1H-cyclopenta [b] benzofuran derivatives for prevention and treatment of viral diseases

Abstract

The present invention relates to a novel therapeutic use of 1H-cyclopenta [b] benzofuran derivatives, in particular for the treatment or prevention of diseases caused by or associated with viral infections. The invention also relates to methods of treating or preventing diseases caused by or associated with viral infections. In addition, the present invention relates to a pharmaceutical composition for treating or preventing a disease caused by or associated with a viral infection.

Description

[0001] The present invention relates to a new therapeutic use of 1H-cyclopenta[b]benzofuran derivatives, in particular a new use in the treatment or prevention of diseases caused by viral infections or diseases associated with viral infections. The present invention also relates to a method for treating or preventing diseases caused by viral infections or diseases associated with viral infections. The present invention also relates to a pharmaceutical composition for treating or preventing diseases caused by viral infections or diseases associated with viral infections. Background of the Invention

[0003] Viral infections pose a major challenge to public health systems worldwide. Despite rapid scientific progress in the field of virology, most viral infections lack effective treatment options and vaccines, which continue to cause losses. Emerging viral diseases pose a major threat, mainly because of their rapid spread and the inherent difficulties in developing effective vaccines and treatment regimens against such novel pathogens within a short time frame. Therefore, there is a need to develop broad-spectrum antiviral compounds that are effective against a variety of viruses. Most of the antiviral drugs currently available target one or more components directly related to the viral life cycle. Therefore, this activity is often limited to closely related viruses, which are usually within the same viral family. Selected nucleoside analogs, including cidofovir, favipiravir, and ribavirin, have been shown to be effective against a wide range of viruses, but there is a major risk of antiviral resistance, mainly in RNA viruses.

[0004] Viruses are infectious organic structures that are transmitted extracellularly in the form of viral particles but can replicate only intracellularly within a suitable host cell. They are not themselves composed of one or more cells. All viruses contain a program for their replication and spread (some viruses also contain other accessory components), but they have neither independent replication nor their own metabolism and thus rely on the metabolism of the host cell. Viruses attach to surface molecules of the host cell and import their genetic material into it. This penetrates into the cell nucleus and alters the cell's own DNA. Virions (genome and proteins) are sometimes massively replicated in infected cells through existing organelles.

[0005] Viral particles outside the cell are called virions. A virion is a particle containing nucleic acid - deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) - and usually has an enclosed protein coat (capsid). However, for example, there is no capsid in influenza viruses, but rather ribonucleoproteins. Some virions also have an envelope of biological membrane, the lipid bilayer of which is scattered with viral membrane proteins. This is called a viral envelope. Before the start of the replication phase, a virion that temporarily has a viral envelope in addition to the capsid is called an enveloped virus, while a virus without such an envelope is called a non-enveloped virus.

[0006] R. Madhugiri et al., Advances in Virus Research, Volume 96, 2016, 127 summarized the synthesis of coronavirus RNA and discussed the structural and functional features of known cis - acting RNA elements located in the 5'- and 3'- untranslated regions (UTRs).

[0007] Previous studies have shown that Silvesterol (CAS 697235 - 38 - 4) is a flavagline derivative that acts as an effective and selective inhibitor of the RNA helicase eIF4A and has broad - spectrum antiviral activity against diseases such as Ebola virus and coronavirus. Silvesterol is difficult to synthesize due to its cyclopenta - dibenzo - furan ring, and thus several modified synthetic flavaglines have been designed and at least successfully used in in vitro pre - clinical studies. Several studies have shown that Silvesterol has broad - spectrum antiviral activity against coronaviruses, SARS, and MERS viruses (C. Müller et al., Antiviral research 150, 2018, 123).

[0008] Similar studies have been conducted on other eIF4A inhibitors. R. Cencic et al., J. Virology, 2011, 6381 described the compound 4E2RCat (432499 - 63 - 3), an inhibitor of the eIF4E - eIF4G interaction, which is able to block the replication of coronaviruses.

[0009] E. Gordon et al., bioRxiv, March 22, 2020 pertains to the knowledge of finding the molecular details of SARS - CoV - 2 infection. Thus, viral proteins in human cells have been cloned, labeled, and expressed. It has been identified that human proteins are physically connected to each other. In addition, 66 druggable human proteins or host factors targeted by 69 existing FDA - approved drugs, drugs in clinical trials, and / or pre - clinical compounds have been identified, particularly eFT226 (zotatifin). The efficacy of these compounds was evaluated in live SARS - CoV - 2 infection assays.

[0010] eFFECTOR’s Therapeutic, April 30, 2020 reported that the oncology drug product zotatifin showed antiviral activity against SARS - CoV - 2.

[0011] EP2457907 relates to flavaline derivatives and their use as neuroprotective agents, cardioprotective agents and anti-tumor agents. In particular, EP2457907 discloses the use of said flavaline derivatives in the treatment of neuropathy. Neuropathy may be caused by HIV infection. This document discloses the flavaline compounds FL42 and FL44.

[0012] EP3639820 relates to flavaline derivatives and their use as inhibitors of KRAS oncogene activation.

[0013] However, there is still a great demand for compounds with broad-spectrum antiviral properties.

[0014] Therefore, an object of the present invention is to provide pharmaceutically active compounds having the ability to inhibit viral activity. Summary of the Invention

[0016] The present invention relates to compounds of formula (I)

[0017]

[0018] or a pharmaceutically acceptable salt thereof, wherein

[0019] R 1 is selected from C1-C4 alkyl, wherein the alkyl is unsubstituted or substituted by 1, 2 or 3 substituents R a ;

[0020] C3-C7 heterocycloalkyl which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R e , and wherein the heterocycloalkyl is attached to the remainder of the molecule through a carbon atom;

[0021] NR 2 R 3 wherein R 2 and R 3 are independently of each other selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl and C3-C7 heterocycloalkyl which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents R h and wherein the alkyl is unsubstituted or substituted by 1, 2 or 3 substituents R a and wherein the cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents R bSubstituted;

[0022] R 2 and R 3 together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated heterocycle, wherein the heterocycle has 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R d Substituted;

[0023] R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated bicyclic, tricyclic or tetracyclic ring system, which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R f Substituted;

[0024] R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spiro moiety, which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R g Substituted;

[0025] R a is selected from halogen, OH, C3-C7 cycloalkyl, C1-C3 alkoxy, phenyl, NR 5a R 5b , C1-C4-alkylsulfonyl, C3-C7 heterocycloalkyl, which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, and wherein C3-C7 cycloalkyl and phenyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from F, Cl, Br and OH;

[0026] R b is selected from halogen, OH and C1-C3 alkoxy;

[0027] R cSelected from hydrogen, C1-C4-alkyl, C3-C7-cycloalkyl, C1-C4-haloalkyl, C1-C4-cyanoalkyl, carbonyloxy-C1-C4-alkyl, and C1-C4-hydroxyalkyl;

[0028] R d Selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, carboxyl, carbonyloxy-C1-C4-alkyl, and NR 5a R 5b ;

[0029] R e Selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, carbonyloxy-C1-C4-alkyl, and C1-C4-haloalkoxy;

[0030] R f Selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, and NR 5a R 5b ;

[0031] R g Selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy;

[0032] R h Selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, and C1-C4-haloalkoxy;

[0033] R 4 Selected from Cl, CN, and C3-C7-cycloalkyl;

[0034] R 5a and R 5b are each independently selected from hydrogen, C1-C4-alkyl, and C3-C7-cycloalkyl;

[0035] R 6 Selected from hydrogen and F;

[0036] R 7 Selected from hydrogen and C1-C2-alkyl;

[0037] Provided that if R 6 is H, then R 7 is C1-C2-alkyl, and if R 6 is F, then R 7 is hydrogen;

[0038] R 8 selected from OCH3, OCD3;

[0039] R 9 selected from OCH3, OCD3;

[0040] It is used for treating or preventing diseases caused by viral infections or diseases related to viral infections.

[0041] Preferably, the present invention relates to a compound of formula (I)

[0042]

[0043] or a pharmaceutically acceptable salt thereof, wherein

[0044] R 1 is selected from C1-C4 alkyl, wherein the alkyl is unsubstituted or substituted by 1, 2 or 3 substituents R a substituted;

[0045] C3-C7 heterocycloalkyl, which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R e substituted, and wherein the heterocycloalkyl is connected to the rest of the molecule through a carbon atom;

[0046] NR 2 R 3 wherein R 2 and R 3 are independently of each other selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl and C3-C7 heterocycloalkyl, which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents R h substituted, and wherein the alkyl is unsubstituted or substituted by 1, 2 or 3 substituents R a substituted, wherein the cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents R b substituted;

[0047] R 2 and R 3 together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated heterocycle, wherein the heterocycle has 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c, O, S, SO and SO2, and wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R d substituted;

[0048] R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated bicyclic, tricyclic or tetracyclic ring system containing 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members selected from N, NR c , O, S, SO and SO2, and wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R f substituted;

[0049] R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spiro moiety containing 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members selected from N, NR c , O, S, SO and SO2, and wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R g substituted;

[0050] R a is selected from halogen, OH, C3-C7 cycloalkyl, C1-C3 alkoxy, phenyl, NR 5a R 5b , C1-C4-alkylsulfonyl, C3-C7 heterocycloalkyl containing 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members selected from N, NR c , O, S, SO and SO2, and wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, and wherein C3-C7 cycloalkyl and phenyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from F, Cl, Br and OH;

[0051] R b is selected from halogen, OH and C1-C3 alkoxy;

[0052] R c is selected from hydrogen, C1-C4-alkyl, C3-C7 cycloalkyl, C1-C4-haloalkyl, C1-C4-cyanoalkyl, carbonyloxy-C1-C4-alkyl and C1-C4-hydroxyalkyl;

[0053] R dSelected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, carboxyl, carbonyloxy-C1-C4-alkyl and NR 5a R 5b ;

[0054] R e Selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, carbonyloxy-C1-C4-alkyl and C1-C4-haloalkoxy;

[0055] R f Selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and NR 5a R 5b ;

[0056] R g Selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;

[0057] R h Selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;

[0058] R 4 Selected from Cl, CN and C3-C7 cycloalkyl;

[0059] R 5a and R 5b Are independently of each other selected from hydrogen, C1-C4-alkyl and C3-C7 cycloalkyl;

[0060] R 6 Selected from hydrogen and F;

[0061] R 7 Selected from hydrogen and C1-C2-alkyl;

[0062] Provided that if R 6 is H, then R 7 is C1-C2-alkyl, and if R 6 is F, then R 7 is hydrogen;

[0063] R 8 Selected from OCH3, OCD3;

[0064] R 9 Selected from OCH3, OCD3;

[0065] It is used for treating or preventing diseases caused by viral infections or diseases associated with viral infections, wherein the diseases are selected from viral infections caused by positive single-stranded RNA viruses ((+) ssRNA) and negative single-stranded RNA viruses ((-) ssRNA).

