Antiviral 1,3-dioxoindene compounds

Abstract

This disclosure provides 1,3-dioxoindene compounds as described herein, along with pharmaceutically acceptable salts, pharmaceutical compositions containing such compounds, and methods of using these compounds, salts, and compositions to treat viral infections. This disclosure provides novel compounds having antiviral activity in vitro. This disclosure also provides pharmaceutical compositions containing the novel compounds, and methods of using the compounds and compositions to inhibit viral replication or reactivation and to treat disease conditions associated with or caused by viruses.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application asserts the interests under Section 119(e) of U.S. Provisional Application No. 63 / 497,972, filed on 24 April 2023, which is incorporated herein by reference in its entirety.

[0002] (Field of Invention) This disclosure relates to a novel 1,3-dioxoindene compound that is an inhibitor of poliovirus. [Background technology]

[0003] Picornaviruses are non-enveloped, positive-stranded single-stranded RNA viruses with RNA genomes 7.2–8.5 kb long. These viruses are very small and spherical, about 22–30 nm in size, and were first identified a long time ago. Viruses belonging to the Picornaviridae family include rhinoviruses, polioviruses, coxsackievirus A, coxsackievirus B, enteroviruses including echoviruses, and hepatitis A virus.

[0004] Diseases caused by picornaviruses are diverse, ranging from respiratory to digestive, circulatory, and skin diseases. Examples include polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular diseases, hepatitis A, myositis, myocarditis, pancreatitis, diabetes, epidemic myalgia, encephalitis, the common cold, herpangina, and foot-and-mouth disease. However, there are no cures for these diseases. Most drugs under development are descathing inhibitors. Viruses belonging to the Picornaviridae family cause a variety of diseases, including the aforementioned respiratory diseases, which pose sanitary, social, and economic problems. Picornaviruses are the main causative agents of waterborne infectious diseases. Because they are very stable and difficult to disinfect, RNA viruses continuously cause related diseases.

[0005] Human rhinovirus (hRV) has recently been associated with the majority of exacerbations of asthma and is known to be present in the bronchial tissue of many stable asthmatic patients. Comparing each bronchial mucosal biopsy specimen taken from asthmatic and non-asthmatic patients, it has been shown that human rhinovirus is detected at a significantly higher frequency in the lower airways of asthmatic patients than in non-asthmatic patients. A correlation has also been reported between the presence of human rhinovirus and the clinical severity of asthma. Furthermore, rhinovirus causes chronic obstructive pulmonary disease, pneumonia, rhinitis, and otitis media, as well as asthma.

[0006] New treatments and therapies for poliovirus are still needed.

[0007] As a result of intensive and thorough research on effective virus growth inhibitors against picornaviruses including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus, the finding that novel 1,3-dioxoindene derivatives exhibit highly inhibitory activity against picornaviruses including coxsackievirus, enterovirus, echovirus, poliovirus, and rhinovirus has been obtained, leading to the present disclosure.

Summary of the Invention

Means for Solving the Problems

[0008] The present disclosure provides novel compounds having antiviral activity in vitro. The present disclosure also provides pharmaceutical compositions containing the novel compounds, as well as methods of using the compounds and compositions for inhibiting virus replication or reactivation and treating disease states associated with or caused by viruses.

[0009] In one aspect, the present disclosure provides a compound of Table 1, or a pharmaceutically acceptable salt thereof, selected from the following.

Table 1

[0010] In one embodiment, the present disclosure provides compounds from Table 2, or pharmaceutically acceptable salts thereof, selected from the following: [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Modes for carrying out the invention]

[0011] For the purposes of interpreting this specification, the following definitions shall apply, and wherever used in the singular form, the plural form shall also be included.

[0012] The terms used herein have the following meanings unless the context clearly indicates otherwise:

[0013] As used herein, the term “subject” refers to an animal. In certain embodiments, an animal is a mammal. A subject can also refer to, for example, primates (e.g., humans), cattle, sheep, goats, horses, dogs, cats, rabbits, rats, mice, fish, and birds. In certain embodiments, a subject is a human. As used herein, “patient” refers to a human subject. As used herein, a subject “needs” treatment if such a subject would benefit from such treatment in biological, medical, or quality of life.

[0014] As used herein, the terms “inhibit” or “suppress” refer to the reduction or suppression of a given condition, symptom, disorder, or disease, or a significant decrease in the baseline activity of a biological activity or process.

[0015] As used herein, the terms “to treat” or “to cure” any disease or disorder mean, in one embodiment, improving the disease or disorder (i.e., delaying, preventing, or reducing the progression of the disease or at least one of its clinical symptoms). In another embodiment, “to treat” or “to cure” means alleviating or improving at least one physical parameter, including one that may not be recognizable by the patient. In yet another embodiment, “to treat” or “to cure” means modulating the disease or disorder by any means, either physically (e.g., stabilizing recognizable symptoms), physiologically (e.g., stabilizing physical parameters), or both. In yet another embodiment, “to treat” or “to cure” means preventing or delaying the onset, development, or progression of the disease or disorder.

[0016] Where used herein, “a,” “an,” “the,” and similar terms (in particular, in the context of the claims) should be construed to encompass both singular and plural forms unless otherwise specified herein or unless the context clearly contradicts this.

[0017] All methods described herein may be carried out in any preferred order, unless otherwise indicated herein or unless it is clearly inconsistent with the context. The use of any and all examples or exemplary phrases (e.g., "etc.") provided herein is intended solely to clarify the disclosure and not to limit the scope of the claimed disclosure.

[0018] Various embodiments of this disclosure are described herein. It will be understood that features identified in each embodiment may be combined with other specific features to provide further embodiments. The embodiments listed below are representative of this disclosure.

[0019] Embodiment 1. A compound selected from the following or a pharmaceutically acceptable salt thereof. [Table 5]

[0020] Embodiment 2. A compound selected from the following or a pharmaceutically acceptable salt thereof. [Table 4-1] [Table 4-2] [Table 4-3]

[0021] Embodiment 3. The compound is [ka] The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0022] Embodiment 4. The compound is [ka] The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0023] Embodiment 5. The compound is [ka] The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0024] Embodiment 6. The compound is [ka] The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0025] Embodiment 7. The compound is [ka] The compound of Embodiment 1, or a pharmaceutically acceptable salt thereof.

[0026] Embodiment 8. A pharmaceutical composition for preventing or treating a viral disease, comprising a compound described in any one of Embodiments 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or excipient.

[0027] Embodiment 9. A combination comprising a compound described in any one of Embodiments 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in Embodiment 8, and one or more therapeutic agents.

[0028] Embodiment 10. A method for treating a viral disease, comprising administering a therapeutically effective amount of any one of Embodiments 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in Embodiment 8, or the combination described in Embodiment 9, to the target.

[0029] Embodiment 11. Use of any one of the compounds described in Embodiments 1 to 7 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition described in Embodiment 8, or the combination described in Embodiment 9, for the prevention or treatment of a viral disease.

[0030] Embodiment 12. Use of a compound described in any one of Embodiments 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in Embodiment 8, or a combination described in Embodiment 9, for the manufacture of a pharmaceutical for the treatment of a viral disease.

[0031] Embodiment 13. The use of the pharmaceutical composition described in Embodiment 8, or the combination described in Embodiment 9, or the method described in Embodiment 10, or the use described in Embodiment 11 or 12, wherein the viral disease is caused by poliovirus.

[0032] Embodiment 14. The use of the pharmaceutical composition described in Embodiment 8, or the combination described in Embodiment 9, or the method described in Embodiment 10, or the use described in Embodiment 11 or 12, wherein the viral disease is caused by a coxsackievirus.

[0033] Embodiment 15. The use of the pharmaceutical composition described in Embodiment 8, or the combination described in Embodiment 9, or the method described in Embodiment 10, or the use described in Embodiment 11 or 12, wherein the viral disease is caused by an echovirus.

