
Compound 8d (1.87 g, 5.43 mmol) was dissolved in methanol (11 mL), tetrahydrofuran (22 mL) was added, and a sodium hydroxide solution (prepared by dissolving sodium hydroxide (2.26 g, 56.48 mmol) in water (22 mL)) was added dropwise and stirred at room temperature for 4 hours. And (3) evaporating the organic solvent under reduced pressure, adjusting the pH to 7 by using a 2N HCl solution, and adjusting the pH to 3-4 by using the 2N HCl solution. Extraction with ethyl acetate (40 mL. times.3), combining the organic phases, washing with saturated brine (60 mL. times.2), drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure gave a yellow oil. After standing overnight in the refrigerator, the yellow solid compound 8e 1.53 g was obtained, yield: 85.3 percent.
Compound 8e (750 mg, 2.27 mmol) and polyphosphoric acid (23 g) were mixed well and heated in an oil bath at 120 ℃ for 5 hours. After cooling to room temperature, 120 mL of ice-water was added, and the mixture was stirred to completely dissolve the viscous substance, followed by extraction with ethyl acetate (40 mL. times.3). The organic phases were combined, washed successively with a saturated sodium bicarbonate solution (60 mL. times.2) and a saturated brine (60 mL. times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate (V/V) = 20/1) to obtain 170 mg of a white solid compound 8 (nuclear magnetic confirmed structure), yield: 24.0 percent.1H NMR (500 MHz, CDCl3) δ(ppm) 7.90 (dd, J = 10.0, 3.0 Hz, 1 H), 7.82 (d, J = 8.0 Hz, 1 H), 7.67 (d, J = 7.5 Hz, 1 H), 7.45 (t, J = 8.0 Hz, 1 H), 7.30 (dd, J = 8.5, 5.0 Hz, 1 H), 7.16 (td, J = 8.0, 3.0 Hz, 1 H), 4.18 (s, 2 H).
9.4, 7-Difluorodibenzo [ b, e ] thiazepin-11 (6H) -one (Compound 9)
Figure 128016DEST_PATH_IMAGE012
In a reaction flask, compound 9a (1.0 g, 6.49 mmol) and dichloromethane (20 mL) were sequentially added, stirred and dissolved, water (20 mL) was added, bromine (1.04 g, 6.51 mmol) was slowly dropped, stirred at room temperature overnight, dichloromethane (40 mL) was added, stirred and left to stand, an organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give compound 9b as a white solid, 1.36g, yield 90%, and the crude product was used as it was in the next reaction.
Compound 9b (1.36 g, 5.84 mmol) and DMF (6 mL) were added sequentially to a reaction flask, dissolved with stirring, 2-fluoro-thiophenol (898.5 mg, 7.01 mmol) was added, stirring was carried out, anhydrous potassium carbonate (1.61g, 11.68 mmol) was added, reaction was carried out overnight with stirring at room temperature, DMF was evaporated, the product was extracted with MeOH, methanol was evaporated, the residue was dissolved in dilute hydrochloric acid to pH = 3, the product was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give compound 9c 1.5g as a white solid, yield 92%, and the crude product was used directly in the next reaction. ESI (-) MS showed correct molecular weight at M/z 279 (M-1).
The reaction solution bottle was charged with the compound 9c (1.5 g, 5.35 mmol) and PPA (20 g, 204.1 mmol) in that order at 1200Stirring at the temperature of C for reaction for 3h, adding ethyl acetate and water quenching reaction liquid, collecting an organic layer, evaporating a solvent, and purifying residues by SiO2 column chromatography (petroleum ether/ethyl acetate elution) to obtain an off-white solid compound 9 (nuclear magnetic confirmed structure) of 650 mg with a yield of 46%.1H NMR(CDCl3, 500MHz): 7.96-7.98(m,1H), 7.17-7.33(m, 5H), 4.14 (s,2H)。
10.8, 9-Difluorodibenzo [ b, e ] thiazepin-11 (6H) -one (Compound 10)
Figure 855801DEST_PATH_IMAGE013
In a reaction flask, compound 10a (1.0 g, 5.81 mmol) and dichloromethane (20 mL) were sequentially added, dissolved with stirring, water (20 mL) was added, bromine (928.5 mg, 5.81 mmol) was slowly dropped, 30% aqueous hydrogen peroxide (658.7 mg, 5.81 mmol) was added, stirred at room temperature overnight, dichloromethane (40 mL) was added, stirred and allowed to stand, the organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give compound 10b as a white solid, 1.22g, yield 90%, and the crude product was used as it was in the next reaction.
In a reaction flask, 10b (1.22 g, 5.84 mmol) and DMF (7 mL) were added sequentially, stirred to dissolve, sodium thiophenolate (926.4 mg, 7.01 mmol) was added, stirred, anhydrous potassium carbonate (1.61g, 11.68 mmol) was added, stirred at room temperature overnight, DMF was evaporated, product was extracted with MeOH, methanol was evaporated, residue was dissolved in dilute hydrochloric acid pH = 3, product was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, solvent was evaporated to give white solid compound 10c 1.5g, yield 92%, crude product was used directly in the next reaction. ESI (-) MS showed correct molecular weight at M/z 279 (M-1).
Intermediate 2 (1.5 g, 5.35 mmol) and PPA (20 g, 204.1 mmol) were added to a reaction flask in this order at 120 deg.f0Stirring at the temperature of C, reacting for 1h, adding ethyl acetate and water quenching reaction liquid, collecting an organic layer, evaporating a solvent, and purifying residues by SiO2 column chromatography (petroleum ether/ethyl acetate elution) to obtain 100mg of a white-like solid compound 10 (nuclear magnetic confirmed structure) with the yield of 8%.1H NMR(CDCl3, 500MHz)： 8.21-8.23(d,J=8.0Hz，1H)，7.50-7.54(m,1H)，7.36-7.40(m,2H), 7.29-7.31(m,1H)，7.02-7.06(m, 1H), 4.00 (s,2H)。
11.3, 10-Difluorodibenzo [ b, e ] thiazepin-11 (6H) -one (Compound 11)
Figure 203605DEST_PATH_IMAGE014
In a reaction flask, 11a (500 mg, 3.24 mmol) and dichloromethane (10mL) were sequentially added, and stirred to dissolve, water (10mL) was added, bromine (517.8 mg, 3.24 mmol) was slowly dropped, 30% hydrogen peroxide solution (367.3 mg, 3.24 mmol) was added, and stirred at room temperature overnight, and dichloromethane (40 mL) was added, and stirred and allowed to stand, and the organic layer was collected, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give a white solid compound 11b 670 mg, yield 90%, and the crude product was used as it was in the next reaction.
Compound 11b (670 mg, 5.84 mmol) and DMF (4 mL) were added sequentially to a reaction flask, dissolved with stirring, 3-fluoro-thiophenol (898.5 mg, 7.01 mmol) was added, stirring was performed, anhydrous potassium carbonate (1.61g, 11.68 mmol) was added, reaction was stirred at room temperature overnight, DMF was evaporated, the product was extracted with MeOH, methanol was evaporated, the residue was dissolved in dilute hydrochloric acid to pH = 3, the product was extracted with ethyl acetate, washed with saturated brine, dried over anhydrous sodium sulfate, the solvent was evaporated to give compound 11c 900mg as a white solid, yield 92%, and the crude product was used directly in the next reaction. ESI (-) MS showed correct molecular weight at M/z 279 (M-1).
The reaction solution bottle was charged with the compound 11c (900 mg, 3.21 mmol) and PPA (20 g, 204.1 mmol) in that order at 1200Stirring at the temperature of C for reaction for 6h, adding ethyl acetate and water quenching reaction liquid, collecting an organic layer, evaporating a solvent, and purifying residues by SiO2 column chromatography (petroleum ether/ethyl acetate elution) to obtain a white-like solid compound 11 (a nuclear magnetic confirmed structure) of 250 mg with the yield of 30%.1H NMR(CDCl3, 500MHz)：8.10-8.13(m,1H)，7.38-7.42(m,1H), 7.03-7.08(m,2H), 6.95-7.00(m, 2H), 4.04 (s,2H)。
12.7-chloro-2-fluoro-dibenzo [ b, e ] thiazepin-11 (6H) -one (Compound 12)
Figure 737355DEST_PATH_IMAGE015
In a reaction flask, compound 12a (1 g, 5.86 mmol) and DMF (5 mL) were sequentially added, stirred and dissolved, anhydrous potassium carbonate (2.43 g, 17,58 mmol) was added, stirred at room temperature for 50min, iodoethane (1.37 g, 8.79 mmol) was added, stirred at room temperature for reaction overnight, ethyl acetate 50mL and water (10mL) were added, shaken, allowed to stand, and layered, the organic layer was collected, washed with saturated brine, and the solvent was evaporated to give compound 12b 550 mg as a colorless liquid, which was used in the next reaction in a yield of 47%, and the crude product was used as it was.