[0066] In particular, the present invention relates to a compound of formula (I)

[0067]

[0068] or a pharmaceutically acceptable salt thereof, wherein

[0069] R 1 is selected from C1-C4 alkyl, wherein the alkyl is unsubstituted or substituted by 1, 2 or 3 substituents R a ;

[0070] C3-C7 heterocycloalkyl, which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c 、O, S, SO and SO2, and wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R e and wherein the heterocycloalkyl is attached to the remainder of the molecule through a carbon atom;

[0071] NR 2 R 3 wherein R 2 and R 3 are independently of each other selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl and C3-C7 heterocycloalkyl, which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c 、O, S, SO and SO2, and wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents R h and wherein the alkyl is unsubstituted or substituted by 1, 2 or 3 substituents R a and wherein the cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents R b ;

[0072] R 2 and R 3 together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated heterocycle, wherein the heterocycle has 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c 、O, S, SO and SO2, and wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R dSubstituted;

[0073] R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated bicyclic, tricyclic or tetracyclic ring system containing 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members selected from N, NR c , O, S, SO and SO2, and wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R f Substituted;

[0074] R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spiro moiety containing 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members selected from N, NR c , O, S, SO and SO2, and wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R g Substituted;

[0075] R a is selected from halogen, OH, C3-C7 cycloalkyl, C1-C3 alkoxy, phenyl, NR 5a R 5b , C1-C4-alkylsulfonyl, C3-C7 heterocycloalkyl containing 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members selected from N, NR c , O, S, SO and SO2, and wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, and wherein C3-C7 cycloalkyl and phenyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from F, Cl, Br and OH;

[0076] R b is selected from halogen, OH and C1-C3 alkoxy;

[0077] R c is selected from hydrogen, C1-C4-alkyl, C3-C7 cycloalkyl, C1-C4-haloalkyl, C1-C4-cyanoalkyl, carbonyloxy-C1-C4-alkyl and C1-C4-hydroxyalkyl;

[0078] R d is selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, carboxyl, carbonyloxy-C1-C4-alkyl and NR 5a R 5b;

[0079] R e is selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, carbonyloxy-C1-C4-alkyl and C1-C4-haloalkoxy;

[0080] R f is selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and NR 5a R 5b ;

[0081] R g is selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;

[0082] R h is selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;

[0083] R 4 is selected from Cl, CN and C3-C7-cycloalkyl;

[0084] R 5a and R 5b are each independently selected from hydrogen, C1-C4-alkyl and C3-C7-cycloalkyl;

[0085] R 6 is selected from hydrogen and F;

[0086] R 7 is selected from hydrogen and C1-C2-alkyl;

[0087] Provided that if R 6 is H, then R 7 is C1-C2-alkyl, and if R 6 is F, then R 7 is hydrogen;

[0088] R 8 is selected from OCH3, OCD3;

[0089] R 9 is selected from OCH3, OCD3;

[0090] It is used for treating or preventing diseases, wherein the diseases are selected from viral infections caused by positive single-stranded RNA viruses ((+) ssRNA) and negative single-stranded RNA viruses ((-) ssRNA).

[0091] The present invention also relates to a method for treating or preventing a disease caused by a viral infection or a disease associated with a viral infection as defined in the context, the method comprising administering a therapeutically effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0092] Preferably, the present invention also relates to a method for treating or preventing a disease caused by a viral infection or a disease associated with a viral infection, wherein the disease is selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA) as defined in the context, the method comprising administering a therapeutically effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0093] In particular, the present invention also relates to a method for treating or preventing a disease, wherein the disease is selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA) as defined in the context, the method comprising administering a therapeutically effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0094] The present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined in the context or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier, which is used for treating or preventing a disease caused by a viral infection or a disease associated with a viral infection.

[0095] Preferably, the present invention also relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined in the context or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier, which is used for treating or preventing a disease caused by a viral infection or a disease associated with a viral infection, wherein the disease is selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA).

[0096] In particular, the present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) as defined in the context or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier, which is used for treating or preventing a disease, wherein the disease is selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA).

[0097] The present invention also relates to the use of a compound of formula (I) as defined herein in inhibiting viral activity. In particular, the present invention relates to the use of a compound of formula (I) as defined herein in inhibiting viral activity.

[0098] Preferably, the present invention also relates to the use of a compound of formula (I) as defined herein in inhibiting viral activity. In particular, the present invention relates to the use of a compound of formula (I) as defined herein in inhibiting viral activity, wherein the virus is selected from positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA).

[0099] Description of the Invention

[0100] The present invention has the following advantages:

[0101] - The compounds of the present invention exhibit favorable virus inhibitory effects. (+)ssRNA viruses such as coronaviruses and picornaviruses rely on host 5'-cap-dependent and cap-independent strategies for initiating viral mRNA translation.

[0102] - Some viruses utilize plasma membrane-associated inhibins to enter host cells.

[0103] - The present invention describes a class of molecules that target PHB and eIF4A complexes in the plasma membrane and thus prevent virus entry and replication.

[0104] Compound of formula (I)

[0105] Unless otherwise expressly stated herein, references in the singular form may also include the plural form. For example, "a" and "an" may mean one, or one or more.

[0106] In the context of the present invention, the prefix C n -C m denotes the number of carbon atoms that a molecule or residue so designated may contain.

[0107] In the context of the present invention, the expression "C1-C4-alkyl" refers to a straight-chain or branched-chain saturated hydrocarbon group having 1-4 carbon atoms. C1-C4-alkyl is, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl.

[0108] In the context of the present invention, the expression "C1-C4-alkoxy" refers to a straight-chain or branched-chain saturated C1-C4-alkyl as defined above, which is bonded through an oxygen atom. An alkoxy having 1 or 2 carbon atoms is preferred. C1-C2-alkoxy is methoxy or ethoxy. C1-C4-alkoxy is, for example, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), butoxy, 1-methylpropoxy (sec-butoxy), 2-methylpropoxy (isobutoxy) or 1,1-dimethylethoxy (tert-butoxy).

[0109] In the context of the present invention, the expression "carbonyloxy-C1-C4-alkyl" refers to a straight-chain or branched saturated C1-C4-alkyl as defined above, which is bonded via a carboxyl group.

[0110] In the context of the present invention, the expressions "haloalkyl" and "haloalkoxy" refer to partially or fully halogenated alkyl or alkoxy groups. In other words, one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms bonded to one or more carbon atoms of an alkyl or alkoxy group, are replaced by halogen atoms, in particular by fluorine or chlorine.

[0111] In the context of the present invention, the expression "hydroxyalkyl" refers to a partially or fully hydroxylated alkyl group. In other words, one or more hydrogen atoms, for example 1, 2, 3, 4 or 5 hydrogen atoms bonded to one or more carbon atoms of an alkyl group, are replaced by hydroxy atoms.

[0112] In the context of the present invention, the expression "C3-C7-cycloalkyl" refers to a monocyclic cycloaliphatic group having 3 - 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl, preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0113] The expression "halogen" in each case means fluorine, chlorine, bromine or iodine.

[0114] In the context of the present invention, the expression "3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated heterocycle containing 1, 2 or 3 heteroatoms or heteroatom-containing groups, wherein those heteroatoms (groups) selected from N, O, S, NR c 、SO and SO2 are ring members" refers to a monocyclic or polycyclic group linked to the rest of the molecule via a nitrogen ring member. "Heterocycle" also particularly includes "polycycles", such as bicyclic, tricyclic or tetracyclic ring systems, wherein one of the above-mentioned monocyclic heterocyclic residues is condensed or bridged with at least one further identical or different heterocycle or at least one cycloalkyl as defined above in each case. Examples of 3-, 4-, 5-, 6- or 7-membered saturated heterocycles include: aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, pyrazolinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2,4-oxadiazolidinyl, 1,2,4-thiadiazolidinyl, 1,2,4-triazolidinyl, 1,3,4-oxadiazolidinyl, 1,3,4-thiadiazolidinyl, 1,3,4-triazolidinyl, piperidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, hexahydropyrimidinyl, piperazinyl, 1,3,5-hexahydrotriazinyl, 1,2,4-hexahydrotriazinyl, morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 1-oxothiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, 1,1-dioxothiomorpholinyl, hexahydroaza yl, hexahydrooxa radical, hexahydrodiazanyl radical, hexahydrooxadiazanyl radicals and the like. Examples of 3-, 4-, 5-, 6- or 7-membered partially unsaturated heterocycles include: pyrrolinyl, isoxazolinyl, isothiazolinyl, dihydropyrazolyl, tetrahydropyridyl, tetrahydropyridazinyl, tetrahydropyrimidinyl and tetrahydropyrimidinyl. Examples of 3-, 4-, 5-, 6- or 7-membered polycyclic ring systems, especially bicyclic, tricyclic or tetracyclic ring systems include: 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl.

[0115] In the context of the present invention, the expression "C3-C7 heterocycloalkyl" refers to a saturated alicyclic group having 3-7, preferably 3-6 ring atoms, wherein 1, 2 or 3 of the ring carbon atoms are replaced by a heteroatom or a heteroatom-containing group, which is preferably selected from NR c , O, S, SO and SO2, and may optionally be substituted. In the case of substitution, these heterocycloaliphatic groups preferably have 1, 2 or 3, particularly preferably 1 or 2, especially 1 substituent. Heterocycloalkyl refers to a monocyclic group attached to the rest of the molecule through a carbocyclic member. Such heterocycloaliphatic residues are for example aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, 1,2,4-oxadiazolidinyl, 1,2,4-thiadiazolidinyl, 1,2,4-triazolidinyl, 1,3,4-oxadiazolidinyl, 1,3,4-thiadiazolidinyl, 1,3,4-triazolidinyl, piperidinyl, hexahydropyridazinyl, hexahydropyrimidinyl, hexahydropyrimidinyl, piperazinyl, 1,3,5-hexahydrotriazinyl, 1,2,4-hexahydrotriazinyl, morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 1-oxothiomorpholinyl, 1-oxothiomorpholinyl, 1,1-dioxothiomorpholinyl, 1,1-dioxothiomorpholinyl, hexahydroazanyl radical, hexahydrooxanyl radical, hexahydrodiazanyl radical, hexahydrooxadiazanyl radical and the like.

[0116] In the context of the present invention, the expression "spiro ring" refers to a compound having at least two molecular rings and having only one common atom.

[0117] Compounds of formula (I), in particular of formula (I.a), (I.b), (A), (B), (C), (D), (E), (F), (G), (H), (I), (J), (K), (L), (M), (N), (O), (P), (Q), (R), (S), (T), (U), (V), (W), and mixtures of their enantiomers which can form salts are also within the scope of the present invention. As used herein, the term "salt" refers to acid and / or base salts formed with inorganic and / or organic acids and bases. Preferably pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts, however, other salts are also useful, for example in separation or purification steps which may be used during the preparation. For example, salts of compounds of formula (I), in particular of formula (I.a), (I.b), (A), (B), (C), (D), (E), (F), (G), (H), (I), (J), (K), (L), (M), (N), (O), (P), (Q), (R), (S), (T), (U), (V), (W) or mixtures of their enantiomers can be formed by reacting a compound of formula (I), in particular of formula (I.a), (I.b), (A), (B), (C), (D), (E), (F), (G), (H), (I), (J), (K), (L), (M), (N), (O), (P), (Q), (R), (S), (T), (U), (V), (W) or mixtures 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 in equimolar amounts.

