Baricitinib derivatives and uses thereof

Abstract

The application discloses a baloxavir derivative and a use thereof, and belongs to the field of pharmacy. The baloxavir derivative, a stereoisomer, a crystalline hydrate, a deuterium derivative, a solvate, a prodrug, a pharmaceutically acceptable salt of the baloxavir derivative, and a structure formula of the baloxavir derivative are shown as formula I, wherein sEH inhibitor is a residue after esterification of a soluble epoxide hydrolase inhibitor. The use is a use of the baloxavir derivative or a pharmaceutical composition thereof in preparation of anti-inflammatory and antiviral drugs. The application simultaneously inhibits an NF-kappa B pathway and targets a viral cap-dependent endonuclease by synthesizing a twin drug by connecting a series of sEH inhibitors with BAX to exert a double role of anti-inflammation and antiviral. New compounds with anti-inflammatory and antiviral activities are identified in vitro and in vivo.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmacy, and relates to a baloxavir derivative and use thereof. BACKGROUND

[0002] Seasonal influenza is an acute respiratory infectious disease caused by influenza virus, which is highly contagious and rapidly spreading, and is a major global public health problem. Most hospitalizations and deaths are attributed to complications such as pulmonary fibrosis, bacterial pneumonia, acute respiratory distress syndrome, and congestive heart failure. In the early stage of influenza virus infection, influenza can induce upregulation of TLR3 protein levels, activate the NF-κB signaling pathway and mitochondrial-associated oxidative stress, and then cause the host's immune system, thereby activating the inflammatory response to eliminate the virus. However, the production of inflammatory mediators does not decrease with the decrease in viral load, resulting in the accumulation of excessive inflammatory cytokines in the later stage of infection, which can cause further damage to the host. The currently approved anti-influenza drugs do not address the host's excessive inflammatory response, highlighting the urgent need to take strategies to alleviate this response during viral infection. High-dose glucocorticoid therapy has been shown to alleviate lung injury in patients with severe influenza pneumonia, however, it can also reduce viral clearance and prolong recovery time. The combined use of antiviral drugs and anti-inflammatory drugs can raise concerns about drug metabolism-related side effects, particularly the potential for liver and kidney damage. In addition, when multiple drugs need to be taken, patients often show poor compliance. Therefore, the applicant proposes a new method to combine antiviral and anti-inflammatory compounds into one entity to achieve both therapeutic effects in the treatment of influenza virus infection.

[0003] Baloxavir marboxil (MBAX) is currently the first EU-approved single-dose oral antiviral drug for children, which is used for the treatment of uncomplicated influenza and post-exposure prophylaxis in people aged 1 year and older. The active form of baloxavir acid inhibits the transcription of influenza virus by blocking the endonuclease activity of the PA protein. The keto-enol structure of baloxavir (BAX) has very low intestinal membrane transport rate due to its hydrophilicity. In order to improve the bioavailability of baloxavir, the hydroxyl group in the keto-enol structure is replaced, forming baloxavir ester.

[0004] EETs, which are metabolized by cytochrome P450s enzyme pathway of arachidonic acid (AA), are closely related to inflammation. Studies have found that inhibition of NF-κB activity is the key to the anti-inflammatory effect of EpFAs including EETs. There are three ways for EETs to inhibit the activity of NF-κB: first, by inhibiting the activation of NF-κB by tumor necrosis factor (TNF-α) through inhibiting IκB kinase; second, by inhibiting the transcription of NF-κB and AP-1 through activating PPARγ; and third, by directly inhibiting the activity of inflammatory factor PGE2 downstream of the NF-κB signaling pathway, which is an effect that non-steroidal anti-inflammatory drugs and steroidal anti-inflammatory drugs do not have. EETs produced by the CYP450 metabolic pathway of AA have many physiological functions, such as anti-inflammatory, analgesic, anti-ischemic, anti-angiogenic, anti-proliferative, cardiovascular protection, and metabolic disease regulation. EETs and the pro-inflammatory metabolites of prostaglandins and leukotrienes formed by the COX and LOX metabolic pathways of AA form the pro-inflammatory / anti-inflammatory balance of the body, and play a very important role in maintaining the balance of inflammation / anti-inflammation in the body. sEH inhibitors can stabilize endogenous EpFAs (EETs), so sEH is a potential therapeutic target for pain and inflammatory diseases.

[0005] After searching, it has not been found that the sEH inhibitor is connected with BAX to synthesize a twin drug to simultaneously inhibit the NF-κB pathway and target viral cap-dependent endonuclease to exert the dual effects of anti-inflammatory and anti-viral. SUMMARY

[0006] The present application connects a series of sEH inhibitors with BAX to synthesize a twin drug to simultaneously inhibit the NF-κB pathway and target viral cap-dependent endonuclease to exert the dual effects of anti-inflammatory and anti-viral, and identifies new compounds with anti-inflammatory and anti-viral activity in vitro and in vivo.

[0007] In order to achieve the above-mentioned purpose, the technical scheme adopted by the present application is as follows.

[0008] In a first aspect, the present application provides a baloxavir derivative, a stereoisomer thereof, a crystalline hydrate thereof, a deuterated compound thereof, a solvate thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof,

[0009] The structural formula of the baloxavir derivative is shown as formula I:

[0010]

[0011] wherein sEH inhibitor is the residue after esterification of a soluble epoxide hydrolase inhibitor.

[0012] Preferably, the soluble epoxide hydrolase inhibitor contains a substituted benzene ring or a substituted adamantane.

[0013] Preferably, the soluble epoxide hydrolase inhibitor is at least one of t-AUCB, 12-{[(tricyclo[3.3.1.13dec-1-ylamino)carbonyl]amino}dodecanoic acid (AUDA), (S)-1-(4-(3-(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylic acid, 7-{[(tricyclo[3.3.1.13dec-1-ylamino)carbonyl]amino}heptanoic acid, 4-(((1r,4r)-4-(2-(3-fluoro-4-(trifluoromethoxy)phenyl)acetamido)cyclohexyl)oxy)benzoic acid, t-TUCB, 12-({[(1,3-dimethyltricyclo[3.3.1.13dec-7-yl)amino]carbonyl}amino)dodecanoic acid, 12-{[({4-[(trifluoromethyl)oxy]phenyl}amino)carbonyl]amino}dodecanoic acid, 12-{[({3-fluoro-4-[(trifluoromethyl)oxy]phenyl}amino)carbonyl]amino}dodecanoic acid, 11-{[(tricyclo[3.3.1.13dec-1-ylamino)carbonyl]amino}undecanoic acid, 11-({[(3,5-dimethyltricyclo[3.3.1.13dec-1-yl)amino]carbonyl}amino)undecanoic acid, 8-{[(tricyclo[3.3.1.13dec-3-ylamino)carbonyl]amino}octanoic acid, 12-[({[1-(tricyclo[3.3.1.13dec-1-yl)ethyl]amino}carbonyl)amino]dodecanoic acid, 12-[({[1-(tricyclo[3.3.1.13dec-1-yl)ethyl]amino}carbonyl)amino]dodecanoic acid, 12-({[(bicyclo[2.2.1]hept-2-en-6-ylmethyl)amino]carbonyl}amino)dodecanoic acid. 3,7 3,7 3,7 3,7 3,7 3,7 3,7 3,7 In some embodiments, the compound of Formula I is selected from the following compounds:

[0014]

[0015]

[0016]

[0017] In a second aspect, the present application provides a pharmaceutical composition comprising the above-mentioned baloxavir derivative, stereoisomer, crystalline hydrate, deuterated compound, solvate, prodrug or pharmaceutically acceptable salt thereof.

[0018] Preferably, the pharmaceutical composition further comprises a traditional Chinese medicine component and / or a western medicine component.

[0019] ​​​​​​​​Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier.

[0020] Preferably, the pharmaceutical composition is a tablet, a pill, a cream, a lotion, an ointment, a suspension, a lyophilized agent, a capsule, a sustained-release agent, a granule, a powder, an injection agent or a spray.

[0021] In a third aspect, the present application provides use of the above-mentioned baloxavir derivatives, stereoisomers thereof, crystalline hydrates thereof, deuterium derivatives thereof, solvates thereof, prodrugs thereof, pharmaceutically acceptable salts thereof or pharmaceutical compositions in the preparation of anti-inflammatory and antiviral drugs.

[0022] Preferably, the virus is an influenza virus.

[0023] Further preferably, the influenza virus is an influenza A virus and / or an influenza B virus.

[0024] Further preferably, the influenza virus is at least one of H1N1, H5N1, H7N9, H3N2 and an influenza B virus.

[0025] Further preferably, the influenza virus is at least one of H1N1, H3N2 or an influenza B virus.

[0026] In a fourth aspect, the present application provides use of the above-mentioned baloxavir derivatives, stereoisomers thereof, crystalline hydrates thereof, deuterium derivatives thereof, solvates thereof, prodrugs thereof or pharmaceutically acceptable salts thereof or pharmaceutical compositions in the preparation of NF-κB signaling pathway inhibitors.

[0027] The anti-inflammatory and antiviral drugs or NF-κB signaling pathway inhibitors in the present application are suitable for humans or animals.

[0028] Preferably, the animals include bovids, equids, ovines, porcines, canids, felids, leporids, avian animals, rodents or primates.

[0029] Advantages of the present application

[0030] (1) The present application simultaneously inhibits the NF-κB pathway and targets viral cap-dependent endonuclease by synthesizing a twin drug by connecting a series of sEH inhibitors with BAX to exert the dual effects of anti-inflammation and antiviral, and identifies new compounds with anti-inflammatory and antiviral activity in vitro and in vivo.

[0031] (2) Compared with BAX and MBAX, the baloxavir derivatives of the present application have better anti-influenza virus effects.

[0032] (3) The widely used anti-viral drugs in clinic, such as oseltamivir and baloxavir, are all recommended to be administered within 48 hours after infection to effectively protect influenza patients. The baloxavir derivative of the present application still has good protective effect when administered within 48-96 hours after influenza virus infection. BRIEF DESCRIPTION OF DRAWINGS

[0033] Figure 1 Inhibition of H1N1 virus protein expression by MBAX, ATV-114 and AUDA in cell lines with high and low AADAC enzyme expression.

[0034] Figure 2 Anti-inflammatory activity of ATV-114 by inhibiting NF-κB signaling, wherein A is the inhibition of LPS-induced inflammatory protein expression in RAW264.7 cells by different concentrations of MBAX, ATV-114 and AUDA, and B is the inhibition of LPS-induced NF-κB transcriptional activation in RAW264.7 cells transfected with NF-κB luciferase reporter plasmid by different concentrations of MBAX, ATV-114 and AUDA.

