Substituted 3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-diones, pharmaceutical compositions thereof, methods for production and uses thereof

Abstract

Influenza is an acute infectious respiratory disease caused by influenza viruses. It is part of the group of acute respiratory viral infections (ARVIs). It can spread in epidemic and pandemic forms. Currently, more than 2,000 variants of influenza viruses that differ in antigenic range have been identified. Given that influenza poses a serious threat to public health (globally, these annual epidemics result in 3–5 million cases of severe illness, millions of hospitalizations, and as many as 650,000 deaths), it seems appropriate to search for new anti-influenza drugs with improved characteristics. The inventors have surprisingly found that previously unknown substituted 3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-diones of general formula 1, their stereoisomers, their prodrugs, pharmaceutically acceptable salts, solvates, hydrates, and their crystalline or polycrystalline forms, are effective agents for the prevention and treatment of viral diseases, including influenza. JPEG2022539939000051.jpg4354In formula, R 1 is (6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl, (7,8-difluoro-4,9-dihydrothieno[2,23-c][2]benzothiepin-4-yl, (3,4-difluorophenyl)(phenyl)methyl, (3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl, diphenylmethyl, bis(4-fluorophenyl)-methyl; R 2is hydrogen or a protecting group selected from the group including (C1-C3 alkyl)oxycarbonyloxy, {[(C1-C3 alkyl)oxycarbonyl]-oxy}methoxy, {[2-(C1-C3 alkyl)oxyethoxy]carbonyl}oxy, ({[(1R)-2-[(C1-C3 alkyl)oxy]-1-methylethoxy}carbonyl)oxy, {[(3S)-ethoxyfuran-3-yloxy]-carbonyl}oxy, [(ethoxy-2H-pyran-4-yloxy)carbonyl]oxy, {[(1-acetylazetidin)-3-yloxy]carbonyl}oxy, {[(C1-C3 alkyl)oxycarbonyl]-oxy}methoxy, ({[2-(C1-C3 alkyl)oxyethoxy]carbonyl}oxy)methoxy.

Description

[Technical field]

[0001] The present invention relates to novel compounds, substituted 3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-diones, which are effective tools for the prevention and treatment of viral diseases, including influenza. [Background technology]

[0002] Influenza is an acute infectious respiratory disease caused by the influenza virus. It is part of the group of acute respiratory viral infections (ARVI). It can spread in epidemic and pandemic forms. Currently, more than 2000 variants of influenza viruses have been identified, which differ in terms of antigenic range. According to WHO estimates, between 250 and 500 people worldwide die annually from any variant of the virus during seasonal epidemics, most of them over 65 years of age, and the number of deaths can reach a million within a few years.

[0003] The virus was first isolated in the 1930s. Influenza virus belongs to the family of RNA-containing viruses, the Orthomyxoviridae (Latin: Orthomyxoviridae). This family includes seven types of viruses, such as influenza A virus, influenza B virus, influenza C virus, and influenza D virus. Three types of influenza viruses, identified by antigenic differences in nucleoproteins and matrix proteins, infect vertebrates as follows: influenza A virus infects humans, other mammals, and birds, and is responsible for all influenza pandemics; influenza B virus infects humans and seals; influenza C virus infects humans, pigs, and dogs; influenza D virus (isolated in 2012) infects livestock. To the inventors' knowledge, influenza D does not infect human cells.

[0004] Viruses containing three subtypes of hemagglutinin (HA) surface proteins (H1, H2, H3) and two subtypes of neuraminidase (NA) (N1, N2) are of epidemic importance to humans. Influenza viruses types A and B contain NA and NA as the major structural and antigenic components of the virus particle that have hemagglutinating and neuraminidase activities. Influenza type C viruses do not have neuraminidase but instead have hemagglutinin esterase (penetrating) protein (HEF).

[0005] An important achievement in modern biology and medicine is the development and introduction of practical methods for the treatment of viral infections based on the use of specific inhibitors that block the functional activity of the virus at different stages of its replication cycle with the aim of eliminating the cause of the disease.

[0006] Most of the anti-influenza drugs currently on the market are inhibitors of neuraminidase (zanamivir, oseltamivir, peramivir) or the M2 protein that forms a proton ion channel (amantadine, rimantadine) [Hayden, FG Antivirals for influenza: historical perspectives and lessons learned. Antiviral Res 71, 372-8 (2006).]. However, these targets, especially the latter, are not directly involved in the viral RNA-dependent RNA polymerase chain reaction (RNA-dependent RNA polymerase chain reaction). Due to the inability of the repolymerase (RdRp) to modify RNA during replication, it is prone to rapid mutations that may confer antiviral resistance. Indeed, the World Health Organization's Global Influenza Program has reported that >99% of seasonal influenza A strains are currently resistant to amantadine and rimantadine [Barr, IG et al., WHO recommendations for the viruses used in the 2013-2014 Northern Hemisphere influenza vaccine: Epidemiology, antigenic and genetic characteristics of influenza A (H1N1 )pdm09, A(H3N2) and influenza B viruses collected from October 2012 to January 2013. Vaccine 32, 4713-25 (2014).] This has led to the search for new antiviral compounds targeting other important viral processes [Yen, HL Current and novel antiviral strategies for influenza infection. Curr Opin Virol 18, 126-134 (2016).] In this regard, the RNA-dependent RNA polymerase (RdRp) or RNA replicase of influenza viruses is an attractive drug target in its own right, since drug resistance develops relatively slowly, persists in genotypes, and is important for viral replication.

[0007] In the past decade, our understanding of influenza virus RdRp has advanced dramatically through the elucidation of the high-resolution structure of the influenza endonuclease [Dias, A. et al., The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature 2009, 458, 914-918. Pflug, A. et al., Structure of influenza A polymerase bound to the viral RNA promoter. Nature 2014, 516, 355-360.] and the discovery of the complete heterotrimeric RdRp structure [Hengrung, N. et al., Crystal structure of the RNA-dependent RNA polymerase from influenza C virus. Nature 2015, 527, 114-117.].

[0008] Influenza virus RdRp, once located in the nucleus of infected cells, is presented by a heterotrimer consisting of three subunits: PA, PB1 and PB2. RdRp is involved in the replication and transcription of eight different RNA segments of the viral genome. The viral polymerase synthesizes viral mRNAs using short capped primers of the host cell. These capped primers are derived from cellular transcripts (RNAs) using a unique cap-dependent mechanism. In infected cells, the PB2 viral subunit binds to the cap of pre-mRNA at its 5' end. These PB2 subunit-bound capped-RNAs are then cleaved by the viral endonuclease after 10-13 nucleotides. Biochemical and structural studies have shown that the active center of the endonuclease is located in the amino-terminal site of 209 amino acid residues of the PA subunit. This domain has endogenous RNA and DNA endonuclease activity that is strongly activated by manganese ions. This corresponds to the observations that reported the dependence of the endonuclease activity of the intact three-subunit polymerase on manganese [Dias, A. et al., 2009]. The possibility of inhibiting this endonuclease activity in the case of 4-substituted 2,4-dioxobutanoic acids (e.g., compounds A1 and A2) was first established about a quarter century ago [J. Tomassini et al., Inhibition of cap (m7GpppXm)-dependent endonuclease of influenza virus by 4-Substituted 2,4-dioxobutanoic acid compounds. Antimicrob. Agents Chemoter. 1994, 2827-2837].

[0009] [ka]

[0010] Shortly thereafter, inhibitors of the natural cap-dependent transcriptase of influenza A and B viruses were identified, including flutamide (A3) [J. Tomassini et al., A Novel Antiviral Agent Which Inhibits the Endonuclease of Influenza Viruses. Antimicrob. Agents Chemoter. 1996, 1189-1193], as well as the synthetic drug favipiravir (A4) [Furuta Y. et al., T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections. Antiviral Research. 2009, 82 (3), 95-102.] and pimoxivir (A5) [Clark, MP et al., Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2. J. Med. Chem. 2014, 57, 6668 ~6678. Byrn, RA et al., Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit. Antimicrob. Agents Chemother. 2015, 59, 1569-1582. https: / / ichgcp.net / clinical-trials-registry / NCT02342249] and other substituted 2,6-diketopiperazines isolated from cultures of Delitschia confertaspora.

[0011] [ka]

[0012] Favipiravir (A4) is a broad-spectrum drug targeted to multiple viral RdRps, including influenza viruses. It was approved for emergency use in the event of an influenza pandemic in Japan in 2014 and in the United States in 2015, but there are some significant concerns regarding the toxicity of the drug [Nagata, T. et al., Favipiravir: a new medication for the Ebola virus disease pandemic. Disaster Med Public Health Prep 9 , 79–81 (2015).

[0013] Pimodivir (A5) is an innovative inhibitor of influenza virus replication that blocks the PB2 activity of the influenza virus polymerase complex [Clark, MP et al., Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2. J. Med. Chem. 2014, 57, 6668~6678. Byrn, RA et al., Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit. Antimicrob. Agents Chemother. 2015, 59 , 1569-1582. https: / / ichgcp.net / clinical-trials-registry / NCT02342249]. This The drug is in phase 3 clinical trials to evaluate the efficacy and safety of pimoxivir in combination with standard treatment in younger, adult, and elderly patients infected with influenza A [https: / / clinicaltrials.gov / ct2 / show / NCT03376321].

[0014] Relatively recently, inhibitors A6 and A7 [EP2620436B1 (priority 2010), https: / / patents.google.com / patent / EP2620436B1], A8, and A9 [US9827244B Polyheterocyclic cap-dependent endonuclease inhibitors containing substituted 2,4-dioxobutanoic acid fragments have been patented, such as A10, A11 [WO2016175224A1; WO2018030463 (Priority 2016)] and A12 [WO2016175224A1; WO2018030463 (Priority 2016)].

[0015] [ka]

[0016] The most potent drug in this range of inhibitors is believed to be baloxavir A10 (baloxavir acid, BXA, (12aR)-7-hydroxy-12-[(11S)-5,11-dihydro[1]benzothiepino[3,4-b]pyridin-5-yl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione), the prodrug of which is baloxavir marboxil A11 (BXA), which has the trade name Xofluza®. The vaccine, named XM (S-033188), was approved in Japan and the United States in 2018 for treating influenza A and B infections.

[0017] Exofluza® is the first influenza treatment in nearly 20 years. An oral antiviral drug with a new mechanism of action [S. Omoto et al., Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Scientific Reports 2018, 8, Paper number: 9633]. [Prior art documents] [Patent documents]

[0018] [Patent Document 1] EP2620436B1 (priority 2010) [Patent Document 2] US9827244B2 (priority 2016) [Patent Document 3] WO2016175224A1 [Patent Document 4] WO2018030463 (Priority 2016) [Non-patent literature]

[0019] [Non-Patent Document 1] Hayden, FG Antivirals for influenza: historical perspectives and lessons learned. Antiviral Res 71, 372–8 (2006). [Non-Patent Document 2] Barr, IG et al., WHO recommendations for the viruses used in the 2013~2014 Northern Hemisphere influenza vaccine:Epidemiology, antigenic and genetic characteristics of influenza A(H1N1)pdm09, A(H3N2) and influenza B viruses collected from October 2012 to January 2013. Vaccine 32, 4713~25 (2014). [Non-Patent Document 3] Yen, HL Current and novel antiviral strategies for influenza infection. Curr Opin Virol 18, 126-134 (2016). [Non-Patent Document 4] Dias, A. et al., The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature 2009, 458, 914-918. Pflug, A. et al., Structure of influenza A polymerase bound to the viral RNA promoter. Nature 2014, 516, 355-360. [Non-Patent Document 5] Hengrung, N. et al., Crystal structure of the RNA-dependent RNA polymerase from influenza C virus. Nature 2015, 527, 114~117. [Non-Patent Document 6] Dias, A. et al., The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature 2009, 458, 914-918. Pflug, A. et al., Structure of influenza A polymerase bound to the viral RNA promoter. Nature 2014, 516, 355-360. [Non-Patent Document 7] Hengrung, N. et al., Crystal structure of the RNA-dependent RNA polymerase from influenza C virus. Nature 2015, 527, 114~117. [Non-Patent Document 8] J. Tomassini et al., Inhibition of cap (m7GpppXm)-dependent endonuclease of influenza virus by 4-Substituted 2,4-dioxobutanoic acid compounds. Antimicrob. Agents Chemoter. 1994, 2827-2837 [Non-Patent Document 9] J. Tomassini et al., A Novel Antiviral Agent Which Inhibits the Endonuclease of Influenza Viruses. Antimicrob. Agents Chemoter. 1996, 1189~1193 [Non-Patent Document 10] Furuta Y. et al., T-705 (favipiravir) and related compounds: Novel broad-spectrum inhibitors of RNA viral infections. Antiviral Research. 2009, 82 (3), 95~102. [Non-Patent Document 11] Clark, MP et al., Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2. J. Med. Chem. 2014, 57, 6668~6678. Byrn, RA et al., Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit.Antimicrob. Agents Chemother. 2015, 59, 1569~1582. https: / / ichgcp. net / clinical-trials-registry / NCT02342249 [Non-Patent Document 12] Nagata, T. et al., Favipiravir: a new medication for the Ebola virus disease pandemic. Disaster Med Public Health Prep 9, 79–81 (2015). [Non-Patent Document 13] Clark, MP et al., Discovery of a novel, first-in-class, orally bioavailable azaindole inhibitor (VX-787) of influenza PB2. J. Med. Chem. 2014, 57, 6668~6678. Byrn, RA et al., Preclinical activity of VX-787, a first-in-class, orally bioavailable inhibitor of the influenza virus polymerase PB2 subunit. Antimicrob. Agents Chemother. 2015, 59, 1569~1582. https: / / ichgcp. net / clinical-trials-registry / NCT02342249 [Non-Patent Document 14] https: / / clinicaltrials.gov / ct2 / show / NCT03376321 [Non-Patent Document 15] S. Omoto et al., Characterization of influenza virus variants induced by treatment with the endonuclease inhibitor baloxavir marboxil. Scientific Reports 2018, 8, Paper number: 9633 Summary of the Invention [Problem to be solved by the invention]

[0020] Considering the fact that influenza poses a serious threat to public health (globally, annual epidemics cause 3-5 million cases of severe illness, millions of hospitalizations, and up to 650,000 deaths worldwide), it is worth searching for new anti-influenza drugs with improved characteristics. [Means for solving the problem]

[0021] The inventors have surprisingly found that the previously unknown substituted 3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-diones of general formula 1, their stereoisomers, their prodrugs, pharmacologically acceptable salts, solvates, hydrates, as well as their crystalline or polycrystalline forms, including the novel compounds, pharmaceutical compositions, are effective anti-influenza agents.

[0022] [ka] In the formula, R 1 is 6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl, 7,8-difluoro-4,9-dihydrothieno[2,23-c][2]benzothiepin-4-yl, (3,4-difluorophenyl)(phenyl)methyl, (3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl, diphenylmethyl, (3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl, diphenylmethyl, bis(4-fluorophenyl)methyl; R 2 is hydrogen or a protecting group.

