Compounds for the prevention and treatment of viral diseases

Abstract

This invention relates to novel therapeutic uses of 1H-cyclopenta[b]benzofuran derivatives, specifically, for the treatment or prevention of viral infections or diseases associated with viral infections, and / or for use as a viral inhibitor. Furthermore, this invention relates to methods for the treatment or prevention of viral infections or diseases associated with viral infections. Moreover, this invention relates to pharmaceutical compositions for use in the treatment or prevention of viral infections or diseases associated with viral infections.

Description

[Technical Field]

[0001] This invention relates to novel therapeutic uses of 1H-cyclopenta[b]benzofuran derivatives, specifically novel uses for the treatment or prevention of viral infections or diseases associated with viral infections, and / or for use as a viral inhibitor. The invention further relates to methods for treating or preventing diseases associated with viral infections. Furthermore, the invention relates to pharmaceutical compositions for use in the treatment or prevention of diseases associated with viral infections. Background of the Invention

[0002] Viral infections pose a major challenge to public health systems worldwide. Despite rapid scientific advancements in virology, effective treatments and vaccines for most viral infections remain scarce and a significant problem. Emerging viral diseases pose a major threat, primarily due to their rapid spread and the inherent difficulty of developing effective vaccines and treatments for such new pathogens in a short timeframe. Therefore, there is a need to develop broad-spectrum antiviral compounds effective against multiple viruses. Most antiviral agents currently available target one or more components directly related to the viral life cycle. Consequently, their effects tend to be limited, often to closely related viruses within the same viral family. Certain nucleoside analogs, including cidofovir, favipiravir, and ribavirin, have been shown to be effective against a wide range of viruses, but they carry a significant risk of developing antiviral resistance, primarily against RNA viruses.

[0003] Viruses are infectious organic structures that spread outside of cells as virions through transmission, but can only replicate inside suitable host cells. Viruses themselves are not composed of one or more cells. All viruses contain a program for replication and spread (some also contain other auxiliary components), but they do not replicate independently or have their own metabolism; they are therefore dependent on the host cell's metabolism. Viruses attach to the surface molecules of host cells and introduce their genetic material there. This penetrates the cell nucleus and modifies the cell's own DNA. The viral body (genome and proteins) sometimes replicates extensively within the infected cell via existing organelles.

[0004] Extracellular viral particles are called virions. Virions are particles containing nucleic acid (either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA)) and are usually encased in a protein capsule (capsid). However, influenza viruses lack a capsule and instead have ribonucleoproteins. Some virions have an envelope formed by a biological membrane. Viral membrane proteins are scattered within the lipid bilayer of the biological membrane. This is called the viral envelope. Virions that temporarily possess a viral envelope in addition to the capsid until the replication stage begins are called enveloped viruses, while viruses that do not have such an envelope are called unenveloped viruses.

[0005] In R. Madhugiri et al., Advances in Virus Research, Vol.96, 2016, p. 127, RNA synthesis in coronaviruses is summarized, and the structural and functional characteristics of known cis-acting RNA elements in the 5' and 3' untranslated regions (UTRs) are discussed.

[0006] Previous studies have shown that silvesterol (CAS 697235-38-4), a flavaglin derivative, acts as a potent and selective inhibitor of the RNA helicase enzyme eIF4A and possesses broad-spectrum antiviral activity against diseases such as Ebola and coronavirus. Silvesterol has been difficult to synthesize due to its cyclopentabenzofuran ring. Therefore, several modified synthetic flavaglins have been designed and successfully used, at least in in vitro preclinical studies. Several studies have already demonstrated that silvesterol possesses broad-spectrum antiviral activity against coronaviruses, SARS, and MERS viruses (C. Muller et al., Antiviral Research 150, 2018, 123).

[0007] Wintachai et al., Microbiol Immunol., 2015, 59, 129-141, evaluates flavagrin, particularly FL3 and FL23, as an inhibitor of chikungunya virus.

[0008] Similar studies have been conducted on other eIF4A inhibitors. R. Cencic et al., J. Virology, 2011, 6381, describe how the compound 4E2Rcat (432499-63-3), an inhibitor of the eIF4E-eIF4G interaction, can inhibit coronavirus replication.

[0009] E. Gordon et al., bioRxiv (March 22, 2020), are exploring knowledge about the molecular details of SARS-CoV-2 infection. For this purpose, viral proteins were cloned, tagged, and expressed within human cells. Furthermore, 66 drug-mockable human proteins or host factors, particularly zotatifine (eFT226), have been identified that are targeted by 69 existing FDA-approved drugs, drugs in clinical trials, and / or preclinical compounds. The efficacy of these compounds has been evaluated using live SARS-CoV-2 infection assays.

[0010] eFFECTOR's Therapeutic (April 30, 2020) reported that the antitumor drug zotatifine showed antiviral activity against SARS-CoV-2.

[0011] However, there remains a strong demand for compounds that exhibit broad-spectrum antiviral properties.

[0012] Therefore, the object of the present invention is to provide a pharmaceutically active compound that has inhibitory activity against viral activity. [Overview of the Initiative]

[0013] The present invention provides for the use of compounds of formula (I) for the treatment or prevention of viral infections or diseases associated with viral infections. With respect to JPEG2026512831000001.jpg5365, its prodrug or isotope concentrate, or pharmaceutically acceptable salts or solvates thereof, in the formula, R 1 It is selected from CN and hydrogen, R 2 It is selected from hydrogen and halogens.