[0035] Figure 3 Preventing nuclear export of RNP by inhibiting nuclear translocation of NF-κB by ATV-114.

[0036] Figure 4 Anti-influenza virus effect, wherein A is the body weight change within 14 days after 12h oral administration after infection of mice with A / PR / 8 / 34, B is the survival within 14 days after 12h oral administration after infection of mice with A / PR / 8 / 34, C is the body weight change within 14 days after oral administration at different time points of 48, 72, 96h after infection of mice with A / PR / 8 / 34, D is the survival within 14 days after oral administration at different time points of 48, 72, 96h after infection of mice with A / PR / 8 / 34, E is the body weight change within 14 days after 12h oral administration after infection of mice with A / PR / 8 / 34 with NA-H274Y strain, and F is the body weight change within 14 days after 12h oral administration after infection of mice with A / PR / 8 / 34 with NA-H274Y strain. DETAILED DESCRIPTION

[0037] TERMS

[0038] The following terms and phrases, as used herein, have the following meanings, unless otherwise stated:

[0039] "Room temperature" in the present invention refers to ambient temperature, which is from 10 °C to 40 °C. In some embodiments, "room temperature" refers to a temperature from 20 °C to 30 °C; in other embodiments, "room temperature" refers to a temperature from 25 °C to 30 °C; in yet other embodiments, "room temperature" refers to 10 °C, 15 °C, 20 °C, 25 °C, 30 °C, 35 °C, 40 °C, etc.

[0040] "Residue after esterification" in the present invention refers to the fragment remaining after the carboxyl group of the soluble epoxide hydrolase inhibitor forms an ester linkage with the hydroxyl group of baloxavir.

[0041] Baloxavir derivatives

[0042] "Stereoisomers" refer to compounds which have the same chemical constitution, but differ in the arrangement of atoms or groups in space. Stereoisomers include enantiomers, diastereomers, conformers (rotamers), geometric isomers (cis / trans) isomers, atropisomers, etc.

[0043] The compounds of Formula I in the present invention can have chiral centers, such as chiral carbons. The compounds thus include racemic mixtures of all stereoisomers, including enantiomers, diastereomers, and atropisomers. In addition, the compounds of the present invention include optically active isomers which are enriched or resolved at any or all of the asymmetric chiral atoms. In other words, the approximate chiral centers are provided as chiral isomers or racemic mixtures. Mixtures of racemic and diastereomeric forms, as well as isolated or synthetic, substantially optically pure isomers, are within the scope of the present invention. The racemic mixtures are separated into their individual, substantially optically pure isomers by known techniques, such as, for example, salt formation with an optically active base (e.g., acid or base) which is then converted back to the optically active material. In most cases, the synthesis of the desired optically active isomer is achieved by chiral specific reactions starting from the appropriate stereoisomer of the desired starting material.

[0044] "Hydrate" refers to an association including solvent molecules which are water.

[0045] "Deuterated" is one or more hydrogens in a compound or group are replaced by deuterium. Deuterated can be mono-substituted, di-substituted, poly-substituted, or per-substituted.

[0046] "Solvate" refers to an association including 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, and aminoethanol.

[0047] "Prodrug" is used in its broadest sense and includes those derivatives that are transformed in vivo to the compounds of the application. Such derivatives would be obvious to those skilled in the art in view of the teachings herein and include, for example, those described by E. Roche, in "Prodrugs as Novel Delivery Systems," Vol. 14, ACS Symposium Series, 1989. The most commonly used prodrugs are ester derivatives, but other prodrugs are also available.

[0048] Preferred prodrugs are those that increase the bioavailability of the compounds of this application when such compounds are administered to a patient (e.g., by allowing an orally administered compound to be more readily absorbed into the blood) or enhance delivery of the parent compound to a biological compartment (e.g., the brain or lymphatic system) relative to the parent species.

[0049] The compounds of the application can be in crystalline form either as individual compounds or as solvates either as hydrates or with other solvents. Methods of solvation are well known in the art. Suitable solvates are pharmaceutically acceptable solvates.

[0050] "Pharmaceutically acceptable" means a molecular entity and composition that is physiologically tolerable and does not typically produce an allergic or similar untoward reaction, such as gastrointestinal upset, dizziness, and the like, when administered to a human. Preferably, the term "pharmaceutically acceptable" as used herein means approved by a regulatory agency of the Federal or a state government or listed in the Chinese Pharmacopoeia, the U.S. Pharmacopeia, or other generally recognized pharmacopeia for use in animals, more particularly in humans.

[0051] "Pharmaceutically acceptable salts" include, for example, salts of appropriate bases derived from inorganic bases such as ammonium or alkali or alkaline earth hydroxides, for example, Na + , Li + , K + , Ca +2 , and Mg +2) and ammonium. Physiologically acceptable salts of nitrogen atoms or amino groups include: (a) acid addition salts with inorganic acids, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid and the like; (b) salts with organic acids, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, isethionic acid, lactobionic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid, malonic acid, sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate, pamoate, salicylic acid, stearic acid, phthalic acid, mandelic acid, lactic acid, ethanesulfonic acid, lysine, arginine, glutamic acid, glycine, serine, threonine, alanine, isoleucine, leucine and the like; and (c) salts with elemental anions, for example, chloride, bromide and iodide. Physiologically acceptable salts of hydroxyl compounds include the anion of the compound in combination with a suitable cation such as Na + and NR4 + a suitable cation.

[0052] For therapeutic use, the "acceptable" according to the present application are physiologically acceptable, i.e. they are salts derived from physiologically acceptable acids or bases. However, salts of acids or bases that are not physiologically acceptable can also be used, for example, in the preparation or purification of physiologically acceptable compounds. All salts, whether derived from physiologically acceptable acids or bases, are within the scope of the present application.

[0053] The compounds of Formula I or their pharmaceutically acceptable salts can exist as different polymorphs or pseudopolymorphs. As used herein, the term "polymorph" refers to the ability of a crystalline compound to exist in different crystal structures. Polymorphism can result from differences in packing of the same molecule in the crystal lattice (packing polymorphism) or from packing differences between different conformers of the same molecule (conformational polymorphism). As used herein, the term "pseudopolymorph" refers to the ability of a hydrate or solvate of a compound to exist in different crystal structures. Pseudopolymorphs of the present application can exist due to differences in packing of the crystal lattice (packing pseudopolymorphism) or due to packing differences between different conformers of the same molecule (conformational pseudopolymorphism). The present application encompasses all polymorphs and pseudopolymorphs of the compounds of Formula I and their pharmaceutically acceptable salts.

[0054] The compounds of Formula I or pharmaceutically acceptable salts thereof can also exist as amorphous solids. As used herein, an amorphous solid is one in which there is no long-range order of the positions of the atoms in the solid. This definition also applies when the crystal size is 2 nanometers or less. Additives, including solvents, can be used to establish the amorphous forms of the present application. The present application encompasses all amorphous forms of the compounds of Formula I and their pharmaceutically acceptable salts.

[0055] "Post-esterification residue" is the carboxylic acid fragment remaining after the ester linkage is formed between the carboxyl group of the soluble epoxide hydrolase inhibitor and the hydroxyl group of baloxavir.

[0056] "Substituted" is where one or more hydrogen atoms of a benzene ring or adamantane are each independently replaced by a non-hydrogen substituent.

[0057] Screening of compositions having anti-inflammatory and antiviral activity

[0058] The baloxavir derivatives described herein are useful for treating or preventing influenza virus infection in animals or humans. However, during the screening of compounds capable of anti-inflammatory and anti-influenza virus activity, cell-based and animal (rodent) assays are the primary screening tools.

[0059] Screening of compositions of the present application for baloxavir derivatives having anti-inflammatory and antiviral activity is performed by any conventional technique for evaluating anti-inflammatory and anti-influenza virus activity. In the context of the present application, typically, compositions are first screened for anti-inflammatory and antiviral activity, and then compositions exhibiting anti-inflammatory and antiviral activity are screened for in vivo activity. Compositions having an in vitro Ki (inhibition constant) of less than about 5 x 10 -6 M and preferably less than about 1 x 10 -7 Compositions having an in vitro Ki (inhibition constant) of less than about 5 x 10

[0060] Pharmaceutical compositions

[0061] The pharmaceutical compositions set forth herein comprise the baloxavir derivatives described above and pharmaceutically acceptable excipients. In certain embodiments, the baloxavir derivatives set forth herein are provided in the pharmaceutical compositions in an effective amount (e.g., a therapeutically effective amount).

[0062] The pharmaceutical compositions of the present application are formulated with conventional carriers and excipients, which are selected in accord with ordinary prudence with respect to the intended performance of the active ingredient. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical formulation. Formulations of the present application, whether for veterinary or human use, comprise at least one active ingredient as defined above together with one or more acceptable carriers therefore and optionally other therapeutic ingredients, especially additional therapeutic ingredients as disclosed herein. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not injurious to the subject in need thereof.

[0063] The pharmaceutical compositions set forth herein can be prepared by any of the methods known to the pharmaceutical art. In general, such preparative methods include the step of bringing into association the baricitinib derivative (i.e., the "active ingredient") with a carrier or excipient and / or one or more other accessory ingredients, and then, if necessary and / or desirable, shaping and / or packaging the product into a desired single- or multi-dose unit.

[0064] The pharmaceutical compositions of the present application can be prepared according to known methods, such as those set forth in the General Rules for Preparations of the Chinese Pharmacopoeia, Japanese Pharmacopoeia 16th Edition, United States Pharmacopoeia, and European Pharmacopoeia 9th Edition. Depending on the dosage form, the pharmaceutical compositions of the present application can be suitably administered to a patient.

[0065] The pharmaceutical compositions can be prepared, packaged, and / or sold in a bulk amount. Also, the pharmaceutical compositions can be prepared, packaged, and / or sold as a single unit dose. A "unit dose" is a discrete amount of the pharmaceutical composition comprising a predetermined quantity of an active ingredient. The quantity of the active ingredient is generally equal to a dose, or a fraction thereof, that is appropriate for administration of the active ingredient to a subject in need thereof.

[0066] The active ingredients, pharmaceutically acceptable excipients in the pharmaceutical compositions set forth herein will vary depending on the identity, size, and / or condition of the subject being treated and further depending on the route of administration of the composition. The pharmaceutical compositions can comprise between 0.1% and 100% (w / w) of the active ingredient.

[0067] The pharmaceutically acceptable excipients used in the preparation of the pharmaceutical compositions provided include inert diluents, dispersing and / or granulating agents, surface active agents and / or emulsifiers, disintegrants, binders, preservatives, buffers, lubricants, and / or oils. The pharmaceutical compositions can also contain excipients such as cocoa butter and suppository waxes, colorants, coatings, sweetening, flavoring, and perfuming agents.