[0023] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout the specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0024] The term "aryl," as used herein, unless otherwise specified, includes substituted or unsubstituted phenyl (Ph), biphenyl, or naphthyl, preferably the term aryl refers to substituted or unsubstituted phenyl. The aryl group may be substituted with one or more moieties selected from hydroxyl, F, Cl, Br, I, amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, and phosphonate, either unprotected or protected as known to those skilled in the art, e.g., as described in TW Greene and PGM Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley & Sons, 1999. do.

[0025] The term "heteroaryl," as used herein, refers to a monocyclic or polycyclic aromatic radical having one or more ring atoms selected from S, 0, and N; the remaining ring atoms are carbon. Heteroaryls include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, or quinoxalinyl.

[0026] The term "alkyl" as used herein refers to straight or branched chain alkyl groups containing 1 to 6 carbon atoms. of refers to a hydrated hydrocarbon radical. Examples of C1-C6 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, and tert-butyl.

[0027] The term "protecting group," as used herein, refers to a substituent attached to the oxygen of an alcohol group and is generally used to block or protect the functionality of an alcohol or any other hydroxy compound without preventing interaction with compounds having a different functionality (see Greene's Protective Groups in Organic Synthesis. Editor: Peter GM Chapter 2, Protection for the Hydroxyl Group, Including 1,2- and 1,3-Diols. Pages 17-471, 2014. https: / / onlinelibrary.wiley.com / doi / book / 10.1002 / 9781118905074). The protecting group is preferably selected from the group comprising (C1-C3 alkyl)oxycarbonyloxy, {[(C1-C3 alkyl)oxycarbonyl]-oxy}methoxy, {[2-(C1-C3 alkyl)oxyethoxy]carbonyl}oxy, ({[(1R)-2-[(C1-C3 alkyl)oxy]-1-methylethoxy]}carbonyl)oxy, {[(3S)-ethoxyfuran-3-yloxy]-carbonyl}oxy, [(ethoxy-2H-pyran-4-yloxy)carbonyl]oxy, {[(1-acetylazetidin)-3-yloxy]carbonyl}oxy, {[(C1-C3 alkyl)oxycarbonyl]oxy}methoxy, ({[2-(C1-C3 alkyl)oxyethoxy]carbonyl}oxy)methoxy.

[0028] The term "prodrug" refers to a compound of the present invention that is chemically or metabolically cleaved to a compound of the present invention that has pharmaceutical activity in vivo, by solvolysis or under physiological conditions. Prodrugs often provide better solubility, tissue compatibility, delivery, or timed release in mammals (Bungard, H., Design of products, pp. 7-9, pp. 21-24, Elsevier, Amsterdam 1985). Prodrugs include acid derivatives well known to those skilled in the art, such as esters prepared by reacting a parent acidic compound with a suitable alcohol, or amides prepared by reacting a combination of parent acidic compounds with a suitable amine. Examples of prodrugs include, but are not limited to, acetates, formates, benzoates, or other acylated derivatives of alcohol or amine functional groups within the scope of the compounds of the present invention.

[0029] The term "active ingredient" (pharmaceutical substance), as used herein, refers to a compound or substances, synthetic or other (biotechnological, botanical, animal, fungicidal, etc.) that exhibit pharmacological activity, which is the active ingredient of a pharmaceutical composition. ) refers to physiologically active compounds of natural origin.

[0030] The term "pharmaceutical product" as used herein refers to a compound (or a mixture of compounds constituting a pharmaceutical composition) in the form of a finished product, such as a tablet, capsule, injectable, ointment, or other dosage form, intended to restore, improve, or alter physiological function in humans and animals, as well as for the treatment and prevention of disease, diagnosis, anesthesia, contraception, cosmetology, and the like.

[0031] The term "therapeutic cocktail" refers to a simultaneously administered combination of two or more pharmaceutical agents that exhibit different mechanisms of pharmacological action and are directed against various biological targets involved in the pathogenesis of a disease.

[0032] The term "pharmaceutical composition" refers to a composition comprising at least one of the components selected from the group consisting of pharma- ceutically acceptable and pharmacologically compatible fillers, solvents, diluents, carriers, excipients, dispersants, and sensing agents, delivery agents, such as preservatives, stabilizers, fillers, disintegrants, wetting agents, emulsifiers, suspending agents, thickeners, sweeteners, flavorings, fragrances, antibacterial agents, fungicides, lubricants, and long-term delivery control agents, the selection and ratio of these components being dependent on the nature and route of administration and dosage. Examples of suitable suspending agents are ethoxylated isostearyl alcohol, polyoxyethylene, sorbitol and sorbitol ethers, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof. Protection from microorganisms can be provided using various antibacterial and antifungal agents, such as parabens, chlorobutanol, sorbic acid, and the like. The composition may also contain isotonic agents, such as sugars, sodium chloride, and the like. The sustained action of the composition can be achieved by using a substance that slows down the absorption of the active ingredient, such as aluminum monostearate and gelatin. Examples of suitable carriers, solvents, diluents and delivery agents include water, ethanol, polyhydric alcohols and their mixtures, natural oils (e.g. olive oil), and organic esters (e.g. ethyl oleate) for injection. Examples of fillers are lactose, milk sugar, sodium citrate, calcium carbonate, calcium phosphate, etc. Examples of disintegrants and dispersants are starch, alginic acid and its salts, and silicates. Examples of lubricants are magnesium stearate, sodium lauryl sulfate, talc, and high molecular weight polyethylene glycol. Pharmaceutical compositions for oral, sublingual, transdermal, intramuscular, intravenous, subcutaneous, and local or rectal administration of the active ingredient, alone or in combination with another active ingredient, can be administered to animals and humans in standard dosage forms as a mixture with conventional pharmaceutical carriers.Suitable standard dosage forms include oral forms, such as tablets, gelatin capsules, pills, powders, granules, chewing gum, and oral solutions or suspensions; sublingual and buccal dosage forms; aerosols; implants; topical, transdermal, subcutaneous, intramuscular, intravenous, intranasal, or intraocular administration forms; and rectal administration forms.

[0033] The term "inert filler" as used herein refers to compounds used to form pharmaceutical compositions, and includes excipients that are generally safe, non-toxic, not biologically or otherwise harmful, and acceptable for pharmaceutical use in animals and humans. Although the compounds of the present invention may be administered individually, they will generally be administered in admixture with one or more pharma- ceutically acceptable excipients, diluents, or carriers selected according to the expected route of drug administration and standard pharmaceutical practice.

[0034] The term "pharmaceutically acceptable salts" refers to both relatively non-toxic organic and inorganic salts of the acids and bases claimed herein. The salts may be obtained by in situ synthesis, isolation, or purification of the compounds, or they may be specially prepared. In particular, base salts may be specially prepared from the purified free base of the compounds claimed herein and a suitable organic or inorganic acid. The salts thus prepared may be used in combination with other salts, such as acetaldehyde, acetone, ethyl acetate, ethyl ketone, ethyl phosphate, ethyl ketone ... Examples of salts include hydrochlorides, hydrobromides, sulfates, bisulfates, phosphates, nitrates, acetates, oxalates, valeriates, oleates, palmitates, and stearates. Examples of suitable salts include salts of the formula (I), (II), (III), (IV ... Pharm. Sci. 1977, 66:1-19). The acid salts claimed herein are They can also be specially prepared by reacting the purified acid with a suitable base to produce metal salts and amines. The metal salts include sodium, potassium, calcium, barium, zinc, magnesium, lithium, and aluminum salts, of which sodium and potassium salts are preferred. Suitable inorganic bases used to produce metal salts include sodium hydroxide, carbonates, bicarbonates, and hydrides; potassium hydroxide and bicarbonate, lithium hydroxide; calcium hydroxide; magnesium hydroxide; and zinc hydroxide. Organic bases used to produce the acid salts claimed herein include amines and amino acids that are sufficiently basic to form stable salts and are suitable for medical use (particularly, they must have low toxicity). The amines include ammonia, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, benzylamine, dibenzylamine, dicyclohexylamine, piperazine, ethylpiperidine, tris(hydroxymethyl)aminomethane, and the like. Additionally, salts can be prepared using tetraalkylammonium hydroxides, such as choline, tetramethylammonium, tetraethylammonium, etc. The amino acid can be selected from the basic amino acids: lysine, ornithine, and arginine.

[0035] The term "crystalline form" refers to a material structure in which the molecules are packed to form a crystal lattice.

[0036] The term "polycrystalline morphology" refers to a polycrystalline material structure consisting of multiple small single crystals or crystallites of a particular crystalline morphology.

[0037] The term "therapeutically effective amount" as used herein refers to the amount of a substance, prodrug, or drug required to alleviate the symptoms of a disease in a subject. The dose of the substance, prodrug, or drug will be that which meets the individual requirements in each particular case. The dose can vary widely depending on a number of factors such as the severity of the disease to be treated, the age and general condition of the patient, other medicines used in the treatment of the patient, the mode and route of administration, and the experience of the attending physician. For oral administration, the daily dose is approximately 0.01 to 10 g, both in monotherapy and / or in combination therapy, including all values ​​therebetween. The preferred daily dose is about 0.1 to 7 g. Usually, a higher loading dose is given at the beginning of treatment for relief or elimination of the virus, followed by a reduction in the dose to a level sufficient to prevent an infection outbreak.

[0038] The term "solvate" refers to a complex or aggregate formed by one or more molecules of a solute, i.e., the compound of the present invention or its pharma- ceutical acceptable salt, and one or more molecules of a solvent.Said solvate is typically a crystalline solid with a fixed solute-solvent molar ratio.Representative solvents include, but are not limited to, water, ethanol, isopropanol, acetic acid, etc.When the solvent is water, the solvate formed is a hydrate.

[0039] The term "subject" refers to mammals, such as, but not limited to, cows, pigs, sheep, chickens, turkeys, buffaloes, llamas, ostriches, dogs, cats, and humans, with human subjects being the most preferred. Treatment of a subject can involve administering to the subject a prodrug of any of the general formula 1, its steroids, or the like. It is contemplated that the present invention may include the use of rhodium, isotopically enriched analogs, pharma- ceutically acceptable salts, hydrates, solvates, and crystalline or polymorphic forms or combinations thereof with another compound, such as an HCV NS5A inhibitor.

[0040] summary The inventors have surprisingly found that the hitherto unknown substituted 3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-diones of general formula 1, their stereoisomers, their prodrugs, pharma- ceutically acceptable salts, solvates, hydrates, as well as crystalline or polycrystalline forms thereof, or pharmaceutical compositions comprising this novel compound, are effective anti-influenza drugs.

[0041] [ka] In the formula, R 1 is 6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl, 7,8-difluoro-4,9-dihydrothieno[2,23-c][2]benzothiepin-4-yl, (3,4-difluorophenyl)(phenyl)methyl, (3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl, diphenylmethyl, bis(4-fluorophenyl)methyl; R 2 is hydrogen or a protecting group selected from the group including benzyl(C1-C3 alkyl)oxycarbonyloxy, {[(C1-C3 alkyl)oxycarbonyl]-oxy}methoxy, {[2-(C1-C3 alkyl)oxyethoxy]carbonyl}oxy, ({(1R)-2-[(C1-C3 alkyl)oxy]-1-methylethoxy]}carbonyl)oxy, {[(3S)-ethoxyfuran-3-yloxy]-carbonyl}oxy, [(ethoxy-2H-pyran-4-yloxy)carbonyl]oxy, {[(1-acetylazetidin)-3-yloxy]carbonyl}oxy, {[(C1-C3 alkyl)oxycarbonyl]oxy}methoxy, ({[2-(C1-C3 alkyl)oxyethoxy]carbonyl}oxy)methoxy.

[0042] Preferred compounds are (12aR)-12-(6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl)- of general formula 1.1 3,4,12,12a-Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, (12aR)-12-[(10S)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]- of general formula 1.2 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, (12aR)-12-[(10R)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]- of general formula 1.3 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1 ,2,4]triazine-6,8-dione, its stereoisomers, their prodrugs, pharma- ceutically acceptable salts, solvates, hydrates, and crystalline or polycrystalline forms thereof. [ka] In the formula, R 2 has the value given above.

[0043] More preferred compounds are (12aR)-7-benzyloxy-12-(6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl)- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.1.1), (12aR)-7-benzyloxy-12-[(10S)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.2.1), (12aR)-7-benzyloxy-12-[(10R)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]- 3,4,12,12a-Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.3.1), (12aR)-7-Hydroxy-12-(6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl)- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.1.2), (12aR)-7-Hydroxy-12-[(10S)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.2.2), (12aR)-7-Hydroxy-12-[(10R)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.3.2), (12aR)-12-(6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl)-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl methyl carbonate (1.1.3), (12aR)-12-[(10S)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f] [1,2,4]Triazin-7-yl methyl carbonate (1.2.3), (12aR)-12-[(10R)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]-6,8-dioxo- 3,4,12,12a-Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl methyl carbonate (1.3.3), {[(12aR)-12-(6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl)-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl]oxy}methyl methyl carbonate (1.1.4), ({(12aR)-12-[(10S)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.2.4), ({(12aR)-12-[(10R)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.3.4), These include their stereoisomers, their prodrugs, pharma- ceutically acceptable salts, solvates, hydrates, as well as their crystalline or polycrystalline forms. [ka] [ka]

[0044] Preferred compounds are (12aR)-12-(7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl)- of general formula 1.4 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, (12aR)-12-[(10S)-7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl]- of general formula 1.5 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, (12aR)-12-[(10R)-7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl]- of general formula 1.6 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, its stereoisomers, their prodrugs, pharma- ceutically acceptable salts, solvates, hydrates, and crystalline or polycrystalline forms thereof. [ka] In the formula, R 2 has the value given above.

[0045] More preferred compounds are (12aR)-7-benzyloxy-12-(7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl)- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione 1.4.1, (12aR)-7-benzyloxy-12-[(10S)-7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione 1.5.1, (12aR)-7-benzyloxy-12-[(10R)-7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione 1.6.1, (12aR)-7-Hydroxy-12-(7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl)- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione 1.4.2, (12aR)-7-Hydroxy-12-[(10S)-7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione 1.5.2, (12aR)-7-Hydroxy-12-[(10R)-7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione 1.6.2, (12aR)-12-(7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl)-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl methyl carbonate 1.4.3, (12aR)-12-[(10S)-7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl]-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl methyl carbonate 1.5.3, (12aR)-12-[(10R)-7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl]-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1 ,2,4]triazin-7-yl methyl carbonate 1.6.3, {[(12aR)-12-(7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl)-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl]oxy}methyl methyl carbonate 1.4.4, {[(12aR)-12-[(10S)-7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl]-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl]oxy}methyl methyl carbonate 1.5.4, {[(12aR)-12-[(10R)-7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl]-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl]oxy}methyl methyl carbonate 1.6.4, These include their stereoisomers, their prodrugs, pharma- ceutically acceptable salts, solvates, hydrates, as well as crystalline or polycrystalline forms thereof. [ka] [ka]

[0046] Preferred compounds are (12aR)-12-[(3,4-difluorophenyl)(phenyl)methyl]- of general formula 1.7 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, (12aR)-12-[(R)-(3,4-difluorophenyl)(phenyl)methyl]- of general formula 1.8 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, (12aR)-12-[(S)-(3,4-difluorophenyl)(phenyl)methyl]- of general formula 1.9 3,4,12,12a-Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, These include their stereoisomers, their prodrugs, pharma- ceutically acceptable salts, solvates, hydrates, as well as crystalline or polycrystalline forms thereof. [ka] In the formula, R 2 has the value given above.