[0034] Embodiment 16. The use of the pharmaceutical composition described in Embodiment 8, or the combination described in Embodiment 9, or the method described in Embodiment 10, or the use described in Embodiment 11 or 12, wherein the viral disease is caused by an enterovirus.

[0035] Embodiment 17. The use of the pharmaceutical composition described in Embodiment 8, or the combination described in Embodiment 9, or the method described in Embodiment 10, or the use described in Embodiment 11 or 12, wherein the viral disease is caused by a rhinovirus.

[0036] Embodiment 18. The use of the pharmaceutical composition described in Embodiment 8, or the combination described in Embodiment 9, or the method described in Embodiment 10, or the use described in Embodiment 11 or 12, wherein the viral disease is caused by a picornavirus.

[0037] Embodiment 19. The use of the pharmaceutical composition according to Embodiment 8, the combination according to Embodiment 9, the method according to Embodiment 10, or the method according to Embodiment 11 or 12, wherein the viral disease is polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

[0038] Another embodiment provides the above-mentioned compound, or a pharmaceutically acceptable salt thereof, as a pharmaceutical.

[0039] The scope also includes the use of the compounds described herein or pharmaceutically acceptable salts thereof for the manufacture of pharmaceuticals for the treatment or prevention of viral diseases and / or infectious diseases in humans.

[0040] The scope includes pharmaceutical compositions comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0041] According to a further embodiment of this model, the pharmaceutical composition further comprises a therapeutically effective amount of at least one other antiviral agent.

[0042] This disclosure also provides the use of the above-described pharmaceutical compositions for treating viral infections or other viruses in humans who have or are at risk of having a viral infection.

[0043] This disclosure also provides the use of the above-described pharmaceutical compositions for treating viral diseases or other viral infections in humans who have or are at risk of having a viral disease.

[0044] Another embodiment relates to a method for treating or preventing viral diseases and / or infections in humans by administering to humans an antivirally effective amount of the compound described herein, a pharmaceutically acceptable salt thereof, or the composition described above, alone, or in combination with at least one other antiviral agent administered together or separately.

[0045] Another aspect relates to a product comprising a composition effective for treating poliovirus disease and / or infection, and packaging material including a label indicating that the composition can be used to treat viral disease and / or infection, wherein the composition comprises a compound described herein by this disclosure or a pharmaceutically acceptable salt thereof.

[0046] An additional embodiment refers to a product comprising a composition effective for treating herpesvirus diseases and / or infections, and packaging material including a label indicating that the composition can be used to treat viral diseases and / or infections, wherein the composition comprises a compound described herein by this disclosure or a pharmaceutically acceptable salt thereof.

[0047] Another aspect relates to a method for inhibiting viral replication, comprising exposing the virus to an effective amount of a compound or salt thereof described herein under conditions that inhibit viral replication. This method can be carried out in vitro or in vivo.

[0048] Furthermore, the use of the compounds or salts thereof described herein for inhibiting viral replication is also included within the scope.

[0049] In one embodiment, a pharmaceutical composition is provided comprising the compound described herein and another therapeutic agent. Optionally, the pharmaceutical composition may include a pharmaceutically acceptable carrier as described above. In some embodiments, the compound described herein is administered together with at least one additional agent selected from those comprising another viral inhibitor.

[0050] These additional agents may be combined with the compounds described herein to create a single pharmaceutical dosage form. Alternatively, these additional agents may be administered separately to the patient as part of multiple dosage forms, for example, using a kit. Such additional agents may be administered to the patient before, concurrently with, or after administration of the compounds described herein or their pharmaceutically acceptable salts.

[0051] The applicable daily dose range for the compounds described herein is typically 0.01 to 100 mg / kg body weight, for example, 0.1 to 50 mg / kg body weight. Each drug dose unit can easily contain 5% to 95% (w / w) of the active compound. Occasionally, such preparations contain 20% to 80% of the active compound.

[0052] The actual pharmacokinetic or therapeutic dose naturally depends on factors known to those skilled in the art, such as the patient's age and weight, route of administration, and severity of the disease. In all cases, the combination is administered in a dosage and manner that allows for the delivery of a pharmacokinetic dose based on the patient's specific condition.

[0053] If a composition described herein includes a combination of a compound described herein with one or more additional therapeutic or prophylactic agents, both the compound and the additional agents should be present at drug dose levels of approximately 10–100%, and sometimes approximately 10–80%, of the drug dose typically administered in a monotherapy regimen.

[0054] Antiviral agents intended for use in such combination therapies include, but are not limited to, agents (compounds or biologics) that are effective in inhibiting the formation and / or replication of viruses in humans, by interfering with either the host or viral mechanism necessary for the formation and / or replication of viruses in humans.

[0055] Many of the compounds described herein contain one or more chiral centers. These compounds may be prepared and used as single isomers or as mixtures of isomers. Methods for separating isomers, including diastereomers and enantiomers, are known in the art, and examples of preferred methods are described herein. In certain embodiments, the compound is used as a single, substantially pure isomer, meaning that at least 90% of the sample of the compound is a specific isomer and less than 10% of the sample is any other isomer or a mixture of isomers. In some embodiments, at least 95% of the sample is a single isomer. Typically, one isomer is more active in the herpesvirus DNA polymerase in vitro assay described herein and becomes the single isomer, so the selection of a preferred isomer is within the range of normal skill levels. If the difference in in vitro activity between isomers is relatively small, e.g., less than about 4 times, the single isomer may be selected based on its activity level for viral replication in cell cultures using methods such as those described herein: e.g., a lower IC 50 or EC 50 You may select an isomer that has the characteristic.

[0056] The compounds described herein may be synthesized by the following general synthetic routes, specific examples of which are described in more detail in the Examples.

[0057] Methods for producing the compounds described herein and intermediates useful for the preparation of the compounds described herein are also provided. Accordingly, this disclosure also includes methods for producing the compounds described herein. This disclosure further includes any variation of the process in which an intermediate product that can be obtained at any stage is used as a starting material and the remaining steps are carried out, or the starting material is formed in situ under reaction conditions, or the reactants are used in the form of their salts or optically pure materials.

[0058] The disclosure also relates to a form of process in which a compound that can be obtained as an intermediate at any stage of the process is used as a starting material and the remaining process steps are carried out, or a form of process in which the starting material is formed under reaction conditions or used in the form of a derivative, such as a protected form or a salt form, or a form of process in which a compound that can be obtained by the process according to the disclosure is produced under process conditions and further processed in situ.

[0059] The terms “optical isomer” or “stereoisomer” refer to any of the various stereoisomer configurations that may exist for a given compound described herein, including geometric isomers. Substituents are understood to be bonded to the chiral center of a carbon atom. The term “chiral” refers to a molecule that possesses non-superimposability with respect to its enantiomer partner, while the term “achiral” refers to a molecule that can be superimposed with respect to its enantiomer partner. Therefore, this disclosure includes enantiomers, diastereomers, or racemates of compounds. “Enantiomers” are a pair of stereoisomers that are mirror images of each other and cannot be superimposed. A 1:1 mixture of a pair of enantiomers is a “racemic” mixture. This term is used as appropriate to refer to racemic mixtures. “Diastereoisomers” are stereoisomers that have at least two chiral atoms but are not mirror images of each other. Absolute stereochemistry is specified according to the Kahn-Ingold-Prelogue RS system. If a compound is a pure enantiomer, the stereochemistry at each chiral carbon may be designated as either R or S. Split compounds whose absolute configuration is unknown may be designated as (+) or (-) depending on the direction in which plane polarization is rotated at the wavelength of the sodium D line (dextrorotatory or levorotatory). Certain compounds described herein may contain one or more chiral centers or axes, and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry.

[0060] Depending on the selection of starting materials and procedures, compounds may exist in one form of one of the possible isomers, or a mixture thereof, depending on the number of chiral carbon atoms, for example, as a pure optical isomer or as an isomer mixture such as a racemic mixture and a mixture of diastereoisomers. This disclosure is intended to include all such possible stereoisomers, including racemic mixtures, diastereomer mixtures, and optically pure forms. Optically active (R)- and (S)-isomers may be prepared using chiral synthons or chiral reagents, or may be divided using prior art. If the compound contains a double bond, the substituent may be in an E configuration or a Z configuration. If the compound contains a disubstituted cycloalkyl, the cycloalkyl substituent may have a cis configuration or a trans configuration. All tautomer forms are also intended to be included.

