Compounds useful for treating influenza virus infections

Abstract

The present invention provides compounds that can inhibit influenza virus replication and are therefore useful for treating viral infections caused by influenza viruses. The present invention also provides pharmaceutical compositions containing these compounds, as well as methods for treating or preventing viral infections caused by influenza viruses using these compounds. TIFF2022541404000057.tif52123

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Application No. 62 / 872,998, filed July 11, 2019, and U.S. Provisional Application No. 62 / 944,309, filed December 5, 2019, the disclosures of each of which are incorporated herein by reference in their entirety. [Background technology]

[0002] The present disclosure relates generally to compounds and compositions that may be useful in the treatment of viral infections.

[0003] Influenza pandemics occur worldwide every autumn and winter. Influenza generally causes a self-limited respiratory illness accompanied by fever for 3-7 days. Despite the availability of influenza vaccines, there are an estimated 1 billion influenza cases worldwide, 3-5 million severe cases, and 290,000-650,000 deaths from influenza-related respiratory illnesses each year (WHO: Global Influenza Strategy 2019-2030 and Iuliano AD et al. Lancet. 2018, 391, 1285-300).

[0004] Influenza viruses belong to the family of Orthomyxoviridae, enveloped viruses with a single negative-stranded RNA genome. In the past decades, two types of anti-influenza virus therapeutics have been commonly used: M2 ion channel inhibitors and neuraminidase inhibitors. However, resistance to M2 ion channel inhibitors has become widespread, and the emergence of neuraminidase inhibitor-resistant viruses remains a threat. Matrix protein 2 (M2) inhibitors (rimantadine and amantadine) inhibit influenza virus replication by blocking the M2 proton channel, but lack activity against influenza B virus (Gu R, Liu LA, Wei D, Trends Pharmacol Sci 2013, 34, 571).

[0005] More effective antiviral drugs are needed for the treatment and prevention of influenza virus infections. Influenza virus RNA-dependent RNA polymerase (RdRp), which has endonuclease activity, performs a process known as "cap snatching" to remove the 5'-terminal cap portion of cellular mRNAs and make them available for primary transcription of viral mRNAs. A ribonucleoprotein complex consisting of PA, PB1 and PB2 subunits is important and essential for "cap snatching". In the treatment of influenza virus infections, the influenza virus polymerase complex has attracted much attention as a target for small molecule inhibitors (Stevaert, A. & Naesens, L, Medicinal Research Reviews 2016, 36, 1127-1173). In 2018, the cap-dependent endonuclease (CEN) inhibitor baloxavir marboxil (Xofluza) was approved in the United States and Japan for the treatment of influenza A and influenza B. Baloxavir marboxil is a prodrug that is converted to its active form, baloxavir, by hydrolysis. Baloxavir inhibits the endonuclease of the polymerase acid (PA) protein of influenza virus, thereby inhibiting the synthesis of viral RNA. However, influenza strains acquired resistance due to the I38T / M / F mutation in 2.2% of recipients in a phase 2 study and about 10% of recipients in a phase 3 study (Shinya O et al., Scientific Reports 2018, 8, 9633). Furthermore, oral administration of baloxavir marboxil and its active ingredient, baloxavir, is less effective.

[0006] Therefore, there is an urgent need to develop new therapeutic agents with improved pharmaceutical and / or biological properties. [Brief description of the drawings]

[0007] Figure 1A and Figure 1B show antiviral efficacy in a mouse model infected with PR / 8 / 34 influenza virus. Figure 1A shows the body weight change when compound B-1, compound C-1, oseltamivir phosphate or vehicle is administered, and Figure 1B shows the survival rate when compound B-1, compound C-1, oseltamivir phosphate or vehicle is administered. Summary of the Invention

[0008] In one embodiment, a compound of formula (I): [ka] wherein R1, R2, R3, R4, m, n, p, and G are as detailed herein, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof is provided.

[0009] In one embodiment, a compound of formula (II): [ka] wherein R1, R2, R3, R4, m, n, p, and G are as detailed herein, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof is provided.

[0010] In some embodiments, the compound of Formula (I) or (II), or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, is Formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3), as detailed herein.

[0011] In another embodiment, a method for treating or preventing influenza virus infection is provided.

[0012] In some embodiments, there is provided a method for treating influenza, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I) or (II), or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

[0013] Also provided is a pharmaceutical composition comprising: (A) a compound as described herein (e.g., a compound of Formula (I) or (II), or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof); and (B) a pharma- ceutically acceptable carrier or excipient. Kits are also provided that include a compound as described herein, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, and, optionally, instructions for use.

[0014] The compounds detailed herein or their pharma- ceutically acceptable salts, stereoisomers or solvates are used as medicaments.The compounds detailed herein or their pharma- ceutically acceptable salts, stereoisomers or solvates are also used in the manufacture of a medicament for the treatment or prevention of influenza virus infection.

[0015] The compounds detailed herein or their pharmacokinetically acceptable salts, stereoisomers or solvates show excellent pharmacokinetic properties and biological activity. For example, there is no effect of food on pharmacokinetic parameters in cynomolgus monkeys. The oral bioavailability in both fasted and fed monkeys is 50% or more. Therefore, the compounds detailed herein or their pharmacokinetically acceptable salts, stereoisomers or solvates show excellent advantages. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] (definition) As used herein, unless otherwise indicated, the terms "a," "an," etc. refer to one or more.

[0017] Unless otherwise indicated, the terms "about" and "approximately" as used herein, when used in reference to a dose, amount, or weight percentage of a component of a composition or dosage form, refer to a dose, amount, or weight percentage that would be recognized by a person skilled in the art to provide an amount equivalent to the pharmacological effect resulting from the specified dose, amount, or weight percentage. Specifically, when the terms "about" and "approximately" are used in reference to a value, they contemplate a range within ±15%, ±10%, ±5%, ±4%, ±3%, ±2%, ±1%, or ±0.5% of the specified value. Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself. For example, a description that refers to "about X" includes a description of "X."

[0018] Unless otherwise indicated, as used herein, "alkyl" refers to any group having a specified number of carbon atoms (i.e., C1-C 10 "C1-C2" refers to and includes saturated linear (i.e., unbranched) or monovalent branched hydrocarbon chains or combinations thereof having 1 to 20 carbon atoms ("C1-C2" means 1 to 10 carbon atoms). 20 alkyl), 1 to 10 carbon atoms ("C1-C 10 alkyl), 6 to 10 carbon atoms ("C6-C 10 An alkyl group is an alkyl group having 1 to 6 carbon atoms ("C1-C6 alkyl"), 2 to 6 carbon atoms ("C2-C6 alkyl"), or 1 to 4 carbon atoms ("C1-C4 alkyl"). Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0019] Unless otherwise specified, as used herein, "cycloalkyl" refers to any group having the specified number of carbon atoms (i.e., C-C 10means 3 to 10 carbon atoms). Cycloalkyl can consist of one ring (e.g., cyclohexyl) or multiple rings (e.g., adamantyl). Cycloalkyls containing more than one ring can be fused, spiro or bridged rings, or combinations thereof. Particular cycloalkyl groups are rings containing 3 to 12 carbon atoms. Preferred cycloalkyls are cyclic hydrocarbons containing 3 to 8 carbon atoms ("C3-C8 cycloalkyl"), 3 to 6 carbon atoms ("C3-C6 cycloalkyl"), or 3 to 4 carbon atoms ("C3-C4 cycloalkyl"). Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.

[0020] "Heterocycle" or "heterocyclic" or "heterocycloalkyl" or "heterocyclyl" refers to a non-aromatic saturated or partially saturated group containing 1-10 ring carbon atoms, preferably 1-8 carbon atoms, more preferably 1-6 carbon atoms; and 1-4 ring heteroatoms, preferably 1-3 heteroatoms, more preferably 1-2 heteroatoms, selected from the group consisting of nitrogen, sulfur, or oxygen. Heterocycles include single rings or multiple fused rings, such as fused bridged rings and spiro rings. In fused ring systems, when the linking moiety is a non-aromatic ring, one or more of the rings can be cycloalkyl, aryl, or heteroaryl. In certain embodiments, the nitrogen and / or sulfur atoms of the heterocyclic group may be optionally oxidized to provide N-oxide, sulfinyl, or sulfonyl moieties.

[0021] "Halo" or "halogen" refers to group 17 elements with atomic numbers 9-85. Preferred halogens include the radicals fluorine, chlorine, bromine and iodine. When the residue is substituted with one or more halogens, it may be referred to using a prefix corresponding to the number of halogen sites to which it is attached, e.g., dihaloaryl, dihaloalkyl, trihaloaryl, etc., referring to aryls and alkyls substituted with two ("di") or three ("tri") halogens, not necessarily the same halogens. Thus, 4-chloro-3-fluorophenyl is included in dihaloaryl. Alkyl groups in which each hydrogen is replaced by a halogen group are referred to as "perhalogenated alkyls." A preferred perhalogenated alkyl group is trifluoromethyl (-CF3).

[0022] A "pharmaceutical acceptable salt" is a salt that retains at least a portion of the biological activity of the free (non-salt) compound and can be administered to an individual as a drug or medicine. Such salts include, for example, (1) acid addition salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.); or acid addition salts formed with organic acids (e.g., acetic acid, oxalic acid, propionic acid, succinic acid, maleic acid, tartaric acid, etc.); (2) salts formed by replacing the acidic protons present in the parent compound with metal ions (e.g., alkali metal ions, alkaline earth metal ions, or aluminum ions); or by coordinating with organic bases. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, etc. Acceptable inorganic salts that can be used for salt formation include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, etc. Pharmaceutically acceptable salts can be prepared in situ during the manufacturing process or are formed during subsequent purification by reacting a purified compound of the invention in its free acid or free base form, respectively, with a suitable organic or inorganic base or acid, respectively, and isolating the salt.

[0023] "Pharmaceutically acceptable carrier" refers to an ingredient in a pharmaceutical formulation, other than an active ingredient, that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0024] The term "excipient" as used herein refers to an inert substance that can be used in the production of a drug or medicament (e.g., a tablet containing a compound of the present invention as an active ingredient). Various substances that can be included in the term "excipient" include, but are not limited to, binders, disintegrants, coating agents, compression / encapsulation aids, creams or lotions, lubricants, solutions for parenteral administration, materials for chewable tablets, sweeteners or flavoring agents, suspending / gelling agents, or any material that can be used as a wet granulation agent. Binders include, for example, carbomer, povidone, xanthan gum, etc.; coatings include, for example, cellulose acetate phthalate, ethylcellulose, gellan gum, maltodextrin, enteric coatings, etc.; compression / encapsulation aids include, for example, calcium carbonate, dextrose, fructose dc (dc = "directly compressible"), honey dc, lactose (hydrate or monohydrate; optionally in combination with aspartame, cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.; disintegrants include, for example, croscarmellose sodium, gellan gum, sodium starch glycolate, etc.; creams or lotions include, for example, lubricants include, for example, magnesium stearate, stearic acid, sodium stearyl fumarate, etc.; chewable tablet materials include, for example, dextrose, fructose dc, lactose (monohydrate, optionally in combination with aspartame or cellulose), etc.; suspending / gelling agents include, for example, carrageenan, sodium starch glycolate, xanthan gum, etc.; sweeteners include, for example, aspartame, dextrose, fructose dc, sorbitol, sucrose dc, etc.; wet granulating agents include, for example, calcium carbonate, maltodextrin, microcrystalline cellulose, etc.