[0118] Unless otherwise indicated, as used herein, the term "pharmaceutically acceptable salt" includes salts containing a pharmacologically acceptable anion or cation, 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, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, mesylate, esylate, sulfate, benzenesulfonate, p-toluenesulfonate and palmoate [i.e., 4,4'-methylene-bis-(3-hydroxy-2-naphthoate)].

[0119] In the context of the present invention, unless otherwise stated, chemical structures which do not explicitly show a particular stereochemical orientation generally refer to all possible stereoisomers and mixtures thereof, for example,

[0120]

[0121] where * designates an asymmetric center.

[0122] A "chiral compound" in the sense 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 chiral centers and no S n -symmetry.

[0123] In the context of the present invention, a "stereoisomer" is a compound having the same constitution but a different arrangement of atoms in three-dimensional space.

[0124] "Enantiomers" are stereoisomers that appear as images mirroring each other. For example, the compounds of formula (I.a) and (I.b) are enantiomers. The "enantiomeric excess" (ee) obtained in an asymmetric synthesis process is given by the formula: ee [%] = (R - S) / (R + S) × 100. R and S are descriptors of the CIP system of the two enantiomers and describe the absolute configuration at the asymmetric atom. An enantiomerically pure compound (ee = 100%) is also referred to as a "pure chiral compound".

[0125] "Diastereomers" are stereoisomers that are not enantiomers of each other.

[0126] The compounds of the present invention can exist in a variety of isomeric forms and can also exist in one or more tautomeric forms, including single tautomers and mixtures of tautomers. The term "isomers" is intended to cover all isomeric forms of the compounds of the present invention, including the tautomeric forms of the compounds.

[0127] Some of the compounds described herein can have asymmetric centers and can therefore exist in different enantiomeric and diastereomeric forms. The compounds of the present invention can be in the form of optical isomers or diastereomers. Accordingly, the present invention includes the compounds of the present invention and their uses as described herein in the form of their optical isomers, diastereomers, and mixtures thereof, including racemic mixtures. The optical isomers of the compounds of the present invention can be obtained by known techniques, such as asymmetric synthesis, chiral chromatography, or by chemical separation of stereoisomers using an optically active resolving agent.

[0128] Unless otherwise indicated, a "stereoisomer" refers to a stereoisomer of a compound that is substantially free of other stereoisomers of that compound. Thus, a stereoisomerically pure compound having one chiral center is substantially free of the opposite enantiomer of that compound. A stereoisomerically pure compound having two chiral centers is substantially free of other diastereomers of that compound. A typical stereoisomerically pure compound contains greater than about 80% by weight of one stereoisomer of the compound and less than about 20% by weight of other stereoisomers of the compound, such as greater 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 greater 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 greater than about 97% by weight of one stereoisomer of the compound and less than about 3% by weight of other stereoisomers of the compound.

[0129] A "stereoisomer" refers to a compound in which the same atoms are bonded by the same bonds but have different three-dimensional structures that are not interchangeable.

[0130] The present invention is concerned with various stereoisomers and mixtures thereof, and includes "enantiomers", which refers to two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0131] The compounds of the present invention or their pharmaceutically acceptable salts may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which, according to absolute stereochemistry, may be defined as (R)- or (S)- or, for amino acids, as (D)- or (L)-. The meaning of the present invention includes all such possible isomers and their racemic and optically pure forms. The 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 such as chromatography or fractional crystallization. Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of racemates (or racemates of salts or derivatives) using, for example, chiral high performance liquid chromatography.

[0132] The relative configuration (relative stereochemistry) in stereochemistry is the arrangement of atoms or groups of atoms described relative to other atoms or groups of atoms in the molecule. In other words, the term describes the position of atoms or groups of atoms in space relative to the positions of other atoms or groups of atoms at other locations in the molecule.

[0133] The absolute configuration (absolute stereochemistry) in stereochemistry is the arrangement of atoms or groups of atoms described independently of any other atoms or groups of atoms in the molecule. This configuration defines a chiral molecular entity and its stereochemical description (e.g., R or S).

[0134] Syn means that, with respect to the orientation of the substituents on the 5-membered ring, they are bonded to (4 asymmetric carbon atoms), and all substitution points are in the same direction relative to the plane of the 5-membered ring.

[0135] The indication (+ / -) in the formula of the present invention means that the compound exists as a racemic mixture.

[0136] A racemic mixture or racemate is defined as a mixture of compounds composed of two molecules that are images and mirror images (i.e., enantiomers) and exist in the form of an equimolar mixture, i.e., in a ratio of 1:1 (50:50).

[0137] Compound of formula (I.a’)

[0138]

[0139] wherein R 1 、R 4 、R 6 、R 7 、R 8 and R 9 has one of the meanings defined above or below, and relates to a compound, wherein the relative stereochemistry of the specified compound is involved.

[0140] The compound of formula (I.a’) has an all-cis relative stereochemistry and is a racemic mixture of two enantiomers (all 4 substituents are oriented and bonded in the same direction on the 5-membered ring).

[0141] A preferred embodiment of the present invention is the racemic mixture of formula (I.a’).

[0142] In other words, the compound (I.a’) ((+ / -)) relates to a mixture of the compounds (I.a) and (I.b) shown below, wherein the ratio of (I.a):(I.b) is 1:1

[0143]

[0144] wherein R 1 、R 4 、R 6 、R 7 、R 8 and R 9 has one of the meanings defined above or below.

[0145] Compound of formula (I)

[0146]

[0147] wherein *designates an asymmetric center, isomers of formula (I.a), (I.b), (I.c), (I.d), (I.e), (I.f), (I.g), (I.h), (I.i), (I.j), (I.k), (I.l), (I.m), (I.n), (I.o) and (I.p):

[0148]

[0149]

[0150]

[0151] wherein R 1 、R 4 、R 6 、R 7 、R 8 and R 9 have one of the meanings defined above or below.

[0152] Compounds of formula (I.a) to (I.p) are assigned according to their absolute stereochemistry.

[0153] In a preferred embodiment, the compound of formula (I) is a mixture of at least two enantiomers (I.a) to (I.p) or a mixture of pharmaceutically acceptable salts thereof, wherein one enantiomer is enriched.

[0154] Preferably, the compound of formula (I) is a mixture of (I.a) and (I.b) or a mixture of pharmaceutically acceptable salts thereof, wherein the enantiomeric excess (ee) of the enantiomer of formula (I.a) is at least 20%, preferably at least 50%, particularly at least 80%, particularly at least 99%.

[0155] Preferably, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are both OCH3.

[0156] Furthermore, preferably, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, wherein R 6 is F, and R 7 is hydrogen.

[0157] Preferably, the compound of formula (I), wherein R 1 is selected from:[[]]

[0158] C1-C4 alkyl, which is unsubstituted or substituted by 1, 2 or 3 substituents R a ; or

[0159] A C3-C7 heterocycloalkyl group, which contains 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members, and is selected from NR c and O, where the heterocycloalkyl group is unsubstituted or substituted by 1, 2 or 3 identical or different groups R e and is connected to the rest of the molecule through a carbon atom; or

[0160] NR 2 R 3 where R 2 and R 3 are independently selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, where the alkyl group is unsubstituted or substituted by 1, 2 or 3 substituents R a and the cycloalkyl group is unsubstituted or substituted by 1, 2 or 3 substituents R b ; or

[0161] R 2 and R 3 together with the nitrogen atom to which they are attached form a 3-, 4-, 5- or 6-membered saturated or partially unsaturated heterocycle, where the heterocycle has 1, 2 or 3 heteroatoms or heteroatom-containing groups as ring members, and is selected from N, NR c , S, SO and SO2, where the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R d ; or

[0162] R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated bicyclic or tricyclic ring system, which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, and is selected from N, NR c , O, S, SO and SO2, and where the heterocycle is unsubstituted or substituted by 1, 2 or 3 identical or different groups R f ; or

[0163] R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spiro moiety, which contains 1, 2 identical or different heteroatoms or heteroatom-containing groups as ring members, and is selected from N, NR c and O, and where the heterocycle is unsubstituted or substituted by 1, 2 or 3 identical or different groups R g ;

[0164] R 4 , R a , R b , R c , R d , Re , R f and R g has one of the meanings as defined in the context.

[0165] Preferably, in the compound of formula (I), R 1 is selected from:

[0166] C1-C4 alkyl, which is unsubstituted or substituted by 1, 2 or 3 substituents R a ;

[0167] NR 2 R 3 , wherein R 2 and R 3 are independently selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, wherein the alkyl is unsubstituted or substituted by 1, 2 or 3 substituents R a ; and the cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents R b ; or

[0168] R 2 and R 3 together with the nitrogen atom to which they are attached form a 3-, 4-, 5- or 6-membered saturated or partially unsaturated heterocycle, wherein the heterocycle has 1, 2 or 3 heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c or O, and the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R d ;

[0169] In particular, R 1 is selected from:

[0170] C3-C7 heterocycloalkyl, which contains 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from NR c and O. The heterocycloalkyl is unsubstituted or substituted by 1 or 2 identical or different groups R e ; and the heterocycloalkyl is attached to the rest of the molecule through a carbon atom; or

[0171] R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated bicyclic ring system, which contains 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N or NR c , preferably R 2 and R 3 together with the nitrogen atom to which they are attached form an 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl ring system; or

[0172] R2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spiro ring moiety which contains 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c and O, preferably R 2 and R 3 together with the nitrogen atom to which they are attached form a 2-oxa-6-azaspiro[3.3]heptan-6-yl spiro compound.

[0173] More preferably, R 1 is selected from:

[0174] C5-C7 heterocycloalkyl which contains 1 or 2 heteroatoms or heteroatom-containing groups as ring members, which are selected from NR c and S, wherein the heterocycloalkyl is attached to the remainder of the molecule through a carbon atom, preferably the C5-C7 heterocycloalkyl is selected from pyrrolidinyl and piperidinyl; or

[0175] NR 2 R 3 wherein R 2 and R 3 are each independently selected from hydrogen and C1-C3 alkyl and C3-C6 cycloalkyl, wherein the alkyl is unsubstituted or substituted by 1 or 2 substituents R a substituted, wherein the cycloalkyl is unsubstituted or substituted by 1 or 2 substituents, preferably hydrogen, C2-C3 alkyl (unsubstituted) and C3-C6 cycloalkyl (unsubstituted); or

[0176] R 2 and R 3 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or partially unsaturated heterocycle which contains 1 or 2 heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , SO2 and O, wherein R c is selected from hydrogen, C1-C4-alkyl, wherein the heterocycle is unsubstituted or substituted by 1 or 2 identical or different groups selected from C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, NH2, N(C1-C2 alkyl)2 and NH(C1-C2 alkyl), preferably R 2 and R 3 together with the nitrogen atom to which they are attached form a pyrrolidine ring, a piperazine ring, an azetidine ring or a morpholine ring, wherein the pyrrolidine ring, piperazine ring, azetidine ring or morpholine ring is unsubstituted or substituted by 1 or 2 substituents selected from C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, NH2, N(C1-C2 alkyl)2, NH(C1-C2 alkyl), carbonyloxy-C1-C2-alkyl; or

[0177] R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated bicyclic ring system which contains 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N or NR c , preferably R 2 and R 3 together with the nitrogen atom to which they are attached form an 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl ring system.