[0047] More preferred compounds are (12aR)-7-Benzyloxy-12-[(3,4-difluorophenyl)(phenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.7.1), (12aR)-7-benzyloxy-12-[(R)-(3,4-difluorophenyl)(phenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.8.1), (12aR)-7-benzyloxy-12-[(S)-(3,4-difluorophenyl)(phenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.9.1), (12aR)-7-Hydroxy-12-[(3,4-difluorophenyl)(phenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.7.2), (12aR)-7-Hydroxy-12-[(R)-(3,4-difluorophenyl)(phenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.8.2), (12aR)-7-Hydroxy-12-[(S)-(3,4-difluorophenyl)(phenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.9.2), (12aR)-12-[(3,4-difluorophenyl)(phenyl)methyl]-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl methyl carbonate (1.7.3), (12aR)-12-[(R)-(3,4-difluorophenyl)(phenyl)methyl]-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl methyl carbonate (1.8.3), (12aR)-12-[(S)-(3,4-difluorophenyl)(phenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl methyl carbonate (1.9.3), ({(12aR)-12-[(3,4-difluorophenyl)(phenyl)methyl]-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.7.4), ({(12aR)-12-[(R)-(3,4-difluorophenyl)(phenyl)methyl]-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.8.4), ({(12aR)-12-[(S)-(3,4-difluorophenyl)(phenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.9.4), its stereoisomers, prodrugs, pharma- ceutically acceptable salts, solvates, hydrates thereof; as well as crystalline or polycrystalline forms thereof. [ka] [ka]

[0048] Preferred compounds are (12aR)-12-[(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]- of general formula 1.10 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, (12aR)-12-[(R)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]- of general formula 1.11 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, (12aR)-12-[(S)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]- of general formula 1.12 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, its stereoisomers, their prodrugs, pharma- ceutically acceptable salts, solvates, hydrates, and crystalline or polycrystalline forms thereof. [ka] In the formula, R 2 has the value given above.

[0049] More preferred compounds are (12aR)-7-Benzyloxy-12-[(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.10.1), (12aR)-7-benzyloxy-12-[(R)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.11.1), (12aR)-7-benzyloxy-12-[(S)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.12.1), (12aR)-7-Hydroxy-12-[(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.10.2), (12aR)-7-Hydroxy-12-[(R)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.11.2), (12aR)-7-Hydroxy-12-[(S)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.12.2), (12aR)-12-[(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl methyl carbonate (1.10.3), (12aR)-12-[(R)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-6,8-dioxo- 3,4,12,12a-Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl methyl carbonate (1.11.3), (12aR)-12-[(S)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl methyl carbonate (1.12.3), ({(12aR)-12-[(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.10.4), ({(12aR)-12-[(R)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.11.4), ({(12aR)-12-[(S)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.12.4), These include their stereoisomers, their prodrugs, pharma- ceutically acceptable salts, solvates, hydrates, as well as their crystalline or polycrystalline forms. [ka] [ka]

[0050] Preferred compounds are (12aR)-12-diphenylmethyl- of the general formula 1.13 3,4,12,12a-Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, These include their stereoisomers, their prodrugs, pharma- ceutically acceptable salts, solvates, hydrates, as well as crystalline or polycrystalline forms thereof. [ka] In the formula, R 2 has the value given above.

[0051] More preferred compounds are (12aR)-7-Benzyloxy-12-diphenylmethyl-3,4,12,12a -ethoxy-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.13.1), (12aR)-7-Hydroxy-12-diphenylmethyl- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.13.2), (12aR)-12-diphenylmethyl-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl methyl carbonate (1.13.3), ({(12aR)-12-diphenylmethyl- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.13.4), These include their stereoisomers, their prodrugs, pharma- ceutically acceptable salts, solvates, hydrates, as well as crystalline or polycrystalline forms thereof. [ka]

[0052] Preferred compounds are (12aR)-12-[bis(4-fluorophenyl)methyl]- of general formula 1.14 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione, These include their stereoisomers, their prodrugs, pharma- ceutically acceptable salts, solvates, hydrates, as well as crystalline or polycrystalline forms thereof. [ka] In the formula, R 2 has the value given above.

[0053] More preferred compounds are (12aR)-7-Benzyloxy-12-[bis(4-fluorophenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.14.1), (12aR)-7-Hydroxy-12-[bis(4-fluorophenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.14.2), (12aR)-12-[bis(4-fluorophenyl)methyl]-6,8-dioxo- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl methyl carbonate (1.14.3), ({(12aR)-12-[bis(4-fluorophenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.14.4), These include their stereoisomers, their prodrugs, pharma- ceutically acceptable salts, solvates, hydrates, as well as crystalline or polycrystalline forms thereof. [ka]

[0054] A further subject of the present invention is a process for producing a compound of general formula 1, comprising the steps of: (12aR)-7-(benzyloxy)- 3,4,12,12a-Tetrahydro- The process comprises the preparation of 7-benzyloxy derivatives 1.1.1 to 1.14.1 by interaction of 1H-[1,4]oxazino[3,4-c]-pyrido[2,1-f][1,2,4]triazine-6,8-dione (2) with 6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-ol (3), or with 7,8-difluoro-7,8-dihydrothieno[2,3-c][2]benzothiepin-4-ol (4), or with (3,4-difluorophenyl)(phenyl)methanol (5), (3,4-difluorophenyl)(2-methylsulfanylphenyl)methanol (6), diphenylmethanol (7), or with bis(4-fluorophenyl)methanol (8), respectively. [ka]

[0055] The resulting 7-benzyloxy derivatives 1.1.1, 1.4.1, 1.7.1, and 1.10.1 are separated into their respective diastereoisomers 1.2.1, 1.3.1, 1.5.1, 1.6.1, 1.8.1, 1.9.1, 1.11.1, and 1.12.1, the structures of which are confirmed by X-ray diffraction (XRD) data. Thus, the diastereoisomers (12aR)-7-(benzyloxy)-12-[(10S)-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.2.1) was recrystallized from ethanol and isopropanol to give orthorhombic crystals, which are the corresponding solvates with ethanol 1.2.1·C2H5OH and isopropanol 1.2.1·i-C3H7OH in the ratios of 4:3 and 8:3 according to XRD data (Figures 1 and 2).

[0056] Diastereomer (12aR)-7-benzyloxy-12-[(S)-(3,4-difluorophenyl)(phenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.9.1) was recrystallized from a dichloromethane-hexane mixture to give what was termed a clintic crystal system by X-ray diffraction analysis (Figure 3).

[0057] The 7-benzyloxy derivatives 1.1.1-1.14.1 are debenzylated by heating in dimethylsulfoxide in the presence of lithium chloride to give the corresponding 7-hydroxy derivatives 1.1.2-1.14.2, the latter being converted to the prodrugs 1.1.3-1.14.3 and 1.1.4-1.14.4. The parent 6.7-difluoro-5.10-dihydrothieno[3,2-c][2]benzothiepin-10-ol (3) is a novel compound and therefore said compound and its method of production are also subject of the present invention. According to the present invention, a method for producing 6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-ol (3) comprises the cyclization of 3,4-difluoro-2-[(3-thienylthio)methyl]-benzoic acid (3.6) in the presence of PCl5 and reduction of the resulting 6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10(5H)-one (3.7) with sodium borohydride (Scheme 1).

[0058] [ka] Scheme 1. Synthesis of 6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-ol (3)

[0059] The parent 7,8-difluoro-7,8-dihydrothieno[2,3-c][2]benzothiepin-10-ol (4) is a novel compound and therefore said compound and its method of production are also subject of the present invention.

[0060] According to the present invention, a method for producing 7,8-difluoro-7,8-dihydrothieno[2,3-c][2]benzothiepin-10-ol (4) comprises the cyclization of 3,4-difluoro-2-[(3-thienylthio)methyl]-benzoic acid (4.3) in the presence of PCl5 and reduction of the resulting 6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10(5H)-one (4.4) with sodium borohydride (Scheme 2).

[0061] [ka] Scheme 2. Synthesis of 7,8-difluoro-7,8-dihydrothieno[2,3-c][2]benzothiepin-10-ol (4)

[0062] The parent (3,4-difluorophenyl)(phenyl)methanol (5) is a novel compound and therefore said compound and its method of production are also subject of the present invention.

[0063] According to the present invention, a method for producing (3,4-difluorophenyl)(phenyl)methanol (5) involves the reduction of 3,4-difluorobenzophenone (5.1) with sodium borohydride (Scheme 3).

[0064] [ka] Scheme 3. Synthesis of (3,4-difluorophenyl)(phenyl)methanol (5)

[0065] The parent (3,4-difluorophenyl)(2-methylsulfanylphenyl)methanol (6) is a novel compound and therefore said compound and the process for its production are also subject of the present invention. According to the present invention, the process for producing (3,4-difluorophenyl)(2-methylsulfanylphenyl)methanol (6) comprises the reduction of (3,4-difluorophenyl)[2-methylsulfanyl)phenyl]methanone (6.6) with sodium borohydride (Scheme 4).

[0066] [ka] Scheme 4. Synthesis of (3,4-difluorophenyl)(2-methylsulfanylphenyl)methanol (6)

[0067] Unlike baloxavir (BXA), the novel 7-hydroxy- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-diones are orally available inhibitors of influenza virus with fairly high bioavailability. At the same time, the Cmax and AUClast of said inhibitors are 1-2 orders of magnitude superior to those of BXA.

[0068] [Table 1] Kel - Emission constant; T1 / 2 - elimination half-life; AUClast - area under the concentration-time curve from time zero to the last quantifiable concentration; AUCinf - the area under the pharmacokinetic curve (concentration-time curve) from time zero to infinity; and MRTlast is the mean residence time in the body from time zero to the last quantifiable concentration.

[0069] The pharmacokinetic parameters in mouse plasma after administration of the novel proinhibitors, specifically Cmax and AUClast (Table 2), are 10-40 times those of baloxavir marboxil (BXM).

[0070] [Table 2]

[0071] The 7-hydroxy derivatives 1.1.2 to 1.14.2 are nanomolar inhibitors of influenza virus isolates. For example, the activity of inhibitors 1.8.2, 1.9.2, 1.13.2 and 1.14.2 against influenza A / California / 2009 (H1N1) isolates in MDCK cell cultures was EC 50 = 2.4 nM, which is roughly consistent with that of baloxavir (EC 50 = 2.4 nM). Influenza isolates A / California / 2009 (H1N1), A / Aichi / 2 / 69 (H3N2), and A / Perth / 265 / 2 in MDCK cell cultures Even the inhibitor 1.3.2 against 009 (H1N1pdm09) (H275Y) exceeds the activity of baloxavir (BXA) under similar conditions (Table 3).

[0072] [Table 3]

[0073] The subject of the present invention relates to the use of 7,8-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-ol (3), 7,8-difluoro-7,8-dihydrothieno[2,3-c][2]benzothiepin-10-ol (4), (3,4-difluorophenyl)(phenyl)methanol (5), (3,4-difluorophenyl)(2-methylsulfanylphenyl)methanol (6), diphenylmethanol (7), and bis(4-fluorophenyl)methanol (8) as intermediates for the synthesis of compounds of general formula 1.

[0074] The subject of the present invention relates to the use of 7-benzyloxy derivatives 1.1.1 to 1.14.1 as intermediates for the synthesis of the respective 7-hydroxy derivatives 1.1.2 to 1.14.2.

[0075] The subject of the present invention relates to the use of 7-hydroxy derivatives 1.1.2 to 1.14.2 as intermediates for the synthesis of drugs 1.1.3 to 1.14.3 and 1.1.4 to 1.14.4.

[0076] The subject of the present invention relates to the use of the 7-hydroxy derivatives 1.1.2 to 1.14.2 or their stereoisomers, pharma- ceutically acceptable salts, solvates, hydrates and crystalline or polycrystalline forms thereof as influenza virus inhibitors.

[0077] The subject of the present invention relates to the use of compounds 1.1.3 to 1.14.3 and 1.1.4 to 1.14.4 or their stereoisomers, pharma- ceutically acceptable salts, solvates, hydrates, and crystalline or polycrystalline forms thereof as influenza virus pro-inhibitors (drugs).

[0078] The subject of the present invention relates to the use of inhibitors 1.1.2 to 1.14.2 or drugs 1.1.3 to 1.14.3 and 1.1.4 to 1.14.4, or their stereoisomers, pharma- ceutically acceptable salts, solvates, hydrates, and crystalline or polycrystalline forms thereof, for the treatment and prevention of viral diseases.

[0079] The subject of the present invention relates to antiviral pharmaceutical compositions containing a compound selected from the group of drugs 1.1.2 to 1.14.2, or 1.1.3 to 1.14.3 and 1.1.4 to 1.14.4, or their stereoisomers, pharma- ceutical acceptable salts, solvates, hydrates, and crystalline or polycrystalline forms thereof, in a therapeutically effective amount for treating or preventing a viral disease.

[0080] More preferably, it is an antiviral pharmaceutical composition comprising a compound selected from the group of drugs 1.1.2 to 1.14.2, or 1.1.3 to 1.14.3 and 1.1.4 to 1.14.4, or a stereoisomer, pharma- ceutical acceptable salt, solvate, hydrate, and crystalline or polycrystalline form thereof, in a therapeutically effective amount for treating or preventing influenza.

[0081] A subject of the present invention also relates to a method for treating and / or preventing a viral disease, which comprises administering to a patient a compound selected from the group of drugs of 1.1.2 to 1.14.2, or of 1.1.3 to 1.14.3 and 1.1.4 to 1.14.4, or their stereoisomers, pharma- ceutically acceptable salts, solvates, hydrates, and crystalline or polycrystalline forms thereof, or a pharmaceutical composition of the invention.

[0082] For treating the above-mentioned diseases, such as influenza in humans, the compounds of the present invention may be administered orally in the form of powders, granules, tablets, capsules, pills, liquids and the like. Or it may be administered parenterally in the form of injections, suppositories, transdermal drug therapy, inhalation, etc. An effective amount of these compounds may be mixed with excipients suitable for the formulation, such as fillers, binders, humidifiers, disintegrators and lubricants, if necessary for the production of pharmaceuticals. In the case of injections, sterilization with a suitable carrier may be performed.

[0083] The pharmaceutical composition of the present invention may be administered orally or parenterally.For oral administration, commonly used dosage forms, such as tablets, granules, powders and capsules, can be produced conventionally.For parenteral administration, suitable commonly used dosage forms, such as injections, can be used.

[0084] An effective amount of the compound of the present invention may be mixed, as necessary to produce a pharmaceutical composition, with various pharmaceutical excipients suitable for the dosage form, such as fillers, binders, disintegrants, and lubricants.