[0025] "Stereoisomers" refers to compounds that differ in one or more stereocenters, such as, but not limited to, the chirality of the constituent atoms of the stereocenter or the constituent atoms associated with a cis or trans configuration of a carbon-carbon double bond or a carbon-nitrogen double bond. Stereoisomers include enantiomers and diastereomers.

[0026] As used herein, "treatment" or "treating" refers to an approach for obtaining beneficial or desired results, such as clinical results. For example, beneficial or desired results may include, but are not limited to, one or more of the following: reducing symptoms of a disease, improving the quality of life of a subject suffering from a disease, reducing the dosage of other medications required to treat a disease, delaying the progression of a disease, and / or extending the lifespan of a patient.

[0027] As used herein, an "effective dosage" or "effective amount" of a compound or salt thereof or pharmaceutical composition is an amount sufficient to obtain a beneficial or desired result. In prophylactic use, the beneficial or desired result may include, for example, eliminating or reducing the risk, reducing the severity of the disease, or delaying the onset of the disease. Here, the risk or disease includes the biochemical, histological and / or behavioral symptoms of the disease, its complications, and intermediate pathological phenotypes that appear during the progression of the disease. In therapeutic use, the beneficial or desired result may include improving, alleviating, reducing, delaying, or reducing one or more symptoms of the disease, improving the quality of life of a subject suffering from the disease, reducing the amount of other medication required to treat the disease, for example, delaying the progression of the disease, and / or enhancing the effect of another medication, such as to extend life. In some embodiments, the effective amount is an amount sufficient to delay progression. In some embodiments, the effective amount is an amount sufficient to prevent or delay recurrence. An effective dosage may be administered one or more times. For the purposes of this disclosure, an effective dosage of a compound or its salt, or pharmaceutical composition is an amount sufficient to perform direct or indirect prophylactic or therapeutic treatment. It is intended and understood that an effective dosage of a compound or its salt, or pharmaceutical composition may or may not be achieved in combination with another drug, compound, or pharmaceutical composition. Thus, "effective dosage" may be contemplated in the context of administering one or more therapeutic agents, and it is contemplated that a single agent is administered in an effective amount in combination with one or more other agents when a desired result can or will be obtained.

[0028] As used herein, the term "patient" refers to a mammal, including a human. Patients include, but are not limited to, humans, cows, horses, cats, dogs, rodents, or primates. In some embodiments, the patient is a human.

[0029] Unless otherwise specified, "substantially pure" contemplates a composition containing less than 10% impurities (e.g., about 9%, 7%, 5%, 3%, 1%, 0.5%).

[0030] It is understood that the embodiments and variations described herein also include embodiments and variations described as "consisting of" and / or "including".

[0031] All cited references, including publications, patents, patent applications, and published patent applications, are incorporated herein by reference in their entirety.

[0032] (compound) In one embodiment, the present invention provides a method for producing a compound of formula (I): [ka] [In the formula, Each R1 is independently selected from the group consisting of H and halogen; Each R2 is independently selected from the group consisting of H and halogen; R3 is selected from the group consisting of H, halogen, Me, CN, and P(O)Me2; each R4 is independently selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl, where any two R4, together with the atom to which they are attached, optionally form a C3-C6 cycloalkyl; n and m are each independently 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; and G is selected from the group consisting of H or C(O)R, C(O)OR, C(O)NR'R, C(R')-OC(O)R, C(R')-OC(O)OR, and C(R')-OC(O)NR'R, each R is selected from the group consisting of C1-C6 alkyl, phenyl, pyridyl, C3-C6 cycloalkyl, and a 4-6 membered heterocyclic ring containing one or two heteroatoms selected from the group consisting of N, O, and S as ring members, where the C1-C6 alkyl, phenyl, pyridyl, C3-C6 cycloalkyl, and the 4-6 membered heterocyclic ring R are optionally independently substituted with one or two substituents selected from the group consisting of H, halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; and Each R' is independently selected from the group consisting of H and C1-C3 alkyl. or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

[0033] Some embodiments include the compound of formula (I-1): [ka] wherein R1, R2, R3, R4, m, n, p, and G are as detailed in formula (I) herein, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

[0034] Some embodiments include the compound of formula (I-2): [ka] wherein R1, n, and G are as detailed in formula (I) herein, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

[0035] Some embodiments include the following: [ka] or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

[0036] Some embodiments include the compound of formula (I-3): [ka] wherein G is as detailed in formula (I) herein, or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

[0037] In another aspect, the present invention relates to a compound of formula (II): [ka] [In the formula, Each R1 is independently selected from the group consisting of H and halogen; Each R2 is independently selected from the group consisting of H and halogen; R3 is P(O)Me2 or P(O)Et2; each R4 is independently selected from the group consisting of C1-C6 alkyl and C3-C6 cycloalkyl, where any two R4, together with the atom to which they are attached, optionally form a C3-C6 cycloalkyl; n and m are each independently 0, 1, 2, 3, or 4; p is 0, 1, 2, or 3; and G is selected from the group consisting of H or C(O)R, C(O)OR, C(O)NR'R, C(R')-OC(O)R, C(R')-OC(O)OR, and C(R')-OC(O)NR'R, each R is selected from the group consisting of C1-C6 alkyl, phenyl, pyridyl, C3-C6 cycloalkyl, and a 4-6 membered heterocyclic ring containing 1 or 2 heteroatoms selected from the group consisting of N, O, and S as ring members, where the C1-C6 alkyl, phenyl, pyridyl, C3-C6 cycloalkyl, and the 4-6 membered heterocyclic ring R are optionally independently substituted with 1 or 2 substituents selected from the group consisting of H, halogen, CN, OH, NH2, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; and Each R' is independently selected from the group consisting of H and C1-C3 alkyl. or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

[0038] Some embodiments have the formula (II-1): [ka] wherein R1, R2, R3, R4, m, n, p, and G are as detailed in formula (II) herein.

[0039] or a pharma- ceutically acceptable salt, stereoisomer or solvate of formula (II-1).

[0040] Some embodiments have the formula (II-2): [ka] wherein R1, n, R3 and G are as detailed in formula (II) herein, or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

[0041] Some embodiments include the compound of formula (II-3): [ka] wherein R3 and G are as detailed in formula (II) herein, or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

[0042] In some embodiments, the present invention provides a compound of formula (I), (I-1), (I-2), (I-3), (II), (II-1), (II-2), or (II-3), wherein G is hydrogen or the following: [ka] or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

[0043] Pharmaceutical Compositions and Formulations The present disclosure includes pharmaceutical compositions of any of the compounds detailed herein or their pharma- ceutically acceptable salts, stereoisomers or solvates. Thus, the present disclosure includes pharmaceutical compositions comprising the compounds detailed herein or their pharma- ceutically acceptable salts, stereoisomers or solvates and a pharma- ceutical acceptable carrier or excipient. In some embodiments, the pharma- ceutical acceptable salt is an acid addition salt, for example, a salt formed with an inorganic or organic acid. The pharmaceutical composition may be in a form suitable for oral, buccal, parenteral, nasal, topical or rectal administration, or for inhalation administration.

[0044] In some embodiments, the compounds detailed herein or their pharma- ceutically acceptable salts, stereoisomers or tautomers may be purified, and compositions comprising the purified compounds are described herein. Compositions comprising the compounds detailed herein or their salts are provided as compositions of substantially pure compounds. In some embodiments, compositions comprising the compounds detailed herein or their salts are substantially pure.

[0045] In some variations, the compounds herein are synthetic compounds manufactured for administration to a subject. In other variations, compositions are provided that contain substantially pure compounds. In other variations, the disclosure encompasses pharmaceutical compositions that include the compounds detailed herein or their pharma- ceutically acceptable salts, stereoisomers, or solvates, and a pharma- ceutically acceptable carrier. In other variations, methods of administering the compounds are provided. The purified forms, pharmaceutical compositions, and methods of administering the compounds are suitable for any of the compounds detailed herein or their forms.

[0046] The compounds detailed herein, or pharma- ceutically acceptable salts, stereoisomers, or solvates thereof, may be formulated into a form that is deliverable by any route, such as orally, mucosally (e.g., nasally, sublingually, vaginally, buccal, or rectally), parenterally (e.g., intramuscularly, subcutaneously, or intravenously), topically, or transdermally. The compounds or salts thereof may be formulated with a suitable carrier to provide delivery forms such as, but not limited to, tablets, caplets, capsules (e.g., hard gelatin capsules or elastic soft gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, poultices, pastes, powders, dressings, creams, patches, aerosols (e.g., for nasal sprays or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions, or water-in-oil liquid emulsions), solutions, and elixirs.

[0047] One or several compounds described herein or their pharma- ceutically acceptable salts, stereoisomers or solvates are used in the manufacture of formulations (e.g., pharmaceutical formulations) by combining one or more compounds or their salts as active ingredients with pharma- ceutical acceptable carriers (e.g., as described above). Depending on the form of treatment for the system (e.g., transdermal patch or oral tablet, etc.), the carriers may be in various forms. In addition, pharmaceutical formulations may contain preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts for adjusting osmotic pressure, buffers, coating agents or antioxidants. Formulations containing compounds may also contain other substances with beneficial therapeutic properties. Pharmaceutical formulations may be manufactured by known pharmaceutical techniques. Suitable formulation methods are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 20th ed. (2000), the contents of which are incorporated herein by reference.

[0048] The compound described herein or its pharma- ceutically acceptable salt, stereoisomer or solvate can be administered to a subject in the form of a generally accepted oral composition, such as tablet, coated tablet, and hard or soft gel capsule, emulsion or suspension.The examples of carriers that can be used to prepare the above composition include lactose, corn starch or its derivatives, talc, stearic acid ester or its salts, etc.The acceptable carriers in soft gel capsules include, for example, vegetable oils, waxes, fats, semi-liquid polyols and liquid polyols.In addition, pharmaceutical preparations can include preservatives, solubilizers, stabilizers, rewetting agents, emulsifiers, sweeteners, dyes, regulators, and salts for adjusting osmotic pressure, buffers, coating agents or antioxidants.

[0049] Any compound described herein or its pharmaceutically acceptable salt, stereoisomer or solvate can be formulated into tablet among any of the above dosage forms.For example, any compound described herein or its pharmaceutically acceptable salt can be formulated into 10mg tablet.

