Compounds for the treatment and prevention of viral diseases.

Abstract

The present invention relates to new therapeutic uses of 1H-Cyclopenta[b]benzofuran derivatives, specifically new uses for the treatment or prevention of viral infections or a disease associated with viral infections and / or for use as inhibitor of viruses. The invention further relates to a method of treatment or prevention of viral infections or diseases associated with viral infections. Moreover, the invention relates to a pharmaceutical composition for use in the treatment or prevention of viral infections or diseases associated with viral infections.

Description

1 / 29 Compounds for the treatment and prevention of viral diseases.

[0001] The present invention relates to novel therapeutic uses of 1H-Cyclopenta[b]benzofuran derivatives, specifically novel uses for the treatment or prevention of viral infections or a disease associated with viral infections and / or for use as a virus inhibitor. The invention further relates to a method of treating or preventing viral infections or diseases associated with viral infections. In addition, the invention relates to a pharmaceutical composition for use in the treatment or prevention of viral infections or diseases associated with viral infections. BACKGROUND OF THE INVENTION

[0002] Viral infections represent a major challenge for public health systems worldwide. Despite rapid scientific progress in the field of virology, the lack of effective therapeutic options and vaccines for most viral infectious diseases continues to take its toll. Emerging viral diseases pose a significant threat, primarily due to their rapid transmission rates and the inherent difficulties associated with developing effective vaccines and treatment options against new pathogens in a short period of time. Therefore, there is a need to develop broad-spectrum antiviral compounds that are effective against multiple viruses. Most currently available antivirals target one or more components directly associated with the virus's replication cycle. Therefore, their activity tends to be limited to closely related viruses, often within the same virus family.Selected nucleoside analogs, including cidofovir, favipiravir, and ribavirin, have been shown to be effective against a wide range of viruses, but pose a significant risk of developing antiviral resistance, particularly among viruses of... Petition 870250083250, dated 09 / 16 / 2025, page 15 / 61 2 / 29 RNA.

[0003] Viruses are infectious organic structures that spread as virions outside of cells (extracellular) by transmission, but as viruses they can only replicate inside a suitable host cell (intracellular). They do not themselves consist of one or more cells. All viruses contain the program for their replication and dissemination (some viruses also contain other auxiliary components), but they do not have independent replication or their own metabolism and therefore depend on the metabolism of a host cell. Viruses bind to molecules on the surface of host cells and introduce their genetic material into them. This penetrates the cell nucleus and alters the cell's own DNA. The body of the virus (genome and proteins) replicates, sometimes on a massive scale, in the infected cell through existing cellular organelles.

[0004] A virus particle outside of cells is called a virion. Virions are particles that contain nucleic acids—deoxyribonucleic acids (DNA) or ribonucleic acids (RNA)—and usually have an enveloping protein coat (capsid). However, a capsid is absent in the influenza virus, for example, which instead has a ribonucleoprotein. Some virions additionally possess an envelope by a biomembrane, whose lipid bilayer is interspersed with viral membrane proteins. This is referred to as the viral envelope. Virions that temporarily have a viral envelope in addition to the capsid until the replication phase begins are referred to as enveloped, and viruses without such an envelope are referred to as non-enveloped.

[0005] R. Madhugiri et al., Advances in Virus Research, Vol. 96, 2016,127, summarizes coronavirus RNA synthesis and discusses the structural and functional characteristics of known cis-acting RNA elements located in the 5'- and 3'-terminal untranslated region (UTR).

[0006] Previous studies have shown that Silvesterol (CAS Petition 870250083250, dated 09 / 16 / 2025, p. 16 / 61 3 / 29 Silvesterol (697235-38-4), a flavaglin derivative, acts as a potent and selective inhibitor of the RNA helicase enzyme elF4A and has broad-spectrum antiviral activity against diseases such as Ebola and coronavirus. Silvesterol was difficult to synthesize due to the cyclopentabenzofuran ring, and therefore several modified synthetic flavaglins were designed and successfully used, at least for preclinical in vitro studies. Some studies have already shown that Silvesterol has broad-spectrum antiviral activity against coronavirus, SARS virus, and MERS (C.Müller et al., Antiviral research 150, 2018, 123).

[0007] Wintachai et al., Microbiol Immunol., 2015, 59, 129-141 refers to the evaluation of flavaglins, in particular FL3 and FL23 as inhibitors of the chikungunya virus.

[0008] Similar studies have been conducted with other elF4A inhibitors. R. Cencic et al., J. Virology, 2011, 6381 describes that the compound 4E2RCat (432499-63-3), an inhibitor of the elF4E-elF4G interaction, is able to block coronavirus replication.

[0009] E. Gordon et al., bioRxiv March 22, 2020, refers to the search for knowledge of the molecular details of SARS-CoV-2 infection. Therefore, viral proteins in human cells were cloned, labeled, and expressed. In addition, 66 human proteins or host factors that could be targeted by drugs, targeted by 69 FDA-approved drugs, drugs in clinical trials, and / or preclinical compounds, were identified, including Zotatifin (eFT226). The efficacy of the compounds is evaluated in live SARS-CoV-2 infection assays.

[0010] eFFECTOR Therapeutics, on April 30, 2020, reported that Zotatifin, an oncology product, exhibits antiviral activity against SARS-CoV-2.

[0011] However, there is still a great demand for additional compounds that exhibit a broad spectrum of properties. Petition 870250083250, dated 09 / 16 / 2025, page 17 / 61 4 / 29 antivirals.