[0068] The present application further provides veterinary compositions comprising at least one active ingredient as defined above and a veterinary carrier therefor.

[0069] The veterinary carrier is a substance with which the veterinary composition is administered and which acts as a vehicle to achieve some purpose and can be a solid, liquid or gaseous substance, which is furthermore inert or acceptable in the veterinary art and compatible with the active ingredient. These veterinary compositions can be administered orally, parenterally or by any other desired route.

[0070] The term "treatment" as used herein, unless otherwise indicated, means reversing, alleviating, lessening, inhibiting the progress of, or preventing the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment" as used herein refers to therapeutic treatment, as that term is defined immediately above.

[0071] An "effective amount" of a compound described herein is an amount sufficient to elicit the desired biological response. An effective amount of a compound described herein can vary depending on such factors as the desired biological endpoint, the pharmacokinetics of the compound, the disorder being treated, the mode of administration, and the age and health of the subject. In certain embodiments, an effective amount is a therapeutically effective amount. Alternatively, in separate methods or uses, the present application can be used prophylactically, where indicated and effective. In certain embodiments, an effective amount is the amount of a compound described herein in a single dose. In certain embodiments, an effective amount is the combined amount of a compound described herein in multiple doses.

[0072] A "therapeutically effective amount" as described herein is an amount that is sufficient to provide a therapeutic benefit in the treatment of a disorder or to delay or minimize one or more symptoms associated with the disorder. A therapeutically effective amount of a baloxavir derivative means an amount of a therapeutic agent that alone, or in combination with other therapies, provides a therapeutic benefit in the treatment of a disorder. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids symptoms, signs, or causes of a disorder, and / or enhances the therapeutic efficacy of another therapeutic agent. In certain embodiments, a therapeutically effective amount is an amount that is sufficient to treat any of the diseases or disorders described herein.

[0073] Route of administration

[0074] The compound(s) of the present application (referred to herein as the active ingredient) are administered by any route appropriate for the condition being treated, e.g., orally, rectally, nasally, pulmonarily, topically (including ophthalmically), and by parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural) routes, etc. It will be appreciated that the preferred route can vary with, for example, the condition being treated. The compounds of the present application are of benefit in that they are orally bioavailable and can be administered orally.

[0075] It should also be noted that the specific dosage and method of use of the baloxavir derivative for each patient will depend on many factors, including the patient's age, weight, sex, natural health, nutritional status, potency of the drug, time of administration, metabolic rate, severity of the condition, and the subjective judgment of the treating physician. The effective dose of the active ingredient depends at least on the nature of the condition to be treated, toxicity (whether the compound is used prophylactically or against active viral infection), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. Dosages of about 0.0001 to about 100 mg / kg body weight per day can be expected; typically, about 0.01 to about 10 mg / kg body weight per day; more typically, about 0.01 to about 5 mg / kg body weight per day; and most typically, about 0.05 to about 0.5 mg / kg body weight per day. For example, for an adult weighing about 70 kg, a candidate daily dose would be in the range of 1 mg to 1000 mg, preferably 5 mg to 500 mg, and can be taken in the form of a single dose or multiple doses.

[0076] In order to enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to further illustrate the present invention in detail.

[0077] The reagents used in the present invention can be purchased from the market or prepared by the method described in the present invention.

[0078] Example 1: 4-[(4-{[(tricyclic[3.3.1.1 3,7 [(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[1,2-e:1',2'-b]thiepin-11-yl]-6,8-dioxyylidene-1,3,4,6,12,12a-hexahydro[1,4]oxazepino[3,4-c]pyrido[2,1-f][1,2,4]triazacyclohexan-7-yl]oxy}methyl benzoate (ATV-103)

[0079]

[0080] 4-[(4-{[(tricyclo[3.3.1.1 3,7Baricitinib (0.5 g, 1.03 mmol), intermediate 1 (0.57 g, 1.24 mmol) and potassium carbonate (0.35 g, 2.57 mmol) were dissolved in 15 mL of acetonitrile and reacted at 80 °C for 8 h. After the reaction solution was cooled to room temperature, it was concentrated to obtain a crude product, which was purified by a flash silica gel chromatography column (0-80% ethyl acetate / petroleum ether) to obtain compound ATV-103 (0.56 g, 59.3%).

[0081] Baricitinib (0.5 g, 1.03 mmol), intermediate 1 (0.57 g, 1.24 mmol) and potassium carbonate (0.35 g, 2.57 mmol) were dissolved in 15 mL of acetonitrile and reacted at 80 °C for 8 h. After the reaction solution was cooled to room temperature, it was concentrated to obtain a crude product, which was purified by a flash silica gel chromatography column (0-80% ethyl acetate / petroleum ether) to obtain compound ATV-103 (0.56 g, 59.3%). 1 H NMR (600 MHz, DMSO-d6) δ 7.92-7.86 (m, 2H), 7.43-7.35 (m, 2H), 7.22 (d, J = 7.8 Hz, 1H), 7.18-7.14 (m, 1H), 7.13-7.08 (m, 1H), 7.08-7.05 (m, 2H), 7.03-7.00 (m, 1H), 6.88-6.84 (m, 1H), 6.00 (d, J = 6.5 Hz, 1H), 5.94 (d, J = 6.5 Hz, 1H), 5.73 (d, J = 7.8 Hz, 1H), 5.62 (d, J = 7.6 Hz, 1H), 5.40 (d, J = 4.0 Hz, 1H), 4.48-4.42 (m, 1H), 4.42-4.38 (m, 1H), 4.27-4.20 (m, 1H), 4.08-4.04 (m, 1H), 3.97 (dd, J = 10.9, 3.1 Hz, 1H), 3.49 (dd, J = 11.3, 3.2 Hz, 1H), 3.43-3.35 (m, 2H), 297-2.91 (m, 1H), 2.88-2.81 (m, 1H), 2.05-1.96 (m, 6H), 1.85 (d, J = 2.9 Hz, 8H), 1.59 (q, J = 3.1 Hz, 6H), 1.49-1.41 (m, 2H), 1.28-1.19 (m, 3H). 13C NMR (151MHz, DMSO-d6) δ173.6,170.8,165.3,162.2,156.9,156.9,154.5,151.9,150.4,150.3,150. 2,148.0,147.9,146.4,146.3,141.2,136.4,134.2,132.7,132.1,130.2,129.4,128.6,127.8,127.0 ,125.5,125.1,125.0,121.7,117.0,116.9,115.7,114.0,88.7,75.0,73.7,69.8,68.8,65.9,60.2,49.8,47.2,46.0,42.5,42.5,40.5,36.6,31.4,30.7,30.1,29.4,26.8,23.6,22.6,21.2,14.6,14.4.

[0082] Example 2: 12-{[(tricyclic[3.3.1.1 3,7 [(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[1,2-e:1',2'-b]thiepin-11-yl]-6,8-dioxyylidene-1,3,4,6,12,12a-hexahydro[1,4]oxazepino[3,4-c]pyrido[2,1-f][1,2,4]triazacyclohexan-7-yl]oxy}methyl ester (ATV-114)

[0083]

[0084] According to the method described in Example 1, 12-{[(tricyclic[3.3.1.1 3,7 ]dec-1-ylamino)carbonyl]amino}dodecanoic acid (AUDA) was used as the starting material to synthesize compound ATV-114, a total of 0.3 g of white solid, with a two-step total yield of 45.6%. 1H NMR (600 MHz, DMSO-d6) δ 7.43 - 7.3 (m, 2H), 7.22 (d, J = 7.7 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.85 (t, J = 7.4 Hz, 1H), 5.73 - 5.69 (m, 3H), 5.58 (t, J = 5.6 Hz, 1H), 5.42 (d, J = 3.1 Hz, 1H), 4.47 - 4.37 (m, 2H), 4.06 (d, J = 14.3 Hz, 1H), 3.99 (dd, J = 11.0, 3.0 Hz, 1H), 3.67 (dd, J = 11.7, 3.3 Hz, 1H), 3.47 (t, J = 10.4 Hz, 1H), 3.32 (s, 1H), 3.31 - 3.26 (m, 1H), 2.98 - 2.86 (m, 3H), 2.31 (t, J = 7.4 Hz, 2H), 2.00 - 1.95 (m, 3H), 1.84 (d, J = 2.9 Hz, 6H), 1.62 - 1.50 (m, 8H), 1.34 - 1.16 (m, 16H). 13 C NMR (151 MHz, DMSO-d6) δ 173.7, 172.9, 157.5, 154.6, 150.6, 150.3, 141.2, 136.4, 134.2, 132.7, 130.2, 129.3, 128.6, 127.8, 127.0, 125.4, 125.2, 125.1, 117.0, 116.9, 113.9, 88.3, 73.7, 69.8, 68.9, 66.2, 49.8, 46.0, 42.5, 40.5, 39.2, 36.6, 34.0, 30.5, 29.5, 29.4, 29.4, 29.4, 29.3, 28.9, 26.9, 24.5, 23.6.

[0085] Example 3: (S)-1-(4-(3-(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3- fluorobenzyl)piperidine-3-carboxylic acid (Intermediate 5)

[0086]

[0087] Into a single neck flask was added 4-(bromomethyl)-2-fluoro-1-nitrobenzene (3.0 g, 12.9 mmol), dry acetonitrile (35 mL), after 4-(bromomethyl)-2-fluoro-1-nitrobenzene was dissolved, potassium carbonate (2.13 g, 15.4 mmol), potassium iodide (0.15 g, 1.29 mmol), (S)-piperidin-3-carboxylic acid ethyl ester (2.03 g, 12.9 mmol) were added, the reaction was refluxed. After 6 h, the reaction was monitored by TLC to be completed. The acetonitrile was removed by reduced pressure concentration, water (20 mL) was added, ethyl acetate (30 mL x 2) was extracted, the combined organic layer was washed with water (20 mL), saturated brine (25 mL) once, the organic phase was concentrated by reduced pressure to give 5.2 g of yellow oil, 4 times of silica gel was packed, 1.2 times of silica gel was mixed, eluent (EA: PE = 1:40), column chromatography to give yellow oil, which was (S)-1-(3-fluoro-4-nitrobenzyl)piperidin-3-carboxylic acid ethyl ester (intermediate 2), yield 4.4 g. The yield was 82%.