[0050] (Usage and Applications) In addition to the disclosed compounds, their pharma- ceutically acceptable salts, stereoisomers, hydrates, solvates, and compositions and combinations comprising these compounds, the present invention further includes methods of their use.

[0051] As shown by the data described herein, the compounds of formula (I) and (II), including all of formula (I-1), (I-2), (I-3), (II-1), (II-2), and (II-3), are inhibitors of influenza virus endonuclease function and inhibit influenza virus replication, and thus are useful for treating or preventing influenza virus infection in humans.

[0052] In another aspect, the present invention provides pharmaceutical compositions comprising a compound of formula (I) or (II) (e.g., a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), and (II-3)) administered in combination with at least one pharma- ceutically acceptable carrier or excipient, and optionally in combination with two or more pharma- ceutically acceptable carriers or excipients. The compounds may be used as pharma- ceutically acceptable salts and hydrates.

[0053] In another aspect, the invention provides a method of treating a subject infected with influenza A, B or C, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (I) or (II) (e.g., a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3)), or any salt, stereoisomer, hydrate, solvate of said compound as described herein, or a pharmaceutical composition comprising said compound. The subject is a human, although the compounds and methods of the invention are suitable for treating species other than humans suffering from influenza A, influenza B, or influenza C, as well as other influenza viruses.

[0054] According to the test data described below, the compounds of the present disclosure, their pharma- ceutically acceptable salts, stereoisomers, solvates show efficacy and drug properties of inhibiting or preventing influenza virus replication, and are therefore indicated for the treatment of inhibiting influenza virus replication, particularly influenza A, influenza B, or influenza C. Thus, the compounds of the present invention are useful for the treatment of infection by influenza virus, particularly influenza A, influenza B, or influenza C, especially in human subjects at risk of or suffering from influenza virus infection. For example, subjects with underlying conditions related to autoimmune or respiratory diseases that may be significantly exacerbated by influenza infection may be treated with the method or compound of the present invention before they exhibit influenza infection symptoms. In other embodiments, the subject of treatment is one who is diagnosed with symptoms consistent with influenza infection. In a further embodiment, the present invention provides the use of the compounds described herein as therapeutic agents. In particular, the compounds are suitable for the treatment of subjects at high risk of or already suffering from influenza virus infection, particularly influenza A, influenza B, or influenza C.

[0055] In another aspect, the present invention provides a method for treating an influenza virus disease, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of formula (I) or (II) as described herein (e.g., a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3)), or a pharma- ceutically acceptable salt, stereoisomer, solvate thereof. In some embodiments, the compound or a pharma- ceutically acceptable salt, stereoisomer, solvate thereof is administered orally. In further embodiments, the disease is selected from influenza A, influenza B, and influenza C. The method generally involves administering to a subject in need of treatment an effective amount of a compound as described herein, or a pharmaceutical composition comprising an effective amount of the compound. The compound may be administered by any suitable method, e.g., as described herein, and administration may be repeated at intervals selected by a physician. In some embodiments, the compound or pharmaceutical composition is administered orally.

[0056] Thus, in a further aspect, the present invention provides the use of a compound of formula (I) or (II) (e.g. a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2) or (II-3)), or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof, in the manufacture of a medicament. In a particular aspect, the medicament is for use in the treatment of influenza virus infection, in particular influenza A, influenza B or influenza C.

[0057] The compounds of the present invention may be administered simultaneously with, before or after one or more therapeutic agents. The compounds of the present invention may be administered separately by the same or different routes of administration, or may be administered together in the same pharmaceutical composition as therapeutic agents. Suitable therapeutic agents used with the compounds of the present invention include antiviral active agents against influenza virus, such as neuraminidase inhibitors (oseltamivir, peramivir, zanamivir and laninamivir, laninamivir octanoate, etc.), and adamantanes (e.g. amantadine and rimantadine). In addition, the compounds may be combined with M2 protein inhibitors, polymerase inhibitors, PB2 inhibitors, favipiravir, Fludase®, beraprost, Neugene®, ribavirin, FluMist Quadrivalent®, Fluarix® Quadrivalent, Fluzone® Quadrivalent, Flucelvax® and FluBlok®.

[0058] In certain aspects, the invention provides a product comprising a compound of Formula (I) or (II) (e.g., a compound of Formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3)), or a pharma- ceutically acceptable salt, stereoisomer, solvate thereof, and at least one other therapeutic agent, as a pharmaceutical combination for simultaneous, separate or sequential use in therapy.

[0059] The present invention also provides a Therapeutic Agent for use in the treatment of a viral infection caused by an influenza virus, particularly influenza A, influenza B or influenza C, wherein the Therapeutic Agent is administered in combination with a compound of Formula (I) or (II) (e.g., a compound of Formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3)), or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof.

[0060] The invention also provides the use of a compound of formula (I) or (II) (e.g., a compound of formula (I-1), (I-2), (I-3), (II-1), (II-2), or (II-3)), or a pharma- ceutically acceptable salt, stereoisomer, solvate thereof, for the treatment of a viral infection caused by an influenza virus, particularly influenza, e.g., influenza A, influenza B, or influenza C, where the subject may have been administered another therapeutic agent prior to (e.g., within 24 hours) administering the compound. The invention also provides the use of another therapeutic agent for the treatment of a viral infection caused by an influenza virus, particularly influenza A, influenza B, or influenza C, where the subject may have been administered a compound of formula (I) or (II) or a pharma- ceutically acceptable salt, stereoisomer, solvate thereof, prior to (e.g., within 24 hours) administering the compound.

[0061] In some embodiments, the combined therapeutic agent is selected from antiviral agents said to be useful for treating infection with influenza virus, such as neuraminidase inhibitors (such as oseltamivir, peramivir, zanamivir, and laninamivir), and adamantanes (such as amantadine and rimantadine).

[0062] The pharmaceutical composition or combination of the present invention in humans will vary depending on the weight, age and individual symptoms, disorders or diseases or severity of the subject to be prescribed. Effective doses will be determined by a physician or clinician to prevent, treat or inhibit the progression of disorders or diseases.

[0063] The above-mentioned dosage properties can be previously demonstrated in vitro and in vivo tests using mammals, such as mice, rats, dogs, monkeys, or organs, tissues and animal specimens isolated therefrom.The present invention further includes a method for preparing the compounds of formula (I) and (II) of the present disclosure (e.g., compounds of formula (I-1), (I-2), (I-3), (II-1), (II-2) or (II-3)).

[0064] In the practice of the method of the present invention, a therapeutically effective amount of any one of the compounds of the present invention or any combination of the compounds of the present invention or their pharma- ceutically acceptable salts or esters is administered, either alone or in combination, in any manner known to those skilled in the art as is common and acceptable. Thus, the compounds or compositions can be administered orally (e.g., buccal), sublingually, parenterally (e.g., intramuscularly, intravenously, or subcutaneously), rectally (e.g., by suppository or wash), transdermally (e.g., by skin electroporation) or by inhalation (e.g., by aerosol) in solid, liquid, or gaseous dosage forms (e.g., tablets and suspensions). Administration can be in a single dosage form, by continuous therapy or by single-dose therapy as appropriate. The therapeutic composition can be in the form of an oil emulsion or dispersion with a lipophilic salt (e.g., pamoic acid), or in the form of a biodegradable sustained-release composition for subcutaneous or intramuscular administration.

[0065] The dosage of the compound administered to a subject (e.g., a human) may vary depending on the particular compound or salt thereof, the method of administration, and the particular disease being treated. In some embodiments, an effective amount of the compound is a dosage between about 0.01 and about 100 mg / kg (body weight) per day; in some embodiments, about 0.05-10.0 mg / kg (body weight); in some embodiments, about 0.10-1.4 mg / kg (body weight). In some embodiments, when administered to a 70 kg human, the dosage range is about 0.7-7000 mg / day; in some embodiments, about 3.5-700.0 mg / day; in some embodiments, about 7-100.0 mg / day. The effective amount or dosage of the compound of the present invention may be determined by routine methods, such as modeling, dose escalation studies, or clinical trials, taking into account multiple factors (e.g., the method or route of administration or drug delivery, the pharmacokinetics of the drug, the severity and course of the disease being treated, the health status, symptoms, and body weight of the subject, etc.). The daily dosage ranges, for example, from about 0.1 mg to 10 g. For example, the oral dosage ranges from about 5 mg to about 500 mg per day, and the intravenous dosage ranges from about 5 mg to about 500 mg per day. The dosage varies depending on the pharmacokinetics of each drug.

[0066] The compounds or compositions of the present invention can be administered according to each effective dosing regimen for a desired period or duration (e.g., at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more). The period or duration varies depending on the patient's tolerance period. In some variations, the compounds are administered daily or intermittently. The compounds can be administered to the subject intermittently (e.g., at least once a day) for a certain period of time. The dosing frequency can be less than once a day (e.g., about once a week). The dosing frequency can be more than once a day (e.g., twice or three times a day). The dosing frequency can be intermittent dosing with a "drug holiday" (e.g., dosing once a day for 7 days followed by a 7-day rest period repeated for any 14-day period, for example, about 2 months, about 4 months, about 6 months or more). Any compound described herein can be administered at any frequency in any dosage described herein.

[0067] (Products and Kits) Furthermore, the present disclosure provides a product that includes the compound of the present disclosure or its salt, and the composition and dosage form described herein, in a suitable package.In some embodiments, the product is used in any of the methods described herein.Suitable packages known to those skilled in the art include, for example, vials, containers, ampoules, bottles, jars, flexible packaging, etc.Furthermore, the product can be sterilized and / or sealed.

[0068] The present disclosure further provides a kit for carrying out the method of the present disclosure, comprising one or more compounds described herein or a composition comprising a compound described herein.The kit can comprise any compound described herein.In some variations, the kit comprises a compound described herein or a pharma-ceutically acceptable salt thereof.The kit can be used for any one or more applications described herein, and therefore can comprise instructions for use in treating the disease described herein.

[0069] Generally, the kit includes a suitable package. The kit may include one or more containers that contain any of the compounds described herein. (When there is more than one component) Each component may be packaged in a separate container, or some components may be combined in one container as long as cross-reactivity and shelf life are acceptable.

[0070] The kit may be an individual dosage package, a bulk package (e.g., a multi-dose package) or a sub-unit dosage package. For example, a kit may be provided that contains a sufficient dose of the disclosed compound and / or a second pharmacoactive compound useful for a disease detailed herein (e.g., hypertension) to provide an effective treatment to a subject over an extended period of time (e.g., optionally 1 week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or more). The kit may also contain multiple dosage forms of the compound and instructions for use, and may be packaged in sufficient quantities for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0071] A set of instructions, which may optionally be included in the kit, will generally be written, although electronic storage media (e.g., magnetic or optical disks) are also acceptable, and will include instructions for use of the components of the methods of the invention. The instructions will be included in the kit and will generally include information regarding the components and their administration to an individual.