[0085] The dose of the compound of the present invention depends on the state of the disease, the route of administration, and the age or weight of the patient. The usual oral dose for adults is 0.1-100 mg / kg per day, preferably 1-20 mg / kg per day. The dosage of the pharmaceutical composition of the present invention is preferably determined based on the age and weight of the patient, the type and severity of the disease, the route of administration, etc. The usual oral dose for adults is in the range of 0.05-100 mg / kg per day, preferably 0.1-10 mg / kg per day. The parenteral dose for adults varies considerably depending on the route of administration, but is generally in the range of 0.005-10 mg / kg per day, preferably 0.01-1 mg / kg per day. The dose may be administered once a day or divided into several daily doses. The compound of the present invention can be used in combination with other medicines (hereinafter referred to as combined medicines) to increase the activity of the compound, reduce the dose of the compound, etc.

[0086] For the treatment of influenza, the compounds of the present invention may be used in combination with neuraminidase inhibitors (e.g., oseltamivir, zanamivir, peramivir, AV-5080, Inabiru, etc. ); RNA-dependent RNA polymerase inhibitors (e.g., Favipiravir); M2-protein inhibitors (e.g., Amantadine); PB2 cap-binding inhibitors, e.g., VX-787; anti-NA antibodies (e.g., MHAA4549A); interferons (e.g., Grippferon), interferon inducers (e.g., Kagocel) ) may be used in combination. Immunoagonists are also considered (e.g., nitazoxanide). In this case, the administration time of the compound of the present invention and the combination drug is not limited. They can be prescribed to the patient who needs it at the same time or at different times. In addition, the compound of the present invention and the combination drug can be administered as two or more compositions, regardless of each active ingredient or one composition containing each active ingredient.

[0087] Therefore, the dose for the combined drug can be selected in relation to the clinical dose. The formulation ratio of the compound of the present invention to the co-administered drug can be appropriately selected according to the patient to be treated, the administration route, the disease to be treated, the symptoms, the combination of drugs, etc. In the case of administration to humans, for example, 1 part by weight of the compound of the present invention can be used in combination with 0.01 to 100 parts by weight of the co-administered drug.

[0088] The invention is illustrated by the following figures. [Brief description of the drawings]

[0089] [Figure 1] Fragments of solvate packaging 1.2.1·C2H5OH (A) and 1.2.1·i-C3H7OH (B) obtained from X-ray crystallography using Platon software. [Diagram 2] Full view of one of the two symmetrically independent solvate molecules 1.2.1·C2H5OH (A) and 1.2.1·i-C3H7OH (B), where atoms with thermal vibration p=50% are represented by ellipses. For clarity, the solvate molecules ethanol and isopropanol are not shown. [Diagram 3] Overall view of molecule 1.9.1 with atoms in thermal vibration p=50% represented by ellipses (A) and a version obtained using the Plato software (B). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0090] Best Practice The present invention is illustrated in more detail by non-limiting examples of the synthesis of compounds of general formula 1 and their testing.

[0091] General Chemical Procedures. All chemicals and solvents were used as obtained from the supplier without further purification. The crude reaction mixtures were concentrated at low pressure by removing the organic solvents on a rotary evaporator.

[0092] Nuclear magnetic resonance (NMR) spectra were recorded at room temperature (rt) using a Bruker DPX-400 spectrometer with tetramethylsilane as internal standard. Chemical shifts (δ) are given in parts per million (ppm) and signals are expressed as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), or br.s. (broad singlet).

[0093] High-resolution mass spectra (HRMS) were obtained using an Orbitrap Elite mass spectrometer equipped with a HESI ion source (Thermo, Bremen, Germany).

[0094] High performance liquid chromatography (HPLC). The purity of the final compound determined by HPLC was greater than 98%. The HPLC conditions for purity assessment were as follows: Shimadzu HPLC, XBridge C18, 4.6 mm x 250 mm (3.5 μm); 0.1% TFA gradient in 5% acetonitrile / water (A) and 0.1% TFA acetonitrile (B); flow rate: 0.5 ml / min; collection time: 20 min; UV wavelength: 214 and 254 nm. The preparative HPLC system included two sets of Shimadzu LC-8A pumps, a Shimadzu SCL10AVP controller, and a Shimadzu SPD10AVP detector. We used a 10 micrometer, 250 mm x 20 mm Reprosil-Pur C18-AQ column. The mobile phase had a gradient of 0.1% TFA in water (A) and 0.1% TFA in acetonitrile (B). LC / MS was performed on a PE Sciex API165 system using positive ion electrospray [M+H]+ and a Shimadzu HPLC system equipped with a Waters XBridge C18 3.5 μm (4.6 mm×150 mm) column. Diastereoisomers were distributed on a chiral HPLC Phenomenex Lux 5u Cellulose-4, AXIA F, 250×30.00 mm. Flow rate: 25 ml / min. Detector: UV, 215 nm.

[0095] X-ray diffraction study of the samples The structure was solved by a straightforward method, F 2 hkl The positions of the hydrogen atoms of the OH groups in the ethanol and isopropanol solvate molecules were determined by difference Fourier synthesis, and the positions of the remaining atoms were calculated geometrically. All hydrogen atoms were refined in an isotropic approximation using the lidar model. SH ELXTL PLUS software [Sheldrick, GM Acta Cryst. 2008, A64:112-122] and Olex2 [Dolomanov, OV et al., J. Appl. Cryst. 2009, 42, 339- 341] was used to perform the calculations.

[0096] Example 1. Synthesis of 6,7-difluorothieno[3,2-c][2]benzothiepin-10(5H)-one (4.1) and 6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-ol (3) (Scheme 1) To a solution of 30 g (174.3 mmol, 1 equiv.) of 3,4-difluoro-2-methylbenzoic acid (3.1) in 300 ml of methanol was added dropwise 207 g (1.74 mol, 10 equiv.) of thionyl chloride. The mixture was heated to boiling under reflux and maintained for 17 h. The reaction was rotary evaporated, the residue was taken up with water, and the product was filtered and air-dried to give 26.4 g of 3,4-difluoro-2-methylbenzoic acid methyl ester (3.2) as a white crystalline powder: 1 H NMR (400 MHz, CDCl3) δ 7.77 - 7.67 (m, 1H), 7.04 (dd, J = 16.9, 8.9 Hz, 1H), 3.91 (s, 3H), 2.56 (d, J = 2.7 Hz, 3H).

[0097] To a solution of 28.0 g (150.4 mmol, 1 equiv.) of the obtained ester 3.2 in 650 ml of carbon tetrachloride, 67.0 g (376.0 mmol, 2.5 equiv.) of N-bromosuccinimide was added at room temperature. The reaction was heated to boiling and 360 mg of benzoyl peroxide (1.5 mmol, 0.01 equiv.) was added in portions. The reaction was stirred at boiling under reflux for 17 hours. The reaction was cooled to room temperature and the precipitate was filtered and washed with carbon tetrachloride. The filtrate was evaporated on a rotary evaporator and the residue was purified by column chromatography (silica gel, ethyl acetate:hexane 1:9) to give 39.9 g of 2-(bromomethyl)-3,4-difluoro-benzoic acid (3.3) methyl ester as a yellow oil that crystallized on standing to give white crystals: 1 H NMR (400 MHz, CDCl3) δ 7.87 - 7.77 (m, 1H), 7.19 (dd, J = 16.8, 8.8 Hz, 1H), 5.02 (d, J = 2.1 Hz, 2H), 3.96 (s, 3H).

[0098] To a suspension of 12.5 g (90.3 mmol, 1.5 eq.) K2CO3 and 3.9 g (12.0 mmol, 0.2 eq.) Cs2CO3 in 70 ml DMF, 7.0 g (60.2 mmol, 1.1 eq.) thiophene-3-thiol (3.4) was added and the mixture was stirred at room temperature for 30 min. Then, 14.5 g (54.7 mmol, 1 eq.) 2-(bromomethyl)-3,4-difluorobenzoic acid methyl ester (3.3) was added to the reaction and the mixture was stirred at room temperature for 17 h. The mixture was evaporated to dryness on a rotary evaporator and 150 ml of ethyl acetate and 250 ml of water were added to the residue. The organic layer was separated and the water was extracted with 150 ml of ethyl acetate. The combined organic extracts were washed with water, then with brine, dried over Na2SO4 and evaporated to dryness on a rotary evaporator. The product was purified by column chromatography (silica gel, hexane:ethyl acetate=1:0-100:1-50:1-10:1) to give 12.2 g of 3,4-difluoro-2-[(3-thienylthio)methyl]benzoic acid methyl ester (3.5) as a yellow oil:1 H NMR (400 MHz, DMSO) δ 7.72 - 7.66 (m, 1H), 7.56 (dd, J = 5.0, 3.0 Hz, 1H), 7.48 - 7.39 (m, 1H), 7.36 (dd, J = 3.0, 1.2 Hz, 1H), 6.94 (dd, J = 5.0, 1.2 Hz, 1H), 4.43 (d, J = 1.6 Hz, 2H), 3.78 (s, 3H).

[0099] To a solution of 7.9 g (26.3 mmol, 1 equiv.) of 3,4-difluoro-2-[(3-thienylthio)methyl]benzoic acid methyl ester (3.5) in 80 ml of methanol was added a solution of 5.0 g (118.4 mmol, 4.5 equiv.) of lithium hydroxide hydrate in 40 ml of water. The mixture was stirred at room temperature for 17 h and evaporated to dryness on a rotary evaporator. To the residue was then added 100 ml of water, 2N HCl until the pH was about 1-3, and the suspension was stirred at room temperature for 30 min. The precipitate was filtered and air-dried to give 7 g of 3,4-difluoro-2-[(3-thienylthio)methyl]benzoic acid (3.6) as a white powder: 1 H NMR (400 MHz, DMSO) δ 13.36 (br.s, 1H), 7.78 - 7.71 (m, 1H), 7.56 (dd, J = 5.0, 3.0 Hz, 1H), 7.47 - 7.34 (m, 2H), 6.98 - 6.92 (m, 1H), 4.48 (s, 2H).

[0100] To a solution of 1.0 g (3.5 mmol, 1 eq.) of 3,4-difluoro-2-[(3-thienylthio)methyl]benzoic acid (3.6) in 120 ml of benzene, 0.87 g (4.2 mmol, 1.2 eq.) of PCl5 was added, the mixture was stirred at reflux for 10 min, boiled, then cooled to room temperature. Argon (weak stream) was passed through the reaction for 30 min to remove hydrogen chloride. The reaction was cooled to 0° C., and 0.91 g (3.5 mmol, 1 eq.) of tin tetrachloride was added dropwise. The reaction was stirred at reflux for 10 min, boiled, then cooled. 70 ml of the ester was then added to the reaction, and the mixture was washed twice with 50 ml of 2N HCl, 50 ml of water, and brine, dried over Na2SO4, and evaporated to dryness on a rotary evaporator. The product was isolated by column chromatography (silica gel, hexane:ethyl acetate=30:1 to 20:1) to give 3.9 g of 6,7-difluorothieno[3,2-C][2]benzothiepin-10(5H)-one (3.7) as a yellow powder: 1 H NMR (400 MHz, DMSO) δ 8.07 (d, J = 5.3 Hz, 1H), 7.64 - 7.47 (m, 2H), 7.23 (d, J = 5.2 Hz, 1H), 4.39 (s, 2H).

[0101] To a suspension of 3.9 g (14.5 mmol, 1 equiv.) of 6,7-difluorothieno[3,2-c][2]benzothiepin-10(5H)-one (3.7) in 100 ml of methanol, 0.28 g (7.3 mmol, 0.5 equiv.) of sodium borohydride was added and the reaction was stirred at room temperature for 30 min. The reaction was rotary evaporated and 100 ml of saturated aqueous NaHCO3 was added to the residue. The product was filtered, washed with water and air-dried to give 3.9 g of 6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-ol (3) as a yellowish powder: 1H NMR (400 MHz, DMSO) δ 7.47 - 7.26 (m, 3H), 6.84 - 6.63 (m, 2H), 6.27 (s, 1H), 4.59 (d, J = 14.2 Hz, 1H), 4.42 (d, J = 14.3 Hz, 1H).

[0102] Example 2. 7,8-Difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-ol (4) (Scheme 2) To a suspension of 8.9 g (64.5 mmol) of K2CO3 and 2.8 g (8.6 mmol) of Cs2CO3 in 50 ml of DMF, 5.0 g (43.0 mmol) of thiophene-2-thiol (4.1) was added and the mixture was stirred at room temperature for 30 min. Then, 11.4 g (43.0 mmol) of 2-(bromomethyl)-3,4-difluoro-p-benzoic acid methyl ester (3.3) was added and the mixture was stirred at room temperature for 17 h. The resulting mixture was evaporated to dryness on a rotary evaporator and 150 ml of ethyl acetate and 250 ml of water were added to the residue. The organic layer was separated and the aqueous layer was extracted with 150 ml of ethyl acetate. The combined organic extracts were washed with water, then with brine, dried over Na2SO4 and evaporated to dryness on a rotary evaporator. The product was purified by column chromatography (silica gel, 1:4 dichloromethane-hexane) to give 9.2 g of 3,4-difluoro-2-[(2-thienylthio)methyl]benzoic acid methyl ester (4.2) as a yellow oil. 1 H NMR (400 MHz, DMSO) δ 7.76 - 7.70 (m, 1H), 7.64 (dd, J = 5.3, 1.2 Hz, 1H), 7.47 (dd, J = 18.1, 8.6 Hz, 1H), 7.00 (dd, J = 5.3, 3.6 Hz, 1H), 6.97 - 6.93 (m, 1H), 4.41 (s, 2H), 3.77 (s, 3H).

[0103] To a solution of 9.2 g (30.6 mmol) of 3,4-difluoro-2-[(2-thienylthio)methyl]-benzoic acid methyl ester (4.2) in 50 ml of methanol was added a solution of 2.6 g (45.9 mmol) of KOH in 50 ml of water. The mixture was stirred at room temperature for 17 h and then the methanol was stripped off under reduced pressure. The aqueous residue was extracted with two 50 ml portions of ether and acidified to about pH 1-3 with 2N HCl. The precipitate was stirred at room temperature for 30 min. The sediment was filtered off and air-dried to give 8.4 g of 3,4-difluoro-2-[ (2-Thienylthio)methyl]benzoic acid (4.3) was obtained as a white powder. 1 H NMR (400 MHz, DMSO) δ 13.36 (s, 1H), 7.81 - 7.74 (m, 1H), 7.63 (dd, J = 5.2, 1.2 Hz, 1H), 7.43 (dd, J = 17.8, 8.7 Hz, 1H), 7.03 - 6.94 (m, 2H), 4.44 (s, 2H).

[0104] To a solution of 4.2 g (4.7 mmol) of 3,4-difluoro-2-[(2-thienylthio)methyl]benzoic acid (4.3) in 70 ml of benzene, 3.7 g (17.6 mmol) of PCl5 was added, the mixture was stirred at reflux for 30 min, brought to boiling, and then cooled to room temperature. Argon (weak stream) was passed through the reaction for 30 min to remove hydrogen chloride. The reaction was cooled to 0° C. in an ice-water bath, and 3.8 g (14.7 mmol, 1 equiv.) of tin tetrachloride was added dropwise. The reaction was stirred at reflux for 30 min, brought to boiling, and then cooled to room temperature. Ether (70 ml) was then added, and the reaction was washed twice with 50 ml each of 2N HCl, 50 ml of water, brine, dried over Na2SO4, and evaporated to dryness on a rotary evaporator. The product was isolated by column chromatography (silica gel, 20:1 hexane:ethyl acetate) to give 1.8 g of 7,8-difluorothieno[2,3-с][2]benzothiepin-4(9H)-one (4.4) as a yellow powder. 1H NMR (400 MHz, DMSO) δ 7.62 - 7.45 (m, 4H), 4.49 (s, 2H).

