1H-Cyclopenta[b]benzofuran Derivatives for the Prevention and Treatment of Viral Diseases

Abstract

The present invention relates to a new therapeutic use of 1H-cyclopenta[b]benzofuran derivatives, specifically to a new use for treating or preventing diseases caused by or associated with viral infection. The present invention further relates to a method for treating or preventing diseases caused by or associated with viral infection. Furthermore, the present invention relates to a pharmaceutical composition for use in treating or preventing diseases caused by or associated with viral infection.

Description

[Technical Field]

[0001] The present invention relates to a new therapeutic use of 1H-cyclopenta[b]benzofuran derivatives, specifically to a new use for treating or preventing diseases caused by or associated with viral infection. The present invention further relates to a method for treating or preventing diseases caused by or associated with viral infection. Furthermore, the present invention relates to a pharmaceutical composition for use in treating or preventing diseases caused by or associated with viral infection. BACKGROUND OF THE INVENTION

[0002] Viral infections pose a major challenge to public health systems worldwide. Despite rapid scientific advances in virology, the lack of effective treatments and vaccines for most viral infections remains a major problem. Emerging viral diseases pose a major threat, primarily due to their rapid transmission and the inherent difficulty of developing effective vaccines and treatments for such new pathogens in a short period of time. Therefore, there is a need to develop broad-spectrum antiviral compounds that are effective against multiple viruses. Most currently available antiviral agents target one or more components directly related to the viral life cycle. As such, their activity tends to be limited to closely related viruses, often within the same viral family. Certain nucleoside analogues, including cidofovir, favipiravir, and ribavirin, have been shown to be effective against a wide range of viruses, but there is a significant risk of developing antiviral resistance, primarily among RNA viruses.

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

[0004] Extracellular virus particles are called virions. Virions are particles containing nucleic acid (either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA)) and are usually enclosed in a protein capsule (capsid). However, influenza viruses lack a capsule and instead contain ribonucleoproteins. Some virions are enveloped by a biological membrane. The lipid bilayer of the biological membrane is interspersed with viral membrane proteins, which is called the viral envelope. Virions that temporarily possess a viral envelope in addition to a capsid until the replication stage begins are called enveloped, while viruses without such an envelope are called non-enveloped.

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

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

[0007] Similar studies have been conducted on other eIF4A inhibitors. R. Cencic et al., J. Virology, 2011, 6381, described that the compound 4E2Rcat (432499-63-3), an inhibitor of eIF4E-eIF4G interaction, can inhibit coronavirus replication.

[0008] E. Gordon et al., bioRxiv (March 22, 2020) explores the molecular details of SARS-CoV-2 infection. To this end, viral proteins in human cells were cloned, tagged, and expressed. Physically associated human proteins were identified. Additionally, 66 druggable human proteins or host factors, notably zotatifin (eFT226), targeted by 69 existing FDA-approved drugs, drugs in clinical trials, and / or preclinical compounds were identified. The efficacy of these compounds was evaluated in a live SARS-CoV-2 infection assay.

[0009] eFFECTOR's Therapeutic (April 30, 2020) reported that the antitumor drug zotatifin showed antiviral activity against SARS-CoV-2.

[0010] EP2457907 relates to flavone derivatives and their use as neuroprotective, cardioprotective and antitumor agents, in particular for treating neurological disorders, which may be caused by HIV infection. This document discloses the flavones FL42 and FL44.

[0011] EP 3639820 relates to flavugin derivatives and their use as inhibitors of KRAS oncogene activation.

[0012] However, there remains a great need for compounds that exhibit broad spectrum antiviral properties. It is therefore an object of the present invention to provide pharmaceutically active compounds that have inhibitory potency against viral activity. Summary of the Invention