[0072] In some embodiments, the present invention provides selenium and / or phosphine containing compounds.

[0073] Among the disclosed embodiments are the following compounds:

[0074] Embodiment 1. Formula (A): TIFF0007631292000013.tif62160[In the formula, R1 is independently selected from H and / or fluoro, where n=0-4; R 2 is independently selected from H and / or fluoro, and m=0-4; R 3is selected from H, F, Cl, Br, Me, CN, and P(O)Me2; R 4 is independently selected from Me and / or fluoro, and p=0-3; G is H or a group selected from C(O)R, C(O)OR, C(O)NR'R, C(R')2-OC(O)R, C(R')2-OC(O)OR, and C(R')2-OC(O)NR, where each R is selected from C1-C6 alkyl, phenyl, pyridyl, C3-C6 cycloalkyl, and a 4-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O, and S as ring members; each R is optionally substituted with 1 or 2 groups selected from H, halogen, CN, OH, amino, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; and Each R' is independently selected from the group consisting of H and C1-C3 alkyl. or a pharma- ceutically acceptable salt or solvate thereof.

[0075] Embodiment 2. The compound of embodiment 1, wherein G is H, or a pharma- ceutically acceptable salt or solvate thereof.

[0076] Embodiment 3. The compound of embodiment 1, wherein G is C(O)R, C(O)OR, C(O)NR'R, C(R')2-OC(O)R, C(R')2-OC(O)OR, or C(R')2-OC(O)NR, where each R is selected from C1-C6 alkyl, phenyl, pyridyl, C3-C6 cycloalkyl, and a 4-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O, and S as ring members; each R is optionally substituted with 1 or 2 groups selected from H, halogen, CN, OH, amino, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; and each R' is independently selected from the group consisting of H and C1-C3 alkyl, or a pharma- ceutically acceptable salt or solvate thereof.

[0077] Embodiment 4. The compound of embodiment 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein G is C(O)R, C(O)OR, C(R')2-OC(O)R, or C(R')2-OC(O)OR, where each R is selected from C1-C6 alkyl, phenyl, pyridyl, C3-C6 cycloalkyl, and a 4-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O, and S as ring members; each R is optionally substituted with 1 or 2 groups selected from H, halogen, CN, OH, amino, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; and each R' is independently selected from the group consisting of H and C1-C3 alkyl.

[0078] Embodiment 5. The compound of embodiment 1, or a pharma- ceutically acceptable salt or solvate thereof, wherein G is C(O)R, C(O)OR, CH2-OC(O)R, and CH2-OC(O)OR, where each R is selected from C1-C5 alkyl, and each R is optionally substituted with one group selected from H, halogen, CN, OH, amino.

[0079] Embodiment 6. 3. The compound of formula B: [ka] or a pharma- ceutically acceptable salt or solvate thereof.

[0080] Embodiment 7. wherein R1 is independently selected from H and / or fluoro, and n=0-4; R 2 is independently selected from H and / or fluoro, m=0-4; R 3is selected from H, F, Cl, Br, Me, CN, and P(O)Me2; G is H or a group selected from C(O)R, C(O)OR, C(O)NR'R, C(R')2-OC(O)R, C(R')2-OC(O)OR, and C(R')2-OC(O)NR, where each R is selected from C1-C6 alkyl, phenyl, pyridyl, C3-C6 cycloalkyl, and a 4-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O, and S as ring members; each R is optionally substituted with 1 or 2 groups selected from H, halogen, CN, OH, amino, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; and each R' is independently selected from the group consisting of H and C1-C3 alkyl.

[0081] Embodiment 8. Formula C: [ka] [In the formula, R1 is independently selected from H and / or fluoro, where n=0-4; G is H or a group selected from C(O)R, C(O)OR, C(O)NR'R, C(R')2-OC(O)R, C(R')2-OC(O)OR, and C(R')2-OC(O)NR, where each R is selected from C1-C6 alkyl, phenyl, pyridyl, C3-C6 cycloalkyl, and a 4-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O, and S as ring members; each R is optionally substituted with 1 or 2 groups selected from H, halogen, CN, OH, amino, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; Each R' is independently selected from the group consisting of H and C1-C3 alkyl. 2. The compound of embodiment 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0082] Embodiment 9. Formula D: [ka] [In the formula, G is H or a group selected from C(O)R, C(O)OR, C(O)NR'R, C(R')2-OC(O)R, C(R')2-OC(O)OR, and C(R')2-OC(O)NR, where each R is selected from C1-C6 alkyl, phenyl, pyridyl, C3-C6 cycloalkyl, and a 4-6 membered heterocycle containing 1 or 2 heteroatoms selected from N, O, and S as ring members; each R is optionally substituted with 1 or 2 groups selected from H, halogen, CN, OH, amino, C1-C3 alkyl, phenyl, C1-C4 alkoxy, C1-C3 haloalkyl, and C1-C3 haloalkoxy; Each R' is independently selected from the group consisting of H and C1-C3 alkyl. 9. The compound of embodiment 8, or a pharma- ceutically acceptable salt or solvate thereof.

[0083] Embodiment 10. or a pharma- ceutically acceptable salt or solvate thereof. The compound of embodiment 9, wherein G is C(O)R, C(O)OR, CH2-OC(O)R, or CH2-OC(O)OR, where each R is selected from C1-C5 alkyl; and each R is optionally substituted with one group selected from H, halogen, CN, OH, amino.

[0084] Embodiment 11. A pharmaceutical composition comprising a compound of embodiment 1 or a pharma- ceutically acceptable salt or solvate thereof, and one or more pharma- ceutically acceptable carriers.

[0085] Embodiment 12. A method for treating influenza, comprising administering to a subject in need of treatment a therapeutically effective amount of a compound of embodiment 1, or a pharma- ceutically acceptable salt or solvate thereof.

[0086] The present invention may be further understood with reference to the following examples, which are offered by way of illustration and not by way of limitation. EXAMPLES

[0087] (Synthesis example) The reagents and solvates used below were obtained commercially. 1 H NMR spectra were recorded on a Varian III plus 300 MHz with TMS as the internal standard. Important peaks are listed in order of multiplicity (s: singlet, d: doublet, t: triplet, q: quartet, m: multiplet, br s: broad singlet), coupling constant in Hertz (Hz) and number of protons. Mass spectrometry results are expressed as mass-to-charge ratios, and the relative abundance of each ion is given in parentheses. Electrospray ionization (ESl) mass spectrometry analysis was performed on an Agilent LC / MSD 1200 Series quadrupole mass spectrometer (column: Welchrom XB-C18 (50 × 4.6 mm, 5 μm); T = 30 °C; flow rate = 1.5 mL / min; detection wavelength: 214 nm).

[0088] The terms "solvent", "inert organic solvent", or "inert solvent" refer to a solvent which is inert under the conditions of the reaction, such as, for example, benzene, toluene, acetonitrile, tetrahydrofuran ("THF"), dimethylformamide ("DMF"), ethyl acetate (EA or EtOAc), dichloromethane (DCM), diethyl ether, methanol, pyridine, formic acid (FA), etc. Unless otherwise specified, the solvates used in the reactions of the present invention are inert organic solvent solvates, and the reactions are carried out under an inert gas, preferably nitrogen and argon. Example 1 Synthesis of 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-1) [ka]

[0089] Synthesis of 4,5-difluoro-3-hydroxyisobenzofuran-1(3H)-one (3) [ka]

[0090] To a solution of LDA (4.8 g, 0.045 mol) in THF (15 mL) was slowly added a solution of 3,4-difluorobenzoic acid (3 g, 0.019 mol) in THF (5 mL) at -40°C. The reaction solution was stirred at -40°C for 1 h, DMF (3.45 g, 0.047 mol) was slowly added, 6 mol / L hydrochloric acid (20 mL) was added to the reaction mixture, and then the organic and aqueous layers were separated. The resulting aqueous layer was extracted with ethyl acetate (30 mL). The organic layers were combined and concentrated to give crude compound 3 (3.55 g), which was used directly in the next step without further purification. MS theoretical: 186; MS found: 185 ([MH] - )

[0091] Synthesis of 4,5-difluoro-3-(phenylselanyl)isobenzofuran-1(3H)-one (5) [ka]

[0092] To a solution of compound 3 (3.5 g, 19 mmol) in toluene (20 mL) was added compound 4 (2 g, 12.5 mmol) and D-camphorsulfonic acid (0.7 g, 3 mmol). The mixture was stirred at 60° C. overnight and then cooled to 5° C. An aqueous solution of sodium hydroxide (7 mL, 2 M) was added to the reaction solution. The temperature was warmed to 25° C. The reaction solution was extracted with toluene (30 mL). The organic layer obtained was concentrated under reduced pressure and purified by flash column chromatography on silica gel (PE:EA = 5:1) to give compound 5 (3 g, 50% yield) as a white solid. 1H-NMR (400MHz, CDCl3): δ 7.48-7.46 (d, J = 6.8Hz, 2H), 7.42-7.34 (m, 1H), 7.30-7.16 (m, 4H), 6.97 (s, 1H); MS theoretical value: 326; MS measured value: 325 ([MH] - )

[0093] Synthesis of 3,4-difluoro-2-((phenylselanyl)methyl)benzoic acid (7) [ka]

[0094] A solution of aluminum chloride (0.8 g, 414 mmol) in toluene (20 mL) was stirred at 0° C. Then, compound 6 (0.8 g, 6 mmol) in toluene (3 mL) was added dropwise to the reaction solution, and the temperature was warmed to 25° C. A solution of compound 5 (1.5 g, 4.6 mmol) in toluene (5 mL) was slowly added to the above reaction solution, and the mixture was stirred at 25° C. for 2.5 hours. After adding 15% aqueous sulfuric acid (5 mL), the resulting reaction mixture was stirred, and the organic layer was separated and concentrated under reduced pressure to obtain compound 7 (2 g) as a yellow solid, which was used directly in the next step without further purification. MS theoretical: 328; MS found: 327 ([MH] - )

[0095] Synthesis of 7,8-difluorodibenzo[b,e]selenpin-11(6H)-one (8) [ka]

[0096] Compound 7 (2 g, 4.6 mmol) was added to polyphosphoric acid (20 g) stirred at 80° C. The temperature was heated to 120° C. and the reaction was maintained for 3 hours. The reaction solution was cooled to 80° C. and water (10 mL) was added slowly. The reaction solution was then further cooled to 30° C. and water (20 mL) was added. The resulting mixture was extracted with ethyl acetate (30 mL). The organic layer was distilled under reduced pressure and then purified by flash column silica gel chromatography (PE:EA=50:1) to give compound 8 (560 mg, 36% yield) as a brown solid. 1 H-NMR (400MHz, CDCl3): δ 8.09-8.07 (m, 1H), 7.40-7.18 (m, 3H), 7.00-6.97 (m, 2H), 4.04 (s, 2H); MS theoretical value: 310; MS measured value: 311([M+H] + )