[0012] It is therefore an objective of the present invention to provide pharmaceutically active compounds that have the ability to inhibit viral activity. SUMMARY OF THE INVENTION

[0013] The invention relates to a compound of formula (I) prodrugs or isotopically enriched forms thereof or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected between CN and hydrogen. R2 is selected from between hydrogen and halogen, for use in the treatment or prevention of viral infections or diseases associated with viral infections.

[0014] In particular, the invention relates to a compound of formula (I) prodrugs or isotopically enriched forms thereof or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected between CN and hydrogen. R2 is selected between hydrogen and halogen. Petition 870250083250, dated 09 / 16 / 2025, page 18 / 61 5 / 29 for use in the treatment or prevention of viral infections or diseases associated with viral infections and / or for use as a virus inhibitor, where the infection or disease is selected from viral infection caused by positive-sense single-stranded RNA viruses ((+) ssRNA) and negative-sense single-stranded RNA viruses ((-) ssRNA).

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

[0016] The invention further relates to compounds of formula (la) or (lb) or an enantiomeric mixture comprising compounds of formula (la) and (lb) or prodrugs or isotopically enriched forms 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, wherein the infection or disease is selected from viral infection caused by positive single-stranded RNA viruses ((+) ssRNA) and negative single-stranded RNA viruses ((-) ssRNA) where R1 and R2 have the same meanings as defined above and below.

[0017] The invention further relates to compounds of formula (la) or (lb) or an enantiomeric mixture comprising compounds of formula (la) and (lb) or prodrugs or isotopically enriched forms thereof or pharmaceutically acceptable salts or solvates thereof, for use as a virus inhibitor. Petition 870250083250, dated 09 / 16 / 2025, p. 19 / 61 6 / 29 where R1 and R2 have the same meanings as defined above and below.

[0018] The invention further relates to a method of treating or preventing viral infections or diseases associated with viral infections, as defined above and below, comprising administering a therapeutically effective amount of at least one compound selected from the compounds of formulas (I), (1a), (1b), an enantiomeric mixture comprising the compounds of formula (1a) and (1b) or prodrugs or isotopically enriched forms thereof or a pharmaceutically acceptable salt or solvate thereof as defined herein in this patent application.

[0019] The invention further relates to a pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound selected from the compounds of formulas (I), (1a), (1b), an enantiomeric mixture comprising the compounds of formula (1a) and (1b) or prodrugs or isotopically enriched forms thereof or a pharmaceutically acceptable salt or solvate thereof, as defined herein in this patent application, and one or more pharmaceutically acceptable excipients or carriers for use in the treatment or prevention of viral infections or diseases associated with viral infections.

[0020] The invention further relates to a pharmaceutical composition comprising a pharmaceutically effective amount of at least one compound selected from the compounds of formulas (1), (1a), (1b), an enantiomeric mixture comprising the compounds of formula (1a) and (1b) or prodrugs or isotopically formed forms Petition 870250083250, dated 09 / 16 / 2025, page 20 / 61 7 / 29 enriched thereof or a pharmaceutically acceptable salt or solvate thereof, as defined herein in this patent application, and one or more pharmaceutically acceptable excipients or carriers for use as a virus inhibitor. DESCRIPTION OF THE INVENTION

[0021] The invention has the following advantages: The compounds according to the invention exhibit advantageous inhibition of the virus. (+)ssRNA viruses, such as coronaviruses and picocoronaviruses, are dependent on host 5' Cap-dependent and independent strategies for the initiation of viral mRNA translation. Some viruses exploit prohibitins associated with the plasma membrane to enter host cells. The present invention describes a class of molecules that target both PHBs in the plasma membrane and the elF4A complex, thereby preventing viral entry and replication. Compounds of formula (I)

[0022] Unless specifically stated otherwise herein, in this patent application, singular references may also include plurals. For example, a and an may refer to either one, or to one or more.

[0023] The term halogen denotes in each case fluorine, chlorine, bromine or iodine, preferably fluorine.

[0024] The term solvate refers to a complex of a compound according to the invention that is coordinated to a solvent molecule to form a specific ratio, in particular, the solvate is a hydrate, meaning a complex formed by the coordination of a compound of the invention with water.

[0025] The compounds of formulas (I), (1a), (1b), (A), (B), an enantiomeric mixture thereof, may form salts, which are also within the scope of this invention. The term salt / salt as used Petition 870250083250, dated 09 / 16 / 2025, p. 21 / 61 8 / 29 herein, in this patent application, denotes acidic and / or basic salts formed with inorganic and / or organic acids and bases. Pharmaceutically acceptable salts (i.e., non-toxic, physiologically acceptable) are preferred, although other salts are also useful, for example, in isolation or purification steps, which may be used during preparation. Salts of the compounds of formulas (I), (1a), (1b), (A), (B), or an enantiomeric mixture thereof, may be formed, for example, by reacting a compound of formulas (I), (1b), (A), (B), or an enantiomeric mixture thereof 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] The expression "pharmaceutically acceptable salt(s), as used herein in this patent application, unless otherwise indicated, includes salts containing pharmacologically acceptable anions or cations, such as chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, sulfate, benzenesulfonate, p-toluenesulfonate and palmoate [i.e., 4,4'-methylene-bis-(3-hydroxy-2-naphthoate)].

[0027] Any compound according to the invention can be prepared and used in prodrug form. A suitable prodrug has one or more chemically or metabolically cleavable groups and becomes, by solvolysis or under physiological conditions, a compound that is pharmaceutically active in vivo. A prodrug can be formed in a conventional manner by reaction of a functional group of the compound (such as an amino, hydroxy or carboxy group). Prodrugs often offer advantages of improved metabolism, potency, solubility, tissue compatibility or delayed release in mammals. Petition 870250083250, dated 09 / 16 / 2025, page 22 / 61 9 / 29

[0028] The term “prodrug” refers to a metabolic precursor of a compound of the invention that is pharmaceutically acceptable. A prodrug may be inactive when administered to a subject in need of it, but is converted in vivo into an active compound of the invention. Prodrugs are typically rapidly transformed in vivo to produce the parent compound of the invention, for example, by hydrolysis in the blood.