[0013] The present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease caused by or associated with a viral infection, JPEG2025530340000001.jpg8090In formula, R 1 but, C1-C4 alkyl, wherein the alkyl is unsubstituted or has 1, 2 or 3 substituents R a C1-C4 alkyl substituted with; C3-C7 heterocycloalkyl, wherein the C3-C7 heterocycloalkyl is one, two or three of the same or different, N, NR C , O, S, SO, and SO2 as ring members, and the heterosilyl group is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R e and wherein said heterocycloalkyl is attached to the remainder of the molecule through a carbon atom; and NR 2 R 3 And, R 2 and R3 are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, and C3-C7 heterocycloalkyl, and the C3-C7 heterocycloalkyl is selected from 1, 2 or 3 of the same or different N, NR C , O, S, SO, and SO2 as ring members, and the heterosilyl group is unsubstituted or contains 1, 2, or 3 substituents R h and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents R a and said cycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents R b is replaced by; 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 heterocyclic ring, said heterocyclic ring containing 1, 2, or 3 identical or different N, NR C , O, S, SO, and SO2 as ring members, and the heterocycle is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R d is replaced by; 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 heterocyclic ring, said heterocyclic ring containing one, two, or three identical or different N, NR C , O, S, SO, and SO2 as ring members, and the heterocycle is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R f is replaced by; or R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spirocyclic ring system, said spirocyclic ring system being composed of one, two or three identical or different N, NR C, O, S, SO, and SO2 as ring members, and the spirocyclic ring is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R g substituted with NR 2 R 3 Selected from; R a is halogen, OH, C3-C7 cycloalkyl, C1-C3 alkoxy, phenyl, NR 5a R 5b , C1-C4 alkylsulfonyl, and C3-C7 heterosilylalkyl, wherein the C3-C7 heterosilylalkyl is selected from the group consisting of 1, 2, or 3 of the same or different, N, NR C , O, S, SO, and SO2 as ring members, wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents selected from halogen, C1-C4 alkyl, and C1-C4 haloalkyl, and the C3-C7 cycloalkyl and phenyl are unsubstituted or substituted with 1, 2, or 3 substituents selected from F, Cl, Br, and OH; R b is selected from halogen, OH and C1-C3 alkoxy; 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; R d is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, carboxy, carbonyloxy-C1-C4-alkyl, and NR 5a R 5b Selected from; R eis 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 is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and NR 5a R 5b Selected from; R g is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; R h is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; R 4 is selected from Cl, CN, and C3-C7 cycloalkyl; R 5a and R 5b are independently selected from hydrogen, C1-C4 alkyl, and C3-C7 cycloalkyl; R 6 is selected from hydrogen and F; R 7 is selected from hydrogen and C1-C2 alkyl; However, R 6 If H, then R 7 is a C1-C2 alkyl, and R 6 If F, then R 7 is hydrogen; R 8 is selected from OCH3 and OCD3; R 9 is selected from OCH3 and OCD3.

[0014] Preferably, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease caused by or associated with a viral infection, wherein said disease is selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA), JPEG2025530340000002.jpg8287In formula, R 1 but, C1-C4 alkyl, wherein the alkyl is unsubstituted or has 1, 2 or 3 substituents R a C1-C4 alkyl substituted with; C3-C7 heterocycloalkyl, wherein the C3-C7 heterocycloalkyl is one, two or three of the same or different, N, NR C , O, S, SO, and SO2 as ring members, and the heterosilyl group is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R e and wherein said heterocycloalkyl is attached to the remainder of the molecule through a carbon atom; and NR 2 R 3 And, R 2 and R 3 are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, and C3-C7 heterocycloalkyl, and the C3-C7 heterocycloalkyl is selected from 1, 2 or 3 of the same or different N, NR C , O, S, SO, and SO2 as ring members, and the heterosilyl group is unsubstituted or contains 1, 2, or 3 substituents R h and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents R a and said cycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents R b is replaced by; 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 heterocyclic ring, said heterocyclic ring containing 1, 2, or 3 identical or different N, NR C , O, S, SO, and SO2 as ring members, and the heterocycle is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R d is replaced by; 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 heterocyclic ring, said heterocyclic ring containing one, two, or three identical or different N, NR C , O, S, SO, and SO2 as ring members, and the heterocycle is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R f is replaced by; or R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spirocyclic ring system, said spirocyclic ring system being composed of one, two or three identical or different N, NR C , O, S, SO, and SO2 as ring members, and the spirocyclic ring is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R g substituted with NR 2 R 3 Selected from; R a is halogen, OH, C3-C7 cycloalkyl, C1-C3 alkoxy, phenyl, NR 5a R 5b , C1-C4 alkylsulfonyl, and C3-C7 heterosilylalkyl, wherein the C3-C7 heterosilylalkyl is selected from the group consisting of 1, 2, or 3 of the same or different, N, NR C, O, S, SO, and SO2 as ring members, wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents selected from halogen, C1-C4 alkyl, and C1-C4 haloalkyl, and the C3-C7 cycloalkyl and phenyl are unsubstituted or substituted with 1, 2, or 3 substituents selected from F, Cl, Br, and OH; R b is selected from halogen, OH and C1-C3 alkoxy; 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; R d is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, carboxy, carbonyloxy-C1-C4-alkyl, and NR 5a R 5b Selected from; 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; 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 Selected from; R g is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; R h is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; R 4 is selected from Cl, CN, and C3-C7 cycloalkyl; R 5a and R 5b are independently selected from hydrogen, C1-C4 alkyl, and C3-C7 cycloalkyl; R 6 is selected from hydrogen and F; R 7 is selected from hydrogen and C1-C2 alkyl; However, R 6 If H, then R 7 is a C1-C2 alkyl, and R 6 If F, then R 7 is hydrogen; R 8 is selected from OCH3 and OCD3; R 9 is selected from OCH3 and OCD3.