[0088] Into a single neck flask was added (S)-1-(3-fluoro-4-nitrobenzyl)piperidin-3-carboxylic acid ethyl ester (3.60 g, 11.6 mmol), 5% Pd-C (0.4 g) and anhydrous ethanol (50 mL), replaced with argon three times, replaced with hydrogen three times, the reaction was stirred at 60 °C for 12 h, the reaction was monitored by TLC to be completed; after the reaction was cooled to room temperature (25 °C), the filtrate was concentrated by reduced pressure to give yellow oil, which was (S)-1-(4-amino-3-fluorobenzyl)piperidin-3-carboxylic acid ethyl ester (intermediate 3), yield 2.86 g, yield 86%.

[0089] Into a three neck flask was added solid phosgene (1.06 g, 3.8 mmol) and dry DCM (30 mL), the cold hydrazine was cooled to below -78 °C, (S)-1-(4-amino-3-fluorobenzyl)piperidin-3-carboxylic acid ethyl ester (2.13 g, 7.6 mmol), triethylamine (1.06 g, 3.980 mmol) in dry dichloromethane (60 mL) was added dropwise, after the dropwise addition was completed, it was moved to room temperature and stirred for 0.5 h, then the reaction was stopped; the obtained reaction liquid was concentrated to dryness by reduced pressure, dry DCM (10 mL) was added to dissolve, to give an isocyanate solution, for standby.

[0090] To a single-neck flask was added memantine (1.48 g, 7.6 mmol), triethylamine (1.54 g, 15.2 mmol), dry dichloromethane (25 mL), dropwise added the above isocyanate solution, reacted at room temperature for 0.5 h, TLC showed that the reaction was complete; the reaction liquid was poured into water (40 mL), extracted with EA (40 mL x 3), then sequentially washed with 1 mol / L HC1 (40 mL x 2), water (40 mL x 2), saturated brine (40 mL) and anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a yellowish oil 3.4 g, which was (S)-1-(4-(3-(1r,3R,5S,7S)-3,5-dimethylmemantine-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylic acid ethyl ester (intermediate 4), which was not purified and directly used in the next step.

[0091] To a single-neck flask was added (S)-1-(4-(3-(1r,3R,5S,7S)-3,5-dimethylmemantine-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylic acid ethyl ester (intermediate 4) (3.4 g, 7.0 mmol), tetrahydrofuran (20 mL) was dissolved, sodium hydroxide (0.36 g, 9.00 mmol), water (10 mL), and refluxed. After 12 h, TLC showed that the reaction was complete; the reaction liquid was concentrated under reduced pressure to remove tetrahydrofuran, the residue was added with water (300 mL) and placed in a cold trap, and the pH was adjusted to 1 with 6N hydrochloric acid (10 mL), a yellowish solid was precipitated, filtered, the filter cake was washed with water (20 mL), and dried in an oven to obtain a crude product 2.96 g (dried in an oven at 60°C for 24 h), which was purified by slurry with petroleum ether and ethyl ether to obtain a yellowish solid, which was (S)-1-(4-(3-(1r,3R,5S,7S)-3,5-dimethylmemantine-1-yl)ureido)-3-fluorobenzyl)piperidine-3-carboxylic acid (intermediate 5) with a yield of 2.8 g, 85.5%.

[0092] Example 4: (3S)-1-{[4-({[(1,3-dimethyltricyclo[3.3.1.13,7 3,7 ]dec-5-yl)amino]carbonyl}amino)-3-fluorophenyl]carbonyl}hexahydropyridine-3-carboxylic acid-{[(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[1,2-e:1',2'-b]thiepac-11-yl]-6,8-dioxo-1,3,4,6,12,12a-hexahydro[1,4]oxazepino[3,4-c]pyrido[2,1-f][1,2,4]triazepin-7-yl]oxy}methyl ester (ATV-116)

[0093]

[0094] Compound ATV-116 was synthesized according to the procedure described in Example 1, starting from (S)-1-(4-(3-(1r,3R,5S,7S)-3,5-dimethyladamantan-1-yl)ureido)-3- fluorobenzyl)piperidine-3-carboxylic acid (Intermediate 5) as a white solid, 0.41 g, 47.1% overall yield for two steps. 1 H NMR (600 MHz, DMSO-d6) δ 8.29 (d, J = 3.2 Hz, 1H), 8.20 (t, J = 8.3 Hz, 1H), 7.43 - 7.35 (m, 2H), 7.27 - 7.17 (m, 2H), 7.17 - 7.07 (m, 3H), 7.00 (s, 1H), 6.83 (s, 1H), 6.57 (s, 1H), 5.70 (d, J = 7.9 Hz, 2H), 5.42 (d, J = 14.4 Hz, 1H), 4.47 - 4.28 (m, 2H), 4.06 (d, J = 14.3 Hz, 1H), 4.00 - 3.94 (m, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.47 (d, J = 10.4 Hz, 1H), 3.31 (s, 2H), 3.11 - 3.04 (m, 1H), 2.91 (s, 1H), 2.62 - 2.56 (m, 1H), 2.11 - 2.07 (m, 1H), 2.05 - 2.00 (m, 1H), 1.76 (d, J = 3.2 Hz, 2H), 1.72 - 1.63 (m, 2H), 1.58 (s, 4H), 1.48 (d, J = 13.3 Hz, 1H), 1.36 - 1.29 (m, 3H), 1.29 - 1.22 (m, 4H), 1.18 (t, J = 7.1 Hz, 1H), 1.12 (s, 2H), 0.83 (s, 6H). 13 C NMR (151 MHz, DMSO-d6) δ 173.6, 172.5, 168.5, 154.5, 153.8, 150.4, 150.3, 150.2, 150.1, 146.4, 141.1, 136.3, 134.2, 132.7, 130.3, 130.2, 129.3, 128.7, 128.7, 128.5, 127.9, 127.0, 125.4, 125.1, 123.9, 119.1, 117.0, 116.9, 114.4, 114.3, 113.9, 88.4, 73.8, 69.8, 68.9, 66.3, 60.2, 52.1, 50.7, 48.0, 45.9, 42.8, 41.2, 40.5, 40.5, 35.3, 32.4, 31.6, 30.5, 30.3, 30.0, 27.0, 26.8, 23.6, 22.6.

[0095] Example 5: 7-{[(tricyclic[3.3.1.1 3,7 ]dec-1-ylamino)carbonyl]amino}heptanoic acid (Intermediate 7)

[0096]

[0097] Solid phosgene (1.06 g, 3.8 mmol) and dry DCM (30 mL) were added to a single-necked flask. The temperature was cooled to below -78°C, and a solution of adamantane amine (1.15 g, 7.6 mmol) and triethylamine (1.06 g, 3.980 mmol) in dry dichloromethane (60 mL) was added dropwise. After completion of the addition, the mixture was stirred at room temperature for 0.5 h, after which the reaction was stopped. The resulting reaction solution was concentrated to dryness under reduced pressure, and dry DCM (10 mL) was added to the residue to dissolve it to obtain an isocyanate solution for later use.

[0098] To a three-necked flask, methyl 7-aminoheptanoate (1.21 g, 7.6 mmol), triethylamine (1.54 g, 15.2 mmol), and dry dichloromethane (25 mL) were added, and the above isocyanate solution was added dropwise. The reaction was allowed to react at room temperature for 0.5 h. TLC showed that the reaction was complete. The reaction solution was poured into water (40 mL) and extracted with EA (40 mL × 3). The product was then washed with 1 mol / L HCl (40 mL × 2), water (40 mL × 2), and saturated brine (40 mL). The product was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give 2.5 g of a light yellow oil, namely methyl 7-(3-(3s,5s,7s)-adamantan-1-yl)ureido)heptanoate (Intermediate 6), which was directly used in the next step without purification.

[0099] To a single-necked flask, 7-(3-(3s,5s,7s)-adamantan-1-yl)ureido)heptanoic acid methyl ester (Intermediate 6) (3.4 g, 10.1 mmol) was added, dissolved in tetrahydrofuran (20 mL), and refluxed with sodium hydroxide (0.48 g, 12.1 mmol) and water (10 mL). After 12 h, TLC showed that the reaction was complete. The reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, and the residue was added with water (300 mL). The mixture was placed in a cold trap and the pH was adjusted to 1 with 6N hydrochloric acid (10 mL). A light yellow solid precipitated and was filtered. The filter cake was rinsed with water (20 mL) to obtain 7-{[(tricyclo[3.3.1.1 3,7 The yield of 2.8 g of 1-decylamino)carbonyl]amino}heptanoic acid (Intermediate 7) was 86.0%.

[0100] Example 6: 7-{[(tricyclic[3.3.1.1 3,7[(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[1,2-e:1',2'-b]thiepin-11-yl]-6,8-dioxyylidene-1,3,4,6,12,12a-hexahydro[1,4]oxazepino[3,4-c]pyrido[2,1-f][1,2,4]triazacyclohexan-7-yl]oxy}methyl ester (ATV-117)

[0101]

[0102] According to the method described in Example 1, 7-{[(tricyclic[3.3.1.1 3,7 ]dec-1-ylamino)carbonyl]amino}heptanoic acid (Intermediate 7) was used as the starting material to synthesize compound ATV-117, a total of 0.56 g of white solid, with a two-step total yield of 52.6%. 1 H NMR (600MHz, DMSO-d6) δ7.44-7.37(m,2H),7.22(d,J=7.8Hz,1H),7.18-7.13(m,1H),7.09(dd,J=8.0,1.3Hz,1H),7.02(dd ,J=8.0,1.5Hz,1H),6.87-6.83(m,1H),5.73-5.68(m,4H),5.60(t,J=5.7Hz,1H),5.43(d,J=13.8Hz,2H),4.47-4.39(m,2H) ,4.06(d,J=14.3Hz,1H),3.99(dd,J=10.9,3.1Hz,1H),3.68(dd,J=11.6,3.3Hz,1H),3.48(t,J=10.4Hz,1H),3.31-3.26(m, 1H),2.98-2.88(m,3H),2.34-2.29(m,2H),1.99-1.94(m,3H),1.83(d,J=2.9Hz,6H),1.62-1.51(m,8H),1.34-1.22(m,6H). 13C NMR (151 MHz, DMSO-d6) δ 173.7, 172.9, 157.5, 154.6, 152.0, 151.9, 150.6, 150.3, 150.2, 148.0, 147.9, 146.4, 141.2, 136.4, 134.2, 132.7, 132.7, 130.2, 129.3, 128.5, 127.8, 127.0, 127.0, 125.4, 125.2, 125.1, 117.1, 116.9, 113.9, 88.3, 73.8, 69.8, 68.9, 66.2, 49.8, 46.0, 42.5, 40.5, 39.2, 36.6, 33.9, 30.4, 29.4, 28.7, 26.7, 24.5, 23.6.