Adding compound 12b (550 mg, 2.77 mmol) and 1, 2-dichloroethane (15 mL) into a reaction flask in sequence, stirring for dissolving, adding N-bromosuccinimide (493.0 mg, 2.77 mmol) and azobisbutyronitrile (45.5 mg, 0.277 mmol) in sequence, heating and refluxing for 2h, cooling the reaction solution to room temperature, evaporating the solvent, and removing the residue through SiO2Column chromatography purification (elution)Preparation: petroleum ether) to give the compound 12c 700mg as a colorless liquid in a yield of 72%.
In a reaction flask, compound 12c (700 mg, 2.52 mmol) and DMF (5 mL) were sequentially added, stirred to dissolve, 4-fluoro-thiophenol (387.1 mg, 3.02 mmol) was added, anhydrous potassium carbonate (696.6 mg, 5.04 mmol) was added under stirring at room temperature, the reaction solution was stirred at room temperature overnight, 10mL of water was added to the reaction solution, extraction was performed with 50mL of methyl t-butyl ether, the organic layer was collected, washed with saturated brine, the solvent was evaporated to give compound 12d 940 mg as a colorless liquid, and the crude product was used directly in the next reaction.
In a reaction flask, compound 12d (940 mg, 2.89 mmol), MeOH (8 mL), THF (16 mL) were added in order, dissolved with stirring, NaOH solution (1.42 g NaOH in 16mL water) was added, stirred at room temperature overnight, the reaction solvent was evaporated, 10mL of 1.2MHCl solution was added, extracted with ethyl acetate (40 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give compound 12e 900mg as a colorless oil, which was used directly in the next reaction. ESI (-) MS showed correct molecular weight at M/z 295 (M-1).
Compound 12e (900 mg, 3.03 mmol) and PPA (20 g, 204.1 mmol) were added sequentially to a reaction flask at 120%0Stirring at C degree for 2 hr, adding ethyl acetate, quenching with water, collecting organic layer, evaporating to remove solvent, and passing residue through SiO2Column chromatography purification (petroleum ether/ethyl acetate elution) afforded compound 12 as an off-white solid (nuclear magnetic confirmed structure) at 350 mg, 50% yield.1H NMR(CDCl3, 500MHz)： 7.86-7.88(d,J=10.0Hz，1H)，7.54-7.56（d，J=8.0Hz，1H），7.41-7.42(d,J=7.5Hz，1H), 7.28-7.32(m,2H), 7.12-7.15(m, 1H), 4.24 (s,2H)。
13.7-chloro-4-fluoro-dibenzo [ b, e ] thiazepin-11 (6H) -one (Compound 13)
Figure 729582DEST_PATH_IMAGE016
Compound 13a (1 g, 5.86 mmol) and DMF (5 mL) were added sequentially to a reaction flask, and stirred to dissolve, anhydrous potassium carbonate (2.43 g, 17.58 mmol) was added, and after stirring at room temperature for 50min, iodoethane (1.37 g, 8.79 mmol) was added, and the reaction was stirred at room temperature overnight, DMF was evaporated, and the residue was purified by SiO2 column chromatography (eluent: petroleum ether) to give compound 13b as a colorless liquid, 700mg, yield 60%.
Adding compound 13b (700 mg, 3.52 mmol) and 1, 2-dichloroethane (15 mL) into a reaction flask in sequence, stirring for dissolving, adding N-bromosuccinimide (626.5 mg, 3.52 mmol) and azobisbutyronitrile (57.8 mg, 0.352 mmol) in sequence, heating and refluxing for 2h, cooling the reaction solution to room temperature, evaporating the solvent, and removing the residue through SiO2Column chromatography purification (eluent: petroleum ether) afforded compound 13c 900mg, yield 72%.
Compound 13c (900 mg, 3.24 mmol) and DMF (5 mL) were added sequentially to a reaction flask, and stirred to dissolve it, 2-fluoro-thiophenol (498.6 mg, 3.89 mmol) was added, and anhydrous potassium carbonate (895.6 mg, 6.48 mmol) was added under stirring at room temperature, and the reaction mixture was stirred at room temperature overnight. 10mL of water was added to the reaction mixture, and the mixture was extracted with 50mL of methyl t-butyl ether, and the organic layer was collected, washed with saturated brine, and the solvent was distilled off to obtain compound 13d (1.2 g, crude product) as a colorless oily substance, which was used directly in the next reaction.
In a reaction flask, compound 13d (1.2 g, crude), MeOH (8 mL), THF (16 mL) were added in order, dissolved with stirring, NaOH solution (1.42 g NaOH in water 16 mL) was added, stirred at room temperature overnight, the reaction solvent was evaporated, 1.2 mL of MHCl solution was added, extracted with ethyl acetate (40 mL), washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated to give compound 13e 1.16g, which was used directly in the next reaction. ESI (-) MS showed correct molecular weight at M/z 295 (M-1).
To the reaction flask were added compound 13e (1.16 g, crude), PPA (20 g, 204.1 mmol) in sequence at 1200Stirring at C degree for 2 hr, adding ethyl acetate, quenching with water, collecting organic layer, evaporating to remove solvent, and passing residue through SiO2Column chromatography purification (petroleum ether/ethyl acetate elution) afforded the compound as a white solidProduct 13 (NMR confirmed structure 340 mg, yield 38%.1H NMR(CDCl3, 500MHz)： 7.91-7.93(d,J=8.0Hz，1H)，7.53-7.55(d,J=8.0Hz，1H), 7.35-7.36(d,J=7.5Hz，7.17-7.28(m, 3H), 4.26 (s,2H)。
14.4-chloro-10-methyl-dibenzo [ b, e ] thiazepin-11 (6H) -one (Compound 14)
Figure 752901DEST_PATH_IMAGE017
Compound 14a (1 g, 6.66 mmol) and DMF (8 mL) were added sequentially to a reaction flask, stirred and dissolved, anhydrous potassium carbonate (2.76 g, 19.98 mmol) was added, stirred at room temperature for 50min, iodoethane (1.56 g, 9.99 mmol) was added, stirred at room temperature for reaction overnight, ethyl acetate 50mL and water (10mL) were added, shaken, allowed to stand, and layered, the organic layer was collected, washed with saturated brine, and the solvent was evaporated to give compound 14b 1.14g as a colorless liquid, which was used in the next reaction in a yield of 96%.
Adding the compound 14b (1.14 g, 6.40 mmol) and 1, 2-dichloroethane (15 mL) into a reaction bottle in sequence, stirring for dissolving, adding N-bromosuccinimide (1.14 g, 6.40 mmol) and azobisbutyronitrile (105.1 mg, 0.64 mmol) in sequence, heating and refluxing for 2h, cooling the reaction solution to room temperature, evaporating the solvent, and passing the residue through SiO2Column chromatography purification (eluent: petroleum ether) gave 14c 420 mg, 25% yield, as a colorless liquid.
Compound 14c (420 mg, 1.63 mmol) and DMF (5 mL) were added to a reaction flask in this order, and dissolved with stirring, 2-chloro-thiophenol (283.4 mg, 1.96 mmol) was added, anhydrous potassium carbonate (450.6 mg, 3.26 mmol) was added with stirring at room temperature, the reaction mixture was stirred at room temperature overnight, 10mL of water was added to the reaction mixture, extraction was performed with 50mL of methyl t-butyl ether, the organic layer was collected, washed with saturated brine, the solvent was evaporated to give compound 14d 600 mg as a colorless oil, and the crude product was used directly in the next reaction.
In a reaction flask, add compound 14d (600 mg, crude), MeOH (8 mL), THF (16 mL) sequentially, stirDissolving, adding NaOH solution (1.42 g NaOH dissolved in 16mL water), and dissolving at 60-70%0C stirring overnight, evaporating the solvent, adding 10mL of 1.2MHCl solution, extracting with ethyl acetate (40 mL), washing with saturated saline, drying over anhydrous sodium sulfate, evaporating the solvent to obtain 14e 520 mg of a colorless liquid compound, and directly using the crude product in the next reaction. ESI (-) MS showed M/z 291 (M-1), correct molecular weight.