[0097] Synthesis of 7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-11-ol (9) TIFF0007631292000022.tif29110

[0098] To a solution of compound 8 (560 mg, 1.8 mmol) in 2-propanol (5 mL) and HO (1.0 mL), NaOH (2 mg) and NaBH4 (24 mg, 0.65 mmol) were added. The reaction mixture was stirred at 40 °C for 2 h and cooled to 25 °C. Water (10 mL) was added to the reaction mixture, and water and HCl were added to adjust the reaction mixture to pH = 6-7. The resulting mixture was extracted with EA (30 mL) and purified by flash column silica gel chromatography (PE:EA = 10:0-10:1) to give compound 9 (460 mg, 80% yield) as a yellow solid. 1H-NMR (300MHz, CDCl3): δ 7.68-7.66 (d, J = 7.5Hz, 1H), 7.29-7.22 (m, 3H), 7.15-7.05 (m, 2H), 6.21-6.21 (d, J = 1.8Hz, 1H), 4.48 (s, 2H), 2.49-2.48 (d, J = 2.7Hz, 1H); MS theoretical value: 312; MS measurement value: 311([MH] - )

[0099] Synthesis of 7,8-difluoro-6,11-dihydrodibenzo[b,e]selenium-11-yl methanesulfonate (10) [ka]

[0100] To a solution of compound 9 (200 mg, 0.64 mmol) in DCM (15 mL) was added TEA (194 mg, 1.9 mmol) at 0° C., followed by MsCl (111 mg, 0.96 mmol) under N2 atmosphere. The reaction was stirred at 0° C. for 2 h. The reaction was diluted with DCM (20 mL) and washed with HCl (1N, 10 mL*3), brine. The organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced pressure to give crude compound 10 (175 mg) as a yellow oil, which was used directly in the next step without further purification.

[0101] Synthesis of 7-(benzyloxy)-12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (12) [ka]

[0102] To a suspension of compound 10 (130 mg, 0.397 mmol) in MeCN (10 mL) was added K2CO3 (82 mg, 0.596 mmol). After stirring at room temperature for 1 h, crude compound 11 (232 mg, 0.596 mmol, synthesized similarly to the method described in JP5971830B1) was added, and the resulting reaction mixture was then stirred at room temperature overnight. The resulting reaction solution was diluted with EA (30 mL), washed with water and brine, concentrated, and purified by preparative HPLC to give compound 12 (85 mg, 34.4% yield) as a yellow solid. MS theoretical: 621; MS measured: 622 ([M+H] + )

[0103] Synthesis of 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-1) [ka]

[0104] To a solution of compound 12 (50 mg, 0.08 mmol) in NMP (1.5 mL), LiCl (34 mg, 0.8 mmol) was added and stirred at 80° C. overnight. The reaction mixture was cooled to room temperature and purified by preparative HPLC to obtain two fractions of A-1 (P1, 7 mg and P2, 7 mg) as pale yellow solids. A-1-P1 and A-1-P2 were both mixtures of two diastereomers.

[0105] A-1-P1: 1H-NMR (400MHz, CDCl3): δ 7.31-7.22 (m, 2H), 7.14-6.98 (m, 3H), 6.93-6.89 (m, 1H), 6.72-6.70 (d, J = 7.6Hz, 1H), 6.08-6.06 (d, J = 7.6Hz, 1H), 5.34 (s, 1H), 5.18-5.14 (m, 1H), 4.71-4.66 (m, 2H), 4.10-4.03 (m, 2H), 3.86-3.82 (m, 1H), 3.66-3.60 (m, 1H), 3.52-3.46 (m, 1H), 3.07-3.00 (m, 1H); LCMS [Mobile phase: 95% water (0.1% TFA) and 5% acetonitrile to 5% water (0.1% TFA) and 95% acetonitrile in 6 min, 0.5 min in final conditions]; Purity >95%, Rt=3.604 min; MS theoretical: 531; MS observed: 532 ([M+1] + )

[0106] A-1-P2: 1 H-NMR (400MHz, CDCl3): δ 7.36-7.18 (m, 4H), 6.93-6.89 (m, 2H), 6.64-6.61 (m, 1H), 6.20-6.17 (d, J = 8Hz, 1H), 5.45-5.41(m, 1H), 5.17 (s, 1H), 4.57-4.51 (m, 2H), 4.13-4.08 (m, 2H), 3.80-3.76 (m, 1H), 3.61-3.56 (m, 1H), 3.47-3.42 (m, 1H), 2.77-2.72 (m, 1H); LCMS [Mobile phase: 70% water (0.1% TFA) and 30% acetonitrile to 30% water (0.1% TFA) and 70% acetonitrile in 6 min, final conditions 0.5 min]; purity >96%, Rt=3.276 min; MS theoretical: 531; MS observed: 532 ([M+1] + )

[0107] Mixtures of stereoisomers (e.g., pairs of enantiomers or mixtures of diastereomers) may be separated by any suitable method, including but not limited to, chiral HPLC. When a mixture of stereoisomers is separated by HPLC, it should be recognized that each resulting stereoisomer or mixture is named sequentially (e.g., P1, P2, etc.), with the numbering sequence referring to the order in which the isomers eluted from the HPLC column. In this example, when a mixture of A-1 is separated by HPLC, it is recognized that the first eluting mixture of diastereomers is named "P1" and the second eluting mixture of diastereomers is named "P2". The absolute stereochemistry of "P1" and "P2" may be obtained by known methods.

[0108] Synthesis of Compounds A-2 to A-9 Compounds A-2 to A-9 were synthesized from the starting material corresponding to 2-formylbenzoic acid in the same manner as for A-1. [ka]

[0109] In some embodiments, the present invention provides (8-fluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-2), (7-fluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-3), (8,9-difluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-4), (10-fluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-5), (6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-6), (7,8,10-trifluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-7), (7,10-difluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-8), and (9-Fluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-9) The present invention provides a compound selected from the group consisting of: Example 2 Synthesis of (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenium-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-1) [ka]

[0110] Synthesis of (R)-7-(benzyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (11-R) [ka]

[0111] Compound 11 (7.0 g, 21.4 mmol) was separated by chiral HPLC (60-40% CO2, solvent (MeOH), column (IA)). Peak 1 was collected to obtain 11-R (3.2 g, yield 45.7%).

[0112] Synthesis of (R)-7-(hexyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (13) [ka]

[0113] To a solution of hexan-1-ol (5.5 g, 55 mmol) in THF (12 mL) was added i-PrMgCl (3.7 mL, 3.7 mmol) and the mixture was stirred at room temperature for 0.5 h. The solution was added to a suspension of compound 11-R (3.0 g, 9.17 mmol) in hexan-1-ol (5.5 g, 55 mmol) and then stirred at room temperature for 24 h. The reaction was quenched with HCl (1N) to pH 7, extracted with EtOAc (20 mL*3), and purified by flash column silica gel chromatography (DCM:MeOH=10:1) to give compound 13 (2.3 g, 78.2% yield) as a white solid, which was used in the next step without further purification. MS theoretical: 321; MS found: 322 ([M+H] + )

[0114] The synthesis of compound 13 from 11-R described above can be catalyzed by other reagents than iPrMgCl, such as Li salt or K salt. For example, LDA (lithium diisopropylamide), alkoxy Li salt or K salt, LHMDS (lithium bis(trimethylsilyl)amide), or KHMDS (potassium bis(trimethylsilyl)amide) are applied to convert compound 11-R to compound 13. [ka]

[0115] Synthesis of (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-(hexyloxy)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (14) [ka]

[0116] To a suspension of 13 (1.7 g, 5.29 mmol) in EA (12 mL) was added hexane (3.5 mL), 9 (1.65 g, 5.3 mmol), T3P (6.75 g, 10.6 mmol), and MeSO3H (1.7 g, 17.7 mmol). The reaction was stirred at 60 °C overnight, and LCMS showed that most of 13 was converted to 14. The resulting reaction mixture was cooled to room temperature, diluted with EA (30 mL), adjusted to pH > 8 with 20% NaOH, extracted with EA, dried over Na2SO4, concentrated, and purified by preparative HPLC (0.1% TFA) to give 14 (1.06 g, 32.6% yield) as an off-white solid. MS theoretical: 615; MS found: 616 ([M+H] + )

[0117] Synthesis of (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenium-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-1) [ka]

[0118] To a suspension of compound 14 (1.06 g, 1.72 mmol) in NMP (5 mL) was added LiCl (724 mg, 17.2 mmol), and the resulting reaction mixture was then stirred for 24 h at 90° C. The reaction solution was purified by preparative HPLC (0.1% TFA) to give compound B-1 (367 mg, 86.3%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ 7.41-7.30 (m, 2H), 7.26-7.19 (m, 2H), 7.13-7.06 (m, 2H), 6.92-6.88 (m, 1H), 5.81 (s, 1H), 5.61-5.59 (d, J = 7.6Hz, 1H), 5.31-5.27 (dd, J = 2Hz and 12.4Hz, 1H), 4.61-4.58 (m, 1H), 4.45-4.42 (m, 1H), 4.13-4.10 (d, J = 12.8Hz, 1H), 4.04-4.01 (m, 1H), 3.70-3.64 (m, 2H), 3.46-3.40 (m, 1H), 3.09-3.02 (m, 1H); LCMS [Mobile phase: 80% water (0.1% TFA) and 20% acetonitrile to 30% water (0.1% TFA) and 70% acetonitrile in 6 min, 0.5 min in final conditions]; Purity >98%, Rt=3.793 min; MS theoretical: 531; MS observed: 532 ([M+1] + )

[0119] Synthesis of compounds B-2 to B-9 Compounds B-2 to B-9 were obtained in the same manner as compound B-1. [ka]

[0120] In some embodiments, the present invention provides a method for the preparation of a composition comprising the steps of: (R)-12-((S)-8-fluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-2), (R)-12-((S)-7-fluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-3), (R)-12-((S)-8,9-difluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-4), (R)-12-((S)-10-fluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-5), (R)-12-((S)-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-6), (R)-12-((S)-7,8,10-trifluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-7), (R)-12-((S)-7,10-difluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-8), and (R)-12-((S)-9-Fluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-9) The present invention provides a compound selected from the group consisting of: Example 3 Synthesis of 2-(((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-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)methoxy)methyl acetate (C-1) [ka]