[0014] In particular, the present invention relates to a compound of formula (I) for use in the treatment or prevention of viral infections or diseases associated with viral infections, and / or as a viral inhibitor. JPEG2026512831000002.jpg5365, With respect to the prodrug or isotopic concentrate thereof, or pharmaceutically acceptable salts or solvates thereof, in the formula, R 1 It is selected from CN and hydrogen, R 2 It is selected from hydrogen and halogens. Infections or diseases are selected from viral infections caused by positive single-stranded positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA).

[0015] The present invention further relates to a compound of formula (I) as defined above and below, for use as a virus inhibitor.

[0016] The present invention further relates to compounds of formula (Ia) or (Ib), enantiomer mixtures comprising compounds of formula (Ia) and (Ib), or prodrugs or isotopic concentrates thereof, or pharmaceutically acceptable salts or solvates thereof, for use in the treatment or prevention of viral infections or diseases associated with viral infections, in particular, selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA). JPEG2026512831000003.jpg53133In formula, R 1 and R 2 This has the same meaning as defined above and below.

[0017] The present invention further relates to compounds of formula (Ia) or (Ib), or enantiomer mixtures comprising compounds of formula (Ia) and (Ib), or prodrugs or isotopic concentrates thereof, or pharmaceutically acceptable salts or solvates thereof, for use as virus inhibitors. JPEG2026512831000004.jpg53133In formula, R 1 and R 2 This has the same meaning as defined above and below.

[0018] The present invention further relates to a method for treating or preventing a viral infection or viral infection-related disease as defined above and below, and includes administering a therapeutically effective amount of at least one compound selected from the compounds of formula (I), (Ia), (Ib), enantiomer mixtures comprising the compounds of formula (Ia) and (Ib), or their prodrugs or isotope-enriched forms as defined herein, or their pharmaceutically acceptable salts or solvates.

[0019] The present invention further relates to a pharmaceutical composition for use in the treatment or prevention of viral infections or viral infection-related diseases, comprising a pharmaceutically effective amount of at least one compound selected from the compounds of formula (I), (I.a), (I.b) as defined herein, a mixture of enantiomers comprising the compounds of formula (I.a) and (I.b), or a prodrug or isotopically enriched form thereof, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers.

[0020] The present invention further relates to a pharmaceutical composition for use as a viral inhibitor, comprising a pharmaceutically effective amount of at least one compound selected from the compounds of formula (I), (I.a), (I.b) as defined herein, a mixture of enantiomers comprising the compounds of formula (I.a) and (I.b), or a prodrug or isotopically enriched form thereof, or a pharmaceutically acceptable salt or solvate thereof, and one or more pharmaceutically acceptable carriers. Description of the Invention

[0021] The present invention has the following advantages. - The compounds of the present invention exhibit excellent viral inhibitory effects. (+) ssRNA viruses such as coronaviruses and picornaviruses utilize host 5'-cap-dependent and cap-independent strategies for the translation initiation of viral mRNA. - Some viruses utilize cell membrane-associated prohibitin for entry into host cells. The present invention provides a group of molecules that target both PHB and the eIF4A complex in the cell membrane, thereby inhibiting viral entry and replication. Compound of formula (I)

[0022] Unless otherwise specifically stated herein, when described in the singular, the plural is also included. For example, "a" and "an" may refer to one or more than one.

[0023] The expression "halogen" in each case indicates fluorine, chlorine, bromine or iodine, preferably fluorine.

[0024] The term "solvate" refers to a complex formed when the compound of the present invention coordinates with a solvent molecule in a specific ratio. In particular, a solvate is a "hydrate," which means a complex formed when the compound of the present invention coordinates with water.

[0025] Compounds of formulas (I), (Ia), (Ib), (A), (B), and mixtures of their enantiomers can form salts. These are also included within the scope of the present invention. As used herein, the term “salt” means an acidic salt and / or basic salt formed with an inorganic acid and / or organic acid and a base. Pharmaceutically acceptable salts (i.e., non-toxic and physiologically acceptable salts) are preferred, but other salts are also useful and can be used, for example, in isolation or purification steps during preparation. Salts of compounds of formulas (I), (Ia), (Ib), (A), (B), and mixtures of their enantiomers can be formed, for example, by reacting a compound of formula (I), (Ia), (Ib), (A), (B), or a mixture of their enantiomers with at least one acid or base. The acid or base is added in an amount suitable for partial or complete neutralization, for example, an equivalent amount.

[0026] As used herein, the term “pharmaceutically acceptable salt” includes, unless otherwise specified, salts containing pharmacologically acceptable anions or cations, such as chlorides, bromides, iodides, nitrates, sulfates, bisulfates, phosphates, hydrogen phosphates, dihydrogen phosphates, isonicotinates, acetates, lactates, salicylates, citrates, acid citrates, tartrates, pantothenates, hydrogen tartrates, ascorbic acid, succinates, maleates, gentisinates, fumarates, glucons, glucarons, saccharates, formates, benzoates, glutamates, methanesulfons, ethanesulfons, sulfates, benzenesulfons, p-toluenesulfons, and palmates [i.e., 4,4'-methylene-bis-(3-hydroxy-2-naphthoate)].

[0027] All compounds according to the present invention can be prepared and used in the form of prodrugs. A suitable prodrug has a chemically or metabolically cleavable group and becomes a pharmacologically active compound in vivo by solvation or under physiological conditions. Prodrugs can be formed by conventional methods by the reaction of the functional group (amino group, hydroxyl group, or carboxyl group, etc.) of the compound. Prodrugs often offer advantages such as improved metabolism, potency, solubility, histocompatibility, or delayed release in mammals.