[0105] To a suspension of 1.8 g (6.7 mmol) of 7,8-difluorothieno[2,3-с][2]benzothiepin-4(9H)-one (4.4) in 50 ml of methanol, 0.25 g (6.7 mmol) of sodium borohydride was added and the reaction was stirred at room temperature for 30 min. The reaction was evaporated on a rotary evaporator, the residue was suspended in 50 ml of methylene chloride and washed with 50 ml of saturated NaHCO3 solution. The methylene solution was dried over Na2SO4 and evaporated to dryness. The residue in the flask was crystallized. The product was washed with water and air-dried to give 1.7 g of 7,8-difluoro-4,9-dihydrothieno[2,3-с][2]benzothiepin-4-ol (4) as a yellowish powder. 1 H NMR (400 MHz, DMSO) δ 7.35 - 7.25 (m, 2H), 7.25 - 7.18 (m, 1H), 7.07 (d, J = 4.7 Hz, 1H), 6.27 (d, J = 4.0 Hz, 1H), 5.96 (d, J = 3.9 Hz, 1H).

[0106] Example 3. 3,4-Difluorophenyl)(phenyl)methanol (5) was prepared from the corresponding ketones 3.7 and 4.4 analogously to the synthesis of alcohols 3 and 4. (3,4-difluorophenyl)(phenyl)methanol (5): LC-MS (ESI, 20 min), 221 (M+H) + ; 1 H NMR (DMSO-d6, 400 MHz) δ7.29-7.42 (m, 6H), 7.17-7.24 (m, 2H), 6.06 (d, J = 4.0 Hz, 1H), 5.71 (d, J = 4.0 Hz, 1H).

[0107] Example 4.( 3,4-Difluorophenyl)(2-methylsulfanylphenyl)methanol (6) To a suspension of 11.0 g (79.4 mmol, 1.5 equiv.) K2CO3 and 3.5 g (10.6 mmol, 0.2 equiv.) Cs2CO3 in 50 ml DMF, 10.0 g (52.9 mmol, 1 equiv.) 1-bromo-2-thiophenol (6.1) was added and the reaction was stirred at room temperature for 30 min. Then, 11.3 g (79.4 mmol, 1.5 equiv.) iodomethane was added and the mixture was stirred at room temperature for 1 h. The mixture was poured into 200 ml water, extracted with diethyl ether, and the combined organic phases were washed with water, then with brine and dried over Na2SO4. The solvent was evaporated to dryness on a rotary evaporator and the product was used in the next step without further purification. The yield of 1-bromo-2-methylsulfanylbenzene (6.2) was 10.4 g (97%) as a yellow oil: 1 H NMR (400 MHz, CDCl3) δ 7.54 (dd, J = 7.9, 1.2 Hz, 1H), 7.36 - 7.28 (m, 1H), 7.15 (d, J = 7.9 Hz, 1H), 7.02 (td, J = 7.8, 1.4 Hz, 1H), 2.49 (s, 3H).

[0108] 18.7 g (118.3 mmol, 1 equiv.) of 3,4- in 374 ml of methylene chloride To the solution of difluoro-p-benzoic acid (6.4), 20.1 g (124.2 mmol, 1.05 equiv.) of CDI was slowly added and the mixture was stirred at room temperature for 15 min until the evolution of CO2 ceased. Then, 12.7 g (130.1 mmol, 1.1 equiv.) of N,O-dimethylhydroxylamine hydrochloride was added and the reaction mixture was stirred at room temperature for 17 h. The mixture was diluted with 400 ml of water, the layers were separated and the aqueous layer was extracted twice with 100 ml portions of methylene chloride. The combined organic layers were washed with 200 ml of water, 100 ml of brine, dried over Na2SO4 and evaporated on a rotary evaporator to give 12 g (50%) of 3,4-difluoro-N-methoxy-N-methylbenzamide (6.5) as a colorless oil: 1 H NMR (400 MHz, CDCl3) δ 7.66 - 7.57 (m, 1H), 7.57 - 7.49 (m, 1H), 7.20 (dd, J = 18.1, 8.3 Hz, 1H), 3.56 (s, 3H), 3.37 (s, 3H).

[0109] To a suspension of 1.49 g (61.4 mmol, 1.2 equiv.) of Mg in 60 ml of THF was added 10.4 g (51.2 mmol, 1 equiv.) of 1-bromo-2-(methylsulfanyl)benzene (6.2) and the mixture was stirred at room temperature for 2 h to give a solution of [2-(methylsulfanyl)phenyl]magnesium bromide (6.3) in THF.

[0110] To a solution of 10.3 g (51.2 mmol, 1 equiv.) of 3,4-difluoro-N-methoxy-N-methylbenzamide (6.5) in 60 ml of THF cooled to (-78) °C (acetone, dry ice), a solution of [2-(methylsulfanyl)phenyl]magnesium bromide (6.3) in THF was added dropwise while maintaining the temperature at (-78) to (-60) °C. The mixture was stirred at (-70) °C for 30 min, then heated to room temperature and stirred for 17 h. The reaction was cooled to 0 °C, 200 ml of 1N HCl was added, and the mixture was stirred in an ice bath for 30 min. Then 50 ml of ethyl acetate and 100 ml of water were added to the mixture, the organic layer was separated, and the aqueous layer was extracted twice with 100 ml portions of ethyl acetate. The combined organic extracts were washed twice with 50 ml portions of water, then with brine, dried over Na2SO4, and evaporated to dryness on a rotary evaporator. The product was purified by column chromatography (silica gel, ethyl acetate:hexane=30:1 to 20:1) to give 3.6 g of (3,4-difluorophenyl)(2-methylsulfanylphenyl)methanone (6.6) as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 7.71 - 7.64 (m, 1H), 7.58 - 7.47 (m, 2H), 7.46 - 7.41 (m, 1H), 7.39 - 7.34 (m, 1H), 7.28 - 7.22 (m, 2H), 2.44 (s, 3H).

[0111] To a solution of 3.6 g (13.6 mmol, 1 equiv.) of (3,4-difluorophenyl)(2-methylsulfanylphenyl)methanone (6.6) in 36 ml of methanol, 0.26 g (6.8 mmol, 0.5 equiv.) of NaBH4 was added, the reaction was stirred at room temperature for 30 min, then rotary evaporated, 10 ml of 2N HCl was added to the residue, and the mixture was stirred at room temperature for 30 min. Saturated NaHCO3 solution (100 ml) was added in portions, and the organic product was extracted three times with 60 ml of ethyl acetate each. The combined extracts were washed with brine, dried over Na2SO4, and rotary evaporated to dryness. The product was purified by column chromatography (silica gel, hexane:ethyl acetate=30:1--15:1--9:1--7:1--5:1) to give 2.9 g of (3,4-difluorophenyl)(2-methylsulfanylphenyl)methanol (77%) as a colorless oil (6): 1 H NMR (400 MHz, DMSO) δ 7.51 (d, J = 7.5 Hz, 1H), 7.38 - 7.26 (m, 4H), 7.23 - 7.17 (m, 1H), 7.13 - 7.07 (m, 1H), 6.10 (d, J = 4.3 Hz, 1H), 5.97 (d, J = 4.3 Hz, 1H), 2.44 (s, 3H).

[0112] Example 5.( 12aR)-7-(benzyloxy)-12-(5,10-dihydro[3,2-с][2]benzothiepin-10-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-с]pyrido[2,1-е][1,2,4]triazine-6,8-dione 1.1.1 and its diastereomers 1.2.1, 1.3.1 3.3 g (10.1 mmol, 1 equiv.) of 7-(benzyloxy)- 3,4,12,12a-Tetrahydro-To a mixture of 1H-[1,4]oxazino[3,4-с]pyrido[2,1-f][1,2,4]triazine-6,8-dione (2) and 4.1 g (15.2 mmol, 1.5 equiv.) of 6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-ol (3) was added 64.3 g (101 mmol, 10 equiv.) of a 50% solution of T3R in ethyl acetate. The reaction was stirred at room temperature for 5 days and poured into a mixture of 200 ml of saturated NaHCO3 solution and 200 ml of ethyl acetate. The aqueous solution was separated and the ethyl acetate layer was washed again with saturated NaHCO3 solution, then with brine, dried over Na2SO4 and evaporated on a rotary evaporator. The product was purified by column chromatography (EtOAc) to give compound 1.1.1 as a white powder (5.7 g, 97%). The resulting mixture of diastereomers was recrystallized from 170 ml of ethyl acetate. The precipitate was filtered and washed with ethyl acetate to give diastereomer 1.3.1 as a white powder (1.46 g, 25%). The filtrate was rotary evaporated to dryness and the residue was separated by chiral HPLC to give diastereomer 1.2.1, which was the first to elute from the column, and diastereomer 1.3.1, which was the second to elute from the column. Additionally, 2.8 g of diastereomer 1.2.1 was recrystallized from 100 ml of isopropanol. Ethanol and The absolute configurations of diastereomers 1.2.1 and 1.3.1 were established based on the XRD data (Table 4) for the orthorhombic solvates obtained by crystallization of diastereomer 1.2.1 from isopropanol and 1.2.1·C2H5 and 1.2.1·i-C3H7 (in a ratio of 4:3 and 8:3, respectively).

[0113] [Table 4]

[0114] Diastereomer 1.2.1: LC MS, m / z 580 (M+1); 1H NMR (400 MHz, DMSO) δ 7.76 (d, J = 5.3 Hz, 1H), 7.56 (d, J = 7.4 Hz, 2H), 7.40 - 7.29 (m, 3H), 7.21 - 7.11 (m, 1H), 7.03 (d, J = 7.7 Hz, 1H), 6.91 (d, J = 5.4 Hz, 1H), 6.83 - 6.75 (m, 1H), 5.76 - 5.65 (m, 2H), 5.34 - 5.22 (m, 2H), 5.15 (d, J = 11.0 Hz, 1H), 4.56 - 4.48 (m, 2H), 4.13 (d, J = 14.4 Hz, 1H), 3.99 - 3.92 (m, 1H), 3.73 - 3.66 (m, 1H), 3.39 (t, J = 10.3 Hz, 1H), 2.96 - 2.86 (m, 1H), 1.04 (d, J = 6.0 Hz, 1H)。

[0115] ジアステレオマー1.3.1:LC MS, m / z 580 (M+1); 1 H NMR (400 MHz, DMSO) 7.57 (d, J = 7.0 Hz, 2H), 7.51 - 7.29 (m, 6H), 7.23 (d, J = 7.7 Hz, 1H), 6.77 (d, J = 5.4 Hz, 1H), 5.88 - 5.80 (m, 2H), 5.49 - 5.34 (m, 1H), 5.25 (d, J = 10.7 Hz, 1H), 5.14 (d, J = 10.8 Hz, 1H), 4.50 - 4.40 (m, 1H), 4.35 (dd, J = 9.9, 2.9 Hz, 1H), 4.07 (d, J = 9.8 Hz, 1H), 3.85 (dd, J = 10.7, 2.8 Hz, 1H), 3.70 - 3.59 (m, 1H), 3.36 (t, J = 10.3 Hz, 1H), 3.28 - 3.19 (m, 1H), 2.99 - 2.81 (m, 1H)。

[0116] Example 6. 12aR)-7-Hydroxy-12-(5,10-dihydro[3,2-с][2]benzothiepin-10-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-с]pyrido[2,1-е][1,2,4]triazine-6,8-dione 1.1.2 and its diastereomers 1.2.2 and 1.3.2 0.173 mol (1 equiv.) of (12aR)-7-(benzyloxy)-12-(5,10-dihydro[3,2-с][2]benzothiepin-10-yl)- in 15 ml of dimethylacetamide 3,4,12,12a-Tetrahydro- To a solution of 1H-[1,4]oxazino[3,4-с]pyrido[2,1-е][1,2,4]triazine-6,8-dione (1.1.1) or its diastereomers 1.2.1 or 1.3.1, 36 mg (0.863 mmol, 5 equiv.) of LiCl was added, and the reaction was heated to 80 °C and stirred for 2 h. The reaction was then rotary evaporated to dryness, 50 ml of 0.5 N aqueous HCl was added to the residue, and the product was extracted three times with 30 ml portions of ethyl acetate. The combined extracts were washed with brine, dried over Na2SO4, and rotary evaporated to dryness. The residue was purified by HPLC to give inhibitor 1.1.2 (LC MS, m / z 454 (M+1)) or its diastereomers 1.1.2, 1.3.2 (LC MS, m / z 454 (M+1)). According to NMR data, inhibitor 1.1.2 is a mixture of diastereomers 1.2.2 and 1.3.2 in a 65:35 ratio.

[0117] Diastereomer 1.2.2: LC MS, m / z 454 (M+1); 1 H NMR (400 MHz, DMSO) δ7.53 - 7.37 (m, 3H), 7.14 (d, J = 7.8 Hz, 1H), 6.77 (d, J = 5.3 Hz, 1H), 5.86 (s, 1H), 5.69 (d, J = 7.7 Hz, 1H), 5.41 (d, J = 14.1 Hz, 1H), 4.42 (d, J = 10.6 Hz, 2H), 4.09 (d, J = 14.2 Hz, 1H), 3.90 - 3.81 (m, 1H), 3.70 - 3.56 (m, 2H), 3.46 - 3.39 (m, 2H), 3.00 (s, 1H).

[0118] Diastereomer 1.3.2: LC MS, m / z 454 (M+1); 1 H NMR (400 MHz, DMSO) δ7.76 (d, J = 5.3 Hz, 1H), 7.20 (dd, J = 18.5, 8.3 Hz, 1H), 7.05 - 6.87 (m, 3H), 5.84 (s, 1H), 5.56 (d, J = 7.7 Hz, 1H), 5.28 (d, J = 14.9 Hz, 1H), 4.57 (dd, J = 9.8, 2.8 Hz, 1H), 4.49 (d, J = 11.8 Hz, 1H), 4.13 (d, J = 14.5 Hz, 1H), 4.01 - 3.93 (m, 1H), 3.76 - 3.68 (m, 1H), 3.62 (t, J = 10.3 Hz, 1H), 3.49 - 3.39 (m, 2H), 3.05 - 2.94 (m, 1H).

[0119] Example 7. {(12aR)-12-[(10S)-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]-4,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-6-yl}oxy)methyl methyl carbonate 1.1.4 and its diastereoisomers 1.2.4, 1.3.4 To a suspension of 0.5 mmol of compound 1.1.2 or its diastereomers 1.2.2, 1.3.2 in 1 ml of dimethylacetamide, 93 mg (0.75 mmol) of chloromethyl methyl carbonate, 137 mg (1.0 mmol) of potassium carbonate, and 82 mg (0.5 mol) of potassium iodide were added, and the reaction was heated to 60° C. and stirred for 48 h. The reaction was evaporated to dryness on a rotary evaporator, 10 ml of 0.5 N HCl was added to the residue, and the product was extracted three times with 30 ml portions of EtOAc. The combined extracts were washed with 30 ml of saturated aqueous NaHCO3 solution, dried over Na2SO4, and evaporated to dryness on a rotary evaporator. The residue was purified by HPLC to give the prodrug 1.1.4 (LC MS, m / z 578 (M+1)) or its diastereoisomers 1.2.4 (LC MS, m / z 578 (M+1)), 1.3.4 (LC MS, m / z 578 (M+1)).