[0015] In particular, the present invention relates to a compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease, said disease being selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA), JPEG2025530340000003.jpg7988In formula, R 1 but, C1-C4 alkyl, wherein the alkyl is unsubstituted or has 1, 2 or 3 substituents R a C1-C4 alkyl substituted with; C3-C7 heterocycloalkyl, wherein the C3-C7 heterocycloalkyl is one, two or three of the same or different, N, NR C , O, S, SO, and SO2 as ring members, and the heterosilyl group is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R eand wherein said heterocycloalkyl is attached to the remainder of the molecule through a carbon atom; and NR 2 R 3 And, R 2 and R 3 are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, and C3-C7 heterocycloalkyl, and the C3-C7 heterocycloalkyl is selected from 1, 2 or 3 of the same or different N, NR C , O, S, SO, and SO2 as ring members, and the heterosilyl group is unsubstituted or contains 1, 2, or 3 substituents R h and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents R a and said cycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents R b is replaced by; 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 heterocyclic ring, said heterocyclic ring containing 1, 2, or 3 identical or different N, NR C , O, S, SO, and SO2 as ring members, and the heterocycle is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R d is replaced by; 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 heterocyclic ring, said heterocyclic ring containing one, two, or three identical or different N, NR C , O, S, SO, and SO2 as ring members, and the heterocycle is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R f is replaced by; or R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spirocyclic ring system, said spirocyclic ring system being composed of one, two or three identical or different N, NR C , O, S, SO, and SO2 as ring members, and the spirocyclic ring is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R g substituted with NR 2 R 3 Selected from; R a is halogen, OH, C3-C7 cycloalkyl, C1-C3 alkoxy, phenyl, NR 5a R 5b , C1-C4 alkylsulfonyl, and C3-C7 heterosilylalkyl, wherein the C3-C7 heterosilylalkyl is selected from the group consisting of 1, 2, or 3 of the same or different, N, NR C , O, S, SO, and SO2 as ring members, wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents selected from halogen, C1-C4 alkyl, and C1-C4 haloalkyl, and the C3-C7 cycloalkyl and phenyl are unsubstituted or substituted with 1, 2, or 3 substituents selected from F, Cl, Br, and OH; R b is selected from halogen, OH and C1-C3 alkoxy; 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; R d is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, carboxy, carbonyloxy-C1-C4-alkyl, and NR 5a R5b Selected from; 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; 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 Selected from; R g is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; R h is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; R 4 is selected from Cl, CN, and C3-C7 cycloalkyl; R 5a and R 5b are independently selected from hydrogen, C1-C4 alkyl, and C3-C7 cycloalkyl; R 6 is selected from hydrogen and F; R 7 is selected from hydrogen and C1-C2 alkyl; However, R 6 If H, then R 7 is a C1-C2 alkyl, and R 6 If F, then R 7 is hydrogen; R 8 is selected from OCH3 and OCD3; R 9 is selected from OCH3 and OCD3.

[0016] The present invention further relates to a method for treating or preventing a disease caused by or associated with a viral infection, as defined above and below, said method comprising administering a therapeutically effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0017] Preferably, the present invention further relates to a method for treating or preventing a disease caused by or associated with a viral infection, as defined above and below, wherein said disease is selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA), said method comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined herein.

[0018] In particular, the present invention further relates to a method for treating or preventing a disease, said disease being selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA) as defined above and below, said method comprising administering a therapeutically effective amount of a compound of formula (I) as defined herein or a pharmaceutically acceptable salt thereof.

[0019] The present invention further relates to a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above and below, and a pharmaceutically acceptable diluent or carrier, for use in the treatment or prevention of a disease caused by or associated with a viral infection.

[0020] Preferably, the present invention further relates to a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above and below, and a pharmaceutically acceptable diluent or carrier, for use in the treatment or prevention of a disease caused by or associated with a viral infection, said disease being selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA).