[0029] In other words, under the terms of the present invention, prodrugs are compounds which are metabolized in vivo to give compounds of the invention of formula I. Typical examples of prodrugs are, for example, described in C.G. Wermeth (editor): The Practice of Medicinal Chemistry, Academic Press, San Diego, 1996, pages 67-715 as well as J. Rautio et al., NATURE REVIEWS, Drug Discovery, Vol. 17, 2018, p. 559. Examples are phosphates, carbonates, carbamates, amino acids, esters (carboxylic acid esters), ethers, amides, peptides, ureas and the like. In the present case, suitable prodrugs may be compounds of formula I in which the hydroxyl group is attached to any group which, when the prodrug of the compound of the invention is administered to a mammalian subject, cleaves to form a free hydroxyl group.

[0030] The terms “viral infections” and “viral diseases” refer to the entry of viruses into an organism, as well as their colonization and multiplication. The resulting disease is the viral infection.

[0031] The term “diseases associated with viral infections” refers to diseases resulting from a viral infection. The associated disease is preferentially selected from among pulmonary inflammation, respiratory distress, pulmonary fibrosis, pneumonia, cytokine storm, acute liver injury, septic shock, acute kidney injury, pancreatic injury, peripheral nervous system complications (such as impaired ability to taste, smell and visual impairment), muscle pain, Petition 870250083250, dated 09 / 16 / 2025, p. 23 / 61 10 / 29 Inflammation of the heart muscle, blood clots in the veins, decreased blood flow in the coronary arteries, cardiogenic shock, heart failure, impaired consciousness, brain inflammation, irritation and swelling of the brain and blood vessels, acute cerebrovascular complications (such as stroke, seizures and slurred speech), arrhythmia, myocarditis, thrombotic events, rhabdomyolysis, neurocognitive deficits, cancer, and sensory and motor deficits.

[0032] In the context of the present invention, a chemical structure that does not explicitly show a specific stereochemical orientation generally means all possible stereoisomers and mixtures thereof, unless otherwise indicated, for example, H3CO OH HO I R2h3co—vjz o R1 in which * designates the chiral centers.

[0033] “Chiral compounds” within the meaning of the invention are compounds that do not contain an improper axis of rotation (Sn). In the context of the present invention, they are in particular compounds with at least four chiral centers and without Sn symmetry.

[0034] “Stereoisomers” in the context of the invention are compounds of identical constitution but with different atomic arrangements in three-dimensional space.

[0035] “Enantiomers” are stereoisomers, which behave as mirror images of each other, for example, the compounds of formulas (la) and (lb) are enantiomers. The “enantiomeric excess” (ee) achieved during asymmetric synthesis is given here by the following formula: ee [%]=(RS) / (R+S)x100.

[0036] R and S are the CIP system descriptors for the configuration of a stereocenter to describe the absolute configuration in a Petition 870250083250, dated 09 / 16 / 2025, p. 24 / 61 11 / 29 asymmetric (carbon) atom. The enantiomerically pure compound (ee=100%) is also referred to as a "homochiral compound".

[0037] “Diastereomers” are stereoisomers, which are not enantiomeric with each other.

[0038] The compound of the invention may exist in several isomeric forms, as well as in one or more tautomeric forms, including both single tautomers and mixtures of tautomers. The term “isomer” is intended to encompass all isomeric forms of a compound of this invention, including tautomeric forms of the compound.

[0039] Some compounds described herein may have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. A compound of the invention may be in the form of an optical isomer or a diastereomer. Consequently, the invention encompasses compounds of the invention and their uses as described herein, in this patent application, in the form of their optical isomers, diastereomers and mixtures thereof, including a racemic mixture. Optical isomers of the compounds of the invention may be obtained by known techniques, such as asymmetric synthesis, chiral chromatography or via chemical separation of stereoisomers through the use of optically active resolving agents.

[0040] Unless otherwise indicated, “stereoisomer” means a stereoisomer of a compound that is substantially free of other stereoisomers of that compound. Thus, a stereomerically pure compound with one chiral center will be substantially free of the opposite enantiomer of the compound. A stereomerically pure compound having two chiral centers will be substantially free of other diastereomers of the compound. A typical stereomerically pure compound comprises 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. Petition 870250083250, dated 09 / 16 / 2025, page 25 / 61 12 / 29 by weight of one stereoisomer of the compound and less than about 10% by weight of the 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 the 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 the other stereoisomers of the compound.

[0041] A “stereoisomer” refers to a compound formed by the same atoms linked by the same bonds, but with different three-dimensional structures, which are not interchangeable. The present invention contemplates several stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0042] The compounds of the invention or their pharmaceutically acceptable salts or solvates may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers and other stereoisomeric forms which may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or as (D)- or (L)- for amino acids. The present invention is intended to include all such possible isomers, as well as their racemic 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 resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high-performance liquid chromatography.

[0043] Relative configuration in stereochemistry (relative stereochemistry) is the arrangement of atoms or groups of atoms that is described in relation to other atoms or groups of atoms in the molecule. In other Petition 870250083250, dated 09 / 16 / 2025, page 26 / 61 13 / 29 words, this term describes the position of atoms or groups of atoms in space relative to other atoms or groups of atoms that are located elsewhere in the molecule.