[0028] The term "prodrug" refers to a pharmaceutically acceptable metabolic precursor of the compound of the present invention. While a prodrug may be inactive when administered to a subject requiring it, it is converted in vivo to the active compound of the present invention. Typically, prodrugs are rapidly converted in vivo to the parent compound of the present invention, for example, by hydrolysis in the blood.

[0029] In other words, in this invention, the term "prodrug" refers to a compound that is metabolized in vivo to form the compound of formula (I) of the present invention. Typical examples of prodrugs are described, for example, in "The Practice of Medicinal Chemistry" by C.G. Wermeth (ed.), Academic Press, San Diego, 1996, pp. 671-715, and in "NATURE REVIEWS, Drug Discovery," Vol. 17, 2018, p. 559, by J. Rautio et al. Examples include phosphates, carbonates, carbamates, amino acids, esters (carboxylic acid esters), ethers, amides, peptides, and urea. In this case, a suitable prodrug may be the compound of formula (I). The hydroxyl group in the formula is attached to any group that, when the prodrug of the compound of the present invention is administered to a mammal, is cleaved to form a free hydroxyl group.

[0030] The terms "viral infection" and "viral disease" refer to the process by which viruses invade, establish themselves in, and multiply within a living organism. The resulting illness is a viral infection.

[0031] The term "disease associated with viral infection" refers to a disease caused by viral infection. The associated diseases are preferably selected from pulmonary inflammation, dyspnea, pulmonary fibrosis, pneumonia, cytokine storm, acute liver injury, septic shock, acute kidney injury, pancreatic injury, peripheral nervous system complications (such as taste disorder, olfactory disorder, visual disorder, etc.), myalgia, myocardial inflammation, venous thrombosis, reduced blood flow in the coronary artery, cardiogenic shock, heart failure, disturbance of consciousness, cerebral inflammation, inflammation and swelling of the brain and blood vessels, acute cerebrovascular complications (such as stroke, seizure, convulsion, etc.), arrhythmia, myocarditis, thrombotic events, rhabdomyolysis, neurocognitive disorder, cancer, and sensory and motor disorders.

[0032] In the present invention, a chemical structure that does not explicitly indicate a specific stereochemical orientation generally means all possible stereoisomers and mixtures thereof, unless otherwise specified. For example, JPEG2026512831000005.jpg4465 (where * indicates a chiral center).

[0033] A "chiral compound" in the meaning of the present invention is a compound that does not contain an improper axis of rotation (S n ). In the context of the present invention, they are, in particular, compounds having at least four asymmetric centers and having no S n symmetry.

[0034] In the context of the present invention, a "stereoisomer" is a compound having the same structure but a different atomic arrangement in three-dimensional space.

[0035] An "enantiomer" is a stereoisomer that behaves such that the images are mirror images of each other. For example, the compounds of formula (I.a) and (I.b) are enantiomers. The "enantiomeric excess" (ee) achieved in asymmetric synthesis is given herein by ee[%]=(R - S) / (R + S)×100. R and S are descriptors of the CIP system of two enantiomers and describe the absolute configuration on the chiral atom. An enantiomerically pure compound (ee = 100%) is also called a "homochiral compound".

[0036] "Diastereomers" are stereoisomers that are not enantiomers of each other.

[0037] The compounds of the present invention may exist in the form of one or more tautomers, including various isomeric forms, as well as both single tautomers and mixtures of tautomers. The term "isomer" is intended to encompass all isomeric forms of the compounds of the present invention, including the tautomeric forms of the compounds.

[0038] Some of the compounds described herein may have a chiral center and therefore exist in the form of different enantiomers and diastereomers. The compounds of the present invention may take the form of optical isomers or diastereomers. Accordingly, the present invention encompasses the optical isomers, diastereomers and mixtures thereof, including racemic mixtures of the compounds of the present invention described herein, and their uses. Optical isomers of the compounds of the present invention may be obtained by known techniques such as asymmetric synthesis and chiral chromatography, or by chemical separation of stereoisomers using optically active separation agents.

[0039] Unless otherwise specified, “stereoisomer” means one stereoisomer of a compound that substantially does not contain any other stereoisomers of that compound. Thus, a stereoisomerically pure compound having one chiral center will substantially not contain any opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will substantially not contain any other diastereomers of the compound. A typical stereoisomerically pure compound contains more than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, for example, more than about 90% by weight of one stereoisomer of the compound and less than about 10% by weight of other stereoisomers of the compound, or more than about 95% by weight of one stereoisomer of the compound and less than about 5% by weight of other stereoisomers of the compound, or more than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound.

[0040] A "stereoisomer" refers to a compound consisting of the same atoms that are bonded together by the same bonds but have incompatible and different three-dimensional structures. This invention aims to introduce various stereoisomers and mixtures thereof, and therefore includes "enantiomers," which refer to two stereoisomers that are mirror images of each other and whose molecules cannot be superimposed.

[0041] The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more chiral centers, and therefore may result in enantiomers, diastereomers, and other stereoisomers, which, from an absolute stereochemical standpoint, can be defined as (R)- or (S)- or (D)- or (L)- in the case of amino acids. The present invention means to include all such possible isomers, as well as their racemates and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or they may be separated using conventional techniques, such as chromatography and fractionation crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from suitable optically pure precursors, or separation of racemates (or racemates of salts or derivatives) using, for example, chiral high-pressure liquid chromatography.

[0042] In stereochemistry (relative stereochemistry), relative configuration refers to the arrangement of an atom or group of atoms relative to other atoms or groups of atoms within a molecule. In other words, this term describes the position of an atom or group of atoms in space relative to other atoms or groups of atoms located elsewhere within the molecule.