[0121] To a suspension of compound B-1 (400 mg, 0.75 mmol) in DMA (10 mL), chloromethyl methyl carbonate (187 mg, 1.5 mmol), K2CO3 (210 mg, 1.5 mmol), KI (125 mg, 0.75 mmol) were added, and the reaction mixture was then stirred overnight at 50° C. The resulting reaction solution was diluted with EA (20 mL), washed with water, followed by brine, and purified by preparative HPLC (0.1% TFA) to give compound C-1 (237 mg, 50.8%) as a white solid. 1H-NMR (400MHz, DMSO-d6): δ 7.36-7.34 (d, J = 7.6Hz, 1H), 7.27 (s, 1H), 7.22-7.20 (d, J = 8Hz, 1H), 7.13-6.84 (m, 5H), 6.18-6.16 (d, J = 7.6Hz, 1H), 5.88 (s, 2H), 5.40 (s, 1H), 5.18-5.15 (dd, J = 2.8Hz and 12.8Hz, 1H), 4.65-4.60 (m, 2H), 4.08-3.99 (m, 2H), 3.86 (s, 3H), 3.81-3.77 (m, 1H), 3.58-3.42 (m, 2H), 3.01-2.93 (m, 1H); LCMS [Mobile phase: 70% water (0.1% TFA) and 30% acetonitrile to 30% water (0.1% TFA) and 70% acetonitrile in 6 min, 0.5 min in final conditions]; Purity >97%, Rt=3.424 min; MS theoretical: 619; MS found: 620 ([M+1] + )

[0122] Synthesis of compounds C-2 to C-9 Compounds C-2 to C-9 were obtained in the same manner as compound C-1. [ka]

[0123] In some embodiments, the present invention provides a method for the preparation of a composition comprising the steps of: ((R)-12-((S)-8-fluoro-6,11-dihydrodibenzo[b,e]selenpin-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)methyl methyl carbonate (C-2), (((R)-12-((S)-7-fluoro-6,11-dihydrodibenzo[b,e]selenpin-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)methyl methyl carbonate (C-3), (((R)-12-((S)-8,9-difluoro-6,11-dihydrodibenzo[b,e]selenpin-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)methyl methyl carbonate (C-4), (((R)-12-((S)-10-fluoro-6,11-dihydrodibenzo[b,e]selenpin-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)methyl methyl carbonate (C-5), ((R)-12-((S)-6,11-dihydrodibenzo[b,e]selenpin-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)methyl methyl carbonate (C-6), ((R)-6,8-dioxo-12-((S)-7,8,10-trifluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-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)methyl methyl carbonate (C-7), ((R)-12-((S)-7,10-difluoro-6,11-dihydrodibenzo[b,e]selenpin-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)methyl methyl carbonate (C-8), and ((R)-12-((S)-9-fluoro-6,11-dihydrodibenzo[b,e]selenpin-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)methyl methyl carbonate (C-9) The present invention provides a compound selected from the group consisting of: Example 4

[0124] Synthesis of compounds D-1 to D-9 Compounds D-1 to D-9 were obtained according to the following procedure: To a suspension of compound B-1 (0.10 mmol) and potassium carbonate (138 mg, 0.22 mmol) in water (1.0 mL), tetrabutylammonium hydrogen sulfate (34 mg, 0.10 mmol) and dichloromethane (0.5 mL) were added, and the mixture was stirred at room temperature for 10 minutes. To this reaction solution, a solution of the corresponding iodide (0.22 mmol) in dichloromethane (0.5 mL) was added, and the mixture was stirred for another 2 hours. Water was then added to the resulting reaction solution, the dichloromethane layer was separated, and the aqueous layer was extracted once with dichloromethane. The combined extracts were washed with brine and then dried over sodium sulfate. The solvent was concentrated, and the resulting residue was purified by silica gel column chromatography. [ka]

[0125] In some embodiments, the present invention provides a method for the preparation of a composition comprising the steps of: ((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-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)methyl ethyl carbonate (D-1), 1-(((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-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)ethyl methyl carbonate (D-2), ((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-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)methyl acetate (D-3), ((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-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)methyl isopropyl carbonate (D-4), (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-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 acetate (D-5), ((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-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)methyl(2-methoxyethyl)carbonate (D-6), ((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-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)methyl L-valine ester (D-7), 1-(((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-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)ethyl L-valine ester (D-8), and ((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-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)methyl L-leucine ester (D-9) The present invention provides a compound selected from the group consisting of: Example 5 7-(Benzyloxy)-9-bromo-12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (15) [ka]

[0126] Step 1. To a suspension of compound 11 (150 mg, 0.458 mmol) in EA (3.2 mL), hexane (1.25 mL) was added and stirred at room temperature for 10 min, T3P (1.5 g, 2.36 mmol) was added, the mixture was stirred at room temperature for 30 min, 7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-ol (175 mg, 0.51 mmol) was added, the reaction mixture was stirred at 35° C. overnight, MeSO3H (80 mg, 0.83 mmol), 7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-ol (178 mg, 0.67 mmol) in EA (0.5 mL) were added. The mixture was stirred at 55° C. overnight, and LCMS showed that most of compound 11 had disappeared. The mixture was cooled to room temperature, diluted with EA (30 mL), washed with water, brine, dried over Na2SO4, filtered, and the filtrate was concentrated. The resulting residue was slurried in MTBE (10 mL) and PE (20 mL), filtered, and dried under vacuum to give the compound: 7-(benzyloxy)-12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (205 mg, 78.1% yield) as a yellow solid, which was used directly in the next step without further purification. MS theoretical: 573; MS found: 574 (M+H + )

[0127] Step 2. To a mixture of 7-(benzyloxy)-12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (50 mg, 0.087 mmol) in CCl4 (10 mL) and DMF (0.2 mL) was added NBS (31 mg). The mixture was then stirred at room temperature overnight, washed with water, and dried over Na2SO4. The organic layer was removed from the solvent, and the resulting residue was purified by preparative HPLC to give compound 15 (20 mg, 35.3% yield) as a light yellow solid. Combined with another batch, a total of 65 mg of compound 15 was obtained. 1 H-NMR (400MHz, CDCl3): δ 7.62-7.60 (m, 4H), 7.52 (s, 1H), 7.39-7.36 (m, 9H), 7.32-7.04 (m, 5H), 6.99-6.96 (m, 1H), 6.82-6.77 (m, 1H), 6.70-6.67 (m, 1H), 6.39-6.37 (d, J = 7.6Hz, 1H), 6.13-6.09 (m, 1H), 5.69-5.60 (m, 2H), 4.46-5.40 (m, 2H), 5.23-5.18 (m, 3H), 5.02 (s, 1H), 4.70-4.62 (m, 2H), 4.50-4.35 (m, 2H), 4.09-3.71 (m, 6H), 3.43-3.23 (m, 4H), 2.95-2.72 (m, 2H); LCMS [Mobile phase: 60% water (0.1% TFA) and 40% acetonitrile to 50% water (0.1% TFA) and 50% acetonitrile in 6 min, 0.5 min in final conditions]; Purity >96%, Rt=3.385 min; MS theoretical: 651, 653; MS observed: 652, 654 (M+1 + )

[0128] Example 6 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (E-1a and E-1b) [ka]

[0129] Step 1: 7-(benzyloxy)-12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (16a and 16b) A solution of compound 15 (46 mg, 0.071 mmol) in 1,4-dioxane (8 mL), Cs2CO3 (205 mg, 0.63 mmol), dimethylphosphine oxide (112 mg, 1.42 mmol), KI (60 mg, 0.36 mmol), Pd(OAc)2 (24 mg, 0.107 mmol) and Xantphos (88 mg, 0.152 mmol) was added to a test tube and the mixture was bubbled with N2 for 3 min. The test tube was sealed and the mixture was reacted at 95 °C under microwave for 3 h. The reaction mixture was concentrated, water (10 mL) was added, extracted with EA (10 mL*3), and purified by preparative TLC (PE:EA=1:2) to give compound 16a (5 mg, 10.9% yield) and compound 16b (10 mg, 21.8% yield) as yellow solids (MS theoretical: 649; MS measured: 650 ([M+H] + )). In this example, when the mixture of stereoisomers was separated by HPLC, the first eluting mixture was designated "16a" and the second eluting mixture was designated "16b." 16a and 16b are each mixtures of two diastereomers.

[0130] Step 2: Synthesis of 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (E-1a and E-1b)

[0131] To a solution of 16a (5 mg, 0.0077 mmol) in NMP (1.5 mL) was added LiCl (7.2 mg, 0.17 mmol), and the reaction solution was stirred at 80° C. overnight. The solution was then directly purified by preparative HPLC (0.1% TFA) to give compound E-1a (2.7 mg, 52.1% yield) as a white solid. 1 H-NMR (400MHz, MeOH-d4): δ 7.41-7.39 (d, J = 7.2Hz, 1H), 7.28-7.12 (m, 4H), 7.00-6.94 (m, 1H), 6.79-6.76 (m, 1H), 5.45 (s, 1H), 5.44-5.26 (dd, J = 2Hz, 1H), 4.49-4.34 (m, 3H), 4.07-4.03 (d, J = 14.8Hz, 1H), 3.96-3.92 (dd, J = 2.8Hz, 1H), 3.68- 3.54 (m, 2H), 3.41-3.38 (m, 1H), 2.82-2.75 (m,1H), 1.56-1.52 (d, J = 14.4Hz, 3H), 1.40-1.36 (d, J = 14Hz, 3H); LCMS [Mobile phase: 95% water (0.1% TFA) and 5% acetonitrile to 5% water (0.1% TFA) and 95% acetonitrile in 6 min, 0.5 min in final conditions]; Purity >97%, Rt=3.567 min; MS theoretical: 559; MS found: 560 ([M+1] + )

[0132] To a solution of compound 16b (10 mg, 0.015 mmol) in NMP (1.5 mL), LiCl (7.2 mg, 0.17 mmol) was added, and the reaction solution was stirred at 80° C. overnight. The solution was directly purified by preparative HPLC (0.1% TFA) to obtain compound E-1b (4.4 mg, 43.6% yield) as a white solid. 1 H-NMR (400MHz, MeOH-d4): δ 7.73-7.70 (d, J = 10.4Hz, 1H), 7.33-7.19 (m, 4H), 6.93-6.86 (m, 2H), 5.67 (s, 1H), 5.51-5.47 (dd, J = 2.4Hz, 1H), 4.72-4.63 (m, 3H), 4.16-4.13 (d, J = 14Hz, 1H), 4.11-4.04 (m, 1H), 3.81- 3.70 (m, 2H), 3.54-3.47 (m, 1H), 3.18-3.11 (m,1H), 1.66-1.63 (d, J = 14.4Hz, 3H), 1.46-1.42 (d, J = 14Hz, 3H); MS theoretical value: 559; MS measurement value: 560([M+H] + ); LCMS [Mobile phase: 80% water (0.1% TFA) and 20% acetonitrile to 30% water (0.1% TFA) and 70% acetonitrile in 6 min, 0.5 min in final conditions]; Purity >98%, Rt=3.271 min; MS theoretical: 559; MS observed: 560 ([M+1] + )

[0133] Like 16a and 16b, E-1a and E-1b are each mixtures of two diastereomers.