[0103] Example 7: 4-(((1r,4r)-4-(2-(3-fluoro-4-(trifluoromethoxy)phenyl)acetamido)cyclohexyl)oxy)benzoic acid (Intermediate 11)

[0104]

[0105] Into a single neck flask was added tert-butyl (1r,4r)-4-hydroxycyclohexyl)carbamate (3.0 g, 13.95 mmol), dry DMF (10 mL), NaH (0.62 g, 15.5 mmol) was added under cooling below 0 °C, the reaction was moved to room temperature for 0.5 h, then 4-fluorobenzonitrile (1.69 g, 13.95 mmol) was added, the reaction was monitored by TLC after 6 h, the reaction was complete. The reaction was poured into 200 mL ice water, white solid precipitated, suction filtration, dried to get tert-butyl ((1r,4r)-4-(4-cyanophenoxy)cyclohexyl)carbamate (Intermediate 8), yield 3.61 g, 82% yield.

[0106] Into a single neck flask was added Intermediate 8 (3.61 g, 11.42 mmol), CF3COOH (3 mL) and DCM (10 mL), stirred at room temperature for 6 h, the reaction was monitored by TLC, the reaction was complete; the solvent was removed under reduced pressure, without purification, directly into the next step.

[0107] Into a three neck flask was added solid phosgene (1.69 g, 5.71 mmol) and dry DCM (50 mL), hydrazine was cooled below -78 °C, the isocyanate solution prepared in the previous step was added dropwise, a solution of triethylamine (6.92 g, 68.52 mmol) in dry dichloromethane (60 mL), after dropwise, the reaction was moved to room temperature and stirred for 0.5 h, then the reaction was stopped; the resulting reaction was concentrated to dryness under reduced pressure, the residue was dissolved in dry DCM (10 mL) to get an isocyanate solution, ready for use.

[0108] Into a single-necked flask was added 3-fluoro-4-(trifluoromethoxy)aniline (2.22 g, 11.42 mmol), triethylamine (6.92 g, 68.52 mmol), dry dichloromethane (50 mL), dropwise added the above isocyanate solution, reacted at room temperature for 0.5 h, TLC showed that the reaction was complete; the reaction solution was poured into water (40 mL), extracted with EA (40 mL x 3), then sequentially washed with 1 mol / L HC1 (40 mL x 2), water (40 mL x 2), saturated brine (40 mL), and anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain 1-((1r,4r)-4-(4-cyanophenoxy)cyclohexyl)-3-(3-fluoro-4-(trifluoromethoxy)phenyl)urea (intermediate 10), which was used directly in the next step without purification.

[0109] Into a single-necked flask was added the intermediate 10 obtained in the previous step, tetrahydrofuran (30 mL) was dissolved, sodium hydroxide (0.55 g, 13.70 mmol), water (10 mL), and refluxed. After 12 h, TLC showed that the reaction was complete; the reaction solution was concentrated under reduced pressure to remove tetrahydrofuran, the residue was added with water (300 mL), placed in a cold trap, and adjusted to pH 3 with 6N hydrochloric acid (10 mL), a light yellow solid was precipitated, filtered, and the filter cake was washed with water (20 mL) to obtain 4-(((1r,4r)-4-(2-(3-fluoro-4-(trifluoromethoxy)phenyl)acetamido)cyclohexyl)oxy)benzoic acid (intermediate 11) in a yield of 4.06 g, with a yield of 78.0%.

[0110] Example 8: ((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-6,8-dioxo-3,4,6,8,12-12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)benzoic acid methyl ester (ATV-123)

[0111]

[0112] According to the method described in Example 1, 4-(((1r,4r)-4-(2-(3-fluoro-4-(trifluoromethoxy)phenyl)acetamido)cyclohexyl)oxy)benzoic acid (intermediate 11) was used as the raw material to synthesize compound ATV-123, which was 0.59 g of white solid, with a total yield of 54.7% in two steps. 1H NMR (600 MHz, DMSO-d6) δ 8.71 (s, 1H), 7.91-7.85 (m, 2H), 7.66 (dd, J = 13.4, 2.5 Hz, 1H), 7.38-7.35 (m, 2H), 7.21 (d, J = 7.8 Hz, 1H), 7.16-7.12 (m, 1H), 7.10-7.04 (m, 4H), 7.01 (dd, J = 8.0, 1.5 Hz, 1H), 6.86-6.82 (m, 1H), 6.30 (d, J = 7.6 Hz, 1H), 5.98 (d, J = 6.5 Hz, 1H), 5.93 (d, J = 6.6 Hz, 1H), 5.73-5.68 (m, 2H), 5.39 (dd, J = 14.4, 2.4 Hz, 1H), 4.50-4.43 (m, 1H), 4.39 (dd, J = 9.9, 3.1 Hz, 1H), 4.26-4.18 (m, 1H), 4.04 (d, J = 14.3 Hz, 1H), 3.95 (dd, J = 10.9, 3.1 Hz, 1H), 3.57-3.44 (m, 2H), 3.38 (t, J = 10.4 Hz, 1H), 3.31 (s, 1H), 2.96-2.90 (1H), 2.86-2.80 (m, 1H), 2.08-2.01 (m, 2H), 1.95-1.88 (m, 2H), 1.53-1.44 (m, 2H), 1.41-1.33 (m, 2H). 13 C NMR (151 MHz, DMSO-d6) δ 173.6, 165.3, 162.1, 155.0, 154.6, 154.5, 153.3, 151.9, 151.8, 150.4, 150.3, 150.2, 147.9, 146.4, 146.3, 141.9, 141.8, 141.2, 136.4, 134.2, 132.7, 132.1, 130.2, 129.4, 128.8, 128.8, 128.6, 127.8, 127.0, 127.0, 125.5, 125.1, 125.0, 124.7, 123.2, 121.8, 121.5, 119.8, 117.0, 116.9, 115.7, 114.0, 114.0, 114.0, 106.1, 106.0, 88.7, 74.8, 73.7, 69.8, 68.8, 65.9, 60.2, 47.7, 46.0, 40.5, 30.3, 30.0, 23.6, 21.2, 14.5.

[0113] Example 9: (((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-6,8- dioxo-3,4,6,8,12,12a-hexahydro-lH-[l,4-c]oxazino[3,4-c]pyrido[2,l- f][l,2,4]triazin-7-yl)oxy)methyl 4-(((l r,4r)-4-(3-(4-(trifluoromethoxy))(ATV-126

[0114]

[0115] According to the method described in Example 1, compound ATV-126 was synthesized from t-TUCB as starting material, 0.43 g of white solid, the total yield of two steps was 46.7%. 1 H NMR (600 MHz, DMSO-d6) δ 8.51 (s, 1H), 7.90 (d, J = 8.8 Hz, 2H), 7.50-7.45 (m, 2H), 7.39 (dd, J = 8.4, 5.1 Hz, 2H), 7.22 (dd, J = 8.1, 2.8 Hz, 3H), 7.18-7.14 (m, 1H), 7.12-7.06 (m, 3H), 7.02 (dd, J = 7.9, 1.5 Hz, 1H), 6.88-6.83 (m, 1H), 6.20 (d, J = 7.6 Hz, 1H), 6.00 (d, J = 6.6 Hz, 1H), 5.95 (d, J = 6.6 Hz, 1H), 5.76-5.69 (m, 2H), 5.41 (dd, J = 14.4, 2.4 Hz, 1H), 4.52-4.45 (m, 1H), 4.41 (dd, J = 9.9, 3.1 Hz, 1H), 4.27-4.20 (m, 1H), 4.06 (d, J = 14.3 Hz, 1H), 3.97 (dd, J = 10.9, 3.1 Hz, 1H), 3.58-3.47 (m, 2H), 3.40 (t, J = 10.4 Hz, 1H), 2.98-2.91 (m, 1H), 2.88-2.81 (m, 1H), 2.10-2.03 (m, 2H), 1.94 (dd, J = 13.1, 3.9 Hz, 2H), 1.55-1.45 (m, 2H), 1.43-1.32 (m, 2H). 13C NMR (151MHz, DMSO-d6) δ173.6,165.3,162.1,154.9,154.5,150.4,150.3,146.4,146. 3,142.4,141.2,140.3,136.4,134.2,132.7,132.7,132.1,130.2,129.4,128.6,127. 8,127.0,125.5,125.1,125.1,122.1,121.8,121.5,119.8,119.0,117.0,116.9,115.7,114.0,88.7,74.9,73.7,69.8,68.8,65.9,47.6,46.0,40.5,30.4,30.0,23.6,14.6.

[0116] Example 10: 12-({[(1,3-dimethyltricyclo[3.3.1.1 3,7 [(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[1,2-e:1',2'-b]thiepin-11-yl]-6,8-dioxyylidene-1,3,4,6,12,12a-hexahydro[1,4]oxazepino[3,4-c]pyrido[2,1-f][1,2,4]triazacyclohexan-7-yl]oxy}methyl] ...

[0117]

[0118] According to the method described in Examples 1 and 5, 12-({[(1,3-dimethyltricyclo[3.3.1.1 3,7 ]dec-7-yl)amino]carbonyl}amino)dodecanoic acid was used as the raw material to synthesize compound ATV-140, a total of 0.38 g of white solid, with a two-step total yield of 41.9%. 1H NMR (600 MHz, DMSO-d6) δ 7.41 (dd, J = 8.2, 5.6 Hz, 2H), 7.22 (d, J = 7.8 Hz, 1H), 7.18 - 7.12 (m, 1H), 7.12 - 7.07 (m, 1H), 7.04 - 7.00 (m, 1H), 6.89 - 6.83 (m, 1H), 7.30 - 5.66 (m, 4H), 5.57 (t, J = 5.6 Hz, 1H), 5.43 (d, J = 12.9 Hz, 2H), 4.47 - 4.38 (m, 2H), 4.09 - 3.97 (m, 2H), 3.67 (dd, J = 11.6, 3.4 Hz, 1H), 3.48 (t, J = 10.4 Hz, 1H), 3.31 - 3.26 (m, 1H), 2.97 - 2.91 (m, 1H), 2.89 (q, J = 6.5 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 2.04 - 2.01 (m, 1H), 1.67 (d, J = 3.2 Hz, 2H), 1.57 - 1.45 (m, 6H), 1.33 - 1.19 (m, 20H), 1.07 (s, 2H), 0.79 (s, 6H). 13 C NMR (151 MHz, DMSO-d6) δ 173.7, 172.9, 157.6, 154.6, 150.6, 150.2, 141.1, 136.4, 134.3, 132.7, 130.2, 129.3, 128.6, 127.8, 127.0, 125.4, 125.2, 125.1, 117.0, 116.9, 113.9, 88.3, 73.7, 69.8, 68.9, 66.2, 60.2, 51.4, 50.8, 48.6, 46.0, 42.9, 41.0, 40.5, 39.2, 34.0, 32.4, 32.3, 30.6, 30.5, 30.1, 29.5, 29.4, 29.4, 29.3, 28.9, 26.9, 24.5, 23.6, 21.2, 14.6.