[0120] Example 8. 12aR)-12-[(10S)-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]-4,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-6-yl methyl carbonate 1.1.3 and its diastereoisomers 1.2.3, 1.3.3 Prodrug 1.1.3 (LC MS, m / z 548 (M+1)), 1.2.3 (LC 1.1.2 (LC MS, m / z 548 (M+1)) and 1.3.3 (LC MS, m / z 548 (M+1)) were prepared as in Example 6 using chloroformate methyl ester for the carbomethoxylation of compounds 1.1.2, 1.2.2, and 1.3.2, respectively.

[0121] Example 9. 12aR)-7-(benzyloxy)-12-(7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione 1.4.1 and its diastereomers 1.5.1, 1.6.1 To a solution of 4.6 mmol of 7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-ol (4) in 50 ml of pyridine, 0.52 g (4.6 mmol) of mesyl chloride was added dropwise at 0° C., and the resulting mixture was stirred at room temperature for 24 hours. Then, 7-(benzyloxy)- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-с]pyrido[2,1-f][1,2,4]triazine-6,8-dione (2) was added and the mixture was stirred for another 24 hours at 70° C. Pyridine was evaporated under reduced pressure; the residue was dissolved in 100 ml of methylene chloride, washed with 50 ml of water, dried over sodium sulfate and evaporated. The resulting product was purified by column chromatography on silica gel with pure ethyl acetate to give (12aR)-7-(benzyloxy)-12-(7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl)-(1.5.1, 1.6.1) consisting of diastereomers 1.5.1, 1.6.2, 1.7.3, 1.8.4, 1.9.5, 1.10.6.7, 1.11.8.8, 1.12.4.9, 1.13.1, 1.14.1, 1.15.1, 1.16.1, 1.17.1, 1.18.1, 1.19.1, 1.20.1, 1.21.1, 1.22.1, 1.23.1, 1.24.1, 1.25.1, 1.26.1, 1.27.1, 1.28.1, 1.29.1, 1.30.1, 1.31.1, 1.32.1, 1.33.1, 1.34.1, 1.35.1, 1.36.1, 1.37.1, 1.38.1, 1.39.1, 1.40.1, 1.41.1, 1.42.1, 1.43 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione 1.4.1 was obtained and isolated on a preparative chiral column Phenomenex Lux 5u cellulose-4, AXIAF, 250×30.00 mm. Flow rate: 25 ml / min; detector: UV, 254 nm; constant mobile phase composition: 80:20 acetonitrile-isopropanol.

[0122] (12aR)-7-(benzyloxy)-12-(7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-yl)- 3,4,12,12a-Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.4.1: LC MS m / z 580 (M+1); 1 H NMR (400 MHz, DMSO) δ 7.61 - 7.51 (m, 2.6H), 7.48 - 7.29 (m, 3.8H), 7.25 (d, J = 7.7 Hz, 0.4H), 7.20 - 7.09 (m, 1H), 7.02 (dd, J = 12.0, 6.5 Hz, 1.2H), 6.76 - 6.67 (m, 0.6H), 6.26 (d, J = 5.2 Hz, 0.4H), 5.83 (s, 0.4H), 5.73 - 5.66 (m, 1.2H), 5.48 (d, J = 14.6 Hz, 0.4H), 5.35 - 5.26 (m, 1.6H), 5.18 - 5.10 (m, 1H), 4.54 - 4.41 (m, 1H), 4.36 - 4.29 (m, 1H), 4.24 (d, J = 14.5 Hz, 0.6H), 4.18 (d, J = 14.3 Hz, 0.4H), 3.94 (d, J = 7.6 Hz, 0.6H), 3.84 (d, J = 7.8 Hz, 0.4H), 3.72 - 3.61 (m, 1H), 3.42 - 3.32 (m, 1.4H), 3.29 - 3.20 (m, 1H), 2.91 (t, J = 11.0 Hz, 0.4H), 2.83 (t, J = 10.9 Hz, 0.6H).

[0123] Diastereomer 1.5.1: IC MS m / z 580 (M+1); 1 H NMR (400 MHz, DMSO) δ 7.54 (t, J = 5.5 Hz, 3H), 7.38 (t, J = 7.2 Hz, 2H), 7.33 (t, J = 7.2 Hz, 1H), 7.22 - 7.11 (m, 1H), 7.02 (dd, J = 12.0, 6.5 Hz, 2H), 6.76 - 6.67 (m, 1H), 5.73 - 5.66 (m, 2H), 5.35 - 5.26 (m, 2H), 5.14 (d, J = 10.9 Hz, 1H), 4.49 (d, J = 11.8 Hz, 1H), 4.32 (d, J = 6.9 Hz, 1H), 4.24 (d, J = 14.5 Hz, 1H), 3.94 (d, J = 7.6 Hz, 1H), 3.68 (d, J = 8.8 Hz, 1H), 3.39 - 3.34 (m, 1H), 3.29 - 3.21 (m, 1H), 2.83 (t, J = 10.9 Hz, 1H).

[0124] Diastereomer 1.6.1: IC MS m / z 580 (M+1); 1 H NMR (400 MHz, DMSO) δ 7.57 (d, J = 6.9 Hz, 2H), 7.48 - 7.29 (m, 5H), 7.25 (d, J = 7.7 Hz, 1H), 7.11 (d, J = 5.2 Hz, 1H), 6.26 (d, J = 5.2 Hz, 1H), 5.83 (s, 1H), 5.48 (d, J = 14.6 Hz, 1H), 5.29 (d, J = 11.0 Hz, 1H), 5.12 (d, J = 10.9 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.33 (d, J = 7.0 Hz, 1H), 4.18 (d, J = 14.3 Hz, 1H), 3.84 (d, J = 7.8 Hz, 1H), 3.65 (d, J = 11.2 Hz, 1H), 3.42 - 3.34 (m, 2H), 3.25 (t, J = 10.7 Hz, 1H), 2.91 (t, J = 11.0 Hz, 1H).

[0125] Example 10. 7-Hydroxy-(12aR)-12-(7,8-difluoro-4,9-dihydrothieno[2,3-с][2]benzothiepin-4-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-с]pyrido[2,1-f][1,2,4]triazine-6,8-dione 1.4.2 and its diastereomers 1.5.2 and 1.6.2 To a solution of 0.14 mmol of the 7-benzyloxy derivative 1.4.2, 1.5.2 or 1.6.2 in 5 ml of dimethylacetamide, 9 mg (0.70 mmol) of LiCl was added and the reaction was heated to 80° C. and stirred for 3 h. The reaction was rotary evaporated to dryness and the residue was purified by HPLC to give the respective product 1.4.2, 1.5.2 or 1.6.2.

[0126] 7-Hydroxy-(12aR)-12-(7,8-difluoro-4,9-dihydrothieno[2,3-с][2]benzothiepin-4-yl)- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-с]pyrido[2,1-f][1,2,4]triazine-6,8-dione 1.4.2: LC MS, m / z 454 (M+1); 1 H NMR (400 MHz, DMSO) δ7.53 (d, J = 5.2 Hz, 0.5H), 7.44 (dd, J = 18.2, 8.4 Hz, 0.5H), 7.38 - 7.31 (m, 0.5H), 7.27 - 7.13 (m, 1.5H), 7.03 (d, J = 5.3 Hz, 0.5H), 6.97 (d, J = 7.7 Hz, 0.5H), 6.92 - 6.85 (m, 0.5H), 6.42 (d, J = 5.3 Hz, 0.5H), 5.87 (s, 0.5H), 5.80 (s, 0.5H), 5.69 (d, J = 7.6 Hz, 0.5H), 5.56 (d, J = 7.7 Hz, 0.5H), 5.48 (d, J = 13.5 Hz, 0.5H), 5.33 (d, J = 14.4 Hz, 0.5H), 4.53 - 4.35 (m, 2H), 4.30 - 4.14 (m, 1H), 3.96 (dd, J = 10.6, 2.7 Hz, 0.5H), 3.90 - 3.81 (m, 0.5H), 3.69 (t, J = 12.4 Hz, 1H), 3.59 (t, J = 10.3 Hz, 1H), 3.46 - 3.41 (m, 1H), 3.08 - 2.97 (m, 0.5H), 2.91 (t, J = 11.0 Hz, 0.5H)。

[0127] ジアステレオマー1.5.2:LC MS, m / z 454 (M+1); : 1 H NMR (400 MHz, DMSO) δ 11.80 (br.s, 1H), 7.43 (dd, J = 18.2, 8.6 Hz, 1H), 7.38 - 7.29 (m, 1H), 7.17 (t, J = 6.3 Hz, 2H), 6.42 (d, J = 5.2 Hz, 1H), 5.87 (s, 1H), 5.69 (d, J = 7.6 Hz, 1H), 5.49 (d, J = 14.7 Hz, 1H), 4.55 - 4.33 (m, 2H), 4.19 (d, J = 14.4 Hz, 1H), 3.86 (d, J = 8.0 Hz, 1H), 3.67 (d, J = 9.2 Hz, 1H), 3.59 (t, J = 10.4 Hz, 1H), 3.40 (t, J = 10.5 Hz, 1H), 3.03 (t, J = 11.0 Hz, 1H)。

[0128] ジアステレオマー1.6.2:LC MS, m / z 454 (M+1); 1H NMR (400 MHz, DMSO) δ 11.77 (s, 1H), 7.53 (d, J = 5.1 Hz, 1H), 7.21 (dd, J = 17.9, 8.6 Hz, 1H), 7.03 (d, J = 5.2 Hz, 1H), 6.97 (d, J = 7.6 Hz, 1H), 6.93 - 6.82 (m, 1H), 5.80 (s, 1H), 5.56 (d, J = 7.6 Hz, 1H), 5.33 (d, J = 14.6 Hz, 1H), 4.48 (d, J = 12.6 Hz, 1H), 4.39 (d, J = 7.6 Hz, 1H), 4.25 (d, J = 14.5 Hz, 1H), 3.96 (d, J = 8.6 Hz, 1H), 3.71 (d, J = 9.3 Hz, 1H), 3.59 (t, J = 10.2 Hz, 1H), 3.42 (t, J = 10.8 Hz, 1H), 2.91 (t, J = 11.2 Hz, 1H).

[0129] Example 11. {(12aR)-12-[(4S)-7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-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 carbonate 1.5.4 and and ({(12aR)-12-[(4R)-7,8-difluoro-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-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 carbonate 1.6.4 Prodrugs 1.5.4 and 1.6.4 were prepared starting from the respective diastereomers 1.5.2 and 1.6.2 under conditions similar to those described in Example 6. Prodrug 1.5.4: LC MS, m / z 578 (M+1). Prodrug 1.6.4: LC MS, m / z 578 (M+1).

[0130] Example 12.( 12aR)-7-(benzyloxy)-12-[(3,4-difluorophenyl)(phenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione 1.7.1 and its diastereomers 1.8.1, 1.9.1 900 mg (2.7 mmol) of (12aR)-7-(benzyloxy)- in 17.5 g (27.0 mmol) of 50% T3R in ethyl acetate 3,4,12,12a-Tetrahydro-To a mixture of 1H-[1,4]oxazino[3,4-с]pyrido[2,1-f][1,2,4]triazine-6,8-dione (2) and 605 mg (2.7 mmol) of (3,4-difluorophenyl)(phenyl)methanol (5), 528 mg (5.4 mmol) of methanesulfonic acid was added and the mixture was stirred at 70 ° C for 16 h. The reaction was cooled to room temperature, then 50 ml of ethyl acetate was added, and the mixture was washed with 50 ml of saturated NaHCO3 solution, dried over Na2SO4, and evaporated to dryness on a rotary evaporator. The resulting product was purified by column chromatography on silica gel with pure ethyl acetate and the respective fractions were evaporated to give 240 mg of product (1.7.1): LC MS (20 min): Rt = 15.53 (220 nm), m / z 530 (M + 1), which was (12aR)-7-(benzyloxy)-12-[(R)-(3,4-difluorophenyl)(phenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione ( 1.8.1) and (12aR)-7-(benzyloxy)-12-[(S)-(3,4-difluorophenyl)(phenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione ( 1.9.1) which was separated on a preparative chiral column Phenomenex Lux 5u Cellulose-4, AXIA F, 250 x 30.00 mm. Flow rate: 25 ml / min; detector: UV, 254 nm; constant mobile phase composition: 80:20 acetonitrile-isopropanol.

[0131] Diastereomer 1.8.1: 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 6.6 Hz, 2H), 7.40 - 7.33 (m, 4H), 7.25 - 7.17 (m, 3H), 7.12 (t, J = 7.6 Hz, 2H), 6.93 (d, J = 7.5 Hz, 2H), 6.73 (d, J = 7.7 Hz, 1H), 5.75 (d, J = 7.9 Hz, 1H), 5.59 (d, J = 10.7 Hz, 1H), 5.45 (d, J = 10.8 Hz, 1H), 5.39 (s, 1H), 4.65 (d, J = 13.8Hz, 1H), 4.58 - 4.50 (m, 1H), 3.97 (d, J = 10.4 Hz, 1H), 3.73 (d, J = 8.9 Hz, 1H), 3.37 - 3.22 (m, 2H), 2.96 (t, J = 10.9 Hz, 1H).

[0132] Diastereomer 1.9.1: 1 H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 7.2 Hz, 2H), 7.50 - 7.32 (m, 8H), 7.06 - 6.95 (m, 1H), 6.91 - 6.76 (m, 2H), 6.61 - 6.46 (m, 1H), 5.94 (d, J = 7.9 Hz, 1H), 5.64 (d, J = 10.7 Hz, 1H), 5.47 (d, J = 10.8 Hz , 1H), 5.36 (s, 1H), 4.60 (t, J = 12.8 Hz, 2H), 3.95 (d, J = 10.7 Hz, 1H), 3.71 (d, J = 8.8 Hz, 1H), 3.39 - 3.20 (m, 2H), 2.99 - 2.83 (m, 1H).

[0133] After crystallization of diastereomer 1.9.1 from a mixture of dichloromethane-hexane, the obtained crystals were analyzed using XRD method. The obtained data (Figure 3, Table 5) confirmed its stereochemical structure.