[0134] Example 7 Synthesis of (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (E-1c) [ka]

[0135] Step 1: Synthesis of ((R)-9-bromo-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-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)methyl methyl carbonate (18) To a solution of compound 17 (6 g, 10.5 mmol, commercially available) in DMF (30 mL) was added NBS (2.8 g, 15.7 mmol), and the reaction mixture was then stirred at room temperature overnight. Water (120 mL) was added to the reaction mixture, the reaction mixture was filtered, the resulting cake was washed with water and dried under vacuum to give compound 18 (7.1 g, 100% yield) as a light yellow solid, which was used directly in the next step without further purification. MS theoretical: 649; MS found: 650 ([M+H] + )

[0136] Step 2: Synthesis of (R)-9-bromo-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (19)

[0137] To a suspension of compound 18 (6.0 g, 9.2 mmol) in NMP (36 mL) was added LiCl (3.8 g, 92 mmol), and then the reaction mixture was stirred at 80° C. overnight. The reaction mixture was diluted with EA (50 mL), washed with water, brine, dried over Na2SO4, and filtered. The filtrate was concentrated to give crude compound 19 (5.2 g) as a pale solid, which was used directly in the next step without further purification. MS theoretical: 560; MS found: 561 ([M+H] + ).

[0138] Step 3: Synthesis of (R)-7-(benzyloxy)-9-bromo-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (20)

[0139] To a solution of compound 19 (5.2 g, 9.2 mmol) in DMA (50 mL) was added K2CO3 (2.54 g, 18.4 mmol), KI (1.53 g, 9.2 mmol), BnBr (3.15 g, 18.4 mmol), and then the reaction mixture was stirred at 50 °C overnight. The reaction mixture was diluted with EA (50 mL), washed with water, brine, and purified by preparative HPLC to give compound 20 (4.9 g, 81.8%) as a pale yellow solid. MS theoretical: 651; MS found: 652 ([M+H] + )

[0140] Step 4: Synthesis of (R)-7-(benzyloxy)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (21)

[0141] To a solution of compound 20 (2.0 g, 3.07 mmol) in MeCN (90 mL), dimethylphosphine oxide (2.78 g, 35.6 mmol), TEA (2.2 g, 21.8 mmol), Pd(dppf)Cl2 (500 mg) were added, and the reaction was flushed with N2 three times. The reaction mixture was stirred at 90 °C under N2 for 20 h. After cooling to room temperature, the reaction mixture was concentrated to dryness, diluted with water, extracted with EA (50 mL * 3), dried over Na2SO4, and concentrated. The reaction mixture was purified by flash column silica gel chromatography (DCM:MeOH = 10:1) to give compound 21 (1.8 g, 90% yield) as a yellow solid. MS theoretical: 649; MS measured: 650 ([M + H] + )

[0142] Step 5: Synthesis of (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (E-1c)

[0143] To a suspension of compound 21 (2 g, 3 mmol) in NMP (7 mL) was added LiCl (1.3 g, 30 mmol), and the reaction mixture was then stirred overnight at 80° C. The reaction was purified by preparative HPLC (0.1% TFA) to give compound E-1c (1.1 g, 63.8%) as an off-white solid. 1 H-NMR (400MHz, DMSO-d6): δ 7.47-7.39 (m, 3H), 7.18-7.14 (m, 1H), 7.10-7.08 (m, 1H), 6.99-6.97 (m, 1H), 6.87-6.83 (m, 1H), 5.80 (s, 1H), 5.43-5.39 (dd, J = 2.4 Hz and 14Hz, 1H), 4.59-4.55 (dd, J = 2.8 Hz and 10Hz, 1H), 4.46-4.42 (m, 1H), 4.11-4.01 (m, 2H)), 3.77- 3.67 (m, 2H), 3.47-3.41 (m, 1H), 3.10-3.03 (m,1H), 1.46-1.43 (d, J = 14.4Hz, 3H), 1.23-1.19 (d, J = 14.4Hz, 3H); LCMS [Mobile phase: 80% water (0.1% TFA) and 20% acetonitrile to 30% water (0.1% TFA) and 70% acetonitrile in 6 min, 0.5 min in final conditions]; Purity >98%, Rt=3.184 min; MS theoretical: 559; MS measured: 560 ([M+1] + )

[0144] Synthesis of compounds E-2 to E-10 Compounds E-2 to E-10 were obtained according to the following procedure: To a suspension of compound E-1c (0.10 mmol) and potassium carbonate (138 mg, 0.22 mmol) in water (1.0 mL), tetrabutylammonium hydrogen sulfate (34 mg, 0.10 mmol) and dichloromethane (0.5 mL) were added, and the mixture was stirred at room temperature for 10 minutes. To this reaction solution, a solution of the corresponding iodide (0.22 mmol) in dichloromethane (0.5 mL) was added, and the mixture was stirred for another 2 hours. Water was then added to the resulting reaction solution, the dichloromethane layer was separated, and the aqueous layer was extracted once with dichloromethane. The combined extracts were washed with brine and then dried over sodium sulfate. The solvent was concentrated, and the resulting residue was purified by silica gel column chromatography. [ka]

[0145] In some embodiments, the present disclosure provides the following: ((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-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)methyl ethyl carbonate (E-2), ((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-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)methyl methyl carbonate (E-3), ((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-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)methyl acetate (E-4), ((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-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)methyl isopropyl carbonate (E-5), (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-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 acetate (E-6), ((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-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)methyl(2-methoxyethyl)carbonate (E-7), ((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-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)methyl L-valine ester (E-8), 1-(((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-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)ethyl L-valine ester (E-9), and ((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin-11-yl)-9-(dimethylphosphoryl)-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)methyl L-leucine ester (E-10) The present invention provides a compound selected from the group consisting of:

[0146] Example 8 Synthesis of (R)-9-(diethylphosphoryl)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]-thiepin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (F-1) [ka] Step 1: To a solution of compound 20 (200 mg, 0.307 mmol) in MeCN (9 mL), diethylphosphine oxide (390 mg, 3.68 mmol), TEA (220 mg, 2.18 mmol), Pd(dppf)Cl2 (60 mg) were added and filled with N2 three times. The reaction was stirred at 90 °C under N2 for 20 h. After cooling to room temperature, the mixture was concentrated to dryness, diluted with water, extracted with EA (5 mL * 3), dried over Na2SO4, and concentrated. The resulting crude was purified by flash column silica gel chromatography (DCM:MeOH = 10:1) to give compound 22 (150 mg, 72.1% yield) as a yellow solid. MS theoretical: 677; MS measured: 678 ([M + H] + )

[0147] Step 2: To a suspension of compound 22 (150 mg, 0.22 mmol) in NMP (1 mL), LiCl (93 mg, 2.2 mmol) was added and then stirred overnight at 80° C. The reaction solution was directly purified by preparative HPLC (0.1% TFA) to give compound F-1 (77 mg, 59.2%) as a white solid. 1 H-NMR (400MHz, DMSO-d6): δ 7.50-7.47 (d, J = 9.6Hz, 3H), 7.42-7.39 (m, 2H), 7.11-7.08 (m, 2H), 7.03-7.02 (m, 1H), 6.88-6.84 (m, 1H), 5.82 (s, 1H), 5.39-5.35 (m, 1H), 4.59-4.55 (dd, J = 2.8 Hz and 9.6Hz, 1H), 4.45-4.42 (m, 1H), 4.12-4.04 (m, 2H), 3.72-3.66 (m, 2H), 3.49-3.42 (m, 1H), 3.09-3.02 (m, 1H), 1.79-1.70 (m, 2H), 1.65-1.42 (m, 2H), 0.87-0.79 (m, 3H), 0.70-0.62 (m, 3H); LCMS [Mobile phase: 70% water (0.1% TFA) and 30% acetonitrile to 40% water (0.1% TFA) and 60% acetonitrile in 6 min, 0.5 min in final conditions]; Purity > 99%, Rt=2.864 min; MS theoretical: 587; MS measured: 588 ([M+1] + )

[0148] Biological Examples The activity of the compounds according to the invention can be assessed by the following in vitro and in vivo methods.

[0149] Example 9 Representative compounds of the present invention were tested in an in vitro assay using the test assay described herein.

[0150] Influenza virus cap-dependent endonuclease (CEN) inhibition assay Assay buffer 2 solution (20 mM Tris, 150 mM NaCl, 2 mM MnCl2, 10 mM β-mercaptoethanol, 0.2% Trition-X100, pH 7.9), 6-fold diluted compound solution, and 100 nM influenza virus CEN PAn enzyme dilution solution (2X) were prepared. 9 μL of the enzyme dilution solution was added to each well of a 384-well plate (Corning, 3676), then 3 μL of the 6-fold diluted compound solution was added to the 384-well plate, centrifuged at 200 g for 60 seconds at room temperature, and then the plate was incubated at 25° C. for 20 minutes. The results are shown in Table 1 below.

[0151] The following steps were performed in dark: Prepare 600 nM influenza PA ssDNA substrate 2 dilution (3X). 6 μL of 3-fold diluted substrate solution was added to each well of a 384-well plate to initiate the reaction and incubated for 4 hours at 37° C. Data were collected with a microplate reader (Ex / Em=485 nm / 535 nm, VICTOR Nivo).

[0152] Data analysis was performed as follows: Z' factor=1-3*(SD Max +SD Min ) / (average Max -average Min ) CV Max =(SD Max / average Max )*100% CV Min =(SD Min / average Min )*100% S / B = signal / background Vehicle control (Max): 0.1% DMSO Positive control (Min): 1.000 nM baloxavir acid I C 50 Value calculation formula: Y=min+(max-min) / (1+10^((LogIC 50 -X)*Hill coefficient) X: log value of compound; Y: % inhibition

[0153] As listed in Table 1, representative compounds (other than prodrug C-1) exhibited strong inhibitory effects on cap-dependent endonuclease activity. Table 1. Inhibitory effect on the enzymatic activity of cap-dependent endonucleases [Table 1]

[0154] In vitro antiviral activity MDCK cells were seeded in 96-well plates at a density of 15,000 cells / well and cultured overnight at 37°C and 5% CO2. The following day, serially diluted compounds and viruses were added to the cells. The resulting cultures were kept at 35°C-37°C and 5% CO2 for an additional 5 days until the virus infection in the virus control (cells infected with virus without compound treatment) showed significant cytopathic effect (CPE). The antiviral activity of the compounds at each concentration was calculated based on their ability to protect against virus-induced CPE relative to the virus control.

[0155] In parallel, the cytotoxicity of the compounds was evaluated under the same conditions without virus infection. Cell viability was measured using CCK8 according to the manufacturer's instructions.