The reaction solution bottle was charged with 14e (520 mg, 1.78 mmol) and PPA (20 g, 204.1 mmol) in this order, and the mixture was poured into a flask containing 120 g of PPA0Stirring at C degree for 2 hr, adding ethyl acetate, quenching with water, collecting organic layer, evaporating to remove solvent, and passing residue through SiO2Column chromatography purification (petroleum ether/ethyl acetate elution) afforded compound 14 (nuclear magnetic confirmed structure) as a yellow solid, 150 mg, 31% yield.1H NMR（CDCl3， 500MHz）： 7.83-7.85（d，J=8.0Hz，1H），7.46-7.48（d，J=8.0Hz，1H），7.29-7.32（m，1H），7.17-7.20（d，J=8.0Hz，1H），7.13-7.15（m，1H），7.09-7.10（d，J=7.5Hz，1H），4.03（s，2H），2.24(s, 3H)。
15.10-chloro-4-fluoro-dibenzo [ b, e ] thiazepin-11 (6H) -one (Compound 15)
Figure 197789DEST_PATH_IMAGE018
Compound 15a (1 g, 5.86 mmol) and DMF (8 mL) were added sequentially to a reaction flask, stirred to dissolve, cesium carbonate (3.82 g, 11.72 mmol) was added, stirred at room temperature for 50min, iodoethane (1.37 g, 8.79 mmol) was added, stirred at room temperature overnight, DMF was evaporated, the residue was extracted with MeOH2 × 50mL, evaporated to dryness to give 15b as a colorless liquid compound, yield 71%, and the crude product was used directly in the next reaction.
Adding compound 15b (830 mg, 4.18 mmol) and 1, 2-dichloroethane (15 mL) in turn into a reaction flask, stirring for dissolving, adding N-bromosuccinimide (744.0 mg, 4.18 mmol) and azobisbutyronitrile (68.6 mg, 0.418 mmol) in turn, heating and refluxing for 2h, cooling the reaction solution to room temperature, evaporating the solvent, and removing the residual solventSiO material2Column chromatography purification (eluent: petroleum ether) gave 15c 600 mg, 52% yield, as a colorless liquid.
In a reaction flask, compound 15c (600 mg, 2.16 mmol) and DMF (5 mL) were added in this order, stirred and dissolved, 2-fluoro-thiophenol (332.0 mg, 2.59 mmol) was added, anhydrous potassium carbonate (597.1 mg, 4.32 mmol) was added under stirring at room temperature, the reaction solution was stirred at room temperature overnight, 10mL of water was added to the reaction solution, extraction was performed with 50mL of methyl t-butyl ether, the organic layer was collected, washed with saturated brine, the solvent was evaporated to give compound 15d 1.0g (crude product), and the crude product was used directly in the next reaction.
In a reaction flask, compound 15d (1.0 g, crude), MeOH (8 mL), THF (16 mL) were added sequentially, dissolved with stirring, and NaOH solution (1.42 g NaOH in 16mL water) was added at 50-60%0C stirring overnight, evaporating the reaction solvent, adding 10mL of 1.2MHCl solution, extracting with ethyl acetate (40 mL), washing with saturated saline, drying over anhydrous sodium sulfate, evaporating the solvent to obtain 15e 700mg, and directly using the crude product in the next reaction. ESI (-) MS showed correct molecular weight at M/z 295 (M-1).
The reaction solution bottle was charged with compound 15e (700 mg, 2.36 mmol) and PPA (20 g, 204.1 mmol) in that order at 1200Stirring at C degree for 2 hr, adding ethyl acetate, quenching with water, collecting organic layer, evaporating to remove solvent, and passing residue through SiO2Column chromatography purification (petroleum ether/ethyl acetate elution) gave 150 mg of off-white solid compound 15 (nuclear magnetic confirmed structure) in 23% yield.1H NMR（CDCl3， 500MHz）：7.72-7.74（d，J=8.0Hz，1H），7.35-7.36（d，J=5.5Hz，1H），7.16-7.25（m，4H），4.05（s，2H）。
16.2-fluoro-dibenzo [ b, e ] thiazepin-11 (6H) -one (Compound 16)
Figure 600476DEST_PATH_IMAGE019
Compound 16a (1.0 g, 7.34 mmol) and DMF (6 mL) were added to a reaction flask in this order, and stirred to dissolve, cesium carbonate (4.78 g, 14.68 mmol) was added, and after stirring at room temperature for 50min, iodoethane (1.72 g, 11.01 mmol) was added, and stirred at room temperature overnight to react, methyl tert-butyl ether (50 mL) was added, water (10mL) was added, and the mixture was shaken, allowed to stand, separated into layers, an organic layer was collected, washed with saturated brine, and the solvent was evaporated to give compound 16b as a colorless liquid, which was used in the next reaction in 83% yield.
Adding the compound 16b (1.0 g, 6.09 mmol) and 1, 2-dichloroethane (15 mL) into a reaction bottle in sequence, stirring for dissolving, adding N-bromosuccinimide (1.08 g, 6.09 mmol) and azobisbutyronitrile (100 mg, 0.609 mmol) in sequence, heating and refluxing for 5h, cooling the reaction liquid to room temperature, evaporating the solvent, and removing the residue through SiO2Column chromatography purification (eluent: petroleum ether) gave 16c 800 mg, 54% yield, of the compound as a colorless liquid.
In a reaction flask, compound 16c (800 mg, 3.29 mmol) and DMF (5 mL) were sequentially added, stirred to dissolve, 2-fluoro-thiophenol (506.3 mg, 3.95 mmol) was added, anhydrous potassium carbonate (909.4 mg, 6.58 mmol) was added under stirring at room temperature, the reaction solution was stirred at room temperature overnight, 10mL of water was added to the reaction solution, extraction was performed with 50mL of methyl t-butyl ether, the organic layer was collected, washed with saturated brine, the solvent was evaporated to give compound 16d 1.0g (crude product) as a colorless liquid, and the crude product was used directly in the next reaction.
In a reaction flask, compound 16d (1.0 g, crude), MeOH (8 mL), THF (16 mL) were added in order, dissolved with stirring, NaOH solution (1.42 g NaOH in water 16 mL) was added, stirred at room temperature overnight, the reaction solvent was evaporated, 1.2MHCl solution 10mL was added, extraction was performed with ethyl acetate (40 mL), washing with saturated brine, drying over anhydrous sodium sulfate, and the solvent was evaporated to give compound 16e 900mg as a white solid with a yield of 99%. ESI (-) MS showed correct molecular weight at M/z 261 (M-1).
The reaction solution bottle was charged with compound 16e (900 mg, 3.43 mmol) and PPA (20 g, 204.1 mmol) in this order, and the mixture was poured into the flask, and the mixture was poured into a flask and stirred at 120 deg.C0Stirring at C degree for 2 hr, adding ethyl acetate, quenching with water, collecting organic layer, evaporating to remove solventThe residue is treated with SiO2Column chromatography purification (petroleum ether/ethyl acetate elution) afforded compound 16 (nuclear magnetic confirmed structure) as an off-white solid, 210 mg, in 25% yield.1H NMR（CDCl3， 500MHz）： 7.93-7.96（d，J=10.5Hz，1H），7.64-7.66（d，J=8.0Hz，1H），7.47-7.50（m，1H），7.34-7.38（m，1H），7.31-7.33（m，1H），7.21-7.23（m，1H），7.10-7.13（m，1H），4.05（s，2H）。
Synthesis of substituted-dibenzothiazepine chloride and substituted-dibenzothiazepine chloride:
17.5-chloro-10, 11-dihydro-5H-dibenzo [ a, d ] [7] annulene (Compound 17)
Figure 712789DEST_PATH_IMAGE020
Compound 17a (1.13 g, 5 mmol) was dissolved in methanol (10mL) and stirred at-5 ℃ for 0.5 h, sodium borohydride (0.38 g, 10 mmol) was added to the reaction 5 times, after which stirring was continued at-5 ℃ for 0.5 h, moved to room temperature and stirred for 3h, water (40 mL) was added, stirring was continued for 1h, filtered under reduced pressure, and the filter cake was vacuum dried to give 1.02g of white solid 17b (nuclear magnetic confirmed structure), yield: 89.5 percent.1H NMR: (400 MHz, CDCl3) δ 7.54 - 7.43 (m, 2H), 7.26 - 7.14 (m, 6H), 5.97 (d, J = 2.8 Hz, 1H), 3.52 - 3.37 (m, 2H), 3.21 - 3.06 (m, 2H), 2.36 - 2.23 (m, 1H)。
In a reaction flask, compound 17b (1.02 g, 4.85 mmol), 1MSOCl were added in sequence2-CH2Cl2The solution (10mL) was stirred at room temperature overnight, TLC showed complete reaction, and concentrated to dryness under reduced pressure to give 171.05 g of dark green oily compound, which was used in the next reaction without purification.