[0061] Any resulting mixture of isomers can be separated into pure or substantially pure geometric isomers, optical isomers, or diastereomers based on the physicochemical differences of their components, for example, by chromatography and / or fractional crystallization.

[0062] Any resulting racemic product or intermediate can be separated into optical counterparts by known methods, for example, by separating its diastereomer salt obtained using an optically active acid or base and liberating the optically active acidic or basic compound. In particular, the compounds described herein can be separated into their optical counterparts by fractional crystals of salts formed with an optically active acid (e.g., tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-thuloyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid) using a basic moiety. Racemic products can also be separated by chiral chromatography, for example, high-pressure liquid chromatography (HPLC) using a chiral adsorbent.

[0063] Furthermore, the compounds described herein (including their salts) may be obtained in the form of hydrates or may include other solvents used for their crystallization. The compounds described herein may, intrinsically or by design, form solvates with pharmaceutically acceptable solvents (including water). Thus, this disclosure is intended to encompass both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of a compound described herein (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are known to be harmless to recipients, such as water and ethanol, and are commonly used in the pharmaceutical art. The term "hydrate" refers to a complex in which the solvent molecule is water.

[0064] The compounds described herein (including their salts, hydrates, and solvates) may be polymorphic in nature or by design.

[0065] As used herein, the term “salt” refers to an acid-addition or base-addition salt of a compound described herein. “Salt” includes, in particular, “pharmaceutically acceptable salt.” “pharmaceutically acceptable salt” refers to a salt that retains the biological efficacy and properties of a compound described herein and is not typically biologically or otherwise undesirable. In many cases, the compounds described herein can form acidic and / or basic salts in the presence of an amino group and / or a carboxyl group or similar group.

[0066] Pharmacologically acceptable acid addition salts include inorganic and organic acids, such as acetate, aspartate, benzoate, besilate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphor sulfonate, chloride / hydrochloride, chlorotheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, and laurate. It can be formed from lyl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate.

[0067] Examples of inorganic acids that can induce salt formation include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid.

[0068] Examples of organic acids that can induce salt formation include acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, and sulfosalicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.

[0069] Examples of inorganic bases that can be used to derive salts include ammonium salts and metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly preferred salts being ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0070] Examples of organic bases that can derive salts include primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Specific organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0071] The pharmaceutically acceptable salts of the present disclosure can be synthesized from the basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic form of these compounds with a stoichiometric amount of a suitable base (such as Na, Ca, Mg, or K hydroxide, carbonate, or bicarbonate), or by reacting the free basic form of these compounds with a stoichiometric amount of a suitable acid. Such reactions are typically carried out in water, organic solvents, or mixtures thereof. Generally, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is preferred where feasible. A list of additional suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences," 20th edition, Mack Publishing Company (Easton, Pennsylvania, USA, 1985); and "Handbook of Pharmaceutical Salts: Properties, Selection, and Use," Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0072] Any formula shown herein represents an unlabeled form of a compound described herein, as well as up to three atoms having a non-natural isotopic distribution, for example, deuterium or 13 C or 15It is intended to represent an isotopically labeled form having a site where N is concentrated. The isotopically labeled compound has a structure represented by the formula shown herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number other than the naturally occurring mass distribution. Examples of isotopes that can be usefully incorporated in excess into the compounds described herein include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine, such as, respectively, 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl, 125 I. The present disclosure includes various isotopically labeled compounds described herein, such as 3 H and 14 C and other radioactive isotopes, or 2 H and 13 C and other non-radioactive isotopes that are present at levels substantially exceeding the normal isotope distribution. Such isotopically labeled compounds are useful in detection techniques or imaging techniques such as metabolic tests (e.g., with 14 C), kinetic studies (e.g., with 2 H or 3 H), positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including tissue distribution assays of drugs or substrates, or in radiotherapy of patients. In particular, the 1814F-labeled compounds may be particularly desirable for PET or SPECT testing. The isotope-labeled compounds described herein can generally be prepared by processes similar to those described in the accompanying examples and preparations, using conventional techniques known to those skilled in the art, or by using appropriate isotope-labeling reagents instead of typically used unlabeled reagents. Labeled samples may be useful in cases of very low isotope uptake, such as when radiolabeling is used to detect trace amounts of compounds.

[0073] Furthermore, heavier isotopes, especially deuterium (i.e., 2 Broader substitutions with H or D may result in certain therapeutic benefits due to greater metabolic stability, such as extended half-life in vivo, reduced drug dose requirements, or improved therapeutic index. In this context, deuterium is considered a substituent of the compounds described herein, and typically, a sample of a compound having deuterium as a substituent is understood to have at least 50% deuterium incorporation at the labeled position. The concentration of such heavier isotopes, specifically deuterium, may be defined by the isotopic enrichment factor. The term "isotopic enrichment factor," as used herein, means the ratio of the isotopic abundance to the natural abundance of a particular isotope. If the substituent in the compounds described herein is deuterium, such compounds have an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation in each designated deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium incorporation), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6600 (99% deuterium incorporation), or at least 6633.3 (99.5% deuterium incorporation) for each designated deuterium atom.

[0074] The pharmaceutically acceptable solvates according to this disclosure are those in which the solvent for crystallization is isotope-substituted, for example, D2O, d 6 -acetone, d 6 -Includes those that may be DMSO.

[0075] Compounds described herein containing groups capable of acting as hydrogen bond donors and / or acceptors may be capable of forming cocrystals with suitable cocrystal-forming agents. These cocrystals may be prepared from the compounds described herein by known cocrystal-forming procedures. Such procedures include grinding, heating, co-sublimation, co-melting, or contact in solution of the compounds described herein and the cocrystal-forming agent under crystallization conditions, and isolation of the cocrystals formed thereby. Suitable cocrystal-forming agents include those described in International Publication No. 2004 / 078163. Accordingly, this disclosure further provides cocrystals comprising the compounds described herein.

[0076] All methods described herein may be carried out in any preferred order, unless otherwise indicated herein or unless it is clearly inconsistent with the context. The use of any and all examples or exemplary phrases (e.g., "etc.") provided herein is intended solely to clarify the disclosure and not to limit the scope of the claimed disclosure.

[0077] The compounds described herein can be administered by known methods, including oral, parenteral, and inhalation. In certain embodiments, the compounds described herein are administered orally as pills, lozenges, troches, capsules, liquids, or suspensions. In other embodiments, the compounds described herein are administered by injection or infusion. Infusion is typically, often, performed intravenously over a period of about 15 minutes to 4 hours. In other embodiments, the compounds described herein are administered by nasal administration or inhalation. Inhalation is particularly useful for the treatment of respiratory infections. Since the compounds described herein exhibit oral bioavailability, in some embodiments, the compounds can be administered orally.

[0078] The compounds described herein may also be used in combination with other agents (combination partners), such as additional antiviral agents, for the treatment of viral infections in subjects.

[0079] The terms “combination / combination / combination” mean either a fixed combination in a single unit dosage form, a combination as separate dosage forms suitable for use together, either simultaneously or sequentially, or a combination as a kit of components for concomitant administration, in which the compounds and combination partners described herein can be administered independently and simultaneously, or separately, or in any combination thereof, within time intervals that allow the combination partners to exhibit a cooperative (e.g., synergistic) effect.

[0080] In certain embodiments of this disclosure, the compounds described herein are used in combination with a second antiviral agent, such as those named herein.

[0081] A second antiviral agent may be administered in combination with the compounds described herein, in which case the second antiviral agent is administered before, simultaneously with, or after one or more of the compounds described herein. If simultaneous administration of the compounds described herein and the second agent is desired and the route of administration is the same, the compounds described herein may be formulated in the same dosage form as the second agent. Examples of dosage forms containing the compounds described herein and the second agent are tablets or capsules.