[0043] In stereochemistry (absolute stereochemistry), absolute configuration is an arrangement of atoms or groups of atoms that is described independently of any other atoms or groups of atoms in a molecule. This type of configuration is defined for chiral molecular entities and their stereochemical descriptions (e.g., R or S).

[0044] Syn means that, with respect to the orientation of the substituents on the bonded five-membered ring (the four chiral carbon atoms), all substituents are oriented in the same direction with respect to the plane of the five-membered ring.

[0045] A racemic mixture or racemic compound is defined as a mixture of compounds consisting of two molecules that are present in equimolar amounts, i.e., in a 1:1 (50:50) ratio, such that their structures are like an image and its mirror image (= enantiomer).

[0046] Furthermore, the compound of formula (I) JPEG2026512831000006.jpg4569 (where * indicates a chiral center) represents the isomers of formulas (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), and (Ip): JPEG2026512831000007.jpg217134JPEG2026512831000008.jpg211135Here, R 1 and R 2 This has either the meaning defined above or below.

[0047] Compounds of formulas (Ia) to (Ip) are identified by their absolute stereochemistry.

[0048] In preferred embodiments, the compound of formula (I) is a mixture of at least two enantiomers (Ia) to (Ip), or a mixture of their prodrugs or isotopic concentrates, or a mixture of their pharmaceutically acceptable salts or solvates, in which case one of the enantiomers is concentrated.

[0049] Preferably, the compound of formula (I) is a mixture of (Ia) and (Ib), or a mixture of pharmaceutically acceptable salts thereof, in which case the enantiomer excess (ee) of the enantiomer of formula (Ia) is at least 20%, preferably at least 50%, particularly at least 80%, and especially at least 99%.

[0050] Preferably, R 1 The present invention relates to a compound of formula (I), a prodrug or isotope concentrate thereof, or a pharmaceutically acceptable salt thereof, wherein CN is CN.

[0051] Furthermore, R 1 CN is R 2 Preferably, the compound of formula (I) of the present invention, or its prodrug or isotopic concentrate, or a pharmaceutically acceptable salt thereof, is selected from hydrogen and F.

[0052] Furthermore, R 2 Preferably, the compound of formula (I) of the present invention, or its prodrug or isotopic concentrate, or a pharmaceutically acceptable salt thereof, is hydrogen.

[0053] Furthermore, R 2 A compound of formula (I) of the present invention, or its prodrug, or a pharmaceutically acceptable salt or solvate thereof, is preferred, wherein F is the most common component.

[0054] Another special embodiment is R 1 and R 2 This is a compound of formula (I) selected from the definitions shown in the first row of Table 1. Table 1: JPEG2026512831000009.jpg23148

[0055] Another special embodiment is a compound selected from A and B, and a mixture of each of compounds A through B and their corresponding enantiomers. JPEG2026512831000010.jpg51125

[0056] Preferably, the compound of formula (A), or a mixture of enantiomers including the compound of formula (A) and its enantiomers, in particular, the enantiomer excess (ee) of the enantiomer of formula (A) is at least 20%, preferably at least 50%, particularly at least 80%, and especially at least 99%.

[0057] Preferably, the compound of formula (B), or a mixture of enantiomers including the compound of formula (B) and its enantiomers, in particular, the enantiomer excess (ee) of the enantiomer of formula (B) is at least 20%, preferably at least 50%, particularly at least 80%, and especially at least 99%.

[0058] Compound A is particularly preferred.

[0059] Compound B is particularly preferred.

[0060] The compounds of the present invention can be synthesized using methods known in the prior art, methods known in organic synthesis chemistry, or variations thereof that will be understood by those skilled in the art.

[0061] virus The present invention provides compounds of formula (I), (Ia), or (Ib), or enantiomer mixtures thereof, as well as pharmaceutically acceptable salts thereof ("Compounds of the Invention"), for use in the treatment or prevention of viral infections or diseases associated with viral infections, as defined herein. The present invention provides compounds of formula (I), (Ia), or (Ib), or enantiomer mixtures thereof, as defined herein, for use as virus inhibitors, and pharmaceutically acceptable salts thereof ("Compounds of the Invention"). Preferably, the disease or infection is selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA).

[0062] (+)ssRNA viruses are a group of related viruses that possess a positive single-strand genome made of ribonucleic acid. This positive genome can function as messenger RNA (mRNA) and can also be directly translated into viral proteins by the ribosomes of the host cell. Positive ssRNA viruses encode RNA-dependent RNA polymerase (RdRp), which is used during genome replication to synthesize a negative ssRNA antigenome. This antigenome is then used as a template to create a new positive ssRNA viral genome.

[0063] In particular, (+)ssRNA viruses belong to families selected from the Togaviridae, Flaviviridae, Coronaviridae, and Retroviridae families.

[0064] The Togaviridae family is a family of enveloped, positively charged single-stranded RNA viruses. It currently includes two genera of enveloped viruses with positively charged single-stranded RNA: the Alphavirus and the Rubellavirus. Alphaviruses transmit disease to humans and animals via insects. Rubella viruses are transmitted only between humans via the respiratory system.

[0065] The Flaviviridae family is a family of enveloped, positive-stranded RNA viruses that primarily infect mammals and birds. These viruses are mainly spread through arthropods (primarily ticks and mosquitoes). The Flaviviridae family includes virus species of the genera Hepacivirus and Flavivirus. Diseases associated with this group include hepatitis, dengue fever, Japanese encephalitis, Kyasanur forest disease, Poissant virus, West Nile fever, yellow fever, and Zika fever.