18.11-chloro-6, 11-dihydrodibenzo [ b, e ] thiazepine (Compound 18)
Figure 641430DEST_PATH_IMAGE021
Compound 18a (1.0 g, 4.42 mmol) was dissolved in methanol (10mL), stirred at-5 ℃ for 0.5 h, sodium borohydride (0.33 g, 8.84 mmol) was added to the reaction in 5 portions, after addition, stirring was continued at-5 ℃ for 0.5 h, moved to room temperature and stirred for 3h, water (40 mL) was added, stirring was continued for 1h, filtered under reduced pressure, and the filter cake was dried under vacuum to give white solid 18b (nuclear magnetic confirmed structure) 0.96 g, yield: 95.0 percent.1H NMR (400 MHz, CDCl3) δ(ppm) 7.53 (d, J = 3.2 Hz, 1 H), 7.46 (dd, J = 5.2, 3.6 Hz, 1 H), 7.29-7.22 (m, 3 H), 7.18-7.11 (m, 3 H), 6.15 (d, J=1.5Hz,1 H), 4.54 (d, J = 13.6 Hz, 1 H), 4.27 (d, J = 13.6 Hz, 1 H), 2.62 (d, J = 1.6 Hz, 1 H).
In a reaction flask, compound 18b (0.96 g, 4.20 mmol), 1MSOCl were added sequentially2-CH2Cl2The solution (10mL) was stirred at room temperature overnight, TLC showed complete reaction, and concentrated to dryness under reduced pressure to give 181.03 g of dark green oily compound, which was used in the next reaction without purification.
19.11-chloro-7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepine (Compound 19)
Figure 839194DEST_PATH_IMAGE022
Compound 19a (1.0 g, 3.81 mmol) was dissolved in methanol (10mL), stirred at-5 ℃ for 0.5 hour, sodium borohydride (0.29 g, 7.62 mmol) was added to the reaction 5 times, after addition, stirring was continued at-5 ℃ for 0.5 hour, moved to room temperature and stirred for 3 hours, water (40 mL) was added, stirring was continued for 1 hour, filtered under reduced pressure, and the filter cake was dried under vacuum to give 0.92 g of white solid 19b (nuclear magnetic confirmed structure), yield: 91.5 percent.1H NMR (400 MHz, CDCl3) δ(ppm) 7.45-7.48 (m, 1H), 7.17-7.20 (m, 2H), 7.13-7.17 (m, 2H), 6.99-7.05 (m, 1H), 6.10 (d, J=3.2Hz, 1H), 4.68 (d, J = 14.4 Hz, 1H), 4.20 (d, J = 14.4 Hz, 1H), 2.72 (d, J = 3.6 Hz, 1H).
In a reaction flask, addThen, compound 19b (0.92 g, 3.48 mmol) and 1MSOCl were added in sequence2-CH2Cl2The solution (10mL) was stirred at room temperature overnight, TLC showed complete reaction, and concentrated to dryness under reduced pressure to give 190.98 g of dark green oily compound, which was used in the next reaction without purification.
Example 1
Synthesis of 5- (10, 11-dihydro-5H-dibenzo [ a, d ] [7] annulen-5-yl) -10-hydroxy-3, 4,4a, 5-tetrahydro-1H-pyrido [1,2-b ] cinnoline-9, 11(2H,11aH) -dione (compound 20):
Figure 511483DEST_PATH_IMAGE023
compound 20a (23.0 g, 99.9 mmol, 1.00 eq), DMSO (230 mL), cyclohexanone (29.42 g, 299.72 mmol, 31.06 mL, 3.00 eq), and pyrrolidine (7.11 g, 99.9 mmol, 8.34 mL, 1.00 eq) were added together in a reaction flask and the system was stirred at 40-50 ℃ for 12 hours. The TLC (ethyl acetate: methanol =20:1, Rf (R1) = 0.8) dot plate monitors the completion of the compound 1 reaction. The reaction was diluted with 200mL of DCM, washed with 1N dilute hydrochloric acid (200mL), separated and the organic phase was washed with saturated aqueous sodium bicarbonate (200mL × 2) and saturated aqueous NaCl (100 mL × 3). The organic phase was concentrated to give crude product which was isolated and purified by column chromatography, LCMS showed target m/z was produced. Compound 20b (13.0 g, 39.6 mmol, 39.6% yield, yellow oil, nuclear magnetic confirmed structure) was obtained.1H NMR: (400 MHz, CDCl3) δ 7.75 - 7.68 (m, 1H), 7.44 - 7.35 (m, 5H), 6.45 - 6.40 (m, 1H), 5.34 - 5.20 (m, 2H), 5.13 (d, J = 11.2 Hz, 0.6H), 5.07 - 5.02 (m, 0.6H), 3.58 (d, J = 4.4 Hz, 0.6H), 3.22 (s, 0.6H), 2.79 - 2.69 (m, 0.7H), 2.60 (d, J = 5.0 Hz, 0.3H), 2.51 - 2.21 (m, 2.7H), 2.11 - 2.01 (m, 1.6H), 1.92 - 1.46 (m, 7H), 1.29 - 1.25 (m, 0.4H), 1.20 (s, 2H)。
Compound 20b (5.00 g, 15.2 mmol, 1.00 eq), MeOH (75 mL), H2O (37 mL) and 2,2,2-trifluoroacetohydrazide (3.90 g, 30.5 mmol, 2.00 eq) were added together in a reaction flask and the system was stirred at 40-50 ℃ for 5 hours. LCMS shows thatTarget m/z generation. The reaction was washed with saturated aqueous NaCl (20mL × 2), the organic phase was concentrated to give a crude product, which was isolated and purified by column chromatography to give compound 20c (2.50 g, 7.71 mmol, 50.6% yield, yellow solid, nuclear magnetic confirmed structure).1H NMR: (400 MHz, CDCl3) δ 7.66 - 7.57 (m, 1H), 7.37 - 7.29 (m, 5H), 6.47 - 6.39 (m, 1H), 5.46 - 5.35 (m, 1H), 5.33 - 5.27 (m, 0.4H), 5.08 (d, J = 11.6 Hz, 0.6H), 4.61 (d, J = 3.4 Hz, 0.6H), 4.48 (d, J = 2.6 Hz, 0.4H), 2.79 - 2.51 (m, 1H), 2.44 - 1.15 (m, 9H)。
Dissolving the compound 20c (2.50 g, 7.71 mmol, 1.00 eq) in 25mL of methanol in a reaction flask, adding NaBH to the system at 0-5 DEG4(0.47 g, 12.42 mmol, 1.61 eq), and the system was stirred at 20 to 30 ℃ for 1 hour. LCMS showed target m/z generation. Adding 2mL of water into the system at 0-5 ℃, then stirring for half an hour at 20-30 ℃, concentrating the reaction solution, filtering, and spin-drying a filter cake to obtain a compound 20d (1.70 g, 5.21 mmol, 67.6% yield, yellow solid, nuclear magnetic confirmation structure).1H NMR: (400 MHz, DMSO-d6) δ 7.51 - 7.31 (m, 6H), 6.44 (d, J = 11.5 Hz, 1H), 6.20 - 6.12 (m, 1H), 5.44 - 5.31 (m, 1.3H), 5.19 (d, J = 10.8 Hz, 0.7H), 5.07 (d, J = 10.9 Hz, 1H), 4.69 - 4.61 (m, 0.7H), 4.48 - 4.40 (m, 0.3H), 3.57 - 3.47 (m, 0.2H), 3.17 - 3.00 (m, 0.8H), 1.84 (br s, 9H)。