[0082] In some embodiments, the combination of the compounds described herein and a second antiviral agent may provide synergistic activity. The compounds described herein and the second antiviral agent may be administered together, separately but simultaneously, or sequentially.

[0083] The “effective amount” of a compound is the amount necessary or sufficient to treat or prevent a viral infection and / or disease or condition described herein. For example, the effective amount of a viral inhibitor compound described herein is sufficient to treat a viral infection in a subject. In another example, the effective amount of an inhibitor is sufficient to treat a viral infection in a subject requiring such treatment. The effective amount may vary depending on factors such as the size and weight of the subject, the type of disease, or the specific compound described herein. For example, the selection of a compound described herein may affect what constitutes the “effective amount.” Those skilled in the art can test the factors described herein and make a determination regarding the effective amount of a compound described herein without excessive experimentation.

[0084] The administration regimen may affect what constitutes the effective dose. The compounds described herein can be administered to subjects either before or after the onset of a viral infection. Furthermore, several divided and staggered dosages may be administered daily or sequentially, or the dose may be administered by continuous infusion or bolus injection. In addition, the dosage of the compounds described herein may be increased or decreased proportionally, as indicated by the urgency of the therapeutic or preventive situation.

[0085] The compounds described herein may be used for the treatment of the conditions, disorders, or diseases described herein, or for the manufacture of pharmaceutical compositions for use in the treatment of these diseases. This disclosure provides methods for using the compounds described herein in the treatment of these diseases, or for preparing pharmaceutical compositions having the compounds described herein for the treatment of these diseases.

[0086] The term "pharmaceutical composition" includes preparations suitable for administration to mammals, such as humans. When a compound described herein is administered pharmacopoeia to a mammal, such as humans, the compound may be given as itself, or as a pharmaceutical composition containing, for example, 0.1 to 99.5% (e.g., 0.5 to 90%) of at least one compound described herein or any subgenus thereof as an active ingredient in combination with a pharmaceutically acceptable carrier or optionally two or more pharmaceutically acceptable carriers.

[0087] The term "pharmaceutically acceptable carrier" is recognized in the art and includes pharmaceutically acceptable materials, compositions, or vehicles suitable for administering the compounds described herein to mammals. The carrier includes liquid or solid fillers, diluents, excipients, solvents, or encapsulating materials and is involved in transporting or delivering the drug of interest from one organ or part of body to another, or to a part of body. Each carrier must be compatible with the other components of the formulation and "acceptable" in the sense that it is not harmful to the patient. Some examples of materials that can function as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose, and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; polyols such as glycerin, sorbitol, mannitol, and polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution, ethyl alcohol; phosphate buffer, and other non-toxic, suitable substances used in pharmaceutical formulations. Typically, pharmaceutically acceptable carriers are sterile and / or substantially free of pyrogens.

[0088] Wetting agents, emulsifiers, and lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colorants, release agents, coating agents, sweeteners, flavoring agents, fragrances, preservatives, and antioxidants, may also be present in the composition.

[0089] Examples of pharmaceutically acceptable antioxidants include: water-soluble antioxidants such as ascorbic acid, cysteine ​​hydrochloride, sodium bisulfate, sodium metabisulfite, and sodium sulfite; oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, and α-tocopherol; and metal chelating agents such as citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, and phosphoric acid.

[0090] The formulations of this disclosure include those suitable for oral, nasal, inhalation, topical, transdermal, oral, sublingual, rectal, vaginal, and / or parenteral administration. The formulations may, for convenience, be presented in unit dosage forms and may be prepared by any method well known in the pharmaceutical field. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces the therapeutic effect. Generally, out of 100 percent, this amount ranges from about 1 percent to about 99 percent, sometimes about 5 percent to about 70 percent, and sometimes about 10 percent to about 30 percent of the active ingredient.

[0091] Methods for preparing these formulations or compositions include the step of associating the compounds described herein with a carrier and optionally one or more minor components. Generally, formulations are prepared by homogeneously and closely associating the compounds described herein with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product.

[0092] Formulations of the present disclosure suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored base, for example, usually sucrose and acacia or tragacanth), powders, granules, or as liquids or suspensions in aqueous or non-aqueous liquids, or as oil-in-water or water-in-oil emulsions, or as elixirs or syrups, or as lozenges (using an inert base such as gelatin and glycerin, or sucrose and acacia), and / or as mouthwashes, each containing a predetermined amount of the compound described herein as an active ingredient. The compound described herein may also be administered as a bolus, lick, or paste.

[0093] In the solid dosage forms of the present disclosure for oral administration (such as capsules, tablets, pills, sugar-coated tablets, powders, and granules), the active ingredient is mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: fillers or bulking agents such as starch, lactose, sucrose, glucose, mannitol, and / or silicic acid; binders such as carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and / or acacia; and glycerol. Wetting agents such as; disintegrants such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; solution retarders such as paraffin; absorption enhancers such as quaternary ammonium compounds; wetting agents such as cetyl alcohol and glycerol monostearate; absorbents such as kaolin and bentonite clay; lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, and mixtures thereof; and colorants. In the case of capsules, tablets, and pills, the pharmaceutical composition may also contain buffers. Similar types of solid compositions may also be used as fillers for soft and hard-filled gelatin capsules, using excipients such as lactose or milk sugar, and high molecular weight polyethylene glycol, etc.

[0094] Tablets may be prepared by compression or molding with one or more optional adjuncts. Compressed tablets may be prepared using binders (e.g., gelatin or hydroxypropyl methylcellulose), lubricants, inert diluents, preservatives, disintegrants (e.g., sodium starch glycolate or cross-linked carboxymethylcellulose sodium), surfactants, or dispersants. Molded tablets may be prepared by molding a mixture of powder compounds moistened with an inert liquid diluent using a suitable machine.

[0095] Tablets, as well as other solid dosage forms of the pharmaceutical compositions of the present invention, such as sugar-coated tablets, capsules, pills, and granules, may optionally be prepared with coatings and shells, such as notches, enteric coatings, and other coatings well known in the field of pharmaceutical formulation. They may also be formulated to provide sustained or controlled release of the active ingredient therein, for example, using various proportions of hydroxypropyl methylcellulose, other polymer matrices, liposomes, and / or microspheres to provide a desired release profile. They may be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating a sterilizer in the form of a sterile solid composition that can be dissolved in sterile water, or by some other sterile injection medium immediately before use. These compositions may also optionally contain an opaque agent, and may optionally release the active ingredient sustainably only in the gastrointestinal tract, or, for example, in a specific part of the gastrointestinal tract. Examples of embedding compositions that may be used include polymer substances and waxes. The active ingredient may also be in microencapsulated form having one or more of the above excipients, as needed.

[0096] Liquid dosage forms for oral administration of the compounds described herein include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredients, the liquid dosage forms may contain, for example, water or other solvents, solubilizers, and emulsifiers, such as inert diluents commonly used in the art, including ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.

[0097] In addition to inert diluents, oral compositions may also contain adjuvants such as humectants, emulsifiers and suspending agents, sweeteners, flavoring agents, colorants, fragrances, and preservatives.

[0098] In addition to the active compound, the suspension may contain a suspending agent, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum methhydroxyoxide, bentonite, agar, and tragacanth, or mixtures thereof.

[0099] Formulations of the pharmaceutical compositions described herein for rectal or vaginal administration may also be presented as suppositories that can be prepared by mixing one or more of the compounds described herein with one or more suitable non-irritating excipients or carriers, for example, cocoa butter, polyethylene glycol, suppository wax, or salicylate, which are solid at room temperature but liquid at body temperature, and therefore melt in the rectum or vaginal cavity to release the active compound.

[0100] Formulations described herein that are suitable for intravaginal administration also include pessaries, tampons, creams, gels, pastes, foams, or sprays containing such carriers, which are known to be suitable in the art.