[0066] Coronavirus is the common name for the families Coronaviridae and Orthocoronaviruses, also known as the Coronavirinae subfamily. The Coronaviridae family is a family of enveloped, positive-stranded RNA viruses. Coronaviruses cause disease in mammals and birds. In humans, the virus causes respiratory infections.

[0067] The Coronaviridae family includes alphacoronaviruses, betacoronaviruses, and virus species of the genus Torovirus. Preferably, the Coronaviridae family is selected from SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-NL63, HCoVC43, and HKU1.

[0068] Of the human coronaviruses, four generally cause mild cold-like symptoms, but the following three are known to cause more serious illnesses and can be fatal: SARS-CoV-1, which causes SARS; MERS-CoV, which causes MERS; and SARS-CoV-2, which causes COVID-19.

[0069] Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1 or SARS-CoV) is a type of coronavirus that causes severe acute respiratory syndrome (SARS). It often causes a serious illness, initially characterized by systemic symptoms such as muscle pain, headache, and fever, followed by respiratory symptoms, mainly cough, shortness of breath, and pneumonia, over a period of 2 to 14 days. Another finding commonly seen in SARS patients is a decrease in the number of lymphocytes circulating in the blood. SARS-CoV is a member of the genus Betacoronavirus and subgenus Embecovirus.

[0070] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a type of coronavirus that causes COVID-19, a respiratory illness. SARS-CoV-2 is a virus of the severe acute respiratory syndrome-associated coronavirus (SARSr-CoV) species, related to the SARS-CoV-1 virus. SARS-CoV-2 is a member of the genus Betacoronavirus and subgenus Embecovirus.

[0071] Middle East Respiratory Syndrome-associated coronavirus (MERS-CoV) is a virus that causes Middle East Respiratory Syndrome (MERS). It is a type of coronavirus that infects humans, bats, and camels. This species is a member of the genus Betacoronavirus and subgenus Merbecovirus.

[0072] Human coronavirus 229E (HCoV-229E) is a type of coronavirus that infects humans and bats. It is one of the viruses that cause the common cold. HCoV-229E is a member of the genus Alphacoronavirus and the subgenus Dubinacovirus.

[0073] Human coronavirus NL63 (HCoV-NL63) is a type of coronavirus, specifically a cetrachovirus belonging to the genus Alphacoronavirus. Infection with this virus has been confirmed worldwide and is associated with many common symptoms and diseases. Associated diseases include mild to moderate upper respiratory tract infections, severe lower respiratory tract infections, croup, and bronchiolitis.

[0074] Human coronavirus OC43 (HCoV-OC43) is a member of the betacoronavirus genus that infects humans and cattle. OC43 is one of seven coronaviruses known to infect humans. It is one of the viruses that cause the common cold. It is a member of the genus Betacoronavirus and subgenus Embecovirus.

[0075] Human coronavirus HKU1 (HCoV-HKU1) is a type of coronavirus found in humans and animals. It causes upper respiratory tract illnesses with cold-like symptoms, but can progress to pneumonia and bronchiolitis. HCoV-HKU1 is a member of the genus Betacoronavirus and subgenus Embecovirus.

[0076] The retroviridae family is a family of enveloped, positive-strand RNA viruses. The retroviridae family includes, in particular, the genera deltoretrovirus and lentivirus. Lentiviruses cause chronic and fatal diseases in humans and other mammalian species, characterized by long incubation periods. This genus includes the human immunodeficiency virus (HIV), which causes AIDS.

[0077] (-)ssRNA viruses are a group of related viruses that possess a negative single-strand genome made of ribonucleic acid. They have a genome that functions as a complementary strand from which messenger RNA (mRNA) is synthesized by the viral enzyme RNA-dependent RNA polymerase (RdRp). During viral genome replication, RdRp synthesizes a positive antigenome and uses it as a template to create the genome-negative strand RNA. (-)ssRNA viruses share several other common characteristics, and most contain a viral envelope surrounding the capsid that encloses the viral genome. The genomes of (-)ssRNA viruses are typically linear, and their genomes are generally segmented.

[0078] Preferably, the (-)ssRNA virus is a member of the families selected from the Arenaviridae, Bornaviridae, Buniviridae, Filoviridae, Othymyxoviridae, Paramyxoviridae, Pneumoviridae, and Rhabdoviridae, particularly the Filoviridae.

[0079] Preferably, the filoviridae family is selected from Bundibugyo Ebola virus, Reston Ebola virus, Sudan Ebola virus, Thai Forest Ebola virus, Zaire Ebola virus, and Bombari Ebola virus.

[0080] As defined above, positive single-chain RNA viruses ((+)ssRNA) and negative single-chain RNA viruses ((-)ssRNA) comprise the majority of known viruses, including many pathogens and clinically less severe pathogens such as rhinoviruses that cause the common cold. Therefore, in one embodiment, the disease is a disease associated with positive single-chain RNA viruses ((+)ssRNA) and negative single-chain RNA viruses ((-)ssRNA).

[0081] In a preferred embodiment, the infectious disease or illness is selected from dengue fever, MERS, COVID-19, SARS, Ebola, AIDS, and Zika fever.