[0178] In particular, R 1 is NR 2 R 3 wherein R 2 and R 3 are independently selected from hydrogen and C1-C3 alkyl and C3-C6 cycloalkyl, wherein the alkyl is unsubstituted or substituted by 1 or 2 substituents R a substituted, wherein the cycloalkyl is unsubstituted or substituted by 1 or 2 substituents, in particular R 2 and R 3 are independently selected from hydrogen, C2-C3 alkyl (which is unsubstituted) and C3-C6 cycloalkyl (which is unsubstituted); or

[0179] R 2 and R 3 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or partially unsaturated heterocycle which contains 1 or 2 heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c and O, wherein R c is selected from hydrogen and C1-C4-alkyl. Preferably, R 2 and R 3 together with the nitrogen atom to which they are attached form a pyrrolidine ring, a piperazine ring, an azetidine ring or a morpholine ring, wherein the pyrrolidine ring, piperazine ring, azetidine ring and morpholine ring are unsubstituted or substituted by 1 or 2 substituents selected from C1-C4-alkyl, C1-C4-hydroxyalkyl and C1-C4-alkoxy.

[0180] In particular, R 1 is selected from methyl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, N,N-diethylamino, N-isopropylamino, N-ethylamino, N,N-methyl-isopropylamino, azetidin-1-yl, morpholin-4-yl, N-cyclopentylamino, [1-(4-fluorophenyl)ethyl]amino, (cyclopropylmethyl)amino, 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl, 1-methylpiperidin-4-yl, thiomorpholin-4-yl-1,1 dioxide (1λ6 -Thiomorpholine-1,1-dionyl), 3-(dimethylamino)azetidin-1-yl, 4-(dimethylamino)piperidin-1-yl, N-ethyl-1-ol-amino, azetidine-3-carbonyloxymethyl, N,N-dimethylaminomethyl, 2-oxa-6-azaspiro[3.3]hept-6-yl and pyrrolidin-3-yl, especially methyl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, N,N-diethylamino, N-isopropylamino, N-ethylamino, N,N-methyl-isopropylamino, azetidin-1-yl, morpholin-4-yl, N-cyclopentylamino, [1-(4-fluorophenyl)ethyl]amino, (cyclopropylmethyl)amino.

[0181] In a first preferred embodiment, R 1 is selected from C1-C4 alkyl, which is unsubstituted or substituted by 1, 2 or 3 substituents R a , in particular, R 1 is selected from C1-C2 alkyl, especially R 1 is methyl.

[0182] In a second preferred embodiment, R 1 is selected from NR 2 R 3 , where R 2 and R 3 are independently of each other selected from hydrogen and C2-C3 alkyl, which is unsubstituted or substituted by 1 or 2 substituents R a , preferably C2-C3 alkyl, which is unsubstituted. In particular, R 1 is hydrogen, and R 2 is C2-C3 alkyl, which is unsubstituted, especially R 1 is hydrogen, and R 2 is selected from ethyl and isopropyl.

[0183] In a third preferred embodiment, R 1 is selected from NR 2 R 3 , where R 2 and R 3 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or partially unsaturated heterocycle, which contains 1 or 2 heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c and O. Preferably, R 2 and R 3Together with the nitrogen atom to which they are attached, form a pyrrolidine ring, a piperazine ring, an azetidine ring or a morpholine ring, where the pyrrolidine ring, piperazine ring, azetidine ring or morpholine ring is unsubstituted or substituted by 1 or 2 substituents selected from C1-C4-alkyl, C1-C4-hydroxyalkyl and C1-C4-alkoxy.

[0184] In particular, R 2 and R 3 Together with the nitrogen atom to which they are attached, form a piperazin-1-yl ring, an azetidin-1-yl or a morpholin-4-yl or a pyrrolidin-1-yl ring, in particular a 4-methyl-piperazin-1-yl ring, a pyrrolidin-1-yl ring, an azetidin-1-yl or a morpholin-4-yl.

[0185] In a fourth preferred embodiment, R 1 is selected from C3-C7 heterocycloalkyl which contains 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members selected from NR c and O, where the heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 identical or different groups R e and where the heterocycloalkyl is attached to the remainder of the molecule through a carbon atom, in particular, R 1 is selected from C5-C7 heterocycloalkyl which contains 1 or 2 heteroatoms or heteroatom-containing groups as ring members selected from NR c and S, where the heterocycloalkyl is attached to the remainder of the molecule through a carbon atom.

[0186] In a fifth preferred embodiment, R 1 is selected from NR 2 R 3 where R 2 and R 3 together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated bicyclic or tricyclic ring system which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members selected from N, NR c , O, S, SO and SO2, and where the heterocycle is unsubstituted or substituted by 1, 2 or 3 identical or different groups R f , in particular, R 1 is selected from NR 2 R 3 where R 2 and R 3 together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated bicyclic ring system which contains 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members selected from N or NR c , preferably R 2 and R 3Together with the nitrogen atom to which they are attached, form an 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl ring system.

[0187] In a sixth preferred embodiment, R 1 is selected from NR 2 R 3 , where R 2 and R 3 , together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated spiro ring moiety containing 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and where the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R g , in particular, R 1 is selected from NR 2 R 3 , where R 2 and R 3 , together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated spiro compound containing 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c and O, and where the heterocycle is unsubstituted or substituted by 1, 2 or 3 identical or different groups R g , preferably R 2 and R 3 , together with the nitrogen atom to which they are attached, form a saturated or partially unsaturated spiro ring moiety containing 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c and O, in particular R 2 and R 3 , together with the nitrogen atom to which they are attached, form a 2-oxa-6-azaspiro[3.3]hept-6-yl spiro compound.

[0188] In particular, R 4 is selected from Cl, CN and C3-C6 cycloalkyl. In particular, R 4 is selected from Cl, CN and cyclopropyl.

[0189] Whether or not it appears, R a is preferably selected from C1-C2-alkyl, C3-C6 cycloalkyl and phenyl, where C3-C6 cycloalkyl and phenyl are unsubstituted or substituted by 1 or 2 substituents selected from F and Cl. In particular, R a is selected from C1-C2-alkyl, C3-C6 cycloalkyl and 4-fluoro-phenyl.

[0190] Whether or not it appears, R b is preferably selected from C1-C2-alkyl.

[0191] Whether it is present or not, R c is preferably selected from hydrogen and C1-C4-alkyl, especially C1-C2-alkyl, especially methyl.

[0192] Whether it is present or not, R d is preferably selected from C1-C4-alkyl, C1-C4-hydroxyalkyl and C1-C4-alkoxy, especially C1-C2-alkyl and C1-C2-hydroxyalkyl.

[0193] Whether it is present or not, R e is selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl and NR 5a R 5b .

[0194] Whether it is present or not, R f is preferably selected from halogen, C1-C4-alkyl and C1-C4-haloalkyl.

[0195] Whether it is present or not, R g is preferably selected from halogen, C1-C4-alkyl and C1-C4-haloalkyl.

[0196] Whether it is present or not, R h is preferably selected from halogen, C1-C4-alkyl and C1-C4-haloalkyl.

[0197] Whether it is present or not, R 5a and R 5b are each independently preferably selected from hydrogen and C1-C4-alkyl.

[0198] Another preferred embodiment is a mixture of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in the context, which is a racemic mixture (I.a')

[0199]

[0200] wherein R 1 , R 4 , R 6 , R 7 , R 8 and R 9 have the meanings as defined above.

[0201] Another preferred embodiment is a compound of formula (I), which is a compound of formula (I.a) or an enantiomeric mixture comprising compounds of formula (I.a) and (I.b) or a pharmaceutically acceptable salt thereof,

[0202]

[0203] wherein R 1 , R 4 , R 6 , R 7 , R 8 and R 9 have the same meanings as defined in the context.

[0204] In particular, the compound of formula (I) is a mixture of (I.a) and (I.b) or a mixture of its pharmaceutically acceptable salts, wherein the enantiomeric excess (ee) of the enantiomer of formula (I.a) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0205] In particular, the compound of formula (I) is the compound (I.a) and its pharmaceutically acceptable salts,

[0206]

[0207] wherein R 1 , R 4 , R 6 , R 7 , R 8 and R 9 have the meanings as defined above.

[0208] Preferably, the compound of formula (I.a) or the racemic mixture (I.a') or the enantiomeric mixture of the compounds of formula (I.a) and (I.b) or their pharmaceutically acceptable salts in different ratios starting from 1:1, wherein R 1 is selected from:

[0209] C1-C4 alkyl, wherein the alkyl is unsubstituted or substituted by 1, 2 or 3 substituents R a ; or

[0210] C3-C7 heterocycloalkyl, which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R e , and wherein the heterocycloalkyl is connected to the rest of the molecule through a carbon atom; or

[0211] NR 2 R 3 wherein R 2 and R 3 are independently of each other selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl and C3-C7 heterocycloalkyl, which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NRc 、 O, S, SO, and SO2, and wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents R h substituted, and wherein the alkyl is unsubstituted or substituted with 1, 2, or 3 substituents R a substituted, wherein the cycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents R b substituted; or

[0212] R 2 and R 3 together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, 6-, or 7-membered saturated or partially unsaturated heterocycle, wherein the heterocycle has 1, 2, or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, selected from N, NR c , O, S, SO, and SO2, and wherein the heterocycle is unsubstituted or substituted with 1, 2, 3, 4, or 5 identical or different groups R d substituted; or

[0213] R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated bicyclic, tricyclic, or tetracyclic ring system, which contains 1, 2, or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, selected from N, NR c , O, S, SO, and SO2, and wherein the heterocycle is unsubstituted or substituted with 1, 2, 3, 4, or 5 identical or different groups R f substituted; or

[0214] R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spiro moiety, which contains 1, 2, or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, selected from N, NR c , O, S, SO, and SO2, and wherein the heterocycle is unsubstituted or substituted with 1, 2, 3, 4, or 5 identical or different groups R g substituted; or

[0215] R a is selected from halogen, OH, C3-C7 cycloalkyl, C1-C3 alkoxy, phenyl, NR 5a R 5b 、 C1-C4-alkylsulfonyl, and C3-C7 heterocycloalkyl, which contains 1, 2, or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, selected from N, NR c, O, S, SO and SO2, and wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, and wherein the C3-C7 cycloalkyl and phenyl are unsubstituted or substituted by 1, 2 or 3 substituents selected from F, Cl, Br and OH;

[0216] R b selected from halogen, OH and C1-C3 alkoxy;

[0217] R c selected from hydrogen, C1-C4-alkyl, C3-C7 cycloalkyl, C1-C4-haloalkyl, C1-C4-cyanoalkyl, carbonyloxy-C1-C4-alkyl and C1-C4-hydroxyalkyl;

[0218] R d selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, carboxyl, carbonyloxy-C1-C4-alkyl and NR 5a R 5b ;

[0219] R e selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, carbonyloxy-C1-C4-alkyl and C1-C4-haloalkoxy;

[0220] R f selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and NR 5a R 5b ;

[0221] R g selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;

[0222] R h selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy;

[0223] R 4 selected from Cl, CN and C3-C7 cycloalkyl;

[0224] R 5a and R 5bindependently selected from hydrogen, C1-C4-alkyl, and C3-C7-cycloalkyl;

[0225] R 6 selected from hydrogen and F;

[0226] R 7 selected from hydrogen and C1-C2-alkyl;

[0227] provided that if R 6 is H, then R 7 is C1-C2-alkyl, and if R 6 is F, then R 7 is hydrogen;

[0228] R 8 selected from OCH3 and OCD3;

[0229] R 9 selected from OCH3 and OCD3.