[0044] Absolute configuration in stereochemistry (absolute stereochemistry) is the arrangement of atoms or groups of atoms that is described independently of any other atom or group of atoms in the molecule. This type of configuration is defined for chiral molecular entities and their stereochemical descriptions (e.g., R or S).

[0045] Syn means that, with respect to the orientation of the substituents on the 5-membered ring to which they are attached (4 asymmetric carbon atoms), all substituents point in the same direction relative to the plane of the 5-membered ring.

[0046] A racemic mixture or racemate is defined as a mixture of compounds consisting of two molecules structured as mirror images (= enantiomers) and which are present in an equimolar mixture, that is, in the proportion of 1:1 (50:50).

[0047] In addition, compounds of formula (I) where * designates the centers of asymmetry, represent the isomers of the formulas (la), (lb), (lc), (ld), (le), (lf), (lg), (lh), (li), (lj), (lk), (ll), (lm), (ln), (lo) and (lp): Petition 870250083250, dated 09 / 16 / 2025, p. 27 / 61 14 / 29 Petition 870250083250, dated 09 / 16 / 2025, p. 28 / 61 15 / 29 where R1 and R2 have one of the meanings as defined above or below.

[0048] Compounds with formulas (la) to (lp) are specified by their absolute stereochemistry.

[0049] In a preferred embodiment, the compound of formula (I) is a mixture of at least two enantiomers (la) to (lp) or a mixture of the prodrugs or isotopically enriched forms thereof, or a mixture of the pharmaceutically acceptable salt or solvate thereof, wherein one enantiomer is enriched.

[0050] Preferably the compound of formula (I) is a mixture of (la) and (lb) or a mixture of pharmaceutically acceptable salts thereof, wherein the enantiomeric excess (ee) of the enantiomer of formula (la) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0051] Preferred compounds of formula (I) according to the invention, or a prodrug or isotopically enriched forms thereof or a pharmaceutically acceptable salt thereof, wherein R1 is CN.

[0052] In addition, they are preferred compounds of formula (I) of Petition 870250083250, dated 09 / 16 / 2025, p. 29 / 61 16 / 29 according to the invention, or a prodrug or isotopically enriched forms thereof or a pharmaceutically acceptable salt thereof, wherein R1 is C and R2 is selected from between hydrogen and F.

[0053] In addition, compounds of formula (I) according to the invention are preferred, either a prodrug or isotopically enriched forms thereof or a pharmaceutically acceptable salt thereof, wherein R2 is hydrogen.

[0054] In addition, compounds of formula (I) according to the invention are preferred, or a prodrug or a pharmaceutically acceptable salt or solvate thereof, wherein R2 is F.

[0055] Another preferred embodiment are compounds of formula (I), where R1 and R2 are selected from the definition given in a row of Table 1: Table 1: Nr. R1 R2 1. CN F 2. CN Hydrogen

[0056] Another preferred embodiment is the selected compounds from A, B and the mixture of each of the compounds A to B with its respective enantiomer:

[0057] Preferably a compound of formula (A) or an enantiomeric mixture comprising the compounds of formula (A) and its enantiomer, in particular wherein the enantiomeric excess (ee) of the enantiomer of formula (A) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least Petition 870250083250, dated 09 / 16 / 2025, page 30 / 61 17 / 29 99%.

[0058] Preferably a compound of formula (B) or an enantiomeric mixture comprising the compounds of formula (B) and its enantiomer, in particular wherein the enantiomeric excess (ee) of the enantiomer of formula (B) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0059] Compound A is particularly preferred.

[0060] Compound B is particularly preferred.

[0061] The compounds of the present invention can be synthesized using methods of prior art knowledge and together with methods of synthetic organic chemistry knowledge or variations thereof as recognized by those skilled in the art. Viruses

[0062] The present invention provides a compound of formulas (I), (la) or (lb) or an enantiomeric mixture as defined herein in this patent application, and pharmaceutically acceptable salts thereof (“compounds of the invention”) for use in the treatment or prevention of viral infections or diseases associated with viral infections.

[0063] The present invention provides a compound of formulas (I), (la) or (lb) or an enantiomeric mixture as defined herein in this patent application, and pharmaceutically acceptable salts thereof (“compounds of the invention”) for use as a virus inhibitor.

[0064] Preferably, the disease or infection is selected from viral infections caused by positive-sense single-stranded RNA viruses (+ssRNA viruses) and negative-sense single-stranded RNA viruses (-ssRNA viruses).

[0065] Positive-strand RNA viruses (+ssRNA viruses) are a group of related viruses that possess positive-sense single-stranded genomes made of ribonucleic acid. The positive-sense genome can act as messenger RNA (mRNA) and can be directly translated. Petition 870250083250, dated 09 / 16 / 2025, p. 31 / 61 18 / 29 in viral proteins by host cell ribosomes. Positive-strand RNA viruses encode an RNA-dependent RNA polymerase (RdRp), which is used during genome replication to synthesize a negative-sense antigenome that is then used as a template to create a new positive-sense viral genome.

[0066] Specifically, the (+) ssRNA virus is an element of a family selected from among Togaviridae, Flaviviridae, Coronaviridae and Retroviridae.

[0067] Togaviridae is a family of enveloped positive-sense RNA viruses. Currently, it includes two genera of enveloped viruses with a single-stranded RNA of positive polarity. Togaviridae includes species of viruses from the genus Alphavirus and the rubella virus. Alphaviruses transmit diseases to humans and animals through insects. The rubella virus is transmitted only between humans via the respiratory route.

[0068] Flaviviridae is a family of enveloped positive-strand RNA viruses that primarily infect mammals and birds. They are primarily spread through arthropod vectors (mainly ticks and mosquitoes). Flaviviridae includes virus species of the genera Hepacivirus and Flavivirus. Diseases associated with this group include hepatitis, dengue fever, Japanese encephalitis, Kyasanur forest disease, Powassan virus, West Nile fever, yellow fever, and Zika fever.