The compound 20d (1.70 g, 5.21 mmol, 1.00 eq), 11-chloro-6, 11-dihydrodibenzo [ b, e ]]The thiazepine (2.38 g, 10.42 mmol, 2.00 eq) and ACN (17 mL) were added together in a reaction flask and the system was stirred at 20-30 ℃ for 1 hour. LCMS showed target m/z generation. The reaction was concentrated to give crude product, which was subjected to HPLC, and the crude product was prepared by reverse phase preparation (column: Phenomenex luna C18250 mm 10um; mobile phase: [ water (0.225% FA) -ACN)]30% -70% of B%, 25 min), and purifying the product by reverse phase preparation (column: Phenomenex luna C18250 mm 10um; mobile phase: water (0.225% FA) -ACN)]40% -75% for 20 min to obtain 20e (0.60 g, 1.16 mmol, 22.2% yield, yellow solid, structure confirmed by nuclear magnetism), and recovering the starting compound 20e (0.30 g).1H NMR: (400 MHz, DMSO-d6) δ 7.36 - 7.06 (m, 11H), 6.94 - 6.86 (m, 1H), 6.82 - 6.65 (m, 2H), 6.27 - 5.99 (m, 0.7H), 5.65 - 5.49 (m, 1.3H), 5.43 - 5.30 (m, 1H), 5.22 - 5.01 (m, 2H), 4.68 - 4.26 (m, 2H), 3.61 - 3.49 (m, 1H), 3.08 - 2.87 (m, 2H), 2.74 (br d, J = 13.9 Hz, 1H), 1.55 - 1.21 (m, 4H), 1.07 - 0.91 (m, 2H), 0.72 - 0.37 (m, 2H)
Dissolve compound 20e (0.60 g, 1.16 mmol, 1.00 eq) in 6mL acetonitrile in a reaction flask, add DMP (491 mg, 1.16 mmol, 358 uL, 1.00 eq) and NaHCO to the system at 0-5 deg.C3(48.6 mg, 578. mu. mol, 22.50 uL, 0.50 eq.) and the system was stirred at 70 to 75 ℃ for 1 hour. TLC (ethyl acetate: methanol = 10: 1, Rf (R1) = 0.5) spot plate monitors that compound 5 is still remaining and a new spot is generated. The reaction solution was saturated with Na2S2O3 Aqueous solution (1 mL. multidot.3) and saturated NaHCO3Aqueous (1 mL x 3) wash, extract with 1mL ethyl acetate, concentrate the organic phase to give crude product, purify the crude product by column chromatography, LCMS shows target m/z formation. Compound 20f (300 mg, 581 umol, 50.2% yield, yellow solid, nuclear magnetic confirmed structure) was obtained.1H NMR: (400 MHz, DMSO-d6) δ 7.57 - 7.51 (m, 1H), 7.50 - 7.44 (m, 2H), 7.38 - 7.30 (m, 5H), 7.22 - 7.09 (m, 4H), 6.96 - 6.70 (m, 2H), 5.67 - 5.60 (m, 1H), 5.47 - 5.38 (m, 1H), 5.31 - 5.12 (m, 3H), 4.66 - 4.52 (m, 0.5H), 4.35 - 4.24 (m, 0.5H), 3.15 - 2.70 (m, 4H), 1.77 - 1.29 (m, 5H), 0.97 - 0.70 (m, 3H)
Compound 20f (0.30 g, 580 umol, 1.00 eq), MeOH (3 mL), and Pd/C (0.03 g, 10% purity) were added together to a reaction flask, and the system was stirred under a hydrogen balloon atmosphere at 10-15 ℃ for 0.2 hour. TLC (ethyl acetate: methanol = 10: 1, Rf (R1) = 0.6) spot plate monitors that compound 6 still remains. The reaction solution was filtered, the filtrate was concentrated, and then dissolved in methanol (3 mL), Pd/C (0.03 g, 10% purity) was added to the system, and the system was stirred at 10 to 15 ℃ for 0.2 hours under a hydrogen balloon atmosphere. LCMS showed target m/z generation. The reaction solution was filtered, and the filtrate was concentrated. The crude product was prepared by reverse phase (column: Phenomenex synergy C18150 × 25 × 10um; mobile phase: [ water (0.225% FA) -ACN]; B%:50% -80%, 8.5 min) to give compound 20 (45 mg, 103 umol, 17.8% yield, 98.0% purity, yellow solid, nuclear magnetic and LCMS confirmed structure, 98% purity from HPLC).1H NMR: (400 MHz, DMSO-d6)δ 8.16 (s, 1H), 7.56 (d, J = 7.5 Hz, 1H), 7.35 - 7.31 (m, 2H), 7.22 - 7.10 (m, 3H), 6.96 - 6.85 (m, 2H), 6.76 - 6.68 (m, 1H), 5.56 - 5.49 (m, 2H), 4.38 - 4.28 (m, 1H), 3.16 - 2.92 (m, 4H), 2.82 - 2.74 (m, 1H), 2.07 (s, 1H), 1.76 - 1.05 (m, 5H), 0.90 - 0.70 (m, 1H)。
Example 2:
synthesis of 1- (7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ] thiazepin-11-yl) -5-hydroxy-2, 3-dihydro-1H-pyrido [1,2-b ] pyridazine-4, 6-dione (Compound 21):
Figure 478302DEST_PATH_IMAGE024
a DMF (1000 mL) solution containing compound 21a (200.0 g, 812.3 mmol, 1.00 eq), iodoethane (228.0 g, 1.46 mol, 116.9 mL, 1.80 eq), DBU (185.5 g, 1.22 mol, 183.7 mL, 1.50 eq) was stirred at 20-300C for 60min, TLC (PE: EA =1:1, Rf= 0.60) indicates completion of the reaction; the reaction mixture was poured into 4L of water and extracted with 3x1000mL ethyl acetate (1000mL x 3); the organic layer was washed with 2 × 1000mL saline (1000mL × 2) and concentrated to give compound 21b (nuclear magnetic confirmed structure) as a yellow oil (190.0 g, 692.8 mmol, 85.3% yield).1H NMR : (400MHz, CHLOROFORM-d) δ 7.74 (d, J = 5.6 Hz, 1H), 7.51 - 7.44 (m, 2H), 7.39 - 7.29 (m, 3H), 6.46 (d, J = 5.6 Hz, 1H), 5.36 - 5.23 (m, 2H), 4.33 (q, J = 7.2 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H)
50-60% DMA (2200 mL) solution of compound 21b (190.0 g, 692.8 mmol, 1.00 eq), N-tert-butyl carbamate (137.3 g, 1.04 mol, 1.50 eq), PPTS (522.3 g, 2.08 mol, 3.00 eq)0C stirring for 60min, TLC (PE: EA =1:2, R)f= 0.15) reaction complete, reaction pour into 10L water, extract with 3x1000mL ethyl acetate (1000mL x 3), 3x1000mL brine (500mL x 3), concentrate, residueThe yellow oil compound 21c (nuclear magnetic structure) was purified by column chromatography (120 g, 309.0 mmol, 44.6% yield).1H NMR:(400 MHz, CHLOROFORM-d) δ7.37 - 7.31 (m, 2H), 7.29 - 7.17 (m, 4H), 6.29 (d, J = 7.9 Hz, 1H), 5.17 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 1.37 (s, 9H), 1.18 - 1.13 (m, 3H)。
A solution of compound 21C (120.0 g, 309.0 mmol, 1.00 eq), 2-propenylethyl ester (61.0 g, 609.3 mmol, 66.2 mL, 1.97 eq), DIEA (47.9 g, 370.7 mmol, 64.6 mL, 1.20 eq) in acetonitrile (1.2L) was stirred at 70-800C for 12h, TLC (PE: EA =1:2, Rf= 0.60) showed complete consumption of compound 3, the reaction mixture was concentrated and the residue was purified by silica gel column chromatography to give compound 21d (100.0 g, 204.7 mmol, 66.3% yield) as a colorless oil for the next reaction.