[0119] Example 11: 12-{[({4-[(trifluoromethyl)oxy]phenyl}amino)carbonyl]amino}dodecanoic acid-{[(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[1,2-e:1',2'-b]thiacycloheptene-11-yl]-6,8-dioxo-1,3,4,6,12,12a-hexahydro[1,4]oxazepino[3,4-c]pyrido[2,1-f][1,2,4]triazepin-7-yl]oxy}methyl ester (ATV-148)

[0120]

[0121] Compound ATV-148 was synthesized according to the procedures described in Examples 1 and 5, starting from 12-{[({4-[(trifluoromethyl)oxy]phenyl}amino)carbonyl]amino}dodecanoic acid as a white solid, 0.45 g, 39.9% overall yield for two steps. 1 H NMR (600 MHz, DMSO-d6) δ 8.59 (s, 1H), 7.50-7.46 (m, 2H), 7.40 (d, J = 6.8 Hz, 2H), 7.21 (t, J = 8.0 Hz, 3H), 7.17-7.13 (m, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.04-7.00 (m, 1H), 6.15 (t, J = 5.7 Hz, 1H), 5.71 (dd, J = 9.7, 6.1 Hz, 4H), 5.42 (dd, J = 14.3, 2.3 Hz, 1H), 4.47-4.39 (m, 2H), 4.05 (d, J = 14.3 Hz, 1H), 3.99 (dd, J = 10.9, 3.0 Hz, 1H), 3.67 (dd, J = 11.6, 3.3 Hz, 1H), 3.47 (t, J = 10.4 Hz, 1H), 3.31-3.25 (m, 1H), 3.06 (q, J = 6.5 Hz, 2H), 2.96-2.90 (m, 1H), 2.31 (t, J = 7.4 Hz, 2H), 1.55-1.50 (m, 2H), 1.42-1.37 (m, 2H), 1.25 (d, J = 5.4 Hz, 15H). 13 C NMR (151 MHz, DMSO-d6) δ 173.7, 172.9, 155.5, 154.6, 152.0, 151.9, 150.6, 150.3, 150.2, 148.0, 147.9, 146.4, 146.3, 142.4, 141.1, 140.4, 136.4, 134.2, 132.7, 132.7, 130.2, 129.3, 128.5, 127.8, 127.0, 125.4, 125.2, 125.1, 123.2, 122.0, 121.5, 119.8, 119.0, 117.0, 116.9, 113.9, 88.3, 73.7, 69.8, 68.9, 66.2, 46.0, 40.5, 39.5, 34.7, 34.0, 30.2, 29.5, 29.4, 29.4, 29.2, 28.9, 28.9, 26.8, 24.5, 23.6, 23.5, 22.9, 19.7, 11.7.

[0122] Example 12: 12-{[({3-fluoro-4-[(trifluoromethyl)oxy]phenyl}amino)carbonyl]amino}dodecanoic acid-{[(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[1,2-e:1',2'-b]thieepin-11-yl]-6,8-dioxy-1,3,4,6,12,12a-hexahydro[1,4]oxazepino[3,4-c]pyrido[2,1-f][1,2,4]triazepin-7-yl]oxy}methyl ester (ATV-149)

[0123]

[0124] ATV-149 was synthesized according to the procedures described in Examples 1 and 5 from 12-{[({3-fluoro-4-[(trifluoromethyl)oxy]phenyl}amino)carbonyl]amino}dodecanoic acid as starting material. 0.47 g of ATV-149 was obtained as a white solid in 45.9% overall yield for the two steps. 1 HNMR (600 MHz, DMSO-d6) δ 8.82 (s, 1H), 7.68 (dd, J = 13.5, 2.5 Hz, 1H), 7.42-7.35 (m, 3H), 7.21 (d, J = 7.7 Hz, 1H), 7.16-7.12 (m, 1H), 7.12-7.08 (m, 2H), 7.02-7.00 (m, 1H), 6.86-6.83 (m, 1H), 6.27 (t, J = 5.7 Hz, 1H), 5.72-5.68 (m, 4H), 5.42 (dd, J = 14.4, 2.3 Hz, 1H), 4.47-4.38 (m, 2H), 4.05 (d, J = 14.3 Hz, 1H), 3.99-3.96 (m, 1H), 3.68-3.64 (m, 1H), 3.47 (t, J = 10.4 Hz, 1H), 3.30-3.25 (m, 1H), 3.06 (q, J = 6.6 Hz, 2H), 2.96-2.90 (m, 3.5 Hz, 1H), 2.30 (t, J = 7.4 Hz, 2H), 1.55-1.49 (m, 2H), 1.42-1.37 (m, 2H), 1.29-1.22 (m, 14H). 13C NMR(151MHz,DMSO-d6)δ173.7,172.9,155.2,154.9,154.6,153.3,150.6,150.3,150.2,146.4,146.3,142.1,142.0,14 1.1,136.4,134.2,132.7,130.2,129.3,128.8,128.7,128.5,127.8,127.0,125.4,125.2,125.1,124.6,121.5,119.8,1 17.0,116.9,114.0,114.0,113.9,106.1,105.9,88.3,73.7,69.8,68.9,66.2,46.0,41.3,40.5,39.5,35.9,34.7,34.4,34.0,30.1,29.5,29.4,29.4,29.2,29.2,28.9,28.9,27.6,26.8,25.2,24.5,23.6,22.9,21.1,20.3,19.7,19.1,11.7.

[0125] Example 13: 11-{[(tricyclic[3.3.1.1 3,7 [(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[1,2-e:1',2'-b]thiepin-11-yl]-6,8-dioxyylidene-1,3,4,6,12,12a-hexahydro[1,4]oxazepino[3,4-c]pyrido[2,1-f][1,2,4]triazacyclohexan-7-yl]oxy}methyl ester (ATV-150)

[0126]

[0127] According to the method described in Examples 1 and 5, 11-{[(tricyclo[3.3.1.1 3,7 ]dec-1-ylamino)carbonyl]amino}undecanoic acid was used as raw material to synthesize compound ATV-150, a total of 0.45 g of white solid, with a two-step total yield of 49.9%. 1H NMR (600 MHz, DMSO-d6) δ 7.43-7.38 (m, 2H), 7.21 (d, J = 7.7 Hz, 1H), 7.15 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.85 (t, J = 7.4 Hz, 1H), 5.73-5.67 (m, 4H), 5.57 (t, J = 5.6 Hz, 1H), 5.41 (s, 1H), 4.46-4.38 (m, 2H), 4.06 (d, J = 14.4 Hz, 1H), 3.99 (dd, J = 10.9, 3.0 Hz, 1H), 3.67 (dd, J = 11.6, 3.3 Hz, 1H), 3.47 (t, J = 10.4 Hz, 1H), 3.30-3.25 (m, 1H), 2.96-2.91 (m, 1H), 2.89 (q, J = 6.5 Hz, 2H), 2.31 (t, J = 7.5 Hz, 2H), 1.99-1.95 (m, 3H), 1.83 (d, J = 2.9 Hz, 6H), 1.62-1.55 (m, 6H), 1.53 (q, J = 7.3 Hz, 2H), 1.33-1.18 (m, 15H). 13 CNMR (151 MHz, DMSO-d6) δ 173.7, 172.9, 157.5, 154.6, 150.6, 150.3, 150.2, 147.9, 146.4, 141.1, 136.4, 134.2, 132.7, 130.2, 129.3, 128.6, 127.8, 127.0, 125.4, 125.2, 125.1, 117.0, 116.9, 113.9, 88.3, 73.7, 69.8, 68.9, 66.2, 49.8, 46.0, 42.5, 40.5, 39.2, 36.6, 34.0, 30.5, 29.5, 29.4, 29.3, 29.3, 29.2, 28.9, 26.9, 24.5, 23.6.

[0128] Example 14: 11-({[(3,5-dimethyltricyclo[3.3.1.13,7 3,7 ]dec-1-yl)amino]carbonyl}amino)undecanoic acid-{[(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[1,2-e:1',2'-b]thiopyel1-yl]-6,8-dioxo-1,3,4,6,12,12a-hexahydro[1,4]oxazepino[3,4-c]pyrido[2,1-f][1,2,4]triazepin-7-yl]oxy}methyl ester (ATV-151)

[0129]

[0130] According to the method described in Examples 1 and 5, 11-({[(3,5-dimethyltricyclo[3.3.1.1 3,7 ]dec-1-yl)amino]carbonyl}amino)undecanoic acid was used as raw material to synthesize compound ATV-151, a total of 0.46 g of white solid, with a two-step total yield of 41.3%. 1 H NMR (600MHz, DMSO-d6) δ7.40(dd,J=8.3,4.7Hz,2H),7.21(d,J=7.8Hz,1H),7.16-7.13(m,1H),7.09(dd,J=8.0,1.3Hz,1H),7.02(dd,J=7.9,1 .5Hz,1H),6.86-6.83(m,1H),5.73-5.68(m,4H),5.57(t,J=5.6Hz,1H),5.43(d,J=12.0Hz,2H),4.46-4.39(m,2H),4.06(d,J=14.3Hz,1H),3. 99(dd,J=10.8,3.1Hz,1H),3.67(dd,J=11.4,3.3Hz,1H),3.47(t,J=10.4Hz,1H),3.31-3.25(m,1H),2.96-2.91(m,1H),2.89(q,J=6.5Hz,2H) ,2.33-2.29(m,2H),2.04-2.01(m,1H),1.66(d,J=3.1Hz,2H),1.54(q,J=7.0Hz,2H),1.48(d,J=5.0Hz,4H),1.33-1.18(m,20H),0.79(s,6H). 13C NMR(151MHz,DMSO-d6)δ173.7,172.9,157.6,154.6,152.0,151.9,150.6,150.3,150.2,148.0,147.9,146.4,146.3, 141.1,136.4,134.2,132.7,130.2,129.3,128.6,127.8,127.0,125.4,125.2,125.1,117.0,116.9,113.9,88.3,73. 7,69.8,68.9,66.2,51.4,50.8,48.6,46.0,42.9,41.3,41.0,40.5,39.2,35.9,34.7,34.4,34.0,32.3,30.6,30.5,30.1,29.5,29.3,29.3,29.0,28.9,27.6,26.9,25.3,24.5,23.6,23.6,23.0,21.1,20.4,19.7,19.1,14.6,14.4,11.7.