[0069] Coronavirus is the common name for Coronaviridae and Orthocoronavirinae, also called Coronavirinae. Coronaviridae is a family of enveloped positive-strand RNA viruses. Coronaviruses cause disease in mammals and birds. In humans, the viruses cause respiratory infections.

[0070] Coronaviridae include species of viruses from the genera alphacoronavirus, betacoronavirus, and torovirus. Preferably, the coronaviridae is selected from SARS-CoV, SARS-CoV-2, MERS-CoV, Petition 870250083250, dated 09 / 16 / 2025, pp. 32 / 61 19 / 29 HCoV-229E, HCoV-NL63, HCoVC43 and HKU1.

[0071] Four human coronaviruses typically cause minor symptoms of a common cold, while three are known to cause more severe and potentially fatal illnesses: SARS-CoV-1, which causes SARS; MERS-CoV, which causes MERS; and SARS-CoV-2, which causes COVID-19.

[0072] Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1 or SARS-CoV) is a strain of coronavirus that causes severe acute respiratory syndrome (SARS). It causes a frequently severe illness and is initially marked by systemic symptoms of muscle pain, headache, and fever, followed in 2–14 days by the onset of respiratory symptoms, primarily cough, dyspnea, and pneumonia. Another common finding in patients with SARS is a decrease in the number of lymphocytes circulating in the blood. SARS-CoV is a member of the genus betacoronavirus and the subgenus embecovirus.

[0073] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a strain of coronavirus that causes COVID-19, a respiratory illness. SARS-CoV-2 is a virus of the species severe acute respiratory syndrome-related coronavirus (SARSr-CoV), related to the SARS-CoV-1 virus. SARS-CoV-2 is a member of the genus betacoronavirus and subgenus embecovirus.

[0074] Middle East respiratory syndrome-related coronavirus (MERS-CoV) is the virus that causes Middle East respiratory syndrome (MERS). It is a species of coronavirus that infects humans, bats, and camels. The species is a member of the genus Betacoronavirus and the subgenus Merbecovirus.

[0075] Human coronavirus 229E (HCoV-229E) is a species of coronavirus that infects humans and bats. It is one of the viruses responsible for the common cold. HCoV-229E is a member of the alphacoronavirus genus and the duvinacovirus subgenus. Petition 870250083250, dated 09 / 16 / 2025, page 33 / 61 20 / 29

[0076] Human coronavirus NL63 (HCoV-NL63) is a species of coronavirus, specifically a Setracovirus of the genus Alphacoronavirus. Infection with the virus has been confirmed worldwide, and it is associated with many common symptoms and illnesses. Associated illnesses include mild to moderate upper respiratory tract infections, severe lower respiratory tract infections, croup, and bronchiolitis.

[0077] Human coronavirus OC43 (HCoV-OC43) is a member of the Betacoronavirus 1 species, which infects humans and cattle. OC43 is one of seven coronaviruses known to infect humans. It is one of the viruses responsible for the common cold. It belongs to the genus Betacoronavirus and the subgenus Embecovirus.

[0078] Human coronavirus HKU1 (HCoV-HKLU) is a species of coronavirus in humans and animals. It causes an upper respiratory illness with symptoms similar to the common cold, but can progress to pneumonia and bronchiolitis. HCoV-HKLU is a member of the genus betacoronavirus and subgenus embecovirus.

[0079] Retroviridae is a family of enveloped positive-strand RNA viruses. Retroviridae includes species of viruses of the genus, among others, deltretrovirus and lentivirus. Lentiviruses cause chronic and fatal diseases characterized by long incubation periods in humans and other mammalian species. The genus includes the human immunodeficiency virus (HIV), which causes AIDS.

[0080] Negative-strand RNA viruses (-ssRNA viruses) are a group of related viruses that possess single-stranded, negative-sense genomes made of ribonucleic acid. They have genomes that act as complementary strands from which messenger RNA (mRNA) is synthesized by the viral enzyme RNA-dependent RNA polymerase (RdRp). During viral genome replication, RdRp synthesizes a positive-sense antigenome that it uses as a template to create Petition 870250083250, dated 09 / 16 / 2025, pp. 34 / 61 21 / 29 a negative-sense genomic RNA. Negative-strand RNA viruses also share a number of other characteristics: most contain a viral envelope that surrounds the capsid, which encloses the viral genome; the genomes of -ssRNA viruses are generally linear, and it is common for their genome to be segmented.

[0081] Preferably, the (-) ssRNA virus is an element of a family selected from arenaviridae, bornaviridae, bunyviridae, filoviridae, othymyxoviridae, paramyxoviridae and pneumoviridaeerhabdoviridae, in particular filoviridae.

[0082] Preferably, filoviridae is selected from Bundibugyo ebolavirus, Reston ebolavirus, Sudan ebolavirus, Tai Forest ebolavirus, Zaire ebolavirus and Bombali ebolavirus.

[0083] As defined above, positive-sense single-stranded RNA viruses ((+) ssRNA) and negative-sense single-stranded RNA viruses ((-) ssRNA) account for a large fraction of known viruses, including many pathogens as well as less clinically severe pathogens such as rhinoviruses that cause the common cold. Therefore, in one embodiment, the infection or disease is an infection or disease caused by both positive-sense single-stranded RNA viruses ((+) ssRNA) and negative-sense single-stranded RNA viruses ((-) ssRNA).

[0084] In a preferred embodiment, the infections or diseases are selected from dengue fever, MERS, COVID-19, SARS, Ebola fever, AIDS, and Zika fever.