[0082] Diseases associated with positive and negative single-chain RNA virus infections include a variety of resulting complications. These complications include dyspnea, pulmonary fibrosis, pneumonia, cytokine storms, acute liver injury, septic shock, acute kidney injury, pancreatic disorders, peripheral nervous system complications (such as taste disorders, olfactory disorders, and visual impairments), myalgia, myocardial inflammation, venous thrombosis, decreased coronary blood flow, cardiogenic shock, heart failure, impaired consciousness, brain inflammation, inflammation and swelling of the brain and blood vessels, acute cerebrovascular complications (such as stroke, seizures, and slurred speech), arrhythmias, myocarditis, thrombotic events, rhabdomyolysis, neurocognitive disorders, and sensory and motor impairments. This invention encompasses complications caused by SARS-CoV-2 infection.

[0083] In one embodiment, the disease is inflammation of the lungs. Preferably, the inflammation of the lungs is caused by a pathogenic infection, bacterial infection, fungal infection, or viral infection, particularly (+) ssRNA viral infection. More preferably, the inflammation of the lungs is caused by a disease selected from the group consisting of pneumonia, acute respiratory disease symptoms (ARDS), CORD, asthma, idiopathic pulmonary fibrosis, allergic rhinitis, rhinitis, and sinusitis. More preferably, the inflammation of the lungs is caused by CORD, asthma, or idiopathic pulmonary fibrosis. Even more preferably, the inflammation of the lungs is caused by CORD. Even more preferably, the inflammation of the lungs is caused by asthma. Even more preferably, the inflammation of the lungs is caused by idiopathic pulmonary fibrosis.

[0084] In one embodiment, the compounds of the present invention are used to treat or prevent hyperinflammation associated with positive single-stranded RNA virus infections, particularly coronavirus infections. Preferably, the compounds of the present invention reduce hyperinflammation associated with coronavirus infections.

[0085] In this specification, the term “pharmaceutically acceptable” is used to mean a compound, material, composition, and / or dosage form that is suitable for use in contact with human or animal tissues, within the bounds of sound medical judgment, without causing excessive toxicity, irritation, allergic reactions, or other problems or complications, and that is commensurate with a reasonable benefit / risk ratio.

[0086] The term "therapeutically effective" refers to the amount of each drug that can achieve the goal of improving disease severity and incidence while avoiding the harmful side effects typically associated with alternative therapies. For example, an effective anticancer drug may extend a patient's survival or improve their quality of life, inhibit rapid cell proliferation associated with neoplasms, or cause neoplasm regression.

[0087] As used herein, the terms “to treat,” “in treatment,” and “treatment” refer to any type of intervention or process performed on or involving the administration of an activator to a subject for the purpose of reversing, mitigating, improving, inhibiting, delaying, or preventing the progression, onset, severity, or recurrence of symptoms, complications, conditions, or biochemical signs associated with the disease. In contrast, “prevention” or “prevention” refers to administration to a subject who does not have the disease in order to prevent the onset of the disease.

[0088] As used herein, the term “cell” means in vitro, ex vivo, or in vivo cell. In the sense of the present invention, ex vivo cells may be part of a tissue sample excised from an organism such as a mammal. In the sense of the present invention, in vitro cells may be cells in cell culture. In the sense of the present invention, in vivo cells are living cells in an organism such as a mammal.

[0089] The term "patient" includes humans and animals receiving either therapeutic or preventive treatment.

[0090] The term "subject" includes any human or animal. For example, the methods and compositions disclosed herein may be used to treat a subject having cancer.

[0091] (Non-human) animals include all vertebrates, including mammals and non-mammals such as cattle, sheep, pigs, goats, horses, poultry, dogs, cats, non-human primates, and rodents. In one embodiment, the subject is a human subject.

[0092] As used herein, the term “formulationally acceptable carrier” means a formulationally acceptable material, composition, or medium, such as a liquid or solid diluent, solvent, excipient, manufacturing aid (e.g., lubricant), or encapsulating material, that is involved in transporting or transferring the compound of interest from one organ or part of body to another. Any carrier must be “acceptable” in the sense that it is compatible with the other components of the formulation.

[0093] Other suitable components include the carriers mentioned above, as well as further additives such as auxiliaries, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, bittering agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispensing agents, etc. Suitable additives are selected according to the nature of the dosage form and formulation and are not harmful to the patient.

[0094] The term "pharmaceutical composition" means a composition comprising the compound of the present invention in combination with at least one further compound selected from the following. a) at least one further pharmaceutically active substance, and b) at least one additional formulation-permissible carrier and / or additive

[0095] When used for therapeutic purposes, at least one compound of formula (I), (Ia), or (Ib), or a mixture of enantiomers as defined above, or a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutically acceptable carrier, is administered as a pharmaceutical composition. The present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I), (Ia), or (Ib), or a mixture of enantiomers as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

[0096] The compounds of the present invention may be administered by any convenient method, such as orally, parenterally, buccally, sublingually, nasally, rectally, intrathecally, or transdermally, or by inhalation (e.g., local administration to the lungs by inhalation). The pharmaceutical composition may be adapted accordingly.

[0097] Compounds of formula (I) that become active when administered orally can be formulated as liquids or solids, such as syrups, suspensions, emulsions, tablets, capsules, or lozenges.

[0098] Liquid formulations typically consist of a suspension or solution of an active ingredient in a suitable liquid carrier, such as an aqueous solvent like water, ethanol, or glycerin, or a non-aqueous solvent like polyethylene glycol or oil. The formulation may also contain suspending agents, preservatives, fragrances, and / or colorants.

[0099] The tablet-form composition can be prepared using any suitable pharmaceutical carrier commonly used in the preparation of solid dosage forms, such as magnesium stearate, starch, lactose, sucrose, and cellulose.