[0134] [Table 5]

[0135] Example 13.( 12aR)-7-Hydroxy-12-[(3,4-difluorophenyl)(phenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.7.2) and its diastereomers 1.8.2 and 1.9.2 To a solution of 64 mg (0.12 mmol) of the (12aR)-7-(benzyloxy) derivative 1.7.1, 1.8.1 or 1.91 in 3 ml of dimethylacetamide was added 40 mg (0.95 mmol) of LiCl and the reaction was heated to 80° C. and stirred for 3 h. The reaction was evaporated to dryness on a rotary evaporator and the residue was purified by HPLC to give (12aR)-7-hydroxy-12-[(3,4-difluorophenyl)(phenyl)methyl]- 3,4,12,12a-Tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.7.2) was obtained: LC MS (20 min) m / z 440 (M+1); 1 According to the H NMR data, the ratio of diastereoisomers 1.8.2 and 1.9.2 in the mixture was 1.5:1; (12aR)-7-hydroxy-12-[(10R)-(3,4-difluorophenyl)(phenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.8.2): LC MS (20 min), Rt = 13.99 (220 nm), m / z 440 (M+1), 1 H NMR (400 MHz, DMSO) δ 7.89 - 7.76 (m, 1H), 7.59 - 7.44 (m, 2H), 7.33 - 7.13 (m, 6H), 5.74 (s, 1H), 5.44 (d, J = 7.6 Hz, 1H), 4.60 (d, J = 7.4 Hz, 1H), 4.37 (d, J = 12.7 Hz, 1H), 3.96 (d, J = 8.3 Hz, 1H), 3.75 - 3.56 (m, 2H), 3.44 - 3.37 (m, 2H), 3.22 - 3.14 (m, 1H), and (12aR)-7-hydroxy-1H-(1H) ... 2-[(10S)-(3,4-difluorophenyl)(phenyl)methyl]- 3,4,12,12a-Tetrahydro- 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.9.2): LC MS (20 min), Rt = 14.32 (220 nm), m / z 440 (M+1), 1 H NMR (400 MHz, DMSO) δ 7.66 (d, J = 7.4 Hz, 2H), 7.46 (t, J = 7.4 Hz, 3H), 7.43 - 7.32 (m, 2H), 7.28 (dd, J = 18.9, 8.6 Hz, 1H), 7.22 - 7.14 (m, 1H), 5.78 (s, 1H), 5.58 (d, J = 7.6 Hz, 1H), 4.52 (dd, J = 10.0, 2.8 Hz, 1H), 4.37 (d, J = 12.0 Hz, 1H), 3.92 (dd, J = 10.8, 2.8 Hz, 1H), 3.69 - 3.60 (m, 2H), 3.42 - 3.35 (m, 1H), 3.03 (t, J = 11.1 Hz, 1H).

[0136] Example 14. (12aR)-12-[(R)-(3,4-difluorophenyl)(phenyl)methyl]-7-hydroxy-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 (1.8.4) and (12aR)-12-[(S)-(3,4-difluorophenyl)(phenyl)methyl]-7-hydroxy-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 (1.9.4) The above compounds were prepared from Example 7 as were compounds 1.1.4, 1.2.4, and 1.3.4.

[0137] Diastereoisomer 1.8.4: LC MS (20 min), m / z 528 (M+1), 1 H NMR (DMSO-d6, 300 MHz, 80 °C) δ 7.76 (m, 1H), 7.48 (m, 2H), 7.35 (m, 1H), 7.24 (m, 5H), 5.73 (m, 1H), 5.66 (m, 3H), 4.57 (m, 1H), 4.37 (m, 1H), 4.00 (m, 1H), 3.75 (s, 3H), 3.71 (m, 1H), 3.43 (m, 1H), 3.30 (m, 1H), 3.10 (m, 1H).

[0138] Diastereoisomer 1.9.4: LC MS (20 min), m / z 528 (M+1),1 H NMR (DMSO-d6, 300 MHz, 80 °C) δ 7.65 (m, 2H), 7.43 (m, 5H), 7.21 (m, 2H), 5.79 (d, J = 8.0 Hz, 1H), 5.70 (m, 3H), 4.51 (m, 1H), 4.36 (m, 1H), 3.97 (m, 1H), 3.75 (s, 3H), 3.68 (m, 1H), 3.45 (m, 1H), 3.29 (m, 1H), 2.95 (m, 1H).

[0139] Example 15.( 12aR)-7-(benzyloxy)-12-{(3,4-difluorophenyl)[2-(methylthio)phenyl]methyl}-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-с]pyrido[2,1-е][1,2,4]triazine-6,8-dione (1.10.1) and its diastereomers 1.11.1 and 1.12.1 400 mg (1.222 mmol, 1 equiv.) of 7-(benzyloxy)- 3,4,12,12a-Tetrahydro- To a mixture of 1H-[1,4]oxazino[3,4-с]pyrido[2,1-f][1,2,4]triazine-6,8-dione (2) and 358 mg (1.344 mmol, 1.1 eq.) of (3,4-difluorophenyl)[2-(methylthio)phenyl]methanol (6) was added 1166.5 mg (1.833 mmol, 1.5 eq.) of 50% T3R in ethyl acetate and 0.4 ml of ethyl acetate. To this suspension was added 235 mg (2.444 mmol, 2 eq.) of methanesulfonic acid and the mixture was heated at 100 °C in a CEM microwave reactor for 5.5 h. Water (4 ml) was added to the reaction mixture while cooling with ice and the mixture was stirred in an ice bath for 1 h. Then 30 ml of water was added and the organic phase was extracted three times with 30 ml of ethyl acetate each. The combined organic layers were washed with saturated NaHCO3 solution, then with brine, dried over Na2SO4, and evaporated to dryness on a rotary evaporator. The product 1.10.1, consisting of its diastereomers 1.11.1 and 1.12.1, was partially debenzylated, and therefore the mixture was used in the next step without further purification. LC MS (3 min): Rt=1.40 (220 nm), m / z 576 (M+1).

[0140] Example 16 (12aR)-7-Hydroxy-12-{(3,4-difluorophenyl)[2-(methylthio)phenyl]methyl}- 3,4,12,12a-Tetrahydro-1H-[1,4]oxazino[3,4-с]pyrido[2,1-е][1,2,4]triazine-6,8-dione (1.10.2) consists of its diastereomers 1.11.2 and 1.12.2 The product prepared in Example 15 was dissolved in 10 ml of dimethylacetamide, and 259 mg (6.11 mmol, 5 eq.) of LiCl was added to the solution. The mixture was heated to 80° C. and stirred for 3 h. The reaction was evaporated to dryness on a rotary evaporator, then 50 ml of 0.5 M HCl was added to the residue, the reaction mixture was stirred at room temperature for 30 min, and the resulting residue was filtered off. The residue was washed with water and air-dried. The product was purified by HPLC. 1 Based on H NMR data, the product 1.10.2 (LC MS (20 min): Rt=14.49 (220 nm), m / z 486 (M+1)) consisted of diastereomers 1.11.2 and 1.12.2 in a 60:40 ratio.

[0141] Example 17.( 12aR)-7-(benzyloxy)-12-diphenylmethyl-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.13.1) 380 mg (1.2 mmol) of 7-(benzyloxy)- in 7.4 g (12.0 mmol) of 50% T3R in ethyl acetate 3,4,12,12a-Tetrahydro- To a mixture of 1H-[1,4]oxazino[3,4-с]pyrido[2,1-f][1,2,4]triazine-6,8-dione (2) and 214 mg (1.2 mmol) diphenylmethanol (7), 223 mg (2.4 mmol) methanesulfonic acid was added and the mixture was stirred at 50 °C for 16 h. The reaction was cooled to room temperature, then 50 ml ethyl acetate was added. The mixture was washed with 50 ml saturated NaHCO3 solution, dried over Na2SO4, and evaporated to dryness on a rotary evaporator. The resulting product was purified by column chromatography on silica gel with ethyl acetate. Evaporation of each fraction gave 407 mg (71%) of product 1.13.1: LC MS (20 min), Rt = 17.10 (220 nm), m / z 494 (M + 1); 1H NMR (400 MHz, DMSO) δ7.66 (d, J = 7.5 Hz, 2H), 7.55 (d, J = 7.3 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.40 - 7.28 (m, 5H), 7.21 (d, J = 7.2 Hz, 2H), 7.19 - 7.09 (m, 3H), 5.66 (s, 1H), 5.57 (d, J = 7.7 Hz, 1H), 5.24 (d, J = 10.8 Hz, 1H), 5.05 (d, J = 10.9 Hz, 1H), 4.53 - 4.45 (m, 1H), 4.40 (d, J = 12.8 Hz, 1H), 3.92 (d, J = 8.2 Hz, 1H), 3.64 (d, J = 9.0 Hz, 1H), 3.45 - 3.37 (m, 1H), 3.23 (t, J = 10.9 Hz, 1H), 2.96 (t, J = 10.9 Hz, 1H).

[0142] Example 18.( 12aR)-7-Hydroxy-12-diphenylmethyl-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.13.2) 360 mg (0.73 mmol) of (12aR)-7-(benzyloxy)-12-diphenylmethyl- in 5 ml of dimethylacetamide 3,4,12,12a-Tetrahydro- To a solution of 1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.13.1), 155 mg (3.65 mmol) of LiCl was added and the reaction was heated to 80° C. and stirred for 3 hours. The reaction was then rotary evaporated to dryness, 50 ml of 0.5 N HCl was added to the residue, and the product was extracted three times with 30 ml portions of EtOAc. The combined extracts were washed with brine, dried over Na2SO4, and rotary evaporated to dryness to give 62 mg of product 1.13.2: LC MS (20 min), Rt=12.85 (220 nm), m / z 404 (M+1); 1H NMR (400 MHz, DMSO) δ7.66 (d, J = 7.3 Hz, 2H), 7.45 (t, J = 7.3 Hz, 2H), 7.40 - 7.33 (m, 1H), 7.28 (s, 2H), 7.25 - 7.13 (m, 4H), 5.68 (s, 1H), 5.44 (d, J = 7.7 Hz, 1H), 4.56 (d, J = 8.0 Hz, 1H), 4.38 (d, J = 13.0 Hz, 1H), 3.94 (d, J = 9.1 Hz, 1H), 3.72 - 3.59 (m, 2H), 3.45 - 3.37 (m, 2H), 3.12 - 3.00 (m, 1H).

[0143] Example 19. {(12aR)-12-diphenylmethyl-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.13.4) Prodrug 1.13.4 was prepared under conditions similar to the synthesis of ({(12aR)-12-[(10S)-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]-4,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-6-yl}oxy)methyl methyl carbonate (1.1.4) as described in Example 7.

[0144] Prodrug 1.13.4: LC MS (20 min), Rt = 12.85 (220 nm), m / z 492 (M+1); 1 H NMR (DMSO-d6, 400 MHz) δ 7.67 (d, J = 7.6 Hz, 2H), 7.46 (t, J = 7.6 Hz, 2H), 7.37 (m, 2H), 7.27 (m, 2H), 7.19 (m, 3H), 5.68 (s, 1H), 5.67 (d, J = 6.8 Hz, 1H), 5.63 (d, J = 7.6 Hz, 1H), 5.61 (d, J = 6.8 Hz, 1H), 4.51 (dd, J1= 10.0 Hz, J2= 2.8 Hz, 1H), 4.34 (d, J = 13.2 Hz, 1H), 3.96 (dd, J1= 10.8 Hz, J2= 2.4 Hz, 1H), 3.72 (s, 3H), 3.68 (dd, J1= 11.2 Hz, J2= 2.8 Hz, 1H), 3.45 (t, J = 10.4 Hz, 1H), 3.26 (m, 1H), 3.01 (dt, J1= 12.4 Hz, J2= 2.8 Hz, 1H).

[0145] Example 20. 12aR)-7-(benzyloxy)-12-[bis(4-fluorophenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.14.1) 0.67 g (3.1 mmol) of 7-(benzyloxy)- in 19.4 g (31.0 mmol) of 50% T3R in ethyl acetate 3,4,12,12a-Tetrahydro- To a mixture of 1H-[1,4]oxazino[3,4-с]pyrido[2,1-f][1,2,4]triazine-6,8-dione (2) and 1.0 g (3.1 mol) of bis(4-fluorophenyl)methanol (8), 0.59 g (6.2 mmol) of methanesulfonic acid was added and the mixture was stirred at 80° C. for 16 h. The reaction was cooled to room temperature, 150 ml of ethyl acetate was added, the reaction was washed with 200 ml of saturated aqueous NaHCO3 solution, dried over Na2SO4, and evaporated to dryness on a rotary evaporator. The product obtained was purified by column chromatography on silica gel with ethyl acetate. Evaporation of the corresponding fractions gave product 1.14.1: LC MS (20 minutes), Rt=15.66(22 0 nm), m / z 530 (M = 1); 1H NMR (400 MHz, DMSO) δ7.76 - 7.67 (m, 2H), 7.55 (d, J = 7.1 Hz, 2H), 7.42 - 7.21 (m, 8H), 6.97 (t, J = 8.7 Hz, 2H), 5.76 (s, 1H), 5.65 (d, J = 7.7 Hz, 1H), 5.24 (d, J = 10.9 Hz, 1H), 5.06 (d, J = 10.8 Hz, 1H), 4.47 (d, J = 7.2 Hz, 1H), 4.40 (d, J = 12.6 Hz, 1H), 3.91 (d, J = 8.3 Hz, 1H), 3.64 (d, J = 9.0 Hz, 1H), 3.42 (t, J = 10.5 Hz, 1H), 3.23 (t, J = 10.8 Hz, 1H), 3.01 (t, J = 11.4 Hz, 1H).

[0146] Example 21.( 12aR)-12-[bis(4-fluorophenyl)methyl]-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 (1.14.2) Product 1.14.2: LC MS (20 minutes), Rt = 12.72 (220 nm), m / z 440; 1 H NMR (400 MHz, DMSO) δ 11.61 (br.s, 1H), 7.76 - 7.64 (m, 2H), 7.39 - 7.18 (m, 5H), 7.03 (t, J = 8.7 Hz, 2H), 5.77 (d, J = 11.9 Hz, 1H), 5.52 (d, J = 7.6 Hz, 1H), 4.63 - 4.46 (m, 1H), 4.37 (d, J = 13.4 Hz, 1H), 3.92 (d, J = 8.1 Hz, 1H), 3.72 - 3.57 (m, 2H), 3.39 (t, J = 10.8 Hz, 1H), 3.11 (t, J = 11.1 Hz, 1H), compound 1.13.2 was synthesized and prepared under the conditions described in Example 17.

[0147] Example 22.( {(12aR)-12-[bis(4-fluorophenyl))methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.14.4) Prodrug 1.14.4 was prepared under the conditions described in Example 7 for the synthesis of ({(12aR)-12-[(10S)-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]-4,8-dioxo-3,4,6,8,12,12a-hexahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-6-yl}oxy)methyl methyl carbonate (1.1.4).

[0148] Prodrug 1.14.4: LC MS (20 min), Rt = 12.85 (220 nm), m / z 528 (M+1); 1 H NMR (DMSO-d6, 400 MHz) δ 7.73 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.27-7.32 (m, 4H), 7.02 (m, 2H), 5.78 (s, 1H), 5.71 (d, J = 7.6 Hz, 1H), 5.68 (d, J = 6.8 Hz, 1H), 5.61 (d, J = 6.8 Hz, 1H), 4.50 (dd, J1= 10.0 Hz, J2= 3.2 Hz, 1H), 4.33 (d, J = 13.2 Hz, 1H), 3.95 (dd, J1= 10.8 Hz, J2= 2.8 Hz, 1H), 3.72 (s, 3H), 3.68 (dd, J1= 11.2 Hz, J2= 3.2 Hz, 1H), 3.46 (t, J = 10.4 Hz, 1H), 3.26 (dt, J1= 11.6 Hz, J2= 2.0 Hz, 1H), 3.05 (dt, J1= 12.4 Hz, J2= 3.2 Hz, 1H).