[0085] Diseases associated with infections by positive-sense single-stranded RNA viruses and infections by negative-sense single-stranded RNA viruses include various complications arising from them. Complications include respiratory distress, pulmonary fibrosis, pneumonia, cytokine storm, acute liver injury, septic shock, acute kidney injury, pancreatic injury, peripheral nervous system complications (such as impaired ability to Petition 870250083250, dated 09 / 16 / 2025, pp. 35 / 61 22 / 29 loss of taste, smell and visual impairment), muscle pain, inflammation of the heart muscle, blood clots in the veins, decreased blood flow in the coronary arteries, cardiogenic shock, heart failure, impaired consciousness, brain inflammation, irritation and swelling of the brain and blood vessels, acute cerebrovascular complications (such as stroke, seizures and slurred speech), arrhythmia, myocarditis, thrombotic events, rhabdomyolysis, neurocognitive deficits and sensory and motor deficits. The present invention encompasses the complications caused by SARS-CoV-2 infection.

[0086] In one embodiment, the disease is pulmonary inflammation. Properly, pulmonary inflammation is caused by pathogenic infection, bacterial infection, fungal infection, or viral infection, in particular an infection by (+)ssRNA viruses. More properly, pulmonary inflammation is caused by a disease selected from the group consisting of pneumonia, acute respiratory distress syndrome (ARDS), COPD, asthma, idiopathic pulmonary fibrosis, allergic rhinitis, rhinitis, and sinusitis. More properly, pulmonary inflammation is caused by COPD, asthma, or idiopathic pulmonary fibrosis. Even more properly, pulmonary inflammation is caused by COPD. Even more properly, pulmonary inflammation is caused by asthma. Even more properly, pulmonary inflammation is caused by idiopathic pulmonary fibrosis.

[0087] In one embodiment, the compounds of the invention are used for the treatment or prevention of hyperinflammation associated with infections by positive-sense single-stranded RNA viruses, in particular coronavirus infection. Preferably, the compounds according to the invention reduce the hyperinflammation associated with coronavirus infection.

[0088] The expression “pharmaceutically acceptable” is used herein, in this patent application, to refer to compounds, materials, compo Petition 870250083250, dated 09 / 16 / 2025, pp. 36 / 61 23 / 29 dosage forms and / or dosage forms that are, within the scope of good medical judgment, suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response or other problem or complication, consistent with a reasonable benefit / risk ratio.

[0089] The term therapeutically effective is intended to qualify the quantity of each agent that will achieve the goal of improving the severity of the disorder and the frequency of incidence, while avoiding adverse side effects typically associated with alternative therapies. For example, effective antiviral agents prolong the patient's survival or quality of life, inhibiting the rapid multiplication of viruses.

[0090] The terms “treat”, “treating” and “treatment”, as used herein in this patent application, refer to any type of intervention or process performed on, or administration of an active agent to, a subject with the aim of reversing, alleviating, improving, inhibiting or delaying or preventing the progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicators associated with a disease. In contrast, “prophylaxis” or “prevention” refers to administration to a subject who does not have a disease to prevent the occurrence of the disease.

[0091] As used herein in this patent application, the term cell is intended to refer to a cell that is in vitro, ex vivo, or in vivo. In the sense of the invention, an ex vivo cell may be part of a tissue sample excised from an organism, such as a mammal. In the sense of the invention, an in vitro cell may be a cell in a cell culture. In the sense of the invention, an in vivo cell is a cell that lives in an organism, such as a mammal.

[0092] The term “patient” includes humans and animals receiving therapeutic or prophylactic treatment. Petition 870250083250, dated 09 / 16 / 2025, pp. 37 / 61 24 / 29

[0093] The term “subject” includes any human or animal. For example, the methods and compositions used herein, in this patent application, can be used to treat a subject with cancer.

[0094] An animal (non-human) includes all vertebrates, for example, mammals and non-mammals, including cows, sheep, pigs, goats, horses, birds, dogs, cats, non-human primates, rodents, etc.

[0095] In one modality, the subject is a human subject.

[0096] The term pharmaceutically acceptable vehicle, as used herein, means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid diluent, solvent, excipient, manufacturing aid (e.g., lubricant) or encapsulating material, involved in carrying or transporting the compound in question from one organ or body part to another organ or body part. Each vehicle must be acceptable in the sense of being compatible with the other ingredients of the formulation.

[0097] Other suitable ingredients are the aforementioned vehicle and other additives, including adjuvants, preservatives, fillers, flow regulators, disintegrants, humectants, emulsifiers, suspending agents, sweeteners, flavoring agents, bittering agents, perfumes, antibacterial agents, antifungal agents, lubricants, dispensing agents, etc. Suitable additives are selected depending on the nature of the administration method and dosage forms; and are not harmful to the patient.

[0098] The term pharmaceutical composition means a composition comprising a compound according to the invention in combination with at least one additional compound selected from a) at least one additional pharmaceutically active substance and b) at least one vehicle and / or pharmaceutical additive Petition 870250083250, dated 09 / 16 / 2025, pp. 38 / 61 25 / 29 additional acceptable.

[0099] For use in therapy, at least one compound of formulas (I), (la) or (lb) or an enantiomeric mixture as defined above or a pharmaceutically acceptable salt or solvate thereof or a pharmaceutically acceptable carrier are generally administered as a pharmaceutical composition. The invention also relates to a pharmaceutical composition comprising at least one compound of formulas (I), (la) or (lb) or an enantiomeric mixture as defined above or a pharmaceutically acceptable salt or solvate thereof and a pharmaceutically acceptable carrier.