[0100] Compositions in capsule form can be prepared using standard encapsulation procedures; for example, pellets containing the active ingredient can be prepared using a standard carrier and then filled into rigid gelatin capsules; or a dispersion or suspension can be prepared using any suitable pharmaceutical carrier such as aqueous gum, cellulose, silicate, or oil, and then the dispersion or suspension can be filled into flexible gelatin capsules.

[0101] Typical parenteral compositions consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or a parenterally acceptable oil (such as polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil, or sesame oil). Alternatively, the solution may be optimized and reconstituted with a suitable solvent immediately before administration.

[0102] Compositions for nasal administration or inhalation (e.g., local administration to the lungs by inhalation) can be conveniently formulated as aerosols, infusions, gels, or powders. Aerosol formulations typically consist of a solution or fine suspension of the active ingredient in a phytochemically acceptable aqueous or non-aqueous solvent and are usually supplied sterile in single or multiple doses in a sealed container that can take the form of a cartridge or refill for use in a spray device. Alternatively, the sealed container may be a disposable administration device such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve suitable for delivering the aerosol to the nasal cavity or bronchi. When the administration form includes an aerosol dispenser, it may contain a compressed gas (such as air) or an organic propellant such as a fluorochlorohydrocarbon or hydrofluorocarbon. Aerosol administration forms may also take the form of a pump atomizer.

[0103] Local administration to the lungs can also be achieved by using a dry powder formulation containing the compound of the present invention in a finely divided form with one or more carriers or other excipients. The dry powder formulation is usually delivered using a dry powder inhaler (DPI).

[0104] Compositions suitable for oral or sublingual administration include tablets, lozenges, and troches in which the active ingredient is combined with sugar and a carrier such as acacia, tragacanth, or gelatin and glycerin.

[0105] For convenience, compositions for rectal administration are in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0106] Compositions suitable for transdermal administration include ointments, gels, and patches. In one embodiment, the composition is in the form of a unit dose, such as a tablet, capsule, or ampoule.

[0107] In one embodiment of the present invention, a compound of formula (I), (Ia), or (Ib), or a mixture of enantiomers as defined above, is used in combination with a further therapeutic agent. When at least one of the compounds of formula (I), (Ia), or (Ib), or the mixture of enantiomers as defined above, is used in combination with other therapeutic agents, the compounds of formula (I), (Ia), or (Ib), or the mixture of enantiomers as defined above, can be administered sequentially or simultaneously by any convenient route. Alternatively, these compounds can be administered separately.

[0108] The present invention will be further described with reference to the following embodiments, but its scope will not be limited to the specific embodiments described. The present invention includes any combination of the described features and, in particular, preferred features that are not mutually exclusive. [Brief explanation of the drawing]

[0109] Figure 1: mRNA from the dual reporter assay is shown. Firefly luciferase (F Luc) is translated by the eIF4F complex, while sea urchin luciferase (R Luc) is translated independently of the complex.

[0110] Figure 2: Shows the 5'UTR sequence of viral mRNA.

[0111] Figure 3: Dual luciferase assay for cap-dependent translation initiation A: Plasmid MAP of the dual luciferase assay system. B: Dual luciferase assay for cap-dependent translational initiation was performed in HeLa cells transfected with the pFR_HCV_xb-based dual luciferase reporter gene. Cells were treated with compound A (200 nM) in serum-free DMEM medium for 24 hours. After incubation, the dual luciferase reporter assay was performed according to the manufacturer's instructions, and luminescence was measured using a multiplate reader. Data were normalized to cells transfected with the indicated variant and exposed to DMSO for 24 hours. DMSO-treated cells were set to 1. Bars represent the mean ± standard error obtained from three independent experiments. (EV corresponds to empty vector) Dual luciferase assay

[0112] Hela cells were cultured in DMEM (10% heat-inactivated FBS, 1 mM sodium pyruvate) and placed in a 6-well cell culture plate in a 1x10⁶ format. 6 Cells were seeded in 2 ml of growth medium at a cell / ml concentration. 2 μg of plasmid was transfected into the cells with 0.5 mM PEI reagent in 200 μl of PBS. The day after transfection, the cells were harvested and seeded onto half the area of ​​a 96-well white plate (Greiner). One day later, the medium was replaced with serum-free DMEM, and the cells were incubated with the compound for 24 hours. The Dual-Glo luciferase assay was performed according to the manufacturer's instructions (Promega, N2920). Luminescence was measured using Tecan Infinite (Tecan).

[0113] example Compound A is compound Regarding JPEG2026512831000011.jpg4961.

Claims

1. Compounds of formula (I) for use in the treatment or prevention of viral infections or diseases associated with viral infections, and / or for use as virus inhibitors. 、 The prodrug or isotopic concentrate thereof, or a pharmaceutically acceptable salt or solvate thereof: R 1 It is selected from CN and hydrogen, R 2 It is selected from hydrogen and halogens. The aforementioned infection or disease is selected from viral infections caused by positive single-stranded RNA viruses ((+) ssRNA) and negative single-stranded RNA viruses ((-) ssRNA).

2. A compound of formula (I) for use in the treatment or prevention of viral infections or diseases associated with viral infections, , its prodrug or isotopic concentrate, or its pharmaceutically acceptable salt or solvate: R 1 It is selected from CN and hydrogen, R 2 It is selected from hydrogen and halogens.

3. A compound of formula (I) according to claim 1 or 2, for use as a virus inhibitor.

4. A compound of formula (I) for use in the treatment or prevention of viral infections or diseases associated with viral infections, and / or for use as a virus inhibitor, as described in any one of claims 1 to 3: The compound of formula (I) is selected from the compound of formula (Ia) or (Ib), or enantiomer mixtures containing the compounds of formula (Ia) and (Ib), their prodrugs or isotopic concentrates, or their pharmaceutically acceptable salts or solvates. In the formula, R 1 and R 2 This has the same meaning as defined in claim 1.