In the range of 20-300C to a solution of compound 21d (100.0 g, 204.7 mmol, 1.00 eq) in ethyl acetate (200mL) was added dropwise a hydrogen chloride-ethyl acetate solution (4M, 500mL, 9.77 eq); stirring the reaction liquid at 20-300 ℃ for 2 h; TLC (PE: EA =1:1, R)f= 0.09) showed the reaction was complete; concentrating the reaction solution; the concentrate was adjusted to pH =8 with Na2CO3 solution (200mL), extracted with 3 × 200mL ethyl acetate (200mL × 3), the organic layer was collected, and concentrated to give compound 21e (80.0 g, crop) as a yellow oil.1H NMR: (400MHz, DMSO-d6) δ 7.84 (d, J = 7.8 Hz, 1H), 7.43 - 7.27 (m, 5H), 6.88 (t, J = 5.8 Hz, 1H), 6.30 (d, J = 7.7 Hz, 1H), 5.09 (s, 2H), 4.23 (q, J = 7.0 Hz, 2H), 4.05 (q, J = 7.1 Hz, 2H), 3.62 - 3.56 (m, 1H), 3.34 (s, 2H), 3.21 (q, J = 6.7 Hz, 2H), 2.41 (t, J = 6.8 Hz, 2H), 1.19 (td, J = 7.1, 11.1 Hz, 6H)。
In the range of 0-100C, to a solution of t-BuOK (60.1 g, 535.5 mmol, 2.60 eq) in THF (800 mL) was added dropwise a solution of compound 21e (80.0 g, 206.0 mmol, 1.00 eq) in THF (800 mL); stirring the reaction solution for 2 hours at 20-300 ℃; TLC (EA: MeOH =20:1, R)f= 0.50) showed the reaction was complete; adding citric acid solution (500 mL), adjusting pH to 7-8 with solid NaHCO3, collecting organic layer, and concentrating to obtain yellow solid compound 21f (nuclear magnetic assayStructure) (50.0 g, 146.0 mmol, 70.9% yield).1H NMR: (400MHz, DMSO-d6) δ 7.73 (d, J = 7.6 Hz, 1H), 7.47 (br d, J = 7.0 Hz, 2H), 7.35 - 7.27 (m, 3H), 6.58 (t, J = 8.3 Hz, 1H), 6.16 (d, J = 7.7 Hz, 1H), 5.08 (s, 2H), 4.26 (q, J = 7.1 Hz, 2H), 3.70 (d, J = 8.3 Hz, 2H), 1.26 (t, J = 7.1 Hz, 3H)
A solution of compound 21f (35.0 g, 102.2 mmol, 1.00 eq), K2CO3 (14.1 g, 102.2 mmol, 1.00 eq), BnBr (17.5 g, 102.2 mmol, 12.1 mL, 1 eq) in DMF (350 mL) was stirred at 20-300C for 2 h; TLC showed the reaction was complete; the reaction mixture was poured into 1500mL of water (1500 mL), extracted with 2-MeTHF (300 mL), concentrated, and the residue was purified by silica gel column chromatography to give 21g (NMR confirmed structure) of the compound as a yellow oil (6.00 g, 13.9 mmol, 13.6% yield).1H NMR: (400MHz, DMSO-d6) δ7.77 (d, J = 7.7 Hz, 1H), 7.38 - 7.21 (m, 10H), 6.60 (t, J = 8.3 Hz, 1H), 6.19 (d, J = 7.6 Hz, 1H), 4.98 (s, 2H), 4.88 (s, 2H), 4.19 - 4.11 (m, 2H), 3.75 (d, J = 8.3 Hz, 2H), 1.17 - 1.14 (m, 3H)。
In the range of 20-300C to a solution of compound 7a (8.00 g, 30.3 mmol, 1.00 eq), 21g (10.4 g, 30.3 mmol, 1.00 eq) in ethyl acetate (100 mL) was added T3P (134.8 g, 211.9 mmol, 126.0 mL, 50% purity, 7.00 eq); stirring the reaction solution at 70-800 ℃ for 1.5 h; TLC (Plate1, PE: EA =1:3) showed complete reaction; cooling the reaction solution to 20-300C, adding ethyl acetate (200ml) for dilution, washing with water (150 ml × 3), drying with Na2SO4, filtering, and concentrating; the residue was purified by column chromatography on silica gel to give the compound as a yellow solid for 21h (16.0 g, 27.2 mmol, 89.8% yield).1H NMR:(400MHz, DMSO-d6) δ 12.31 (s, 1H), 7.51 - 7.49 (m, 8H), 7.38 - 7.11 (m, 6H), 6.78 (m, 2H), 5.79 - 5.73 (m, 1H), 5.56 (d, J = 8.4 Hz , 1H), 3.34 (s, 2H), 5.17 - 5.15 (m, 3H), 4.23 – 4.10 (m, 1H), 3.96 – 3.66 (m, 2H), 1.11 – 1.01 (m, 3H),
A solution of compound 21h (4.00 g, 6.80 mmol, 1.00 eq), NaCl (1.99 g, 34.0 mmol, 5.00 eq) in DMSO (40 mL), water (4 mL) at 140 h0C, stirring for 2 hours; LCMS showed reaction complete; adding water (200mL), extracting with ethyl acetate (40 mL. times.2), washing with brine (40 mL. times.2), and concentrating; the residue was purified by column chromatography and further purified by preparative liquid phase to give compound 21 (26.0 mg, 59.0 umol, 8.68e-1% yield, 96.8% purity) as an off-white solid.
Example 3: synthesis of 5- (7, 8-difluoro-6, 11-dihydrobenzo [ b, e ] thiazepin-11-yl) -10-hydroxy-3, 4,4a, 5-tetrahydro-1H-pyridine [1,2-b ] cinnoline-9, 11(2H,11aH) -dione (Compound 22):
Figure 577845DEST_PATH_IMAGE025
compound 1a (23.0 g, 99.9 mmol), DMSO (230 mL), cyclohexanone (29.42 g, 299.72 mmol, 31.06 mL,) and pyrrolidine (7.11 g, 99.9 mmol, 8.34 mL) were added together to a reaction flask in a system of 40~Stirring at 50 ℃ for 12 hours. The TLC (ethyl acetate: methanol =20:1, Rf (R1) = 0.8) dot plate monitors the completion of the compound 1 reaction. The reaction was diluted with 200mL of DCM, washed with 1N dilute hydrochloric acid (200mL), separated and the organic phase was washed with saturated aqueous sodium bicarbonate (200mL × 2) and saturated aqueous NaCl (100 mL × 3). The organic phase was concentrated to give crude product which was isolated and purified by column chromatography, LCMS showed target m/z was produced. Compound 1b (13.0 g, 39.6 mmol, 39.6% yield, yellow oil, nuclear magnetic confirmed structure) was obtained.1H NMR: (400 MHz, CDCl3) δ 7.75 - 7.68 (m, 1H), 7.44 - 7.35 (m, 5H), 6.45 - 6.40 (m, 1H), 5.34 - 5.20 (m, 2H), 5.13 (d, J = 11.2 Hz, 0.6H), 5.07 - 5.02 (m, 0.6H), 3.58 (d, J = 4.4 Hz, 0.6H), 3.22 (s, 0.6H), 2.79 - 2.69 (m, 0.7H), 2.60 (d, J = 5.0 Hz, 0.3H), 2.51 - 2.21 (m, 2.7H), 2.11 - 2.01 (m, 1.6H), 1.92 - 1.46 (m, 7H), 1.29 - 1.25 (m, 0.4H), 1.20 (s, 2H)。
Compound 1b (5.00 g, 15.2 mmol), MeOH (75 mL), H2O (37 mL) and 2,2,2-trifluoroacetohydrazide (3.90 g, 30.5 mmol) were added together in a reaction flask, system 40~Stir at 50 ℃ for 5 hours. LCMS showed target m/z generation. Saturated aqueous NaCl solution for reaction solution(20 mL. multidot.2) and the organic phase was concentrated to give a crude product which was isolated and purified by column chromatography to give compound 1c (2.50 g, 7.71 mmol, 50.6% yield, yellow solid, nuclear magnetic confirmation of structure).1H NMR: (400 MHz, CDCl3) δ 7.66 - 7.57 (m, 1H), 7.37 - 7.29 (m, 5H), 6.47 - 6.39 (m, 1H), 5.46 - 5.35 (m, 1H), 5.33 - 5.27 (m, 0.4H), 5.08 (d, J = 11.6 Hz, 0.6H), 4.61 (d, J = 3.4 Hz, 0.6H), 4.48 (d, J = 2.6 Hz, 0.4H), 2.79 - 2.51 (m, 1H), 2.44 - 1.15 (m, 9H)。
Compound 1c (2.50 g, 7.71 mmol) was dissolved in 25mL of methanol at 0~Adding NaBH into the system at 5 DEG4(0.47 g, 12.42 mmol) in a 20 nd system~30 0C stirred for 1 hour. LCMS showed target m/z generation. At 0~5 0Add 2mL of water to the system at C, then 20~300C, stirring for half an hour, concentrating the reaction solution, filtering, and spin-drying a filter cake to obtain a compound 1d (1.70 g, 5.21 mmol, 67.6% yield, yellow solid, nuclear magnetic confirmation structure).1H NMR: (400 MHz, DMSO-d6) δ 7.51 - 7.31 (m, 6H), 6.44 (d, J = 11.5 Hz, 1H), 6.20 - 6.12 (m, 1H), 5.44 - 5.31 (m, 1.3H), 5.19 (d, J = 10.8 Hz, 0.7H), 5.07 (d, J = 10.9 Hz, 1H), 4.69 - 4.61 (m, 0.7H), 4.48 - 4.40 (m, 0.3H), 3.57 - 3.47 (m, 0.2H), 3.17 - 3.00 (m, 0.8H), 1.84 (br s, 9H)。
Compound 1d (3 g, 9.19 mmol), ACN (30 mL), Cs2CO3(2.99 g, 9.19 mmol) and 11-chloro-7, 8-difluoro-6, 11-dihydrodibenzo [ b, e ]]The thiazepine (5.20 g, 18.38 mmol) was added together in a reaction flask and the system was at 20~Stirring at 30 ℃ for 12 hours. LCMS showed target m/z generation. The reaction was concentrated to give crude which was prepared by reverse phase (column: Phenomenex luna C18250 x50 mm x10 um; mobile phase: [ water (0.225% FA) -ACN)]30-70 percent of B percent, 25 min) to obtain a compound 1e (2 g, 3.49 mmol, 38.00 percent of yield, yellow solid and nuclear magnetic confirmation structure).1H NMR: (400 MHz, DMSO-d6) δ 7.36 - 7.30 (br s，5H), 7.19-7.02 (m, 5H),6.83-6.77（m，2H），6.29（br s，1H）， 5.86-5.82（d，J=16Hz，1H），5.76（s，1H），5.54-5.52（d，J=8Hz，1H），5.14-5.12（d，J=8Hz，2H），4.52（br s，1H），4.06-4.03（d，J=12Hz,1H）, 2.98-2.92(m,1H),1.53-0.73(m,8H)。
Dissolve Compound 1e (2 g, 3.49 mmol) in a reaction flask with 6mL of DCM at 0~At 5 deg.C, add DMP (1.48 g, 3.49 mmol) and NaHCO to the system3(293.40 mg, 3.49 mmol) in 20~30 0C stirred for 1 hour. LCMS showed target m/z generation. The reaction solution was saturated with Na2S2O3 Aqueous solution (10 mL. multidot.3) and saturated NaHCO3Washing with aqueous solution (10 mL. times.3), extracting with 10mL of ethyl acetate, concentrating the organic phase to give crude product, and separating and purifying the crude product by column chromatography (petroleum ether: ethyl acetate =1:1, R)f (P1) = 0.60, Rf (P2) = 0.55) to give peak1 compound 1f (0.4 g, 700.96 umol, 20.07% yield, yellow solid, Rf = 0.60, nuclear magnetic confirmed structure).1H NMR: (400 MHz, DMSO-d6) δ 7.46 - 7.11 (m，11H), 6.83（br s，2H），5.76（d，J=8Hz，1H），5.72（s，1H），5.44（d，J=12Hz，1H）,5.24（s，2H），4.08（d，J=12Hz,1H）,2.50-0.62(m,9H)。
A solution of compound 1f (50 mg, 0.088 mmol), LiCl (18.6 mg, 0.44 mmol) in DMSO (4 mL), water (0.5 mL) was dissolved at 140 deg.C0C, stirring for 2 hours; LCMS showed reaction complete; adding water (10mL), extracting with ethyl acetate (20 mL. times.2), washing with brine (10 mL. times.2), and concentrating; the residue was purified by column chromatography and further purified by preparative liquid chromatography to give compound 22 (13 mg, 0.027 mmol) as an off-white solid in 31% yield, ESI-MS: M/z 481.1 (M + 1).