[00100] The compounds according to the invention can be administered by any convenient method, for example, by oral, parenteral, buccal, sublingual, nasal, rectal, intrathecal or transdermal administration or by inhalation (for example, for topical administration to the lung by inhalation), and the pharmaceutical compositions adapted accordingly.

[00101] A compound according to the invention, which is active when administered orally, can be formulated as liquids or solids, for example, as syrups, suspensions, emulsions, tablets, capsules or lozenges.

[00102] A liquid formulation will generally consist of a suspension or solution of the active ingredient in one or more suitable liquid vehicles, for example, an aqueous solvent such as water, ethanol or glycerin, or a non-aqueous solvent such as polyethylene glycol or an oil. The formulation may also contain a suspending agent, a preservative, a flavoring agent and / or a colorant.

[00103] A composition in the form of a tablet may be prepared using any one or more suitable pharmaceutical carriers routinely used to prepare solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose. Petition 870250083250, dated 09 / 16 / 2025, pp. 39 / 61 26 / 29

[00104] A composition in the form of a capsule can be prepared using routine encapsulation procedures, for example, pellets containing the active ingredient can be prepared using standard carriers and then filled into a hard gelatin capsule; alternatively, a dispersion or suspension can be prepared using any one or more suitable pharmaceutical carriers, for example, aqueous gums, celluloses, silicates or oils, and the dispersion or suspension then filled into a soft gelatin capsule.

[00105] Typical parenteral compositions consist of a solution or suspension of the active ingredient in a sterile aqueous vehicle or parenterally acceptable oil, for example, polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil or sesame oil. Alternatively, the solution may be optimized and then reconstituted with a suitable solvent just before administration.

[00106] Compositions for nasal or inhalation administration (e.g., for topical administration to the lungs by inhalation) may be conveniently formulated as aerosols, drops, gels, and powders. Aerosol formulations generally comprise a fine solution or suspension of the active ingredient in a pharmaceutically acceptable aqueous or non-aqueous solvent and are generally presented in single or multiple dose quantities in sterile form in a sealed container which may take the form of a cartridge or refill for use with an atomizing device. Alternatively, the sealed container may be a disposable dispensing device, such as a single-dose nasal inhaler or an aerosol dispenser fitted with a metering valve suitable for delivering the aerosol to the nasal or bronchial passages.Where the dispensing form comprises an aerosol dispenser, it shall contain a propellant, which may be a compressed gas, for example, air, or an organic propellant, such as... Petition 870250083250, dated 09 / 16 / 2025, pp. 40 / 61 27 / 29 as a fluorochlorohydrocarbon or hydrofluorocarbon. Aerosol dosage forms may also take the form of pump atomizers.

[00107] Topical administration to the lung can also be achieved by using a dry powder formulation, which contains the compound of the invention in finely divided form, optionally together with one or more vehicles or other excipients. A dry powder formulation is typically administered by delivery using a dry powder inhaler (DPI) device.

[00108] Compositions suitable for oral or sublingual administration include tablets, lozenges and coated tablets where the active ingredient is formulated with a vehicle, such as sugar and acacia, tragacanth or gelatin and glycerin.

[00109] Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base, such as cocoa butter.

[00110] 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.

[00111] In one embodiment of the invention, the compound of formulas (I), (la) or (lb) or an enantiomeric mixture as defined above is used in combination with other therapeutic agents, the compound of formulas (I), (la) or (lb) or an enantiomeric mixture as defined above may be administered sequentially or simultaneously by any convenient route. Alternatively, the compounds may be administered separately.

[00112] The invention will be further illustrated with reference to Petition 870250083250, dated 09 / 16 / 2025, pp. 41 / 61 28 / 29 examples follow, without restricting the scope to the specific embodiments described. The invention includes all combinations of described features and especially those preferred ones that are not mutually exclusive. DESCRIPTION OF THE DRAWINGS Figure 1: The mRNA from the double reporter assay is shown. The Firefly luciferase (F Luc) will be translated by the elF4F complex, and the Renilla luciferase (R Luc) will be translated independently of the complex. Figure 2: The 5'UTR mRNA sequences of the viruses are shown. Figure 3: Dual luciferase assay for Cap-dependent translation initiation.

[00113] Plasmid Map of the dual luciferase assay system. The dual luciferase assay for Cap-dependent translation initiation was performed in HeLa cells transfected with the pFR_HCV_xb-based dual luciferase reporter gene. Cells were treated with A (200 nM) for 24 h in serum-free DMEM. 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 mutant and exposed to DMSO for 24 h. DMSO-treated cells were defined as 1. Bars represent the mean ± SEM of 3 independent experiments. (EV corresponds to empty vector) Dual luciferase assay

[00114] HeLa cells were cultured in DMEM (10% heat-inactivated FBS, 1 mM Sodium Pyruvate) and seeded at 1x10⁶ cells / ml, 2 ml in a 6-well cell culture plate in growth medium. 2 pg of plasmids were transfected into the cells. Petition 870250083250, dated 09 / 16 / 2025, pp. 42 / 61 29 / 29 with 0.5 mM PEI reagent in 200 μL of PBS. One day after transfection, cells were collected and seeded onto 96-well, half-area white plates (Greiner). After an additional day, the medium was changed to serum-free DMEM and the cells were incubated for 24 h with the Compounds. The Dual-GIo Luciferase Assay was performed according to the manufacturer's instructions (Promega, N2920). Luminescence was measured using Tecan infinite (Tecan). EXAMPLES

[00115] Compound A refers to h3co l HO h3co oj NC Petition 870250083250, dated 09 / 16 / 2025, pp. 43 / 61

Claims

1 / 6 CLAIMS 1. Use of a compound, characterized in that it has Formula (I), (I) prodrugs or isotopically enriched forms thereof or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from CN and hydrogen, R2 is selected from hydrogen and halogen, and is for preparation of a composition and / or combination for treatment or prevention of viral infections or diseases associated with viral infections and / or as a virus inhibitor, wherein the infection or disease is selected from viral infection caused by positive single-stranded RNA viruses ((+) ssRNA) and negative single-stranded RNA viruses ((-) ssRNA).