[0101] Dosage forms for topical or transdermal administration of the compounds described herein include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches, and inhalants. The active compounds may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any preservatives, buffers, or propellants as needed.

[0102] In addition to the active compounds described herein, ointments, pastes, creams, and gels may contain excipients such as animal and vegetable fats, oils, waxes, paraffin, starch, tragacanth, cellulose derivatives, polyethylene glycol, silicone, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0103] The powders and sprays may contain excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicate, and polyamide powder, or mixtures thereof, in addition to the compounds described herein. The sprays may further contain conventional propellants such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons such as butane and propane.

[0104] Transdermal patches have the additional advantage of providing controlled delivery of the compounds described herein into the body. Such dosage forms can be prepared by dissolving or dispersing the compounds in a suitable medium. Absorption enhancers can also be used to increase the flow of the compounds across the skin. The rate of such flow can be controlled by providing a rate-controlling membrane or by dispersing the active compound in a polymer matrix or gel.

[0105] Ophthalmic preparations, eye ointments, powders, and liquids are also conceivable as being within the scope of this disclosure.

[0106] The pharmaceutical compositions described herein, suitable for parenteral administration, may contain one or more compounds described herein in combination with one or more pharmaceutically acceptable carriers, such as sterile isotonic aqueous solutions or nonaqueous solutions, dispersions, suspensions, emulsions, or sterile powders, which can be reconstituted into sterile injectable solutions or dispersions immediately before use, and which may contain antioxidants, buffers, bacteriostatic agents, solutes that make the blood and preparation of the intended recipient isotonic, or suspending agents or thickeners.

[0107] Suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions described herein include water, ethanol, glycol ethers, polyols (e.g., glycerol, propylene glycol, and polyethylene glycol), and suitable mixtures thereof, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, maintaining the required particle size in the case of dispersions, and by the use of surfactants.

[0108] These compositions may also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action can be ensured by including various antimicrobial and antifungal agents, such as parabens, chlorobutanol, and phenolsorbic acid. It may also be desirable to include isotonic agents such as sugars and sodium chloride in the composition. In addition, long-term absorption of injectable pharmaceutical forms can be achieved by including absorption-delaying agents such as aluminum monostearate and gelatin.

[0109] In some cases, it is desirable to delay the absorption of a drug from subcutaneous or intramuscular injection in order to prolong its effects. This can be achieved by using a liquid suspension of a crystalline or amorphous material with poor water solubility. The absorption rate of the drug then depends on its dissolution rate, and subsequently on the crystal size and morphology. Alternatively, delayed absorption of a parenterally administered drug form can be achieved by dissolving or suspending the drug in an oily vehicle.

[0110] Injectable depot formulations are prepared by forming a microcapsule matrix of the target compound in a biodegradable polymer such as polylactide-polyglycolide. The drug release rate can be controlled depending on the drug-to-polymer ratio and the properties of the specific polymer used. Other examples of biodegradable polymers include poly(orthoester) and poly(anhydride). Injectable depot formulations can also be prepared by encapsulating the drug in liposomes or microemulsion formulations compatible with body tissues.

[0111] The preparations described herein may be administered orally, parenterally, topically, or rectally. Naturally, they may be administered in a form suitable for each route of administration. For example, they may be administered by injection, infusion, or inhalation in the form of tablets or capsules, by injection, inhalation, eye drops, ointments, suppositories, etc.; topically as lotions or ointments; and rectally as suppositories.

[0112] As used herein, the terms “parenteral administration” and “administered parenterally” mean a mode of administration other than enteral and topical administration, typically by injection, and include, but are not limited to, injections and infusions into veins, muscles, arteries, thetherosclerotics, capsules, orbits, hearts, skin, abdomen, trachea, subcutaneous, subepidermal, intra-articular, subcapsular, subarachnoid, spinal cord, and substernal regions. Occasionally, intravenous infusion is the method of delivery of the compounds described herein. Infusions may be used to deliver a single daily dose or multiple doses. In some embodiments, the compounds described herein are administered by infusion over intervals of 15 minutes to 4 hours, typically 0.5 to 3 hours. Such infusions may be used once daily, twice daily, or up to three times per day.

[0113] When used herein, the terms “systemic administration,” “administered systemically,” “peripheral administration,” and “administered peripherally” mean the administration of a compound, drug, or other material that enters the patient’s system and is therefore administered in a manner other than directly to the central nervous system, such as through metabolism and other similar processes, such as subcutaneous administration.

[0114] These compounds may be administered to humans and other animals for therapeutic purposes by any preferred route of administration, including orally and nasally, for example by spray, rectally, vaginally, parenterally, intracisionally, and topically, in the form of powder, ointment, or drops (including oral and sublingual).

[0115] Regardless of the selected route of administration, the compounds and / or pharmaceutical compositions described herein, which can be used in a preferred hydrated form, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those skilled in the art.

[0116] The actual drug dose levels of the active ingredients in the pharmaceutical compositions described herein may be modified to obtain an amount of the active ingredient that is effective in achieving the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.

[0117] The selected drug dose level depends on a variety of factors, including the activity of the specific compound used herein, or its ester, salt, or amide; the route of administration; the time of administration; the elimination rate of the specific compound used; the duration of treatment; other drugs, compounds, and / or materials used in combination with the specific compound used; the age, sex, weight, condition, overall health, and prior medical history of the patient being treated; and similar factors well known in the pharmaceutical field.

[0118] A physician or veterinarian with ordinary skills in the art can easily determine and prescribe the effective amount of the required pharmaceutical composition. For example, a physician or veterinarian can start with a dose of the compound described herein used in the pharmaceutical composition at a level lower than necessary to achieve the desired therapeutic effect and to gradually increase the drug dose until the desired effect is achieved.

[0119] In general, the preferred daily dose of the compounds described herein is the amount of the compound that is the minimum effective dose to produce a therapeutic effect. Such an effective dose generally depends on the factors described above. Generally, the intravenous and subcutaneous doses of the compounds described herein for a patient, when used for the specified effect, range from about 0.0001 to about 100 mg / kg (body weight) per day, sometimes from about 0.01 to about 50 mg / kg per day, and sometimes from about 0.1 to about 20 mg / kg per day. An effective dose is the amount that prevents or treats a viral infection.

[0120] If necessary, the effective daily dose of the active compound may be administered in unit dosage form, either as a single daily dose or as two, three, four, five, or six or more secondary doses administered separately at appropriate intervals throughout the day. Compounds delivered orally or by inhalation are generally administered in doses of one to four times per day. Compounds delivered by injection are typically administered once daily or every other day. Compounds delivered by infusion are typically administered in doses of one to three times per day. If multiple doses are administered within a day, the doses may be administered at intervals of approximately four hours, six hours, eight hours, or twelve hours.

[0121] While the compounds described herein may be administered individually, they may also sometimes be administered as part of a pharmaceutical composition as described herein. Therefore, methods of using the compounds described herein include administering the compounds as part of a pharmaceutical composition, wherein at least one of the compounds described herein is mixed with a pharmaceutically acceptable carrier before administration. General synthesis procedure

[0122] The compounds described herein may be synthesized by the following general synthetic routes, specific examples of which are described in more detail in the Examples.

[0123] All starting materials, components, reagents, acids, bases, dehydrating agents, solvents, and catalysts used to synthesize the compounds described herein are either commercially available or can be produced by organic synthesis methods known to those skilled in the art ("Houben-Weyl," 4th edition (1952), "Methods of Organic Synthesis," Thieme, Vol. 21). List of Abbreviations Acetyl HCl ethyl acetate DCM Dichloromethane DEA Diethanolamine DIPEA or DIEA N-ethyldiisopropylamine DMF (N,N-dimethylformamide) DMSO (Dimethyl Sulfoxide) EDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide EtOH Ethanol h time HATU O-(7-azabenzotriazol-1-yl)-N,N,N'N'-tetramethyluronium hexafluorophosphate HOBt hydroxybenzotriazole HPLC (High-Performance Liquid Chromatography) IPA Isopropanol L (liters) LCMS (Liquid Chromatography Mass Spectrometry) mg milligrams min mL (milliliter) Rt retention time THF (Tetrahydrofuran)

[0124] The compounds described herein are prepared from commonly available compounds using procedures known to those skilled in the art, taking into consideration the examples provided herein.