Chiral resolution of compound 22 (84 mg) gave isomer 1 (12 mg) as a yellow solid, 99% pure, 83.3% ee, and confirmed structure by nuclear magnetic and mass spectrometry; and isomer 2 (impure). Peak 1:1H NMR: (400 MHz, CDCl3) δ7.23（d，J=7.6Hz，1H），7.12-7.15（m，3H），7.07-7.09（m，1H），6.93（br s，1H），6.83-6.89（m，1H），6.22（d，J=6.8Hz,1H）, 5.44（br s，1H）， 5.37（d，J=13.2Hz，1H），4.10（d，J=13.6Hz，1H）， 3.49（d，J=14.0Hz，1H），3.42-3.44（m，1H），2.72（d，J=13.2Hz，1H），1.97-1.98（m，1H），1.80（br s，1H）， 1.55-1.60（m，1H）， 1.25-1.32（m，3H）， 0.95-0.99（m，1H）; ESI-MS: m/z 481.1 （M+1）。
isomer 2 (impure) was again resolved chirally to give isomer 2 (22 mg) as a yellow solid, 97% pure, 92.9% ee, with nuclear and mass spectral confirmation of structure.1H NMR: (400 MHz, CDCl3) δ6.99-7.27（m，6H），6.78-6.79（m，1H），6.65-6.67（m，1H），5.67-5.73（m，1H），5.46（d，J=14Hz，1H），5.18（s，1H），4.05（d，J=7.6Hz，1H），3.30-3.33（m，1H），3.18（br s，1H），2.66-2.69（m，1H），2.30-2.36（m，2H），1.75-1.93（m，3H），0.87-0.99（m，1H）；ESI-MS: m/z 481.1 （M+1）。
Chiral resolution of compound 22 (64 mg) gave isomer 3(19 mg) as a yellow solid, 94.7% pure, and confirmed structure by nuclear magnetic and mass spectrometry; and isomer 4 (impure).1H NMR: (400 MHz, CDCl3) δ7.41（d，J=7.6Hz，1H），7.12-7.15（m，2H），6.93-6.97（m，2H），6.73-6.74（m，1H），6.33-6.35（m，1H），5.58（d，J=14Hz，1H），5.32（s，1H）, 4.22（d，J=11.6Hz，1H），3.37-3.43（m，2H），2.60（d，J=13.2Hz，1H），2.08-2.10（m，1H），1.80（d，J=9.2Hz，1H），1.53（d，J=13.6Hz，1H），1.25-1.32（m，3H），1.13-1.17（m，1H），0.89-0.96（m，1H）; ESI-MS: m/z 481.1 （M+1）。
Isomer 4 (impure) was again resolved chirally to give isomer 4 (12 mg) as a yellow solid, 90.3% pure, with nuclear magnetic and mass spectral confirmation of structure.1H NMR: (400 MHz, CDCl3) δ7.13-7.18（m，2H），6.91-6.96（m，2H），6.82（d，J=7.6Hz，1H），6.58-6.66（m，1H），5.95（d，J=7.2Hz，1H），5.62（d，J=13.2Hz, 1H），5.04-5.08（m，1H），4.20（d，J=13.6Hz，1H），3.36-3.38（m，1H），3.24（br s，1H），2.60（d，J=12.8Hz，1H），1.98-2.07（m，1H），1.61-1.78（m，1H），1.50-1.54（m，1H），1.07-1.14（m，4H），0.87-0.89（m，1H）; ESI-MS: m/z 481.1 （M+1）。
Example 4: screening experiment of compound in vitro anti-influenza virus activity
In the following examples, the inventors conducted experiments using cytopathic effect (CPE) using a part of the compounds of the present invention as examples, and examined the antiviral activity of the compounds against influenza virus a/WSN/33 (H1N1) and the toxicity against MDCK cells.
The following acronyms are used throughout this embodiment
Figure 590801DEST_PATH_IMAGE026
1. Test materials
1.1 Compounds
Compounds were made up in 100% DMSO solution in 20mM stock. Compounds were tested at 8 concentration points, 4-fold gradient dilution, duplicate wells. The initial test concentrations are shown in table 1.
Figure 942148DEST_PATH_IMAGE027
Cell line
MDCK canine kidney cells were purchased from ATCC. Cells were cultured in EMEM medium (Sigma) supplemented with 10% fetal bovine serum (Hyclone), 2 mM L-glutamine (Gibco), 1% non-essential amino acids (Gibco), 100U/ml penicillin and 100. mu.g/ml streptomycin (Hyclone). OptiPRO SFM medium (Gibco) supplemented with 2 mM L-glutamine, 1% non-essential amino acids, 100U/ml penicillin and 100. mu.g/ml streptomycin was used as the test medium.
Viral strains
Influenza A/WSN/33 (H1N1) strains were purchased from Virapur.
Reagent
The main reagent used in the project is a cell viability detection kit CCK8 (Shanghai Liji biology)
1.5 instruments
The main instrument used in the project is a microplate reader SpectraMax340PC384 (Molecular Device).
Test method
CPE refers to the phenomenon of massive proliferation of the virus in the host cell, leading to cytopathic and even death. By measuring cell viability, the CPE assay is widely used to determine the inhibitory activity of compounds against viruses that cause cytopathic effects. The in vitro inhibitory activity of compounds against influenza A/WSN/33 (H1N1) was tested using the CPE assay. The virus assay methods are summarized in table 2.
Figure 560211DEST_PATH_IMAGE028
MDCK cells were plated at a density of 2,000 cells per well in 384-well cell culture plates and in 5% CO2And cultured overnight in an incubator at 37 ℃. The next day compounds (8 concentration points, 4-fold gradient dilution, double-well) and virus (MOI = 0.04) were added, respectively. The final concentrations of DMSO and pancreatin in the cell culture broth were 0.5% and 2.5. mu.g/ml, respectively. Cells were incubated at 37 ℃ with 5% CO2The culture was continued for 5 days under the conditions until the cytopathic rate in the virus control wells (cells infected with virus, no compound treatment) reached 80-95%. The cytotoxicity test and the antiviral test are carried out simultaneously, the test conditions are consistent, but no virus infection exists.
Cell viability was measured using cell viability assay reagent CCK 8. The antiviral activity and cytotoxicity of the compound are represented by the inhibition rate (%) and cell viability (%) of the compound against the viral-induced cytopathic effect, respectively. The calculation formula is as follows:
Figure 96234DEST_PATH_IMAGE029
note: sample well: compound treating the wells;
virus control wells: cells infected with virus, no compound treatment;
cell control wells: cells, no compound treatment or viral infection;
culture solution control wells: only the culture broth, without cells, viruses or compounds.
Nonlinear fitting analysis of the inhibition rate and cell viability rate of the compound was performed using GraphPad Prism (version 5) software to obtain the EC of the compound50And CC50The value is obtained.
Results
The activity and cytotoxicity of the compounds against influenza A virus/WSN/33 (H1N1) and MDCK are summarized in Table 3.