[0230] Preferably, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are both OCH3.

[0231] Furthermore, preferably, the compound of formula (I) of the present invention or a pharmaceutically acceptable salt thereof, wherein R 6 is F, and R 7 is hydrogen.

[0232] Preferably, the compounds of formula (I.a) and (I.a’), or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from:

[0233] C1-C4 alkyl which is unsubstituted or substituted by 1, 2, or 3 substituents R a ;

[0234] NR 2 R 3 wherein R 2 and R 3 are independently selected from hydrogen, C1-C4 alkyl, and C3-C6 cycloalkyl, wherein the alkyl is unsubstituted or substituted by 1, 2, or 3 substituents R a and the cycloalkyl is unsubstituted or substituted by 1, 2, or 3 substituents R b ; or

[0235] R 2 and R 3 together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, or 6-membered saturated or partially unsaturated heterocycle having 1, 2, or 3 heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR cand O, wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R d substituted.

[0236] In particular, R 1 is selected from:

[0237] C3-C7 heterocycloalkyl which contains 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from NR c and O. Wherein the heterocycloalkyl is unsubstituted or substituted by 1 or 2 identical or different groups R e substituted, and wherein the heterocycloalkyl is linked to the remainder of the molecule through a carbon atom; or

[0238] R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated bicyclic ring system which contains 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N or NR c Preferably, R 2 and R 3 together with the nitrogen atom to which they are attached form an 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl ring system; or

[0239] R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spiro moiety which contains 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c and O, preferably R 2 and R 3 together with the nitrogen atom to which they are attached form a 2-oxa-6-azaspiro[3.3]hept-6-yl spiro compound.

[0240] More preferably, R 1 is selected from:

[0241] C5-C7 heterocycloalkyl which contains 1 or 2 heteroatoms or heteroatom-containing groups as ring members, which are selected from NR c and S, wherein the heterocycloalkyl is linked to the remainder of the molecule through a carbon atom, preferably the C5-C7 heterocycloalkyl is selected from pyrrolidinyl and piperidinyl; or

[0242] NR 2 R 3 wherein R 2 and R 3 are independently of one another selected from hydrogen and C1-C3 alkyl and C3-C6 cycloalkyl, wherein the alkyl is unsubstituted or substituted by 1 or 2 substituents R ais replaced, where the cycloalkyl group is unsubstituted or substituted with 1 or 2 substituents, preferably hydrogen, C2-C3 alkyl (which is unsubstituted), and C3-C6 cycloalkyl (which is unsubstituted); or

[0243] R 2 and R 3 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or partially unsaturated heterocycle containing 1 or 2 heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c 、SO2 and O, where R c is selected from hydrogen, C1-C4-alkyl, where the heterocycle is unsubstituted or substituted with 1 or 2 identical or different groups selected from C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, NH2, N(C1-C2 alkyl)2, and NH(C1-C2 alkyl), preferably R 2 and R 3 together with the nitrogen atom to which they are attached form a pyrrolidine ring, a piperazine ring, an azetidine ring, or a morpholine ring, where the pyrrolidine ring, piperazine ring, azetidine ring, or morpholine ring is unsubstituted or substituted with 1 or 2 substituents selected from C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, NH2, N(C1-C2 alkyl)2, NH(C1-C2 alkyl), carbonyloxy-C1-C2-alkyl; or

[0244] R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated bicyclic ring system containing 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N or NR c ,preferably R 2 and R 3 together with the nitrogen atom to which they are attached form an 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl ring system.

[0245] In particular, R 1 is NR 2 R 3 ,where R 2 and R 3 are independently of each other selected from hydrogen, C1-C3 alkyl, and C3-C6 cycloalkyl, where the alkyl is unsubstituted or substituted with 1 or 2 substituents R a ,where the cycloalkyl is unsubstituted or substituted with 1 or 2 substituents R b ,in particular R 2 and R 3 are independently of each other selected from hydrogen, C2-C3 alkyl (which is unsubstituted), and C3-C6 cycloalkyl (which is unsubstituted); or

[0246] R 2 and R 3 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or partially unsaturated heterocycle which contains 1 or 2 heteroatoms or heteroatom-containing groups as ring members, selected from N, NR c and O, where R c is selected from hydrogen and C1-C4-alkyl. Preferably, R 2 and R 3 together with the nitrogen atom to which they are attached form a pyrrolidine ring, a piperazine ring, an azetidine ring or a morpholine ring, where the pyrrolidine ring, piperazine ring, azetidine ring and morpholine ring are unsubstituted or substituted by 1 or 2 substituents selected from C1-C4-alkyl, C1-C4-hydroxyalkyl and C1-C4-alkoxy.

[0247] In particular, R 1 is selected from methyl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, N,N-diethylamino, N-isopropylamino, N-ethylamino, N,N-methyl-isopropylamino, azetidin-1-yl, morpholin-4-yl, N-cyclopentylamino, [1-(4-fluorophenyl)ethyl]amino, (cyclopropylmethyl)amino, 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl, 1-methylpiperidin-4-yl, thiomorpholin-4-yl-1,1 dioxide (1λ 6 -thiomorpholin-1,1-dionyl), 3-(dimethylamino)azetidin-1-yl, 4-(dimethylamino)piperidin-1-yl, N-ethyl-1-ol-amino, azetidine-3-carbonyloxymethyl, N.N-dimethylaminomethyl(metkyl), 2-oxa-6-azaspiro[3.3]hept-6-yl and pyrrolidin-3-yl, in particular methyl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, N,N-diethylamino, N-isopropylamino, N-ethylamino, N,N-methyl-isopropylamino, azetidin-1-yl, morpholin-4-yl, N-cyclopentylamino, [1-(4-fluorophenyl)ethyl]amino and (cyclopropylmethyl)amino.

[0248] In a first preferred embodiment, R 1 is selected from C1-C4 alkyl which is unsubstituted or substituted by 1, 2 or 3 substituents R a Substituted, in particular, R 1 is selected from C1-C2 alkyl, in particular R 1 is methyl.

[0249] In a second preferred embodiment, R 1 is selected from NR 2 R 3 where R2 and R 3 are each independently selected from hydrogen and C2-C3 alkyl, which is unsubstituted or substituted with 1 or 2 substituents R a substituted, preferably C2-C3 alkyl, which is unsubstituted. In particular, R 1 is hydrogen, and R 2 is C2-C3 alkyl, which is unsubstituted, especially R 1 is hydrogen, and R 2 is selected from ethyl and isopropyl.

[0250] In a third preferred embodiment, R 1 is selected from NR 2 R 3 wherein R 2 and R 3 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or partially unsaturated heterocycle containing 1 or 2 heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c and O. Preferably, R 2 and R 3 together with the nitrogen atom to which they are attached form a pyrrolidine ring, a piperazine ring, an azetidine ring or a morpholine ring, wherein the pyrrolidine ring, piperazine ring, azetidine ring or morpholine ring is unsubstituted or substituted with 1 or 2 substituents selected from C1-C4-alkyl, C1-C4-hydroxyalkyl and C1-C4-alkoxy. In particular, R 2 and R 3 together with the nitrogen atom to which they are attached form a piperazin-1-yl ring, an N-azetidin-1-yl ring or a morpholin-4-yl ring or a pyrrolidin-1-yl ring, especially a 4-methyl-piperazin-1-yl ring, a pyrrolidin-1-yl ring, an azetidin-1-yl or a morpholin-4-yl.

[0251] In a fourth preferred embodiment, R 1 is selected from C3-C7 heterocycloalkyl containing 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from NR c and O, wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2 or 3 identical or different groups R e substituted, and wherein the heterocycloalkyl is attached to the rest of the molecule through a carbon atom, in particular, R 1 is selected from C5-C7 heterocycloalkyl containing 1 or 2 heteroatoms or heteroatom-containing groups as ring members, which are selected from NR c and S, wherein the heterocycloalkyl is attached to the rest of the molecule through a carbon atom.

[0252] In a fifth preferred embodiment, R 1 is selected NR2 R 3 , wherein R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated bicyclic or tricyclic ring system which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycle is unsubstituted or substituted by 1, 2 or 3 identical or different groups R f . In particular, R 1 is selected NR 2 R 3 , wherein R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated bicyclic ring system which contains 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N or NR c . Preferably, R 2 and R 3 together with the nitrogen atom to which they are attached form an 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl ring system.

[0253] In a sixth preferred embodiment, R 1 is selected from NR 2 R 3 , wherein R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spiro moiety which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R g . In particular, R 1 is selected from NR 2 R 3 , wherein R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spiro moiety which contains 1, 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c and O, and wherein the heterocycle is unsubstituted or substituted by 1, 2 or 3 identical or different groups R g . Preferably, R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spiro compound which contains 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR cand O, especially R 2 and R 3 Together with the nitrogen atom to which they are attached, form a 2-oxa-6-azaspiro[3.3]hept-6-yl spirocyclic compound.

[0254] In particular, R 4 is selected from Cl, CN and C3-C6 cycloalkyl. In particular, R 4 is selected from Cl, CN and cyclopropyl.

[0255] Another particular embodiment is a compound of formula (I-A)

[0256]

[0257] wherein R 1 and R 4 are selected from the definitions given in a row of Table 1:

[0258] Table 1:

[0259]

[0260]

[0261]

[0262] Another particular embodiment is a compound of formula (I-A.a')

[0263]

[0264] wherein R 1 and R 4 have one of the meanings selected from the definitions given in a row of Table 1 above.

[0265] Another particular embodiment is a compound of formula (I-A.a)

[0266]

[0267] wherein R 1 and R 4 have one of the meanings selected from the definitions given in a row of Table 1 above.