[0149] Example 23. Evaluation of in vitro activity of novel inhibitors against influenza virus isolates in MDCK cell cultures using an enzyme immunoassay (EIA) procedure. ImQuest BioSciences Protocol 1 (Frederick, MD, USA) was used to determine the activity of compounds against influenza a / California / 2009 (H1N1) isolates.

[0150] Preparation of cells. MDCK cells (canine kidney cells, CCL-34) were obtained from ATCC and passaged in DMEM supplemented with 10% FBS, 2 mM L-glutamine, 100 U / ml penicillin, 100 μg / ml streptomycin, 1 mM sodium pyruvate, and 0.1 mM NEAA, and in T-75 flasks prior to use in the antiviral assay. The day before the assay, the cells were split 1:2 to ensure that they were in the exponential growth phase in the process of infecting them. Determination of cell number and its viability was performed using a hemocytometer and dye exclusion with trypan blue. Cell viability was higher than 95% for cells used in the assay. Cells were cultured at 1×10 cells in tissue culture medium. 4 The cells were resuspended at 100 μl / well and added to flat-bottom microtiter plates in a volume of 100 μl. Plates were incubated overnight at 37° C. / 5% CO2 to allow cell attachment.

[0151] Virus preparation. Influenza A / CA / 04 / 09 (NR-13685-) virus was obtained from BEI Resources (Manassas, VA) and was stored at MDCK. A pool of source viruses was produced by growing them in 100 μl of 100-μl PBS cells. A pre-titrated aliquot of virus was removed from the freezer (-80°C) and allowed to thaw slowly to room temperature in a biosafety cabinet. The virus was resuspended and diluted in assay medium (DMEM plus 2 mM L-glutamine, 100 E / ml penicillin, 100 μg / ml streptomycin, 1 mM sodium pyruvate, 0.1 mM NEAA, and 1 μg / ml TPCK-treated trypsin) to determine the amount of virus to be added to each 100 μl well 4 days after infection that would kill 85-95% of the cells (MOI 0.01).

[0152] Plate format. Each plate contained wells for cell controls (cells only), virus controls (cells and virus), colorimetric drug controls (drug only), and experimental wells (drug, cells, and virus). Samples were tested in triplicate for potency at five half-fold dilutions per compound.

[0153] Efficacy and toxicity of XTT. After incubation at 37° C. in a 5% CO2 incubator, the test plates were stained with XTT (2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino)carbonyl]-2H-tetrazolium hydroxide, Sigma-Aldrich) tetrazolium dye. XTT -Tetrazolium is metabolized by mitochondrial enzymes of metabolically active cells to the soluble product formazan, which allows rapid quantitative analysis of the inhibition of virus-induced cell destruction by antiviral test substances. XTT solution was prepared daily as a stock of 1 mg / ml in RPMI 1640. A solution of phenazine metasulfate (PMS, Sigma-Aldrich) was prepared at a concentration of 0.15 mg / ml in PBS. The plates were prepared and stored in the dark at -20°C. XTT / PMS source material was prepared immediately before use by adding 40 μl PMS per ml of XTT solution. Fifty microliters of XTT / PMS was added to each well and the plate was again incubated at 37°C for 4 hours. The plate was sealed tightly with an adhesive plate sealer and gently shaken or inverted several times to mix the soluble formazan product and the plate was read using a Molecular Devices Vmax microplate reader. and read spectrophotometrically at 450 / 650 nm.

[0154] Data analysis. Raw data was collected from Softmax Pro software. We used the Microsoft software for the analysis by calculating the four fitting parameters. Imported into an Excel XLfit4 spreadsheet.

[0155] Mechnikov Research Institute of Vaccines and Sera (Mechnikov NIIVS, Moscow) Protocol 2 was applied to determine the activity of compounds against influenza isolates A / Aichi / 2 / 69 (H3N2) and A / Perth / 265 / 2009 (H1N1pdm09) (H275Y).

[0156] To determine the anti-influenza activity of novel inhibitors (J and prototypes), MDCK cells were plated in Costar 96-well plates at an average density of 30,000–35,000 cells / well and grown as complete monolayers in Eagle's Minimum Essential Medium (EMEM) in the presence of 5% fetal bovine serum and 10 mM glutamine. Before infection with virus, cells were washed twice with serum-free medium. Test compounds were applied at 100 μg / mL. 100 μl of allantoic virus (0.1-5 PFU / cell) diluted in medium containing 5 μg / ml of TRNC trypsin was added to the wells, except for the cell control. The plates were then incubated for 24 hours at 37°C in 5% CO2. After incubation, the medium was removed and the cells were fixed with 80% acetone in phosphate-buffered saline (PBS) for 20 minutes, the wells were dried and 0.05% Tween 20 combined with PBS (EIA solution). The wells were washed three times with 100 μl of PBS solution containing 1% fetal serum and 0.05% Tween 20, and the cells were incubated for 30 min at 37° C. After removing the solution, 100 μl of monoclonal antibody (MCAS) against the internal protein (NP+M1) of influenza A virus, diluted 1:1000 in EIA solution, was added to the cells. After incubation with the antibody for 1 h at 37° C. and three subsequent washes, 100 μl of rabbit IgG against mouse IgG labeled with horseradish peroxidase, diluted 1:5000, was added to the wells, and the cells were incubated for another 1 h at 37° C. After four washes, bound peroxidase was revealed by adding 100 μl of a 0.05% solution of o-phenylenediamine in 0.003% citrate buffer, pH 5.0, containing 0.003% H2O2, to the wells. The plates were kept in the dark for 15-30 min until color appeared, the reaction was stopped by adding 50 μl of 4N H2SO4, and the optical density (OD) was measured at a wavelength of 450 nm in an automatic spectrophotometer. For cell controls, wells not infected with virus were used. The percentage of virus growth inhibition by the test compound was calculated by the formula: percentage of inhibition = 100 - (OD of experiment - OD of cell control / OD of virus control in the absence of compound - OD of cell control). Four plate wells were used per one point of the experiment. Each value represents the arithmetic mean calculated from this experiment. The concentration of the drug that reduces the OD value by 50% was taken as the 50% inhibitory concentration (IC 50 Table 3 shows the antiviral activity of the novel inhibitors and baloxavir against influenza A virus isolates in MDCK cell culture.

[0157] Example 24. Pharmaceutical composition in tablet form Starch (1700 mg), ground lactose (1700 mg), talc (400 mg), and 1200 mg of prodrug 1.1.4, 1.11.4, or 1.14.4 were mixed and pressed into bars. The bars obtained were crushed into granules and sieved to collect granules of 14-16 mesh size. The granules obtained in this way were pressed into tablets of suitable shape weighing 80 or 160 mg, respectively.

[0158] Example 25. Pharmaceutical composition in capsule form The prodrug of formula 1.1.4 or 1.11.4 or 1.14.4 was thoroughly mixed with lactose powder in a ratio of 2: 1. The resulting powder mixture was filled into suitable sized gelatin capsules at 36 or 72 mg in each capsule. [Industrial Applicability]

[0159] The present invention can be used in human and veterinary medicine.

Claims

1. A substituted 3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-diones of general formula 1, or stereoisomers, pharma- ceutically acceptable salts, solvates or hydrates thereof, or crystalline or polycrystalline forms thereof: 【Chemistry 1】 During the ceremony, R １ is 6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl, (3,4-difluorophenyl)(phenyl)methyl, (3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl, diphenylmethyl, bis(4-fluorophenyl)methyl; R ２ is hydrogen or {[(C １ ~C ３ The protecting group is selected from the group consisting of methyl, methyl, ethyl ...

2. (12aR)-12-(6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-diones of general formula 1.1, (12aR)-12-[(10S)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-diones of general formula 1.2, and (12aR)-12-[(10R)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-diones of general formula 1.3 and its stereoisomers, and its pharma- ceutically acceptable salts, solvates and hydrates, and its crystalline or polycrystalline forms.

2. The compound of claim 1, or a stereoisomer, a pharma- ceutically acceptable salt, a solvate or a hydrate thereof, or a crystal or polycrystal thereof: 【Chemistry 2】 In the formula, R ２ has the same definition as in claim 1.

3. (12aR)-7-hydroxy-12-(6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl)-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.1.2), (12aR)-7-hydroxy-12-[(10S)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.2.2), (12aR)-7-hydroxy-12-[(10R)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.3.2), {[(12aR)-12-(6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl)-6,8-dioxo-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl]oxy}methyl methyl carbonate (1.1.4), ({(12aR)-12-[(10S)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]-6,8-dioxo-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.2.4), and ({(12aR)-12-[(10R)-6,7-difluoro-5,10-dihydrothieno[3,2-c][2]benzothiepin-10-yl]-6,8-dioxo-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.3.4), 3. The compound according to claim 1 or 2, or a stereoisomer, a pharma- ceutically acceptable salt, a solvate or a hydrate, or a crystal or polycrystal thereof, wherein the compound is selected from the group consisting of: 【Chemistry 3】 【Chemistry 4】

4. (12aR)-12-[(3,4-difluorophenyl)(phenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-diones of general formula 1.7, (12aR)-12-[(R)-(3,4-difluorophenyl)(phenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-diones of general formula 1.8, and (12aR)-12-[(S)-(3,4-difluorophenyl)(phenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-diones of general formula 1.9, 2. The compound according to claim 1, wherein the compound is selected from the group consisting of: 【Chemistry 8】 In the formula, R ２ has the same definition as in claim 1.

5. (12aR)-7-hydroxy-12-[(3,4-difluorophenyl)(phenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.7.2), (12aR)-7-hydroxy-12-[(R)-(3,4-difluorophenyl)(phenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.8.2), (12aR)-7-hydroxy-12-[(S)-(3,4-difluorophenyl)(phenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.9.2), ({(12aR)-12-[(3,4-difluorophenyl)(phenyl)methyl]-6,8-dioxo-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.7.4), ({(12aR)-12-[(R)-(3,4-difluorophenyl)(phenyl)methyl]-6,8-dioxo-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.8.4), and ({(12aR)-12-[(S)-(3,4-difluorophenyl)(phenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.9.4), 5. The compound according to claim 1 or 4, or a stereoisomer, a pharma- ceutically acceptable salt, a solvate or a hydrate, or a crystal or polycrystal thereof, wherein the compound is selected from the group consisting of: 【Chemistry 9】 【Chemistry 10】

6. (12aR)-12-[(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione of general formula 1.10, (12aR)-12-[(R)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-diones of general formula 1.11, and (12aR)-12-[(S)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione of general formula 1.12, 2. The compound according to claim 1, wherein the compound is selected from the group consisting of: 【Chemistry 11】 In the formula, R ２ has the same definition as in claim 1.

7. (12aR)-7-hydroxy-12-[(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.10.2), (12aR)-7-hydroxy-12-[(R)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.11.2), (12aR)-7-hydroxy-12-[(S)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.12.2), ({(12aR)-12-[(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-6,8-dioxo-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.10.4), ({(12aR)-12-[(R)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-6,8-dioxo-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.11.4), and ({(12aR)-12-[(S)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.12.4), 7. The compound according to claim 1 or 6, or a stereoisomer, a pharma- ceutically acceptable salt, a solvate or a hydrate, or a crystal or polycrystal thereof, wherein the compound is selected from the group consisting of: 【Chemistry 12】 【Chemistry 13】 8. The compound according to claim 1, wherein the compound is (12aR)-12-diphenylmethyl-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione of the general formula 1.

13.

2. The compound of claim 1 , which is: 【Chemistry 14】 In the formula, R ２ has the same definition as in claim 1.

9. The compound comprising: (12aR)-7-Hydroxy-12-diphenylmethyl-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.13.2), or ({(12aR)-12-diphenylmethyl-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.13.4), 9. The compound according to claim 1 or 8, or a stereoisomer, a pharma- ceutically acceptable salt, solvate or hydrate thereof, or a crystal or polycrystal thereof, which is: 【Chemistry 15】 Claim 10: The compound according to claim 1.14, wherein the compound is (12aR)-12-[bis(4-fluorophenyl))methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione of the general formula 1.14, 2. The compound of claim 1 , which is: 【Chemistry 16】 In the formula, R ２ has the same definition as in claim 1.

11. The compound comprising: (12aR)-7-Hydroxy-12-[bis(4-fluorophenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.14.2), or ({(12aR)-12-[bis(4-fluorophenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.14.4), 11. The compound of claim 1 or 10, or a stereoisomer, pharma- ceutically acceptable salt, solvate or hydrate thereof, or a crystalline or polycrystalline form thereof, 【Chemistry 17】

12. 12. An antiviral pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 2 to 11, or a stereoisomer, a pharma- ceutically acceptable salt, solvate or hydrate thereof, or a crystalline or polycrystalline form thereof, and a pharma- ceutically acceptable excipient.

13. (12aR)-7-hydroxy-12-[(3,4-difluorophenyl)(phenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.7.2), (12aR)-7-hydroxy-12-[(R)-(3,4-difluorophenyl)(phenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.8.2), (12aR)-7-hydroxy-12-[(S)-(3,4-difluorophenyl)(phenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.9.2), (12aR)-7-hydroxy-12-[(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.10.2), (12aR)-7-hydroxy-12-[(R)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.11.2), (12aR)-7-hydroxy-12-[(S)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.12.2), (12aR)-7-hydroxy-12-[bis(4-fluorophenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazine-6,8-dione (1.14.2), ({(12aR)-12-[(3,4-difluorophenyl)(phenyl)methyl]-6,8-dioxo-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.7.4), ({(12aR)-12-[(R)-(3,4-difluorophenyl)(phenyl)methyl]-6,8-dioxo-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.8.4), ({(12aR)-12-[(S)-(3,4-difluorophenyl)(phenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.9.4), ({(12aR)-12-[(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-6,8-dioxo-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.10.4), ({(12aR)-12-[(R)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-6,8-dioxo-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.11.4), ({(12aR)-12-[(S)-(3,4-difluorophenyl)(2-methylsulfanylphenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.12.4), ({(12aR)-12-diphenylmethyl-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.13.4), and ({(12aR)-12-[bis(4-fluorophenyl)methyl]-3,4,12,12a-tetrahydro-1H-[1,4]oxazino[3,4-c]pyrido[2,1-f][1,2,4]triazin-7-yl}oxy)methyl methyl carbonate (1.14.4), A compound selected from the group consisting of:

13. The antiviral pharmaceutical composition according to claim 12, comprising a compound selected from the group consisting of:

14. The pharmaceutical composition according to claim 12 for treating and / or preventing a viral disease, wherein the viral disease is influenza.

15. The antiviral pharmaceutical composition according to claim 12 or 13, which is combined with another pharmaceutical agent selected from the group consisting of oseltamivir, zanamivir, peramivir, AV-5080, favipiravir, amantadine, VX-787, MHAA4549A, glypferon, and kagocel.

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