Figure 330907DEST_PATH_IMAGE030
As is clear from tables 1 and 2, the results of the experiments show that the above-mentioned compounds have excellent inhibitory activity against influenza A virus/WSN/33 (H1N 1).
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
Although embodiments of the present invention have been shown and described above, it is understood that the above embodiments are exemplary and should not be construed as limiting the present invention, and that variations, modifications, substitutions and alterations can be made to the above embodiments by those of ordinary skill in the art within the scope of the present invention.

Claims (10)

1. A compound shown in a general formula I and pharmaceutically acceptable salts, solvates, hydrates, polycrystals, prodrugs, cocrystals, tautomers and stereoisomers thereof,
Figure 867603DEST_PATH_IMAGE001
wherein R is1: is H or-C (═ O) Y1、-C(＝O)-O-Y1、-(CH2)-O-(C＝O)-Y1、-(CH2)-O-(C＝O)-O-Y1、-(CHCH3)-O-(C＝O)-Y1And- (CHCH)3)-O-(C＝O)-O-Y1；
Y1Is optionally substituted C1-10Alkyl, optionally substituted C3-8Cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, mono-substituted amino group, di-substituted amino and-C (R)*)2NHR**(ii) a And each R*And R**Independently is hydrogen or optionally substituted C1-6An alkyl group;
R2and R3Can be independently H, C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN、-COOR*、-OR*、-(CH2)qNR*R**,-C(O)-NR*R**；R2And R3May be linked to form a ring to form an optionally substituted cycloalkyl, an optionally substituted heterocyclyl and an optionally substituted cycloalkenyl; r*And R**Independently H and optionally substituted C1-6An alkyl group; q is 0 to 6;
R4is a structure shown in the following formula
Figure 461396DEST_PATH_IMAGE002
R9And R10Is optionally substituted aryl, and optionally substituted heteroaryl; wherein the substituents are independent C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN、-COOR*、-OR*、-(CH2)qNR*R**,-C(O)-NR*R**；R*And R**Independently H and optionally substituted C1-6Alkyl, q is0-6；
R9And R10Can be connected to form the structure shown as follows:
Figure 663707DEST_PATH_IMAGE003
wherein n and m may independently be 0-3, Q is CR*R**、 NR*、O、S、SO、SO2；R*And R**Independently H and optionally substituted C1-6An alkyl group;
R5,R6is H or is selected from optionally substituted C1-8Alkyl, optionally substituted C2-8Alkenyl, optionally substituted heterocyclic group, optionally substituted C3-8Cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; wherein the substituents may be independent C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN、-COOR*、-OR*、-(CH2)qNR*R**,-C(O)-NR*R**Wherein R is*And R**Independently H and optionally substituted C1-6Alkyl, q is 0 to 6;
R7,R8: is H, C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN、-COOR*、-OR*、-(CH2)qNR*R**,-C(O)-NR*R**；R*And R**Independently H and optionally substituted C1-6An alkyl group; q is 0 to 6; r5、R7Or R6、R8May be joined as a 5-to 8-membered saturated or unsaturated ring, for example a 6-membered ring, which may be carbocyclic or contain an O, N heterocyclic ring.
2. The compound shown in the general formula I and pharmaceutically acceptable salts and solvates thereof comprise hydrates, polycrystals, prodrugs, cocrystals, tautomers and stereoisomers,
wherein the content of the first and second substances,
R1: is H;
R2and R3Can be independently H, C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN、-COOR*、-OR*；R2And R3Optionally substituted cycloalkyl, optionally substituted heterocyclyl and optionally substituted cycloalkenyl can be formed, R*Independently H and optionally substituted C1-6An alkyl group;
R4is a structure shown in the following formula
Figure 306041DEST_PATH_IMAGE002
R9And R10Are optionally substituted aryl, and optionally substituted heteroaryl, which may be joined to form the structure shown below:
Figure 582301DEST_PATH_IMAGE003
wherein n and m may independently be 0-3, Q is CR*R**、 NR*、O、S、SO、SO2；R*And R** Independently H and optionally substituted C1-6An alkyl group;
R5,R6is H or is selected from optionally substituted C1-8Alkyl, optionally substituted C2-8Alkenyl, optionally substituted heterocyclic group, optionally substituted C3-8A cycloalkyl group; wherein the substituents may be independent C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN、-COOR*、-OR*，R*Independently H and optionally substituted C1-6An alkyl group;
R7,R8can be independently H, C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN；
R5、R7Or R6、R8May be joined as a 5-to 8-membered saturated or unsaturated ring, for example a 6-membered ring, which may be carbocyclic or contain an O, N heterocyclic ring.
3. The compound shown in the general formula I and pharmaceutically acceptable salts and solvates thereof comprise hydrates, polycrystals, prodrugs, cocrystals, tautomers and stereoisomers,
wherein the content of the first and second substances,
R1: is H;
R2and R3Can be independently H, C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN；
R4Is a structure shown in the following formula
Figure 143733DEST_PATH_IMAGE002
R9And R10Are optionally substituted aryl, and optionally substituted heteroaryl, which may be joined to form the structure shown below:
Figure 708706DEST_PATH_IMAGE003
wherein n and m may independently be 0-3, Q is O, S, SO2；
R5，R6Optionally substituted C1-8Alkyl, optionally substituted C2-8Alkenyl, optionally substituted heterocyclyl,
Optionally substituted C3-8A cycloalkyl group; wherein the substituents may be independent C1-6Alkyl, -C (O) -C1-6
Alkyl, halogen, -CF3、-CN；
R7,R8Can be independently H, C1-6An alkyl group;
R5、R7or R6、R8May be joined to form a 5-to 8-membered ring, for example a 6-membered ring, which may be carbocyclic or contain O, N heterocycles.
4. The compounds according to formula I and pharmaceutically acceptable salts, solvates thereof include hydrates, polymorphs, prodrugs, co-crystals, tautomers, stereoisomers:
wherein the content of the first and second substances,
R1: is H;
R2and R3Can be independently C1-6Alkyl, halogen, -CF3、-CN；
R4Is a structure shown in the following formula
Figure 4997DEST_PATH_IMAGE002
R9And R10Are optionally substituted aryl, and optionally substituted heteroaryl, which may be joined to form the structure shown below:
Figure 666922DEST_PATH_IMAGE003
wherein n and m may independently be 0-3, Q is O, S;
R5,R6is H or is selected from optionally substituted C1-8Alkyl, optionally substituted C2-8Alkenyl, optionally substituted heterocyclic group, optionally substituted C3-8A cycloalkyl group; wherein the substituents may be independent C1-6Alkyl, -C (O) -C1-6Alkyl, halogen, -CF3、-CN；
R7,R8Can be independently H, C1-6An alkyl group;
R5、R7or R6、R8May be linked to form a ring to form an optionally substituted cycloalkyl group.
5. A compound according to formula I and pharmaceutically acceptable salts, solvates, hydrates, polymorphs, prodrugs, co-crystals, tautomers, stereoisomers thereof, said compound being selected from the group consisting of:
Figure 71359DEST_PATH_IMAGE004
。
6. a pharmaceutical composition comprising an effective amount of a compound of any one of claims 1-5, and pharmaceutically acceptable salts, solvates, including hydrates, polymorphs, prodrugs, co-crystals, tautomers, stereoisomers, pharmaceutical compositions thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combinations thereof.
7. A method for preventing, ameliorating or treating a viral infection comprising administering an effective amount of a compound according to any one of claims 1-5, and pharmaceutically acceptable salts, solvates, including hydrates, polymorphs, prodrugs, co-crystals, tautomers, stereoisomers, pharmaceutical compositions thereof.
8. A method for preventing, ameliorating or treating influenza virus infection, the method comprising administering an effective amount of a compound according to any one of claims 1-5, and pharmaceutically acceptable salts, solvates, including hydrates, polymorphs, prodrugs, co-crystals, tautomers, stereoisomers, pharmaceutical compositions thereof.
9. A method of preventing, ameliorating or treating influenza virus infection in a combination medicament, wherein one medicament is a compound of any one of claims 1-5, and pharmaceutically acceptable salts, solvates, including hydrates, polymorphs, prodrugs, co-crystals, tautomers, stereoisomers thereof; the other medicine is one or more medicines for inhibiting replication of influenza virus infection, and is selected from neuraminidase inhibitor, M2 protein inhibitor, polymerase inhibitor, PB2Inhibitors, immunomodulators; such as zanamivir, oseltamivir, peramivir, laninamivir octanoate, faviravir, beraprost, ribavirin.
10. Use of a compound of any one of claims 1-5, and pharmaceutically acceptable salts, solvates, including hydrates, polymorphs, prodrugs, co-crystals, tautomers, stereoisomers, for the manufacture of a medicament for the treatment and/or prevention, alleviation or treatment of influenza virus infection.
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