[0268] Another particular embodiment is a compound of formula (I), an enantiomeric mixture of compounds of formula (I-A.a) and (I-A.b) or a pharmaceutically acceptable salt thereof,

[0269]

[0270] wherein R 1 and R 4 have one of the meanings selected from the definitions given in a row of Table 1 above.

[0271] In particular, formula (I) is a mixture of compounds (I-A.a) and (I-A.b), wherein the enantiomeric excess (ee) of the enantiomers of formula (I-A.a) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%, and wherein R 1 and R 4 has one of the meanings selected from the definitions given in one row of Table 1 above.

[0272] Another particular embodiment is a mixture of each of the compounds selected from A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W and compound A-V with its corresponding enantiomer:

[0273]

[0274]

[0275]

[0276] or a mixture thereof.

[0277] Preferably a compound of formula (A) or an enantiomeric mixture comprising a compound of formula (A) and its enantiomer, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (A) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0278] Preferably a compound of formula (B) or an enantiomeric mixture comprising a compound of formula (B) and its enantiomer, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (B) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0279] Preferably a compound of formula (C) or an enantiomeric mixture comprising a compound of formula (C) and its enantiomer, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (C) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0280] Preferably a compound of formula (D) or an enantiomeric mixture comprising a compound of formula (D) and its enantiomer, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (D) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0281] The preferred compound of formula (E) or an enantiomeric mixture containing the compound of formula (E) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (E) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0282] The preferred compound of formula (F) or an enantiomeric mixture containing the compound of formula (F) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (F) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0283] The preferred compound of formula (G) or an enantiomeric mixture containing the compound of formula (G) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (G) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0284] The preferred compound of formula (H) or an enantiomeric mixture containing the compound of formula (H) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (H) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0285] The preferred compound of formula (I) or an enantiomeric mixture containing the compound of formula (I) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (I) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0286] The preferred compound of formula (J) or an enantiomeric mixture containing the compound of formula (J) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (J) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0287] The preferred compound of formula (K) or an enantiomeric mixture containing the compound of formula (K) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (K) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0288] The preferred compound of formula (L) or an enantiomeric mixture containing the compound of formula (L) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (L) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0289] The preferred compound of formula (M) or an enantiomeric mixture comprising the compound of formula (M) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (M) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0290] The preferred compound of formula (N) or an enantiomeric mixture comprising the compound of formula (N) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (N) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0291] The preferred compound of formula (O) or an enantiomeric mixture comprising the compound of formula (O) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (O) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0292] The preferred compound of formula (Q) or an enantiomeric mixture comprising the compound of formula (Q) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (Q) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0293] The preferred compound of formula (R) or an enantiomeric mixture comprising the compound of formula (R) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (R) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0294] The preferred compound of formula (S) or an enantiomeric mixture comprising the compound of formula (S) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (S) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0295] The preferred compound of formula (T) or an enantiomeric mixture comprising the compound of formula (T) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (T) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0296] The preferred compound of formula (U) or an enantiomeric mixture comprising the compound of formula (U) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (U) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%.

[0297] Preferably at least a compound of formula (V) or an enantiomeric mixture comprising a compound of formula (V) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (V) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0298] Preferably at least a compound of formula (W) or an enantiomeric mixture comprising a compound of formula (W) and its enantiomers, in particular, wherein the enantiomeric excess (ee) of the enantiomers of formula (W) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0299] In one embodiment, the present invention does not include such compounds, wherein

[0300] R 1 is NH2, R 4 is Cl, R 6 is F, R 7 is hydrogen, R 8 is OCH3, R 9 is OCH3,

[0301] R 1 is N(CH3)2, R 4 is Cl, R 6 is F, R 7 is hydrogen, R 8 is OCH3, R 9 is OCH3.

[0302] Virus

[0303] The present invention provides a compound of formula (I) as defined herein and its pharmaceutically acceptable salts ("compounds of the present invention"), which are used for the treatment or prevention of diseases caused by viral infections or diseases associated with viral infections.

[0304] In the sense of the present invention, the term "disease caused by viral infection" is also referred to as "primary disease", which refers to such a disease that is directly caused by viral infection or is the manifestation of a disease in a series of consecutive diseases (hereinafter referred to as related diseases).

[0305] In the context of the present invention, the term "disease associated with a viral infection" is also denoted as "secondary disease", which firstly refers to such diseases in which another pathogen, such as a bacterium, an allergen, a fungicide, a virus different from the virus of the first viral infection, attacks the organism in which the primary disease has already occurred ("first viral infection"). Diseases associated with a viral infection (secondary diseases) usually occur when the immune system is weakened by the primary disease or the entry barrier of the pathogen is breached by the primary disease. In some diseases, the treatment of the secondary disease may be the most urgent therapeutic problem, as is the case with AIDS. Secondly, the term "secondary disease" refers to subsequent diseases caused by the primary disease. This includes, for example, cardiological and neurological complications as defined hereinafter.

[0306] Preferably, the present invention provides a compound of formula (I) as defined herein and its pharmaceutically acceptable salts, which are used for treating or preventing a disease caused by a viral infection or a disease associated with a viral infection, wherein the disease is selected from viral infections caused by positive single-stranded RNA viruses (+ssRNA viruses) and negative single-stranded RNA viruses (-ssRNA viruses), and in particular for treating or preventing a disease, wherein the disease is selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA).

[0307] Positive-strand RNA viruses (+ssRNA viruses) are a group of related viruses that have a positive-sense single-stranded genome consisting of ribonucleic acid. The positive-sense genome can serve as messenger RNA (mRNA) and can be directly translated into viral proteins by the ribosomes of the host cell. Positive-strand RNA viruses encode RNA-dependent RNA polymerase (RdRp), which is used to synthesize a negative-sense antigenome during genome replication, which then serves as a template for creating new positive-sense viral genomes.

[0308] In particular, the (+)ssRNA viruses are members selected from the families Togaviridae, Flaviviridae, Coronaviridae and Retroviridae.

[0309] The family Togaviridae is a family of enveloped positive-strand RNA viruses. Currently, it includes two genera of enveloped viruses, whose single-stranded RNA has a positive polarity. The family Togaviridae includes virus species in the genera Alphavirus and Rubivirus. Viruses in the genus Alphavirus transmit diseases to humans and animals through insects. Viruses in the genus Rubivirus are only transmitted from person to person through the respiratory tract.

[0310] The Flaviviridae is a family of enveloped positive-strand RNA viruses that mainly infect mammals and birds. They are mainly transmitted by arthropod vectors (primarily ticks and mosquitoes). The Flaviviridae includes virus species in 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.

[0311] Coronavirus is the common name for the family Coronaviridae and the subfamily Orthocoronavirinae, also known as the Coronaviridae family. The Coronaviridae is a family of enveloped positive-strand RNA viruses. The Coronaviridae causes diseases in mammals and birds. In humans, the virus causes respiratory infections.

[0312] The Coronaviridae includes virus species in the genera Alphacoronavirus, Betacoronavirus, and Gammacoronavirus. Preferably, the Coronaviridae is selected from SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-NL63, HCoV C43, and HKU1.

[0313] Four human coronaviruses usually cause mild symptoms of the common cold, while three are known to cause more severe diseases and can be fatal: SARS-CoV-1 that causes SARS; MERS-CoV that causes MERS; and SARS-CoV-2 that causes COVID-19.

[0314] 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 generally severe disease and is initially characterized by systemic symptoms of myalgia, headache, and fever, followed by the onset of respiratory symptoms within 2 - 14 days, mainly cough, dyspnea, and pneumonia. Another common finding 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 the subgenus Embecovirus.

[0315] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a strain of coronavirus that causes COVID-19, a respiratory disease. SARS-CoV-2 is a virus of the species Severe acute respiratory syndrome-related coronavirus (SARSr-CoV), which is related to the SARS-CoV-1 virus. SARS-CoV-2 is a member of the genus Betacoronavirus and the subgenus Embecovirus.

[0316] The Middle East Respiratory Syndrome-related Coronavirus (MERS-CoV) is the virus that causes Middle East Respiratory Syndrome (MERS). It is a coronavirus that infects humans, bats, and camels. This species is a member of the genus Betacoronavirus and the subgenus Merbecovirus.

[0317] Human Coronavirus 229E (HCoV-229E) is a coronavirus species 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 Duvinacovirus.

[0318] Human Coronavirus NL63 (HCoV-NL63) is a coronavirus species, specifically from the genus Alphacoronavirus and the subgenus Setracovirus. Infection with this virus has been confirmed worldwide and is associated with many common symptoms and diseases. Related diseases include mild to moderate upper respiratory tract infections, severe lower respiratory tract infections, croup, and bronchiolitis.

[0319] Human Coronavirus OC43 (HCoV-OC43) is a member of species Betacoronavirus 1 that infects humans and cattle. OC43 is one of the seven coronaviruses known to infect humans. It is one of the viruses that cause the common cold. It belongs to the genus Betacoronavirus and the subgenus Embecovirus.

[0320] Human Coronavirus HKU1 (HCoV-HKU1) is a coronavirus species in humans and animals. It causes upper respiratory tract diseases with symptoms of the common cold, but can progress to pneumonia and bronchiolitis. HCoV-HKU1 is a member of the genus Betacoronavirus and the subgenus Embecovirus.

[0321] The Retroviridae family is a family of enveloped positive-strand RNA viruses. The Retroviridae family specifically includes virus species of the genus Deltaretrovirus and the genus Lentivirus. Lentiviruses cause chronic and fatal diseases in humans and other mammalian species, characterized by a long latency period. This genus includes the Human Immunodeficiency Virus (HIV) that causes AIDS.

[0322] Negative-strand RNA viruses (-ssRNA viruses) are a group of related diseases with a negative-sense single-stranded genome consisting of ribonucleic acid. They have a genome that serves 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-sense antigenome, which serves as a template for creating the genomic negative-sense RNA. Negative-strand RNA viruses also share many other characteristics: most contain a viral envelope surrounding the capsid, which encloses the viral genome, the -ssRNA virus genome is usually linear, and their genomes are usually segmented.

[0323] Preferably, the (-)ssRNA virus is a member selected from the family Arenaviridae, Bornaviridae, Bunyviridae, Filoviridae, Orthomyxoviridae, Paramyxoviridae, Pneumoviridae, and Rhabdoviridae, particularly the family Filoviridae.

[0324] Preferably, the family Filoviridae is selected from Bundibugyo ebolavirus, Reston ebolavirus, Sudan ebolavirus, Taï Forest ebolavirus, Zaire ebolavirus, and Bombali ebolavirus.

[0325] Positive single-strand RNA viruses ((+)ssRNA) and negative single-strand RNA viruses ((-)ssRNA), as defined above, account for a large portion of known viruses, including many pathogens as well as clinically less severe pathogens such as rhinoviruses that cause the common cold. Thus, in one embodiment, the disease is a disease associated with positive single-strand RNA viruses ((+)ssRNA) and negative single-strand RNA viruses ((-)ssRNA).