[0021] In particular, the present invention relates to a pharmaceutical composition comprising at least one compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above and below, and a pharmaceutically acceptable diluent or carrier, for use in the treatment or prevention of a disease, said disease being selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA).

[0022] The present invention further relates to the use of compounds of formula (I) as defined herein for inhibiting viral activity. In particular, the present invention relates to the use of compounds of formula (I) as defined herein for inhibiting viral activity.

[0023] Preferably, the present invention further relates to the use of compounds of formula (I) as defined herein for inhibiting viral activity. In particular, the present invention relates to the use of compounds of formula (I) as defined herein for inhibiting viral activity, wherein said viruses are selected from positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA). Description of the invention

[0024] The present invention has the following advantages: The compounds according to the invention exhibit advantageous virus-inhibiting properties: (+)ssRNA viruses, such as coronaviruses and picocoronaviruses, rely on host 5' cap-dependent and cap-independent strategies for translation initiation of viral mRNAs. - Some viruses utilize membrane-associated prohibitin for host cell entry. - The present invention describes a class of molecules that target PHB both at the cell membrane and in the eIF4A complex, thereby preventing viral entry and replication.

[0025] Compounds of formula (I) Unless otherwise stated herein, references in the singular may include the plural, for example, "a" and "an" may refer to one or more.

[0026] In the context of this invention, the prefix C n -C m indicates the number of carbon atoms that the molecule or residue designated thereby may contain.

[0027] In the context of the present invention, the expression "C1-C4-alkyl" refers to an unbranched or branched saturated hydrocarbon group having 1 to 4 carbon atoms. C1-C4-alkyl is, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl.

[0028] In the context of the present invention, the expression "C1-C4-alkoxy" refers to an unbranched or branched saturated C1-C4-alkyl radical as defined above, which is bonded via an oxygen atom. Alkoxy radicals having 1 or 2 carbon atoms are 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).

[0029] In the context of the present invention, the expression "carbonyloxy-C1-C4-alkyl" designates an unbranched or branched saturated C1-C4-alkyl radical as defined above, which is bonded via a carboxyl group.

[0030] In the context of the present invention, the expressions "haloalkyl" and "haloalkoxy" refer to a partially or fully halogenated alkyl or alkoxy, 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 the alkyl or alkoxy, are replaced by halogen atoms, in particular fluorine or chlorine.

[0031] In the context of the present invention, the expression "hydroxyalkyl" refers to a partially or fully hydroxylated alkyl, 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 the alkyl, are replaced with hydroxy atoms.

[0032] In the context of the present invention, the expression "C3-C7-cycloalkyl" designates a monocyclic alicyclic radical having 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl, preferably cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

[0033] The expression "halogen" means in each case fluorine, chlorine, bromine or iodine.

[0034] In the context of the present invention, "a 3-, 4-, 5-, 6-, or 7-membered saturated or partially unsaturated heterocycle containing 1, 2, or 3 heteroatoms or heteroatom-containing groups" is defined as a heterocyclic ring, wherein said heteroatoms (groups) are selected from the group consisting of N, O, S, NR C, SO, and SO2, and is a ring member." refers to a monocyclic or polycyclic radical that is linked to the rest of the molecule via a nitrogen ring member. "Heterocycle" also includes in particular "polycyclic", e.g., bicyclic, tricyclic or tetracyclic ring systems, in which one of the above monocyclic heterocyclyl residues is in each case fused or bridged with at least one further identical or different heterocycle or at least one cycloalkyl according to the above definitions. Examples of 3-, 4-, 5-, 6-, or 7-membered saturated heterocycles include aziridinyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, 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, Examples of 3-, 4-, 5-, 6-, or 7-membered partially unsaturated heterocycles include pyrrolinyl, isoxazolinyl, isothiazolinyl, dihydropyrazolyl, tetrahydropyridinyl, tetrahydropyridazinyl, tetrahydropyridazinyl, and tetrahydropyrimidinyl. Examples of 3-, 4-, 5-, 6-, or 7-membered polycyclic ring systems, particularly bicyclic, tricyclic, or tetracyclic ring systems, include 8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl.

[0035] In the context of the present invention, the expression "C3-C7 heterocycloalkyl" refers to a saturated alicyclic group having 3 to 7, preferably 3 to 6, ring atoms, in which 1, 2 or 3 ring carbon atoms are preferably NRC , O, S, SO, and SO2, and may be optionally substituted with a heteroatom or heteroatom-containing group. When substituted, these heterocycloalkyl groups preferably have 1, 2, or 3, particularly preferably 1 or 2, and especially 1, substituent. The heterocycloalkyl group refers to a monocyclic radical attached to the rest of the molecule via a carbon ring member. Examples of such heteroaliphatic residues include 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- Examples include 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, hexahydroazepinyl, hexahydrooxepinyl, hexahydrodiazepinyl, and hexahydrooxazepinyl.