[0125] Within the scope of this specification, only readily removable groups that are not components of specific desired final products of the compounds described herein are referred to as “protecting groups” unless otherwise indicated in the context. The protection of functional groups by such protecting groups, the protecting groups themselves, and their cleavage reactions are discussed in standard references, e.g., "Science of Synthesis: Houben-Weyl Methods of Molecular Transformation," Georg Thieme Verlag (Stuttgart, Germany, 2005), p. 41627 (URL: http: / / www.science-of-synthesis.com (electronic edition, Vol. 48)); JFWMcOmie, "Protective Groups in Organic Chemistry," Plenum Press (London and New York, 1973); TW Greene and PGMWuts, "Protective Groups in Organic Synthesis," 3rd edition, Wiley (New York, 1999); "The Peptides"; Vol. 3 (edited by E. Gross and J. Meienhofer), Academic Press (London and New York, 1981); "Methoden der Organischen Chemie" ("Methoden of Organic Chemistry"), Houben This is described in Weyl, 4th edition, Vol. 15 / I, Georg Thieme Verlag (Stuttgart, 1974), H.-D. Jakubke and H. Jeschkeit, "Amino Acids, Peptides, Proteins," Verlag Chemie (Weinheim, Deerfield Beach, and Basel, 1982), and Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharides and Derivatives," Georg Thieme Verlag (Stuttgart, 1974), among others.A key feature of protecting groups is that they can be easily removed (i.e., without the occurrence of unwanted secondary reactions) by means of solvolysis, reduction, photolysis, or alternatively, under physiological conditions (e.g., enzymatic cleavage).

[0126] Salts of the compounds described herein having at least one salt-forming group can be prepared in known ways. For example, salts of the compounds described herein having an acidic group can be formed by treating the compound with a metal compound such as an alkali metal salt of a suitable organic carboxylic acid, e.g., the sodium salt of 2-ethylhexanoic acid, with an organic alkali metal or alkaline earth metal compound such as a sodium or potassium hydroxide, carbonate, or bicarbonate, e.g., the corresponding hydroxide, carbonate, or bicarbonate, with a calcium compound, or with ammonia or a suitable organic amine, sometimes using a stoichiometric amount or a slightly excess of the salt-forming agent. Acid addition salts of the compounds described herein can be obtained in a conventional way, for example, by treating the compound with an acid or a suitable anion exchange reagent. Intramolecular salts of the compounds described herein containing acidic and basic salt-forming groups, e.g., free carboxyl groups and free amino groups, can be formed, for example, by treatment with a weak base or an ion exchanger, or by neutralization to the isoelectric point of the salt, such as an acid addition salt.

[0127] Salts can be converted to free compounds in a conventional manner, and metal salts and ammonium salts can be converted, for example, by treatment with suitable acids and acid addition salts, or by treatment with suitable basic agents.

[0128] A mixture of isomers that can be obtained in accordance with this disclosure can be separated into individual isomers by known methods only; diastereoisomers can be separated, for example, by liquid-liquid separation, recrystallization, and / or by chromatographic separation on silica gel, for example, or by medium-pressure liquid chromatography on a reversed-phase column; and racemates can be separated, for example, by salt formation with an optically pure salt-forming reagent and separation of the mixture of diastereoisomers thus obtained, for example by fractional crystallization, or by chromatography on an optically active column material.

[0129] Intermediates and final products can be post-processed and / or purified according to standard methods, such as chromatography, partitioning, and (re)crystallization. High-resolution mass spectrometry using LC-MS

[0130] ESI-MS data was recorded using an LTQ-XL Orbitrap mass spectrometer (ThermoFisher Scientific) equipped with an electrospray ionization source. The resolution of the MS system was approximately 30,000. Compounds were injected into the mass spectrometer from the sample probe by UPLC (Acquity, Waters). Separation was performed on an Acquity UPLC BEH C18 1×50 mm column at a flow rate of 0.15 mL / min with a gradient of 5% to 95% over 3 minutes. Solvent A was water containing 0.1% trifluoroacetic acid, and solvent B was 75% methanol and 25% isopropyl alcohol containing 0.1% trifluoroacetic acid. The mass accuracy of the system was found to be less than 5 ppm. [Examples]

[0131] The present disclosure is further illustrated by the following examples, which should not be construed as limiting. The assays used throughout the examples are well established in the art. Demonstrations of efficacy in these assays are generally considered predictive of efficacy in the subject. General synthesis

[0132] The compounds in Tables 1 and 2 were prepared, or may be prepared, using appropriate starting materials and reagents, according to the procedure described below in Scheme I, where R 1 and R 2 These terms are defined independently in this specification and in the compounds described in the following examples. Further information relating to the synthesis, including intermediates, reagents, or methods, can be found in WO2021 / 214080, which is incorporated herein by reference. Scheme I [ka]

[0133] Step 1: Dissolve compound I-2 (e.g., 1.2 equivalents) in a solvent (e.g., DMF, 0.1 M) and cool the solution to 0°C. Add EDCI (e.g., 1.5 equivalents) and HOBt (e.g., 1.5 equivalents) at 0°C. Stir at 0°C for 10 minutes, then add compound I-1 (e.g., 1.0 equivalent) and DIPEA (e.g., 2.5 equivalents). Stir the solution overnight at 25°C (e.g., 16 hours). Add H2O and extract with EA. Wash the organic layer with brine, dry over anhydrous Na2SO4, concentrate under vacuum, and purify by silica gel column chromatography to obtain compound I-3.

[0134] Step 2: Dissolve compound I-3 (e.g., 1 equivalent) in EtOH:H2O (e.g., 0.03 M, 10:1). Add Fe (e.g., 3 equivalents) and HCl (e.g., 1 drop) to the solution. Heat the solution at 90°C for 3 hours and cool to room temperature. Evaporate the reaction mixture under vacuum. Dilute the crude product with ethyl acetate and filter through a Celite pad. Evaporate the solution under vacuum and purify by silica gel column chromatography to obtain the desired product.

[0135] Additional information relating to the synthesis, including intermediates, reagents, or methods for preparing the compound of formula I-1 for use in Scheme I, can be found in WO2021 / 214080 and US20140114068, which are incorporated herein by reference. One such method is shown below in Scheme II, where R 1 This is defined in the compounds described herein and in the following examples. Scheme II [ka]

[0136] Step 1: Compound II-1 is reacted with compound II-2 in acetic acid to obtain compound II-3.

[0137] Step 2: Compound II-3 is reacted with oxalyl chloride in a solvent (e.g., DMF (10 parts by volume), DCM / DMF) at a high temperature (e.g., 40°C) to obtain compound II-4.

[0138] Step 3: Compound II-4 is reacted with NH3 in IPA (e.g., 2M) in a solvent (e.g., THF) at -40°C to 0°C for 2 hours to obtain compound I-1.

[0139] Suitable starting materials and reagents can be purchased or prepared by methods known to those skilled in the art. After each reaction is complete, each intermediate or final compound can be recovered and optionally purified by conventional techniques such as neutralization, extraction, precipitation, chromatography, and filtration.

[0140] The compounds in Table 1 were prepared and characterized using appropriate starting materials and reagents, following procedures similar to those described above or procedures known in the art. Example 1: N-((4bR,9bR)-1-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide [ka]

[0141] Example 1 was prepared according to the general synthesis and scheme I described above, using (4bR,9bR)-9b-amino-7-((R)-1-cyclopropylethyl)-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one and 5-(methylsulfonyl)-1H-pyrrole-2-carboxylic acid as compound I-1 and compound I-2, respectively, and according to the general synthesis and scheme II described above, using (R)-3-(1-cyclopropylethyl)phenol as compound II-2. The compounds were further purified by chiral HPLC under the following conditions (injection volume: 2 μL, column: CHIRALPAK AD-3 (0.46 × 5 cm, 3 μm), mobile phase: hexane (0.1% DEA):EtOH (50:50), flow rate: 1.0 mL / min, wavelength: 256 nm) to obtain the title compound (Rt = 5.7 min).