[0326] In a preferred embodiment, the compound of formula (I) is used for treating or preventing a disease caused by a viral infection. In particular, it is used for treating or preventing a disease, wherein the disease is selected from viral infections caused by positive single-stranded RNA viruses ((+) ssRNA) and negative single-stranded RNA viruses ((-) ssRNA), especially wherein the disease is selected from dengue fever, MERS, COVID-19, SARS, Ebola fever, AIDS, and Zika fever.

[0327] In a preferred embodiment, the compound of formula (I) is used for treating or preventing a disease associated with a viral infection.

[0328] Diseases associated with positive single-stranded RNA virus infections and negative single-stranded RNA virus infections include various complications caused thereby. 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 taste, olfactory ability, and vision), myalgia, myocarditis, venous thrombosis, reduced coronary blood flow, cardiogenic shock, heart failure, impaired consciousness, brain inflammation, brain and vascular irritation and swelling, acute cerebrovascular complications (such as stroke, seizure, and slurred speech), arrhythmia, myocarditis, thrombotic events, rhabdomyolysis, neurocognitive deficits, and sensory and motor deficits. The present invention includes complications caused by SARS-CoV-2 infection.

[0329] In one embodiment, the disease is pulmonary inflammation. Appropriately, the pulmonary inflammation is caused by a pathogenic infection, a bacterial infection, a fungal infection, or a viral infection, especially a (+) ssRNA virus infection. More appropriately, the pulmonary inflammation is caused by a disease selected from pneumonia, acute respiratory distress syndrome (ARDS), CORD, asthma, idiopathic pulmonary fibrosis, allergic rhinitis, rhinitis, and sinusitis. More appropriately, the pulmonary inflammation is caused by CORD, asthma, or idiopathic pulmonary fibrosis. Even more appropriately, the pulmonary inflammation is caused by CORD. Even more appropriately, the pulmonary inflammation is caused by asthma. Even more appropriately, the pulmonary inflammation is caused by idiopathic pulmonary fibrosis.

[0330] In one embodiment, the compounds of the present invention are used for treating excessive inflammation associated with positive single-stranded RNA virus infections, such as coronavirus infections. For example, the compounds of the present invention reduce excessive inflammation associated with coronavirus infections.

[0331] The term "pharmaceutically acceptable" is used herein to refer to those compounds, materials, compositions, and / or dosage forms that, within the scope of reasonable medical judgment, are suitable for contact with human and animal tissues, have no excessive toxicity, irritation, allergic response, or other problems or complications, and are commensurate with a reasonable benefit / risk ratio.

[0332] The term "therapeutically effective" is intended to define the amount of each active agent that will achieve the goal of improving the severity and frequency of the disorder while avoiding the adverse side effects typically associated with alternative therapies. For example, an effective anti-cancer agent can extend the survival or quality of life of a patient, inhibit the rapid proliferative cell growth associated with a tumor, or cause the tumor to regress.

[0333] As used herein, the term "treatment" refers to any type of intervention, process, or administration of an active agent to an individual with the aim of reversing, alleviating, improving, inhibiting, or slowing down or preventing the progression, development, severity, or recurrence of symptoms, complications, disorders, or biochemical markers associated with a disease. In contrast, "prevention" refers to the administration to an individual not suffering from a disease to prevent the disease from occurring.

[0334] As used herein, the term "cell" is meant to refer to cells in vitro, ex vivo, or in vivo. In the context of the present invention, ex vivo cells can be a part of a tissue sample excised from an organism, such as a mammal. In the context of the present invention, in vitro cells can be cells in a cell culture. In the context of the present invention, in vivo cells are cells that are alive within an organism, such as a mammal.

[0335] The term "patient" includes humans and animals that are receiving treatment or prophylactic treatment.

[0336] The term "individual" includes any human or animal. For example, the methods and compositions disclosed herein can be used to treat an individual suffering from cancer.

[0337] (Non-human) animals include all vertebrates, such as mammals and non-mammals, including cows, sheep, pigs, goats, horses, poultry, dogs, cats, non-human primates, rodents, etc. In one embodiment, the individual is a human individual.

[0338] As used herein, the phrase "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid diluent, solvent, excipient, preparation aid (such as a lubricant), or encapsulating material, which is involved in carrying or transporting the subject compound from one organ or part of the body to another organ or another part of the body. Each carrier must be "acceptable" in the sense that it is compatible with the other ingredients of the formulation.

[0339] Other suitable ingredients are the above-mentioned carriers and other additives, including adjuvants, preservatives, fillers, flow regulators, disintegrants, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, bittering agents, fragrances, antibacterial agents, antifungal agents, lubricants, dispersants, etc. Suitable additives are selected according to the mode of administration and the nature of the dosage form; and do not cause harm to the patient.

[0340] The term "pharmaceutical composition" refers to a composition comprising a compound of the present invention in combination with at least one additional compound selected from:

[0341] a) at least one additional pharmaceutically active substance; and

[0342] b) at least one additional pharmaceutically acceptable carrier and / or additive.

[0343] For use in therapy, the compounds of formula (I) are generally administered as pharmaceutical compositions. The present invention also relates to pharmaceutical compositions comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0344] The compounds of the present invention can be administered by any convenient method, such as orally, parenterally, buccally, sublingually, nasally, rectally, intrathecally or transdermally, or by inhalation (e.g., by inhalation for topical administration to the lungs), and the pharmaceutical composition is accordingly adjusted.

[0345] The compounds of formula (I) that are active when administered orally can be formulated as liquids or solids, such as syrups, suspensions, emulsions, tablets, capsules or lozenges.

[0346] Liquid formulations generally consist of a suspension or solution of the active ingredient in a suitable carrier, such as an aqueous solvent, such as water, ethanol or glycerol, or a non-aqueous solvent, such as polyethylene glycol or an oil. The formulation can also contain suspending agents, preservatives, flavoring agents and / or coloring agents.

[0347] Compositions in tablet form can be prepared using any suitable pharmaceutical carriers commonly used for the preparation of solid formulations, such as magnesium stearate, starch, lactose, sucrose and cellulose.

[0348] Compositions in capsule form can be prepared using conventional encapsulation methods. For example, granules containing the active ingredient can be prepared using standard carriers and then filled into hard gelatin capsules; alternatively, a dispersion or suspension can be prepared using any suitable pharmaceutical carrier (such as an aqueous gum, cellulose, silicate or oil) and then filled into soft gelatin capsules.

[0349] 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 can be optimized and then reconstituted with a suitable solvent prior to administration.

[0350] Compositions for nasal administration or inhalation (e.g., topical administration to the lung by inhalation) can be conveniently formulated as aerosols, drops, gels, and powders. Aerosols generally contain a solution or fine suspension of the active ingredient in a pharmaceutically acceptable aqueous or non-aqueous solvent and are usually present in a sealed container in sterile form, either as a single dose or multiple doses, which can take the form of a cartridge or be refillable for use with an atomizing device. Alternatively, the sealed container can be a disposable dispensing 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 or bronchial passages. When the dosage form includes an aerosol dispenser, it will contain a propellant, which can be a compressed gas, such as air, or an organic propellant, such as a chlorofluorocarbon compound or a hydrofluorocarbon. The aerosol dosage form can also take the form of a pump nebulizer.

[0351] Topical administration to the lung can also be achieved by using a dry powder formulation, which contains the compound of the present invention in fine powder form, and optionally one or more carriers or other excipients. A dry powder inhaler (DPI) device is typically used to deliver the dry powder formulation.

[0352] Compositions suitable for buccal or sublingual administration include tablets, lozenges, and troches, in which the active ingredient is formulated with a carrier, such as sugar and gum arabic, tragacanth, or gelatin and glycerin.

[0353] Compositions for rectal administration are conveniently in the form of suppositories, which contain a conventional suppository base, such as cocoa butter.

[0354] Compositions suitable for transdermal administration include ointments, gels, and patches. In one embodiment, the composition is in unit dose form, such as a tablet, capsule, or ampoule.

[0355] In one embodiment of the present invention, the compound of formula (I) is used in combination with one or more additional therapeutic agents. When the compound of formula (I) is used in combination with other therapeutic agents, the compound of formula (I) can be administered sequentially or simultaneously by any convenient route. Alternatively, the compound can be administered alone.

[0356] The present invention is further illustrated by reference to the following examples, without limiting the scope to the specific embodiments described. The present invention includes all combinations of the features described, and in particular combinations of the preferred features that are not mutually exclusive.

[0357] Description of the Drawings

[0358] Figure 1 : Shows the mRNA of the dual reporter gene assay. Firefly luciferase (F Luc) is translated by the eIF4F complex, and Renilla luciferase (R Luc) will be translated independently of this complex.

[0359] Figure 2 : Displays the sequence of the 5’UTR of viral mRNA.

[0360] Figure 3 : Displays the dual-luciferase assay for cap-dependent translation initiation. A: Plasmid MAP of the dual-luciferase detection system. B: Dual-luciferase assay for cap-dependent translation initiation was performed in HeLa cells transfected with the dual-luciferase reporter gene based on pFR_HCV_xb. Cells were treated with compounds 1, 2, 3, 4 (100 nM) in serum-free DMEM for 24 h. After incubation, the dual-luciferase reporter assay was performed according to the manufacturer's instructions, and luminescence was measured using a multiplate reader. The data were calibrated against cells transfected with the indicated mutants and exposed to DMSO for 24 h. DMSO-treated cells were set to 1. Bar graphs represent the mean ± SEM from 3 independent experiments. Dot plots represent the values for each experiment (EV corresponds to the empty vector) Example

[0361] Compounds 1, 2, 3, and 4 can be prepared in a manner similar to PCT / EP 2022 / 025396.

[0362] Compound 1:

[0363]

[0364] Compound 2:

[0365] Compound 3:

[0366] Compound 4:

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R 1 selected from C1-C4 alkyl, wherein the alkyl is unsubstituted or substituted by 1, 2 or 3 substituents R a substituted; C3-C7 heterocycloalkyl, which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, selected from N, NR c , O, S, SO and SO2, and wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R e , and wherein the heterocycloalkyl is attached to the remainder of the molecule through a carbon atom; NR 2 R 3 , wherein R 2 and R 3 are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl and C3-C7 heterocycloalkyl, which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents R h , and wherein the alkyl is unsubstituted or substituted by 1, 2 or 3 substituents R a , and wherein the cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents R b ; R 2 and R 3 together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, 6- or 7-membered saturated or partially unsaturated heterocycle, wherein the heterocycle has 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R d substituted; R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated bicyclic, tricyclic or tetracyclic ring system which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and in which the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R f substituted; R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spiro ring moiety which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R g substituted; R a selected from halogen, OH, C3-C7 cycloalkyl, C1-C3 alkoxy, phenyl, NR 5a R 5b , C1-C4-alkylsulfonyl, C3-C7 heterocycloalkyl, which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents, the substituents being selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, and wherein the C3-C7 cycloalkyl and phenyl are unsubstituted or substituted by 1, 2 or 3 substituents, the substituents being selected from F, Cl, Br and OH; R b selected from halogen, OH, and C1-C3 alkoxy; R c selected from hydrogen, C1-C4-alkyl, C3-C7-cycloalkyl, C1-C4-haloalkyl, C1-C4-cyanoalkyl, carbonyloxy-C1-C4-alkyl and C1-C4-hydroxyalkyl; R d selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy, carboxyl, carbonyloxy-C1-C4-alkyl and NR 5a R 5b ; R e selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, carbonyloxy-C1-C4-alkyl and C1-C4-haloalkoxy; R f selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, C1-C4-haloalkoxy and NR 5a R 5b ; R g selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; R h selected from halogen, C1-C4-alkyl, C1-C4-haloalkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy and C1-C4-haloalkoxy; R 4 selected from Cl, CN and C3-C7 cycloalkyl; R 5a and R 5b are each independently selected from hydrogen, C1-C4-alkyl, and C3-C7-cycloalkyl; R 6 selected from hydrogen and F; R 7 selected from hydrogen and C1-C2-alkyl; The condition is that if R 6 is H, then R 7 is a C1-C2-alkyl, and if R 6 is F, then R 7 is hydrogen; R 8 Selected from OCH3, OCD3; R 9 Selected from OCH3, OCD3; it is used for treating or preventing a disease caused by a viral infection or a disease associated with a viral infection, wherein the disease is selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA).