[0131] Example 15: 8-{[(tricyclic[3.3.1.1 3,7 [(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[1,2-e:1',2'-b]thiepin-11-yl]-6,8-dioxyylidene-1,3,4,6,12,12a-hexahydro[1,4]oxazepino[3,4-c]pyrido[2,1-f][1,2,4]triazacyclohexan-7-yl]oxy}methyl octanoate (ATV-157)

[0132]

[0133] According to the method described in Examples 1 and 5, 8-{[(tricyclo[3.3.1.1 3,7 ]dec-3-ylamino)carbonyl]amino}octanoic acid was used as raw material to synthesize compound ATV-157, a total of 0.36 g of white solid, with a two-step total yield of 47.3%. 1HNMR (600 MHz, DMSO-d6) δ 7.41 (dd, J = 9.5, 6.3 Hz, 2H), 7.22 (d, J = 7.7 Hz, 1H), 7.16 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 5.73 - 5.66 (m, 4H), 5.59 (t, J = 5.6 Hz, 1H), 5.43 (d, J = 17.1 Hz, 2H), 4.47 - 4.38 (m, 2H), 4.06 (d, J = 14.4 Hz, 1H), 3.99 (dd, J = 10.9, 3.1 Hz, 1H), 3.68 (dd, J = 11.5, 3.3 Hz, 1H), 3.47 (t, J = 10.4 Hz, 1H), 3.31 - 3.25 (m, 1H), 2.98 - 2.87 (m, 3H), 2.31 (t, J = 7.5 Hz, 2H), 1.97 (s, 3H), 1.83 (d, J = 3.0 Hz, 6H), 1.61 - 1.56 (m, 6H), 1.56 - 1.52 (m, 2H), 1.33 - 1.27 (m, 4H), 1.24 (q, J = 9.7 Hz, 4H). 13 C NMR (151 MHz, DMSO-d6) δ 173.7, 172.9, 157.5, 154.6, 152.0, 151.9, 150.6, 150.2, 148.0, 147.9, 146.4, 146.3, 141.1, 136.4, 134.2, 132.7, 132.7, 130.2, 129.3, 128.6, 127.8, 127.0, 127.0, 125.4, 125.2, 125.1, 117.1, 116.9, 113.9, 88.2, 73.7, 69.8, 68.9, 66.2, 49.8, 46.0, 42.5, 42.1, 40.5, 39.2, 36.6, 34.7, 33.9, 33.6, 30.5, 29.5, 29.4, 29.0, 28.9, 28.7, 26.8, 25.3, 24.4, 23.6.

[0134] Example 16: 12-[({[1-(tricyclo[3.3.1 3,7[(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[1,2-e:1',2'-b]thiepin-11-yl]-6,8-dioxyylidene-1,3,4,6,12,12a-hexahydro[1,4]oxazepino[3,4-c]pyrido[2,1-f][1,2,4]triazacyclohexan-7-yl]oxy}methyl]decanoate (ATV-158)

[0135]

[0136] According to the method described in Examples 1 and 5, 12-[({[1-(tricyclo[3.3.1.1 3,7 ]dec-1-yl)ethyl]amino}carbonyl)amino]dodecanoic acid was used as the raw material to synthesize compound ATV-158, a total of 0.41 g of white solid, with a two-step total yield of 44.3%. 1 HNMR (600MHz, DMSO-d6) δ7.40(t,J=6.5Hz,2H),7.22(d,J=7.7Hz,1H),7.15(t,J=7.7Hz,1H),7.09(d,J=7.9Hz,1H),7.02(d,J=7.7Hz,1H),6.85 (t,J=7.5Hz,1H),5.73-5.68(m,4H),5.65(t,J=5.6Hz,1H),5.50(d,J=9.5Hz,1H),5.43(dd,J=14.1,2.4Hz,1H),4.47-4.38(m,2H),4.06(d,J=1 4.3Hz,1H),3.99(dd,J=11.0,3.1Hz,1H),3.67(dd,J=11.6,3.3Hz,1H),3.47(t,J=10.4Hz,1H),3.31-3.24(m,2H),2.98-2.90(m,3H),2.31(t,J =7.4Hz,2H),1.94-1.89(m,3H),1.64(d,J=12.0Hz,3H),1.61-1.50(m,6 H),1.46(d,J=12.4Hz,4H),1.41(d,J=12.3Hz,3H),1.32-1.19(m,17H). 13C NMR (151MHz, DMSO-d6) δ173.7,172.9,158.3,154.6,152.0,151.9,150.6,150.3,150.2,148.0,147.9,146.4,146. 3,141.1,136.4,134.2,132.7,132.7,130.2,129.3,128.5,127.8,127.0,127.0,125.4,125.2,125.1,117.0,116. 9,113.8,88.3,73.7,69.8,68.9,66.2,53.0,46.0,41.3,40.5,38.5,37.2,36.1,35.9,34.7,34.0,30.5,29.5,29.4,29.4,29.3,29.3,29.0,28.9,28.3,26.9,25.3,24.5,23.6,23.6,22.9,21.1,20.4,19.7,19.1,15.6,14.6,11.7.

[0137] Example 17: (((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiophen-11-yl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4-c]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl)oxy)methyl 12-(3-(((3r,5r,7r)-adamantane (ATV-159)

[0138]

[0139] According to the method described in Examples 1 and 5, 12-[({[1-(tricyclo[3.3.1.1 3,7 ]dec-1-yl)ethyl]amino}carbonyl)amino]dodecanoic acid was used as the raw material to synthesize compound ATV-159, a total of 0.41 g of white solid, with a two-step total yield of 44.3%. 1HNMR (600 MHz, DMSO-d6) δ 7.40 (t, J = 6.6 Hz, 2H), 7.22 (d, J = 7.7 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 7.09 (d, J = 7.9 Hz, 1H), 7.02 (d, J = 7.7 Hz, 1H), 6.85 (t, J = 7.5 Hz, 1H), 5.73 - 5.65 (m, 6H), 5.43 (dd, J = 14.4, 2.4 Hz, 1H), 4.47 - 4.38 (m, 2H), 4.06 (d, J = 14.3 Hz, 1H), 3.99 (dd, J = 10.9, 3.1 Hz, 1H), 3.67 (dd, J = 11.6, 3.4 Hz, 1H), 3.47 (t, J = 10.4 Hz, 1H), 3.31 - 3.25 (m, 1H), 2.98 - 2.90 (m, 3H), 2.68 (d, J = 6.1 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1.93 - 1.88 (m, 3H), 1.65 (d, J = 12.1 Hz, 3H), 1.59 - 1.50 (m, 6H), 1.39 (d, J = 2.8 Hz, 6H), 1.29 - 1.20 (m, 16H). 13 CNMR (151 MHz, DMSO-d6) δ 173.7, 172.9, 158.8, 154.6, 150.6, 150.2, 147.9, 146.4, 146.3, 141.1, 136.4, 134.2, 132.7, 130.2, 129.3, 128.5, 127.8, 127.0, 127.0, 125.4, 125.2, 125.1, 117.0, 116.9, 113.8, 88.3, 73.7, 69.8, 68.9, 66.2, 51.5, 46.0, 39.6, 37.1, 35.9, 34.7, 34.0, 34.0, 33.7, 30.5, 29.5, 29.4, 29.4, 29.3, 29.3, 29.1, 29.0, 28.9, 28.3, 28.2, 26.9, 25.3, 24.7, 24.5, 23.6, 22.9, 19.1, 14.6, 11.7.

[0140] Example 18: 12-({[(bicyclo[2.2.1]hept-2-en-6-ylmethyl)amino]carbonyl}amino)dodecanoic acid-{[(12aR)-12-[(11S)-7,8-difluoro-6,11-dihydrodibenzo[1,2-e:1',2'-b]thiepin-11-yl]-6,8-dioxyylidene-1,3,4,6,12,12a-hexahydro[1,4]oxazepino[3,4-c]pyrido[2,1-f][1,2,4]triazacyclohexan-7-yl]oxy}methyl ester (ATV-160)

[0141]

[0142] According to the method described in Example 1, 0.49 g of compound ATV-160 as a white solid was synthesized using 12-({[(bicyclo[2.2.1]hept-2-en-6-ylmethyl)amino]carbonyl}amino)dodecanoic acid as starting material, with a total yield of 47.1% over two steps. 1 H NMR (600MHz, DMSO-d6) δ7.40(d,J=6.4Hz,2H),7.22(d,J=7.8Hz,1H),7.15(t,J=7.6Hz,1H),7.09(d,J=7.9Hz,1H),7.04-7.00(m,1H),6 .87-6.83(m,1H),6.13(dd,J=5.8,3.0Hz,1H),5.93(dd,J=5.8,2.8Hz,1H),5.77-5.66(m,6H),5.43(dd,J=14.4,2.4Hz,1H),4.47-4.38( m,2H),4.06(d,J=14.3Hz,1H),3.99(dd,J=10.9,3.0Hz,1H),3.67(dd,J=11.5,3.3Hz,1H),3.47(t,J=10.4Hz,1H),3.31-3.25(m,1H),2. 94-2.90(m,3H),2.80-2.72(m,3H),2.31(t,J=7.4Hz,2H),2.13-2.06(m,1H),1.76-1.70(m,1H),1.55-1.49(m,2H),1.36-1.17(m,20H). 13C NMR (151 MHz, DMSO-d6) δ 173.7, 172.9, 158.5, 158.4, 154.6, 152.0, 151.9, 150.6, 150.3, 150.2, 148.0, 147.9, 146.4, 146.3, 141.1, 137.3, 136.9, 136.9, 136.4, 134.2, 132.8, 132.7, 132.7, 130.2, 129.3, 128.5, 127.8, 127.0, 125.4, 125.2, 125.1, 117.0, 116.9, 113.9, 88.3, 73.7, 69.8, 68.9, 66.2, 49.4, 46.0, 45.1, 44.9, 44.1, 43.9, 42.3, 41.6, 41.3, 40.5, 39.6, 35.9, 34.7, 34.4, 34.0, 30.8, 30.5, 30.2, 29.5, 29.4, 29.4, 29.3, 29.3, 29.0, 28.9, 26.9, 25.3, 24.5, 23.6, 23.0, 21.1, 20.4, 19.7, 19.1, 14.6, 14.3, 11.7.