[0142] LCMS-ESI + (m / z):C 26 H 26 N3O6S's [M+H] + Calculated value: 508.15, Measured value: 507.9. Example 2: N-(1-amino-7-((1R,2S)-1,2-dimethylcyclopropyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide [ka]

[0143] Example 2 was prepared using 9b-amino-7-(1R,2S)-1,2-dimethylcyclopropyl)-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one and 5-(methylsulfonyl)-1H-pyrrole-2-carboxylic acid as compound I-1 and compound I-2, respectively, according to the general synthesis and schemes I and II described above, and using 3-((1R,2S)-1,2-dimethylcyclopropyl)phenol as compound II-2, according to the general synthesis and scheme II described above.

[0144] LCMS-ESI + (m / z):C 26 H 26 N3O6S's [M+H] + Calculated value: 508.15, Measured value: 507.9. Example 3: N-(1-amino-7-((1R,2S)-1,2-dimethylcyclopropyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxamide [ka]

[0145] Example 3 was prepared using 9b-amino-7-(1R,2S)-1,2-dimethylcyclopropyl)-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one and 1,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazole-4-carboxylic acid as compound I-1 and compound I-2, respectively, according to the general synthesis and schemes I and II described above, and using 3-((1R,2S)-1,2-dimethylcyclopropyl)phenol as compound II-2, according to the general synthesis and scheme II described above.

[0146] LCMS-ESI + (m / z):C 26 H27 N4O5's [M+H] + Calculated value: 475.20, Measured value: 474.9. Example 4: N-(1-amino-7-((1R,2S)-1,2-dimethylcyclopropyl)-4b-hydroxy-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-6-hydroxypicolinamide [ka]

[0147] Example 4 was prepared using 9b-amino-7-(1R,2S)-1,2-dimethylcyclopropyl)-4b-hydroxy-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one and 6-hydroxypicolinic acid as compound I-1 and compound I-2, respectively, according to the general synthesis and schemes I and II described above, and using 3-((1R,2S)-1,2-dimethylcyclopropyl)phenol as compound II-2, according to the general synthesis and scheme II described above.

[0148] LCMS-ESI + (m / z):C 26 H 24 N3O5's [M+H] + Calculated value: 458.17, Measured value: 457.9. Example 5: N-((4bR,9bR)-1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide [ka]

[0149] 5-(methylsulfonyl)-1H-pyrrole-2-carboxylic acid (227 mg, 1.2 mmol) was dissolved in DMF (10 mL, 0.1 M). The solution was cooled to 0°C. EDCI (288 mg, 1.5 mmol) and HOBt (203 mg, 1.5 mmol) were added at 0°C. After stirring at 0°C for 10 minutes, 9b-amino-4b-hydroxy-7-isopropyl-4-nitro-4b,9b-dihydro-10H-indeno[1,2-b]benzofuran-10-one (340 mg, 1.0 mmol) and DIPEA (0.44 mL, 2.5 mmol) were added. The solution was stirred at 25°C for 16 hours. H2O was added and the solution was extracted with EA. The organic layer was washed with brine, dried over anhydrous sodium 2SO4, concentrated under vacuum, and purified by silica gel column chromatography to obtain N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide.

[0150] N-(4b-hydroxy-7-isopropyl-4-nitro-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide (149 mg, 0.29 mmol) was dissolved in EtOH:H2O (10 mL, 0.03 M, 10:1). Fe (49 mg, 0.90 mmol) and one drop of HCl were added to the solution. The solution was heated at 90°C for 3 hours and then cooled to room temperature. The reaction mixture was evaporated under vacuum. The crude product was diluted with ELISA and filtered through a Celite pad. The solution was evaporated under vacuum and purified by silica gel column chromatography to obtain a racemic mixture, which was separated by SFC (using an AS column; flow rate 5 mL / min, CO2 / MeOH = 80:20; SFC-X5; C2_A20; Rt = 1.68 min and 3.28 min) to obtain N-((4bR,9bR)-1-amino-4b-hydroxy-7-isopropyl-10-oxo-4b,10-dihydro-9bH-indeno[1,2-b]benzofuran-9b-yl)-5-(methylsulfonyl)-1H-pyrrole-2-carboxamide.

[0151] LCMS-ESI + (m / z):C 24 H 24 N3O6S's [M+H] + Calculated value: 482.14, Measured value: 481.9.

[0152] 1 H-NMR: (300MHz-MeOD) δ value: 7.46(t,J=7.7Hz,1H), 7.39(d,J=7.5Hz,1H), 7.02(d,J=7.3Hz,1H), 6.82(d,J=3.9Hz,1H), 6.87(d,J=7 .8Hz,1H), 6.79(d,J=3.9Hz,1H), 6.74(d,J=7.3Hz,1H), 6.68(s,1H), 3.14(s,3H), 2.84(hept,J=7.0Hz,1H), 1.19(d,J=6.9Hz,6H) Biochemical assay Biochemical Example 1: Determination of drug efficacy against picornavirus using a cytopathic effect (CPE) inhibition assay.

[0153] The biological activity of the compounds described herein can be determined by the following method.

[0154] This assay can use HeLa (human cervical cancer cells), MRC-5 (human fetal lung fibroblasts), and RD cells (derived from human rhabdomyosarcoma). For comparison, ribavirin (Riv), preconalil (pleco), and BTA-798 (BTA) are used as controls. The reagents can be dissolved in 100% dimethyl sulfoxide (DMSO) at a concentration of 10-40 mg / mL. The water-soluble reagents can be dissolved in PBS(-) solution and stored at -20°C. On the day of the experiment, they can be used at 3-5 times the concentration so that the dimethyl sulfoxide concentration in each well is 0.5-1%.

[0155] The pharmaceutically effective drug is determined using a virus-induced cytopathic effect (CPE) inhibition assay. For this purpose, virus-suitable cells are grown in a 96-well plate. A virus dilution in DME (DME / 2%FBS) or MEM (MEM / 2%FBS) supplemented with 2%FBS is then inoculated into each well of the plate at a concentration equivalent to 100 CCID50 (50% cell culture infectious dose) in a 100:1 ratio. The cells are incubated at 33°C or 37°C for 30 minutes to 1 hour to allow the virus to adsorb to the cells. After removing the culture medium, aliquots of various drug dilutions are added to each well in 100 μL volumes. Human rhinovirus (HRV) is grown at 33°C, while other viruses are incubated in a CO2 incubator at 37°C for 2-3 days. Alternatively, 50 μL of each drug dilution at twice the concentration is added, followed by 50 μL of the virus dilution, after which the cells are cultured for 2-3 days without removing the medium. The virus is incubated in host HeLa cells at 37°C for 2-3 days in DME / 2% or MEM / 2% FBS.

[0156] In HeLa cells, the MTT assay is used to determine the drug concentration that induces an intermediate response between baseline and maximum, which is called the EC (Energy Control). 50 The drug is measured at the (50% maximum effective concentration). In RD and MRC-5 cells, CPE is determined using FDA (fluorescein diacetate) or MTT. Simulated infection is included at the time of viral inoculation to determine the effect of drug toxicity on efficacy outcomes. A virus-free medium is added to the cell culture and then subjected to the same treatment as the virus-inoculated simulated infected cells. That is, after 1 hour of incubation, the medium is removed and a diluted drug solution in the medium is added again. After incubation for 2-3 days, cells are observed under a microscope and the number of surviving cells in the drug-containing simulated infected well is compared to the number of surviving cells in the drug-free control well. 50% of the cells are killed using the MTT assay. 50The drug is measured at the (50% cytotoxic concentration). In the FDA hydrolysis assay, after removing the culture medium, the FDA is added to each well and incubated for 20-30 minutes. The fluorescence intensity is then measured using a spectrofluorometer to determine the CPE, similar to the MTT. That is, the viability (% viability) of simulated infected cells for cytotoxicity measurement was calculated using the following formula 1: Cellular drug = Survival × [A (drug) - A (background solution) / A (cell control) - A (background × 100% solution)]

[0157] 100% cell viability means that the drug has no cytotoxicity, but the highest level of cytotoxicity is reflected by 0% cell viability. A 50% cytotoxic concentration is defined as the concentration required to reduce cell number by 50%. This drug concentration is calculated using CC. 50 It is expressed as follows. A higher value means lower cytotoxicity.