5. A compound of formula (I) for use in the treatment or prevention of a viral infection or a disease associated with a viral infection as described in any one of claims 1 to 4, and / or for use as a virus inhibitor: The compound of formula (I) is a mixture of (Ia) and (Ib), a prodrug or isotopic concentrate thereof, or a pharmaceutically acceptable salt or solvate thereof, wherein the enantiomer excess (ee) of the enantiomer of formula (Ia) is at least 20%, preferably at least 50%, particularly at least 80%, and especially at least 99%.

6. A compound of formula (I), formula (Ia), or formula (Ib), or a mixture of enantiomers comprising compounds of formula (Ia) and (Ib), or a prodrug or isotope-enriched form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a viral infection or a disease associated with a viral infection, and / or as a viral inhibitor, as described in any one of claims 1 to 5: In the formula, R 1 It is CN.

7. A compound of formula (I), formula (Ia), or formula (Ib), or a mixture of enantiomers comprising compounds of formula (Ia) and (Ib), or a prodrug or isotope-enriched form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a viral infection or a disease associated with a viral infection, and / or as a viral inhibitor, as described in any one of claims 1 to 6: In the formula, R 2 This is selected from hydrogen and F.

8. A compound of formula (I), formula (Ia), or formula (Ib), or an enantiomer mixture containing compounds of formula (Ia) and (Ib), or a prodrug or isotope concentrate thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a viral infection or a disease associated with a viral infection as described in any one of claims 1 to 7, and / or for use as a viral inhibitor: The compound according to any one of claims 1 to 7 is selected from compounds of formulas A and B, and mixtures of each of compounds A to B and their respective enantiomers.

9. A compound of formula (I), formula (Ia), or formula (Ib), or a mixture of enantiomers comprising compounds of formula (Ia) and (Ib), or a prodrug or isotope-enriched form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a viral infection or a disease associated with a viral infection, and / or as a viral inhibitor, as described in any one of claims 1 to 8: The compound according to any one of claims 1 to 8 is selected from compound A and a mixture of compound A and its respective enantiomers.

10. A compound of formula (I), formula (Ia), or (Ib), or an enantiomer mixture comprising a compound of formula (Ia) and (Ib), or a prodrug or isotope-enriched form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a viral infection or a disease associated with a viral infection, and / or as a viral inhibitor, as described in any one of claims 1 to 9: (+) ssRNA viruses are members of families selected from the Togaviridae, Flaviviridae, Coronaviridae, and Retroviridae families.

11. A compound of formula (I), formula (Ia), or formula (Ib), or a mixture of enantiomers comprising compounds of formula (Ia) and (Ib), or a prodrug or isotope-enriched form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a viral infection or a disease associated with a viral infection, and / or as a viral inhibitor, as described in any one of claims 1 to 9: (-)ssRNA viruses are members of families selected from the Arenaviridae, Bornaviridae, Bunyviridae, Filoviridae, Othymyxoviridae, Paramyxoviridae, Pneumoviridae, and Rhabdoviridae families, with a particular emphasis on the Filoviridae family.

12. A compound of formula (I), formula (Ia), or formula (Ib), or a mixture of enantiomers comprising compounds of formula (Ia) and (Ib), or a prodrug or isotope-enriched form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a viral infection or a disease associated with a viral infection, and / or as a viral inhibitor, as described in any one of claims 1 to 10: The Flaviviridae family is selected from dengue virus, Japanese encephalitis virus, Kyasanur forest disease, Pawassan virus, West Nile virus, yellow fever virus, and Zika virus.

13. A compound of formula (I), formula (Ia), or formula (Ib), or an enantiomer mixture containing compounds of formula (Ia) and (Ib), or a prodrug or isotopic concentrate thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a viral infection or a disease associated with a viral infection, as described in any one of claims 1 to 10: The Coronavirus family is selected from SARS-coV, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-NL63, HCoV-C43, and HKU1.

14. A compound of formula (I), formula (Ia), or formula (Ib), or an enantiomer mixture containing compounds of formula (Ia) and (Ib), or a prodrug or isotope concentrate thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a viral infection or a disease associated with a viral infection, and / or as an inhibitor of a virus, as described in any one of claims 1 to 10: The retroviridae family is selected from HIV-1 and HIV-2.

15. A compound of formula (I), formula (Ia), or formula (Ib), or a mixture of enantiomers comprising compounds of formula (Ia) and (Ib), or a prodrug or isotope-enriched form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a viral infection or a disease associated with a viral infection, and / or as an inhibitor of a virus, as described in any one of claims 1 to 9 and 11: The Filoviridae family is selected from Bundibugyo Ebola virus, Reston Ebola virus, Sudan Ebola virus, Thai Forest Ebola virus, Zaire Ebola virus, and Bombari Ebola virus.

16. A compound of formula (I), formula (Ia), or formula (Ib), or a mixture of enantiomers comprising compounds of formula (Ia) and (Ib), or a prodrug or isotope-enriched form thereof, or a pharmaceutically acceptable salt or solvate thereof, for use in the treatment or prevention of a viral infection or a disease associated with a viral infection, and / or as a viral inhibitor, as described in any one of claims 1 to 10 and 12 to 14: The disease or infection will be selected from dengue fever, MERS, COVID-19, SARS, Ebola, AIDS, and Zika fever.

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