2. The compound of formula (I) according to claim 1 for treating or preventing a disease caused by a viral infection or a disease associated with a viral infection, wherein the compound (I) is a mixture of (I.a) and (I.b) or a mixture of pharmaceutically acceptable salts thereof, wherein the enantiomeric excess (ee) of the enantiomer of formula (I.a) is at least 20%, preferably at least 50%, particularly at least 80%, especially at least 99%. wherein R 1 , R 4 , R 6 , R 7 , R 8 , R 9 have the same meaning as defined in claim 1.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof for treating or preventing a disease caused by a viral infection or a disease associated with a viral infection according to any one of the above claims, wherein R 6 is F, and R 7 is hydrogen.

4. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease caused by a viral infection or a disease associated with a viral infection according to any one of the above claims, wherein R 1 is selected from: A C1-C4 alkyl group, which is unsubstituted or substituted by 1, 2 or 3 substituents R a or A C3-C7 heterocycloalkyl group containing 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members, selected from NR c and O, wherein the heterocycloalkyl group is unsubstituted or substituted by 1, 2 or 3 identical or different groups R e and wherein the heterocycloalkyl group is attached to the remainder of the molecule through a carbon atom; or NR 2 R 3 , wherein R 2 and R 3 are each independently selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, wherein the alkyl is unsubstituted or substituted by 1, 2 or 3 substituents R a ; wherein the cycloalkyl is unsubstituted or substituted by 1, 2 or 3 substituents R b ; or R 2 and R 3 together with the nitrogen atom to which they are attached form a 3-, 4-, 5- or 6-membered saturated or partially unsaturated heterocycle, wherein the heterocycle has 1, 2 or 3 heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , S, SO and SO2, wherein the heterocycle is unsubstituted or substituted by 1, 2, 3, 4 or 5 identical or different groups R d ; or R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated bicyclic or tricyclic ring system which contains 1, 2 or 3 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c , O, S, SO and SO2, and wherein the heterocycle is unsubstituted or substituted by 1, 2 or 3 identical or different groups R f ; or R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spiro ring moiety which contains 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c and O, and wherein the heterocycle is unsubstituted or substituted by 1, 2 or 3 identical or different groups R g substituted; R 4 、R a 、R b 、R c 、R d 、R e 、R f and R g has one of the meanings defined in claim 1.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in treating or preventing a disease caused by a viral infection or a disease associated with a viral infection according to any one of the preceding claims, wherein R 1 is selected from NR 2 R 3 , wherein R 2 and R 3 are each independently selected from hydrogen, C1-C3 alkyl, and C3-C6 cycloalkyl, wherein the alkyl is unsubstituted or substituted with 1 or 2 substituents R a , and wherein the cycloalkyl is unsubstituted or substituted with 1 or 2 substituents R b , preferably R 2 and R 3 are each independently selected from hydrogen, unsubstituted C2-C3 alkyl, and unsubstituted C3-C6 cycloalkyl; or R 2 and R 3 together with the nitrogen atom to which they are attached form a 5- or 6-membered saturated or partially unsaturated heterocycle which contains 1 or 2 heteroatoms or heteroatom-containing groups as ring members, selected from N, NR c , SO2 and O, where R c is selected from hydrogen, C1-C4-alkyl, where the heterocycle is unsubstituted or substituted by 1 or 2 identical or different groups selected from C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, NH2, N(C1-C2alkyl)2, NH(C1-C2alkyl) and carbonyloxy-C1-C4-alkyl, preferably, R 2 and R 3 together with the nitrogen atom to which they are attached form a pyrrolidine ring, a piperazine ring, an azetidine ring or a morpholine ring, where the pyrrolidine ring, piperazine ring, azetidine ring or morpholine ring is unsubstituted or substituted by 1 or 2 substituents selected from C1-C4-alkyl, C1-C4-hydroxyalkyl, C1-C4-alkoxy, NH2, N(C1-C2alkyl)2, NH(C1-C2alkyl) and carbonyloxy-C1-C4-alkyl; or A C3-C7 heterocycloalkyl group containing 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members, selected from NR c and O, wherein the heterocycloalkyl group is unsubstituted or substituted by 1 or 2 identical or different groups R e and wherein the heterocycloalkyl group is attached to the remainder of the molecule through a carbon atom; or R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated bicyclic ring system which contains 1 or 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N or NR c Preferably, R 2 and R 3 together with the nitrogen atom to which they are attached form an 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl ring system; or R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spiro ring moiety which contains 2 identical or different heteroatoms or heteroatom-containing groups as ring members, which are selected from N, NR c and O, preferably, R 2 and R 3 together with the nitrogen atom to which they are attached form a 2-oxa-6-azaspiro[3.3]heptan-6-yl spiro compound.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof for treating or preventing a disease caused by a viral infection or a disease associated with a viral infection according to claims 1-4, wherein R 1 is selected from C5-C7 heterocycloalkyl which contains 1 or 2 heteroatoms or heteroatom-containing groups as ring members, which are selected from NR c and S, wherein the heterocycloalkyl is attached to the remainder of the molecule through a carbon atom, preferably, R 1 is selected from pyrrolidinyl and piperidinyl.

7. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of the above claims, for the treatment or prevention of a disease caused by a viral infection or a disease associated with a viral infection, wherein R 1 is selected from methyl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, N,N-diethylamino, N-isopropylamino, N-ethylamino, N,N-methyl-isopropylamino, azetidin-1-yl, morpholin-4-yl, N-cyclopentylamino, [1-(4-fluorophenyl)ethyl]amino, (cyclopropylmethyl)amino, 8-methyl-3,8-diazabicyclo[3.2.1]oct-3-yl, 1-methylpiperidin-4-yl, thiomorpholin-4-yl-1,1-dioxide, 3-(dimethylamino)azetidin-1-yl, 4-(dimethylamino)piperidin-1-yl, N-ethyl-1-hydroxyamino, azetidine-3-carbonyloxymethyl, N,N-dimethylaminomethyl, 2-oxa-6-azaspiro[3.3]hept-6-yl and pyrrolidin-3-yl.

8. The compound of formula (I) according to any one of the above claims for treating or preventing a disease caused by a viral infection or a disease associated with a viral infection, selected from compounds of formula A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, W and mixtures of each of compounds A-W with their corresponding enantiomers or selected from mixtures of two or more of compounds (A)-(W) and their enantiomers.

9. The compound of formula (I) according to any one of the above claims for treating or preventing a disease caused by a viral infection or a disease associated with a viral infection, wherein the (+)ssRNA virus is a member selected from the families Togaviridae, Flaviviridae, Coronaviridae and Retroviridae.

10. The compound of formula (I) according to claims 1-8 for treating or preventing a disease caused by a viral infection or a disease associated with a viral infection, wherein the (-)ssRNA virus is a member selected from the families Arenaviridae, Bornaviridae, Bunyaviridae, Filoviridae, Orthomyxoviridae, Paramyxoviridae, Pneumoviridae and Rhabdoviridae, particularly the family Filoviridae.

11. The compound of formula (I) according to any one of claims 1-9 for treating or preventing a disease caused by a viral infection or a disease associated with a viral infection, wherein the Flaviviridae are selected from dengue virus, Japanese encephalitis, Kyasanur Forest disease, Powassan virus, West Nile fever virus, yellow fever virus and Zika virus.

12. The compound of formula (I) according to any one of claims 1-9 for treating or preventing a disease caused by a viral infection or a disease associated with a viral infection, wherein the Coronaviridae are selected from SARS-coV, SARS-CoV-2, MERS-Cov, HCoV-229E, HCoV-NL63, HCovC43 and HKU1.

13. The compound of formula (I) according to any one of claims 1-9 for treating or preventing a disease caused by a viral infection or a disease associated with a viral infection, wherein the Retroviridae are selected from HIV-1 and HIV-2.

14. A compound of formula (I) according to any one of claims 1 - 8 and 10 for the treatment or prevention of a disease caused by a viral infection or a disease associated with a viral infection, wherein the family Filoviridae is selected from Bundibugyo ebolavirus, Reston ebolavirus, Sudan ebolavirus, Taï Forest ebolavirus, Zaire ebolavirus, and Bombali ebolavirus.

15. A compound of formula (I) according to any one of claims 1 - 9 and 11 - 13 for the treatment or prevention of a disease caused by a viral infection or a disease associated with a viral infection, wherein the disease is selected from dengue fever, MERS, COVID - 19, SARS, Ebola fever, AIDS, and Zika fever.

16. A compound of formula (I) according to any one of the above claims for the treatment or prevention of a disease caused by a viral infection or a disease associated with a viral infection, wherein the associated disease is selected from 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 taste, olfactory ability, and visual impairment), myalgia, myocardial inflammation, venous thrombosis, reduced coronary blood flow, cardiogenic shock, heart failure, impaired consciousness, brain inflammation, brain and vascular irritation and swelling, acute cerebrovascular complications (such as stroke, seizure, and slurred speech), arrhythmia, myocarditis, thrombotic events, rhabdomyolysis, neurocognitive deficits, and sensory and motor deficits.

17. Use of a compound of formula (I) as defined in any one of claims 1 - 8 in inhibiting viral activity.

18. The use of claim 17, wherein the virus is selected from positive - sense single - stranded RNA viruses ((+)ssRNA) and negative - sense single - stranded RNA viruses ((-)ssRNA).

19. A method for the treatment or prevention of a disease caused by a viral infection or a disease associated with a viral infection as defined in claims 1 - 14, the method comprising administering a therapeutically effective amount of a compound of formula (I) as defined in any one of claims 1 - 8 or a pharmaceutically acceptable salt thereof.

20. A pharmaceutical composition comprising at least one compound of formula (I) as defined in claims 1 - 8 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable diluent or carrier, the pharmaceutical composition being for the treatment or prevention of a disease caused by a viral infection or a disease associated with a viral infection.

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