[0143] Example 19: In vitro biological activity study and cytotoxicity study

[0144] Test compounds: the compounds of the present application and the control compound baloxavir. Test method for in vitro biological activity study: MDCK cells were seeded into 96-well cell culture plates at a density of 2,0000 cells per well, then placed in a 37°C, 5% CO2 incubator for overnight culture. The next day, influenza virus A / WSN / 1933 (H1N1) strain was added to each well at a concentration of 2*TCID 90 The cells were cultured for 2 days after the addition of the test compounds. Cell viability was detected using the cell viability detection kit CCK8. The raw data was used for non-linear fitting analysis of the inhibition rate of the compounds by GraphPad Prism 9.0 software to obtain the EC 50 values, see Table 1.

[0145] Test method for cytotoxicity study: the determination of cytotoxicity of the compounds and the determination of antiviral activity were carried out in parallel, except that no virus was added, and the experimental conditions were consistent with the antiviral activity experiment. The cells were cultured for 2 days after the addition of the test compounds. Cell viability was detected using the cell viability detection kit CCK8. The raw data was used for calculation of the cytotoxicity (CC 50 ) of the compounds, see Table 1.

[0146] Table 1. Inhibitory activity and toxicity of compounds against influenza virus A / WSN / 1933 (H1N1)

[0147]

[0148] As shown in Table 1, the EC values ​​of BAX and MBAX for H1N1 50 The values ​​were 2.19nM and 1.68nM, respectively, which are very close to the values ​​previously reported in the literature. In contrast, most of the twin drugs showed strong inhibitory effects against H1N1. Specifically, ATV-114, ATV-148, ATV-149, ATV-150, ATV-151, and ATV-158 showed better anti-influenza virus effects than MBAX, especially ATV-114 had an EC value of 0.17 for H1N1. 50 The inhibitory activity of ATV-114 against various clinical isolates of influenza A and B viruses was evaluated, including the oseltamivir-resistant strain A / PR / 8 / 1934 (NA-H274Y). Notably, ATV-114 exhibited greater inhibitory activity than MBAX against all tested strains. Specifically, against the A / PR / 8 / 1934 (H1N1) virus, ATV-114 was four times more active than MBAX, as shown in Table 2.

[0149] Table 2. Inhibitory activity of ATV-114 and MBAX against different influenza virus strains

[0150]

[0151] Example 20: ATV-114 is more effective than MBAX in inhibiting viral proteins in both cells with high and low AADAC enzyme expression

[0152] In order to exert its antiviral activity, baloxavir must be converted to baloxavir acid, a process that relies on arylacetamide deacetylase (AADAC). AADAC is primarily expressed in the liver, intestine, pancreas, and adrenal glands, with lower levels detected in other tissues. In contrast, carboxylases that hydrolyze ATV-114 into active metabolites AUDA and BAX are widely distributed throughout the body. In the present invention, cells were infected with the H1N1 virus and treated with MBAX, ATV-114, and AUDA under conditions of high and low AADAC expression. Figure 1A-F, wherein A-C represent the inhibitory effect of MBAX, ATV-114 and AUDA on H1N1 viral protein expression in cell lines with high AADAC expression (i.e. Caco-2, HEPG-2 and MDCK cells) at different concentrations; D-F represent the inhibitory effect of MBAX, ATV-114 and AUDA on H1N1 viral protein expression in cell lines with low AADAC expression (A549, Beas-2B and HaCat cells) at different concentrations.

[0153] Figure 1 It was shown that MBAX significantly inhibited the expression of influenza virus nucleoprotein (NP) and polymerase acid (PA) protein, and the therapeutic effect was enhanced in cells showing high AADAC expression. In cells with high AADAC expression, 10 nM of MBAX almost completely inhibited the expression of influenza virus protein, while ATV-114 had a more significant inhibitory effect on viral protein expression in cells with high and low AADAC expression, achieving complete inhibition of viral protein expression at a concentration of 5 nM.

[0154] Example 21: Anti-inflammatory activity of ATV-114 by inhibiting NF-κB signaling

[0155] In this study, the inventors evaluated the anti-inflammatory effect of AUDA in vitro using a LPS-induced RAW264.7 inflammation model, and determined that ATV-114 can successfully hydrolyze AUDA to achieve a similar anti-inflammatory effect. As shown in A of Figure 2 ATV-114 and AUDA inhibited LPS-induced inflammatory protein upregulation and NF-κB pathway activation, while MBAX had no significant effect. Subsequently, the inventors transfected RAW264.7 cells with an NF-κB luciferase reporter plasmid, and the level of luciferase expression represented the transcriptional activity of NF-κB. As shown in B of Figure 2 The NF-κB inhibitor BAY11-7085 almost completely inhibited LPS-induced NF-κB transcriptional activation, and both AUDA and ATV-114 inhibited NF-κB transcription in a concentration-dependent manner, indicating that NF-κB is indeed the target of AUDA, and ATV-114 inhibits NF-κB by releasing AUDA molecules in cells.

[0156] Example 22: Confocal experiment to detect the inhibitory effect of ATV-114 on RNP

[0157] After A549 cells were infected with influenza virus for 6 hours, the viral nucleic acid nucleoprotein complex RNP was released from the nucleus to perform a new round of infection and replication; after the cells were infected with influenza virus, the NF-κB signaling pathway was activated, NF-κB was phosphorylated and entered the nucleus, promoting the release of RNP from the nucleus.

[0158] A549 cells were infected with A / WSN / 1933 virus for 6 hours, indirect immunofluorescence assay was performed using NF-κΒ and NP antibodies, DAPI was used to indicate nuclear localization, scale bar: 10 μm. As shown in Figure 3 ATV-114 inhibited RNP de-nucleation by reducing NF-κΒ nuclear import.

[0159] Example 23: ATV-114 effectively protects mice from death due to influenza virus infection

[0160] The efficacy of ATV-114 in a mouse model of influenza A virus H1N1 infection was evaluated. Mice were infected intranasally with influenza A virus A / PR / 8 / 1934 or A / PR / 8 / 34 with NA-H274Y, and treated with compounds starting at 12, 48, 72 and 96 hours post-infection, respectively, where MBAX, ATV-114 and HEAUDA were co-administered once, and oseltamivir phosphate was administered continuously for three days, once a day. The anti-influenza virus H1N1 effect of the compounds in this model was evaluated by observing the changes in body weight and survival rate of the mice, as shown in Figure 4 BALB / c mice (Southern Medical University Laboratory Animal Center) of grade ATVF were used in the experiment, 6-7 weeks old, half male and half female. The mice were acclimated for at least 3 days in the BSL-2 animal room before the experiment started, and the day of infection was set as day 0 of the experiment.

[0161] Currently, the widely used antiviral drugs in the clinic, such as oseltamivir and baloxavir, are recommended to be administered within 48 hours after infection to effectively protect influenza patients. In the inventors’ study, BALB / c mice were infected with A / PR / 8 / 1934 virus, and MBAX or ATV-114 was administered orally at 48, 72 and 96 hours post-infection, and the survival rate of ATV-114 treatment was still 37.5% at 72 and 96 hours post-infection. In contrast, oseltamivir had no protective effect when administered at 72 and 96 hours post-infection, and MBAX provided only 12.5% survival rate when administered at 72 hours post-infection. These findings highlight the great potential of AUDA’s potent anti-inflammatory effect.

[0162] In addition to the direct damage caused by the virus, an inflammatory cytokine storm also poses a serious threat to lung cells after influenza virus infection. Therefore, although antiviral treatment starting at 72 hours post-infection can inhibit viral replication, high viral load combined with uncontrolled inflammatory response can hinder survival. Due to the effects of cytokine storm and pulmonary fibrosis, surviving mice often recover slowly, leading to irreversible lung damage.

[0163] The results showed that ATV-114 releases AUDA during the mid-stage of viral infection to suppress overactivation of inflammatory pathways, thereby mitigating the effects of the cytokine storm. Simultaneously, ATV-114 releases BAX, rapidly inhibiting viral replication and preventing the production of new progeny viruses, thereby reducing viral load at the source. The dual anti-inflammatory and antiviral effects of ATV-114 provide crucial therapeutic benefits to infected mice during this critical period.

[0164] The methods of the present invention have been described through preferred embodiments. It is apparent that those skilled in the art will be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and spirit of the present invention to implement and apply the technology of the present invention. Those skilled in the art may refer to the disclosure herein and appropriately modify the process parameters to achieve the desired effect. It is particularly important to note that all similar substitutions and modifications apparent to those skilled in the art are considered encompassed by the present invention.

Claims

1. A baloxavir derivative, a deuterated product thereof, or a pharmaceutically acceptable salt thereof, characterized in that: The structural formula of the baloxavir derivative is shown in Formula I: Formula I Among them, sEH inhibitor is the esterified residue of soluble epoxide hydrolase inhibitor; The soluble epoxide hydrolase inhibitors are 12-{[(tricyclo[3.3.1.13,7]dec-1-ylamino)carbonyl]amino}dodecanoic acid, 12-({[(1,3-dimethyltricyclo[3.3.1.13,7]dec-7-yl)amino]carbonyl}amino)dodecanoic acid, 11-{[(tricyclo[3.3.1.1 3,7 ]dec-1-ylamino)carbonyl]amino}undecanoic acid, 11-({[(3,5-dimethyltricyclo[3.3.1.1 3,7 ]dec-1-yl)amino]carbonyl}amino)undecanoic acid, 12-[({[1-(tricyclo[3.3.1.1 3,7 ]dec-1-yl)ethyl]amino}carbonyl)amino]dodecanoic acid.

2. The baloxavir derivative, its deuterated substance or pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound represented by formula I is selected from the following compounds:

3. A pharmaceutical composition, characterized in that The invention comprises the baloxavir derivative according to any one of claims 1 to 2, a deuterated substance thereof or a pharmaceutically acceptable salt thereof.

4. The pharmaceutical composition according to claim 3, characterized in that A pharmaceutically acceptable carrier is included.

5. The pharmaceutical composition according to claim 3, characterized in that The pharmaceutical composition is in the form of tablets, pills, creams, emulsions, ointments, suspensions, lyophilized preparations, capsules, sustained-release preparations, granules, granules, injections or sprays.

6. Use of the baloxavir derivative according to any one of claims 1 to 2, its deuterated product or pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 3 to 5 in the preparation of anti-inflammatory and antiviral drugs.

7. The use according to claim 6, characterized in that The virus is influenza virus.

8. The use according to claim 7, characterized in that The influenza virus is influenza A virus and / or influenza B virus.

9. The use according to claim 7, characterized in that The influenza virus is at least one of H1N1, H5N1, H7N9, H3N2 and influenza B viruses.

10. The use according to claim 7, characterized in that The influenza virus is at least one of H1N1, H3N2 or influenza B virus.

11. Use of the baloxavir derivative, deuterated product or pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, or the pharmaceutical composition according to any one of claims 3 to 5 in the preparation of an inhibitor of the NF-κB signaling pathway.

Images