2. Use of a compound, characterized in that it has Formula (I), (I) prodrugs or isotopically enriched forms thereof or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from CN and hydrogen, Petition 870250083250, dated 09 / 16 / 2025, page 7 / 61 2 / 6 R2 is selected from hydrogen and halogen, and is for the preparation of a composition and / or combination for the treatment or prevention of viral infections or diseases associated with viral infections.

3. Use according to claim 1 or 2, characterized in that said compound is for use as a virus inhibitor.

4. Use, according to any one of claims 1 to 3, characterized in that said compound is selected from compounds of Formula (la) or (lb) or an enantiomeric mixture comprising compounds of Formula (la) and (lb), or prodrugs or isotopically enriched forms thereof or pharmaceutically acceptable salts or solvates thereof, wherein R1 and R2 are as defined in claim 1.

5. Use, according to any one of claims 1 to 4, characterized in that said compound is a mixture of (la) and (lb), prodrugs or isotopically enriched forms thereof or a pharmaceutically acceptable salt or solvate thereof, wherein the enantiomeric excess (ee) of the enantiomer of Formula (la) is at least 20%, at least 50%, at least 80%, or at least 99%.

6. Use, according to any one of claims 1 to 5, characterized in that, in said compound, R1 is CN.

7. Use, according to any one of claims 1 to 6, characterized in that, in said compound, R2 is selected from among hydrogen and F. Petition 870250083250, dated 09 / 16 / 2025, page 8 / 61 3 / 6 8. Use, according to any one of claims 1 to 7, characterized in that said compound is selected from among the compounds of Formulas A and B and the mixture of each of the compounds A to B with its respective enantiomer, 9. Use, according to any one of claims 1 to 8, characterized in that said compound is selected from compound A and from the mixture of compound A with its respective enantiomer, 10. Use, according to any one of claims 1 to 9, characterized in that the (+) ssRNA virus is an element of a family selected from among Togaviridae, Flaviviridae, Coronaviridae and Retroviridae.

11. Use, according to any one of claims 1 to 9, characterized in that the (-) ssRNA virus is an element of a family selected from arenaviridae, bornaviridae, bunyviridae, filoviridae, othymyxoviridae, paramyxoviridae, pneumoviridae and rhabdoviridae, in particular filoviridae.

12. Use, according to any one of claims 1 to 10, characterized in that flaviviridae is selected from Dengue virus, Japanese encephalitis, Kyasanur forest disease, Powassan virus, West Nile virus, Yellow fever virus and Zika virus.

13. Use, according to any one of claims 1 to 10, characterized in that the coronaviridae is selected from SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-NL63, HCovC43 and HKU1.

14. Use, according to any one of claims 1 to 10, characterized in that retroviridae is selected from HIV-1 and HIV-2.

15. Use, according to any one of claims 1 to 9 and 11, characterized in that filoviridae is selected from Bundibuqyo ebolavirus, Reston ebolavirus, Sudan ebolavirus, Tai Forest ebolavirus, Zaire ebolavirus and Bombali ebolavirus.

16. Use, according to any one of claims 1 to 10 and 12 to 14, characterized in that the disease or infection is selected from dengue fever, MERS, COVID-19, SARS, Ebola fever, AIDS and Zika fever.

17. Composition for treatment or prevention of viral infections or diseases associated with viral infections and / or as a virus inhibitor, wherein the infection or disease is selected from viral infection caused by positive single-stranded RNA viruses ((+) ssRNA) and negative single-stranded RNA viruses ((-) ssRNA), and / or for treatment or prevention of viral infections or diseases associated with viral infections, characterized in that it comprises a compound having Formula (I), (I) prodrugs or isotopically enriched forms thereof or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from CN and hydrogen, R2 is selected from hydrogen and halogen, and at least one pharmaceutically acceptable vehicle and / or additional additive.

18. Combination, characterized in that it comprises a compound, as defined in any one of claims 1, 2 and 4 to 10, or a composition, as defined in claim 17, in combination with at least one other compound selected from at least one other pharmacologically active substance.

19. Invention, characterized by the fact that in any form of its embodiment or in any applicable category of claim, for example, product or process or use, or any other type of claim encompassed by the matter initially described, disclosed or illustrated in the patent application, has for example: Compound, which has Formula (I) (I) prodrugs or isotopically enriched forms thereof or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from CN and hydrogen, R2 is selected from hydrogen and halogen, for use in the treatment or prevention of viral infections or diseases associated with viral infections and / or for use as a virus inhibitor, wherein the infection or disease is selected from viral infection caused by positive single-stranded RNA viruses ((+) ssRNA) and viruses Petition 870250083250, dated 09 / 16 / 2025, p.11 / 61 6 / 6 of negative-sense single-stranded RNA ((-) ssRNA); and / or Compound, which has Formula (I), (I) prodrugs or isotopically enriched forms thereof or a pharmaceutically acceptable salt or solvate thereof, wherein R1 is selected from CN and hydrogen, R2 is selected from hydrogen and halogen, for use in the treatment or prevention of viral infections or diseases associated with viral infections; and / or Use of a compound to prepare a medicament, combination and / or composition to treat and / or prevent disorder(s), disease(s) and / or condition(s). Petition 870250083250, dated 09 / 16 / 2025, p. 12 / 61.

Images