[0158] Furthermore, the antiviral effect can be calculated using the following formula 2. Antiviral effect = [A (drug / virus) - A (virus control) / A (cell control) - A (virus control)]

[0159] If the survival rate is 100%, the antiviral effect is 100%, but if the survival rate is 0%, the antiviral effect is absent. The concentration of the drug that allows cells in a virus-infected well to show a 50% survival rate is EC. 50 It is calculated as follows, and the lower this value, the better the antiviral effect.

[0160] Table 1 below shows LCs that exhibit cytotoxicity to compounds in several examples. 50 The concentration of EC, and the activity against numerous rhinoviruses belonging to the Picornavirus family. 50 List the concentrations. Determination of drug efficacy against picornaviruses using a multicycle cytopathic effect (CPE) reduction assay.

[0161] The drug efficacy against picornaviruses will be determined using a multi-cycle CPE reduction assay. First, the antiviral activity of the compound will be determined by a CPE reduction assay based on MIS[3-(4,5-dimethylthiazole-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium].

[0162] Specifically, cells grown in a 96-well plate until confluence were measured to obtain a 50% cell culture infectious dose (CCID). 50 ) is infected with 100 viruses. After an adsorption period of 2 hours at 37°C, the viruses are removed and serial dilutions of the compound are added. The culture is incubated for a further 3 days at 37°C until complete CPE is observed in the infected and untreated virus controls (VC). After removing the medium, 90 μL of culture medium and 10 μL of MTS-phenazine methosulfate (Promega, Leiden, Netherlands) are added to each well. After an incubation period of 2 hours at 37°C, the optical density (OD) of each well is read at 498 nm using a microplate reader.

[0163] The %CPE value used to evaluate antiviral activity is calculated using the following formula 3. %CPE = 100 × [OD(CC) - OD(virus + compound) / OD(CC) - OD(VC)]

[0164] The %CPE value for measuring the cytotoxicity of a drug was calculated using the following formula 4: %CPE = 100 × [OD(CC) - OD(virus + compound) / OD(CC) - OD(blank)]

[0165] In formulas 3 and 4 above, OD(CC) represents the OD of background cell cultures that are not induced by viruses and are not treated with chemicals. OD(VC) represents the OD of a control cell culture that was induced by a virus but not treated with chemicals. OD (virus + compound) represents the OD of a cell culture infected with a virus treated with a concentrated compound. OD (compound) represents the OD of cell cultures treated with concentrated compounds only. OD (Blank) represents the OD of a well to which only cell culture material has been added.

[0166] Effective concentration (EC 50 ) represents the concentration of a drug at which 50% of cells can survive due to CPE of the induced virus, and the cytotoxic concentration (CC) 50 The values ​​represent the concentration of the drug that killed 50% of the cells, and these were calculated using logarithmic interpolation. Biochemical Example 2: In vitro poliovirus type 1 (POV1) antiviral assay

[0167] The in vitro antiviral activity of compounds against poliovirus type 1 (POV-1; Mahoney strain) was tested using Vero 76 cells. The test medium was MEM supplemented with 2% FBS and 50 μg / mL gentamicin.

[0168] The compound was dissolved in DMSO. The compound was serially diluted in test medium using eight semi-logarithmic dilutions, resulting in a starting (high) test concentration of 50 μM. Each dilution was added to 5 wells of a 96-well plate containing 80–100% confluent cells. Three wells of each dilution were infected with the virus, and two wells were left uninfected as a toxicity control. Six wells were infected and left untreated as a virus control, and six wells were left uninfected and untreated as a cell control. The virus was prepared to achieve an MOI of 0.002. Enviroxime was tested in parallel as a positive control. The plates were incubated at 37±2°C and 5% CO2. On day 3 post-infection, when the untreated virus control wells reached maximum CPE, the plates were stained with neutral red dye for approximately 2 hours (±15 minutes). The dye was removed from the supernatant, the wells were washed with PBS, and the incorporated dye was hyperextracted for 30 minutes in 50:50 Sorensen citrate buffer / ethanol, and the optical density was read at 540 nm using a spectrophotometer. The optical density was converted to a percentage of the cell control and normalized to a viral control, and then the concentration of the test compound required to inhibit CPE by 50% (EC50) was calculated by regression analysis. The concentration of the compound that would cause 50% cell death in the absence of the virus (CC50) was similarly calculated. The selection index (SI) was used to divide CC50 by EC50. 50 It is the result of dividing by .

[0169] Table 3 shows the in vitro antiviral results against vaccinia virus. [Table 3]

[0170] As shown in Table 3 above, the compounds according to this disclosure exhibit antiviral activity against poliovirus-1 (POV1).

Claims

1. A compound selected from the following or a pharmaceutically acceptable salt thereof: 【Chemistry 13】

2. A compound selected from the following or a pharmaceutically acceptable salt thereof: Table 6-1 Table 6-2 Table 6-3

3. The aforementioned compound, 【Chemistry 14】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. The aforementioned compound, 【Chemistry 15】 The compound of claim 1 or a pharmaceutically acceptable salt thereof.

5. The aforementioned compound, 【Chemistry 16】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. The aforementioned compound, 【Chemistry 17】 The compound of claim 1 or a pharmaceutically acceptable salt thereof.

7. The aforementioned compound, [Chemistry 18] The compound of claim 1 or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition for preventing or treating a viral disease, comprising a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable diluent or excipient.

9. A combination comprising a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, and one or more therapeutic agents.

10. A method for treating a viral disease, comprising administering a therapeutically effective amount of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, or a combination according to claim 9, to a target.

11. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, or a combination according to claim 9, for the prevention or treatment of a viral disease.

12. Use of a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 8, or a combination according to claim 9, for the manufacture of a pharmaceutical for the prevention or treatment of a viral disease.

13. The pharmaceutical composition according to claim 8, or the combination according to claim 9, or the method according to claim 10, or the use according to claim 11 or 12, wherein the viral disease is caused by poliovirus.

14. The pharmaceutical composition according to claim 8, or the combination according to claim 9, or the method according to claim 10, or the use according to claim 11 or 12, wherein the viral disease is caused by a coxsackievirus.

15. The pharmaceutical composition according to claim 8, or the combination according to claim 9, or the method according to claim 10, or the use according to claim 11 or 12, wherein the viral disease is caused by an echovirus.

16. The pharmaceutical composition according to claim 8, or the combination according to claim 9, or the method according to claim 10, or the use according to claim 11 or 12, wherein the viral disease is caused by an enterovirus.

17. The pharmaceutical composition according to claim 8, or the combination according to claim 9, or the method according to claim 10, or the use according to claim 11 or 12, wherein the viral disease is caused by a rhinovirus.

18. The pharmaceutical composition according to claim 8, or the combination according to claim 9, or the method according to claim 10, or the use according to claim 11 or 12, wherein the viral disease is caused by a picornavirus.

19. The pharmaceutical composition according to claim 8, or the combination according to claim 9, or the method according to claim 10, or the use according to claim 11 or 12, wherein the viral disease is polio, paralysis, acute hemorrhagic conjunctivitis, viral meningitis, hand-foot-and-mouth disease, vesicular disease, hepatitis A, myositis, myocarditis, pancreatitis, diabetes mellitus, epidemic myalgia, encephalitis, influenza, herpangina, foot-and-mouth disease, asthma, chronic obstructive pulmonary disease, pneumonia, sinusitis, or otitis media.

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