[0156] The antiviral activity and cytotoxicity of the compounds were expressed as inhibition rate (%) and survival rate (%), and were calculated by the following formulas, respectively. Inhibition rate (%) = (raw data CPD -average VC ) / (average CC -average VC )*100 Survival rate (%) = (raw data CPD -average MC ) / (average CC -average MC )*100

[0157] Raw Data CPDindicates the value for compound-treated wells. Mean VC ,average CC and the average MC indicates the average value of virus control, cell control (cells not infected with virus and treated with compound) and medium control (medium only) wells, respectively.

[0158] EC was analyzed using GraphPad Prism software. 50 and C.C. 50 The values ​​were calculated using the equation "change in slope of response to log (inhibitor concentration)". The data are listed in Table 2. Representative compounds, especially B-1, showed strong antiviral activity and little cytotoxicity. Table 2. In vitro antiviral activity and cytotoxicity [Table 2]

[0159] Example 10 In vivo antiviral activity Balb / c mice aged 6 to 8 weeks were used in this experiment. On the day of inoculation (day 0), animals were heavily anesthetized, and then influenza virus PR / 8 / 34 diluted solution was pipetted and inoculated via the nasal cavity at a concentration of 1,000 PFU / 50 μL per mouse. B-1 dosing solution was prepared at 0.5 mg / mL in 5% DMSO / 40% PEG400 / 55% water. C-1 dosing solution was prepared at 0.15 mg / mL and 0.5 mg / mL in 5% DMSO / 40% PEG400 / 55% water. Oseltamivir phosphate dosing solution was prepared at 1 mg / mL in PBS (X1). The vehicle was a 5% DMSO / 40% PEG400 / 55% water solution. B-1, C-1, oseltamivir phosphate or vehicle were orally administered in the following regimen: 10 mL / kg / day, twice daily (8 / 16 h) on days 1-7, with the first dose administered 24 h after virus inoculation. Animal weight and survival rate were continuously monitored from day 0 to day 14. Animals that lost more than 35% body weight were euthanized and included in the death count. Animal weight and survival rate were statistically analyzed to evaluate the in vivo efficacy of B-1, C-1, oseltamivir phosphate and vehicle in the influenza infection mouse model. The results are summarized in Figure 1A and Figure 1B.

[0160] The vehicle group experienced substantial weight loss due to infection with influenza virus PR / 8 / 34, and all mice died on day 8. In the C-1 group, weight loss was significantly improved with dosing. When C-1 was administered at 5 mg / kg, weight loss was minimal. Similarly, B-1 was administered at 5 mg / kg, demonstrating strong antiviral efficacy with minimal weight loss. All mice in the B-1 and C-1 groups survived throughout the experiment. When oseltamivir was administered, there was no substantial improvement in weight loss, with 60% of the mice dying.

[0161] Example 11 Drug metabolism and pharmacokinetics of representative compounds were examined.

[0162] Liver Microsome Stability A liver microsome assay was used to evaluate the metabolic stability of A-1-P2. A-1-P2 at a concentration of 1 μM was incubated with 0.5 mg / mL liver microsomes in the presence of cofactors NADPH and UDPGA for 0, 15, 30, 45, and 60 min. Incubations were performed at 37 °C, 5% CO2, and saturated humidity. Compound disappearance was monitored by LC / MS / MS, and t 1 / 2 and intrinsic clearance were calculated. In one embodiment, the t of A-1-P2 determined in various species described herein 1 / 2 and intrinsic clearance are shown in Table 3. Table 3. Liver microsomal stability of A-1-P2 [Table 3]

[0163] Pharmacokinetics in rats Nonfasted male SD rats (6-8 weeks old, 200-300 g, 3 rats per group) were administered B-1 intravenously at 0.25 mg / kg as a bolus dose, and another group was administered B-1 by gavage at 3 mg / kg. Another 3 nonfasted male SD rats were administered C-1 by gavage at 3 mg / kg. Blood samples (~0.2 mL each time) were collected from the jugular vein into tubes containing potassium ethylenediaminetetraacetate (K2EDTA) as an anticoagulant at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after intravenous (IV) administration, and 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after oral (PO) administration. The blood samples were then centrifuged for 5 min in a refrigerated centrifuge at 4 °C. The obtained plasma samples were analyzed using LC / MS / MS to determine the concentration of B-1. WinNonlin (Phoenix TMPharmacokinetic (PK) parameters were calculated using a noncompartmental model in the Pharmacovigilance Labs (Version 8.0) software. The PK results are listed in Table 4. The oral bioavailability of B-1 in rats following oral gavage was 14%, and the oral bioavailability of B-1 following oral gavage of the prodrug C-1 was 30%. In comparison, the oral bioavailability of baloxavir in rats following oral administration of baloxavir was 0.69%, and the oral bioavailability of baloxavir in rats following administration of its prodrug, baloxavir marboxil, ranged from 9.8% to 14.7% (Baloxavir marboxil NDA documents). [Table 4]

[0164] Pharmacokinetics in mice Male CD-1 mice (4-6 weeks old, 20-30 g, 3 mice per group) were administered B-1 intravenously at 1 mg / kg as a bolus dose, and another group was administered C-1 by gavage at 10 mg / kg. All animals had free access to food and water before dosing. Blood samples (~0.03 mL each time) were collected from the jugular vein into tubes containing sodium heparin as an anticoagulant at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after intravenous (IV) administration, and 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours after oral (PO) administration. The blood samples were then centrifuged for 5 min in a refrigerated centrifuge at 4 °C. The obtained plasma samples were analyzed using LC / MS / MS to determine the concentration of B-1. WinNonlin (Phoenix TM Pharmacokinetic (PK) parameters were calculated using a noncompartmental model in the Pharmacokinetics (Pharmaceutical) Software (Version 8.0). The PK results are listed in Table 5. The oral bioavailability of B-1 following oral gavage in mice was 35%, and the oral bioavailability of B-1 following oral gavage of the prodrug C-1 was 55%. [Table 5]

[0165] Pharmacokinetics in monkeys Male cynomolgus monkeys (2-5 years old, 2-5 kg, 3 in each group) were given B-1 by intravenous bolus at 0.25 mg / kg, and another group was given B-1 by oral gavage at 1 mg / kg. Animals in the intravenous group had free access to food and water before dosing (non-fasted), whereas animals in the oral group were fasted overnight before dosing (fasted). C-1 was given by oral gavage at 1 mg / kg to male cynomolgus monkeys (fasted or non-fasted, 3 in each group). After 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours of intravenous (IV) administration and 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours of oral (PO) administration, blood samples (~0.5 mL each time) were collected from the jugular vein into tubes containing potassium ethylenediaminetetraacetate (K2EDTA) as an anticoagulant. The blood samples were then centrifuged for 10 minutes in a refrigerated centrifuge at 2-8°C. The plasma samples obtained were analyzed using LC / MS / MS to determine the concentration of B-1. WinNonlin (Phoenix TM Pharmacokinetic (PK) parameters were calculated using a noncompartmental model in the Pharmacokinetics Lab (Version 8.0) software. The PK results are listed in Table 6. The oral bioavailability of B-1 following oral gavage in monkeys was 27%, and the oral bioavailability of B-1 following oral gavage of the prodrug C-1 was 57% and 53% in fasted and nonfasted conditions, respectively. The feeding condition did not affect the oral absorption of C-1. On the other hand, the oral bioavailability of baloxavir following oral administration of the prodrug: baloxavir marboxil was highly influenced by the feeding condition. The oral bioavailability of baloxavir following oral administration of baloxavir marboxil to nonfasted and fasted monkeys was 10.5-11.5% and 50.6%, respectively (Baloxavir marboxil NDA documents). [Table 6]

[0166] The incorporation of selenium atoms resulted in favorable pharmacokinetic and biological properties. Oral administration of B-1 and C-1 to rats resulted in oral bioavailability of B-1 of 14% and 30%, respectively. Oral bioavailability of B-1 and C-1 to CD-1 mice was 35% and 55%, respectively. Oral administration of B-1 to monkeys resulted in oral bioavailability of B-1 of 27%. Oral gavage administration of the prodrug C-1 to fasted and non-fasted monkeys resulted in oral bioavailability of B-1 of 57% and 53%, respectively. Feeding conditions did not affect the oral absorption of C-1. Furthermore, as illustrated in Figure 1A and Figure 1B, both B-1 and C-1 showed potent antiviral activity in a mouse model infected with influenza virus PR / 8 / 34.

[0167] Example 12 Toxicity studies of C-1 were conducted in Sprague Dawley (SD) rats. 20, 100 and 500 mg / kg of C-1 or vehicle (0.5% w / v CMC-Na and 0.1% v / v Tween-80 / deionized water) were administered by oral gavage once daily for 7 days to Sprague Dawley rats (7-9 weeks old, approximately 250-300 g each male and 200-250 g each female). Eight females and eight males were used in each dose group. No C-1-related toxicological findings (such as abnormal clinical observations, changes in body weight, changes in food consumption and total pathological changes) were observed at all dose levels. C-1 was well tolerated, with a maximum tolerated dose (MTD) of 500 mg / kg / day or more in Sprague Dawley rats.

[0168] It should be understood that the present invention is not limited to the specific embodiments and aspects disclosed above, as variations of the specific embodiments and aspects may be made and are within the scope of the appended claims. All documents referred to or cited in this specification are specifically incorporated by reference.

Claims

1. Formula (I): 【Chemistry 1】 [In the formula, Each R １ is a halogen; Each R ２ is H; R ３ is H; Each R ４ is independently １ -C ６ Alkyl and C ３ -C ６ cycloalkyl; n and m are each independently 1, 2, 3, or 4; p is 0; and G is H or C(R') ２ -O-C(O)OR, R is C １ -C ６ is alkyl; and Each R' is independently H and C １ -C ３ alkyl] or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

2. Formula (I-1): 【Chemistry 2】 or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

2. The compound of claim 1, wherein the compound is:

3. Formula (I-3): 【Chemistry 3】 or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

2. The compound of claim 1, wherein the compound is:

4. 4. The compound of any one of claims 1 to 3, wherein G is H, or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

5. G is CH ２ -O-C(O)OR, where R is independently １ -C ６ The compound of any one of claims 1 to 3, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, wherein R is 1 or 2;

6. G. 【Chemistry 4】 4. The compound according to any one of claims 1 to 3, selected from the group consisting of:

7. The compound is: 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (A-1), (R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-11-yl)-7-hydroxy-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (B-1), and ((R)-12-((S)-7,8-difluoro-6,11-dihydrodibenzo[b,e]selenpin-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)methyl methyl carbonate (C-1) 2. The compound of claim 1, selected from the group consisting of: or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof.

8. A pharmaceutical composition comprising a compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt, stereoisomer or solvate thereof, and one or more pharma- ceutically acceptable carriers.

9. 9. The pharmaceutical composition according to claim 8 for use in the treatment of influenza.

10. 10. Use of a compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt, stereoisomer, or solvate thereof, or a pharmaceutical composition according to claim 8, in the manufacture of a medicament for the treatment of influenza.

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