[0036] In the context of the present invention, the term "spiro" refers to a compound having at least two molecular rings that share only one atom in common.

[0037] Compounds of formula (I), particularly formulas (Ia), (Ib), (A), (B), (C), (D), (E), (F), (G), (H), (I), (J), (K), (L), (M), (N), (O), (P), (Q), (R), (S), (T), (U), (V), and (W), and mixtures of their enantiomers, may form salts, which are also within the scope of the present invention. As used herein, the term "salt" refers to acidic and / or basic salts formed with inorganic and / or organic acids and bases. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful, for example, in isolation or purification steps that may be used during preparation. Salts of compounds of formula (I), in particular of formulae (Ia), (Ib), (A), (B), (C), (D), (E), (F), (G), (H), (I), (J), (K), (L), (M), (N), (O), (P), (Q), (R), (S), (T), (U), (V), and (W), or enantiomeric mixtures thereof, can be prepared, for example, from compounds of formula (I), in particular of formula (Ia) , (Ib), (A), (B), (C), (D), (E), (F), (G), (H), (I), (J), (K), (L), (M), (N), (O), (P), (Q), (R), (S), (T), (U), (V), and (W), or a mixture of enantiomers thereof, with at least one acid or base, said acid or base being added in an amount appropriate for partial or complete neutralization, e.g., equivalent amounts.

[0038] As used herein, unless otherwise indicated, the phrase "pharmaceutically acceptable salt" includes salts containing pharmacologically acceptable anions or cations, such as chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, thenate, tartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, sulfate, benzenesulfonate, p-toluenesulfonate, and palmoate [i.e., 4,4'-methylene-bis-(3-hydroxy-2-naphthoate)] salts.

[0039] In the context of the present invention, chemical structures that do not explicitly depict a particular stereochemical orientation generally refer to all possible stereoisomers and mixtures thereof, unless otherwise indicated. For example: JPEG2025530340000004.jpg6879In the formula, * indicates an asymmetric center.

[0040] A "chiral compound" in the sense of the present invention is one that has an inappropriate axis of rotation (S n In the context of the present invention, they are in particular compounds which have at least four asymmetric centers and do not contain S n It is a compound that has no symmetry.

[0041] In the context of this invention, "stereoisomers" are compounds that are identical in structure but differ in the arrangement of their atoms in three-dimensional space.

[0042] "Enantiomers" are stereoisomers that behave as mirror images of each other, for example, the compounds of formula (Ia) and (Ib) are enantiomers. The "enantiomeric excess" (ee) achieved in asymmetric synthesis is given herein by ee [%] = (RS) / (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. Enantiomerically pure compounds (ee = 100%) are also called "homochiral compounds."

[0043] "Diastereomers" are stereoisomers that are not mirror images of one another.

[0044] The compounds of the present invention can exist in one or more tautomeric forms, including various isomeric forms and both single tautomers and mixtures of tautomers. The term "isomer" is intended to encompass all isomeric forms of the compounds of the present invention, including tautomeric forms of said compounds.

[0045] Some compounds described herein may have asymmetric centers and therefore exist in different enantiomeric and diastereomeric forms. The compounds of the present invention may be in the form of optical isomers or diastereomers. Accordingly, the present invention encompasses the use and use of the compounds of the present invention described herein in the form of their optical isomers, diastereomers, and mixtures thereof, including racemic mixtures. Optical isomers of the compounds of the present invention can be obtained by known techniques, such as asymmetric synthesis or chiral chromatography, or by chemical separation of stereoisomers using optically active resolving agents.

[0046] Unless otherwise indicated, "stereoisomer" means one stereoisomer of a compound that is substantially free of other stereoisomers of that compound. Thus, a stereoisomerically pure compound having one chiral center will be substantially free of the opposite enantiomer of the compound. A stereoisomerically pure compound having two chiral centers will be substantially free of other diastereomers of the 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, e.g., 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.

[0047] "Stereoisomers" refers to compounds consisting of the same atoms joined by the same bonds but having different, incompatible three-dimensional structures.

[0048] The present invention contemplates various stereoisomers and mixtures thereof, and thus includes "enantiomers," which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0049] The compounds of the present invention, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms, which, in terms of absolute stereochemistry, may be defined as (R)- or (S)-, or (D)- or (L)-, in the case of amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from appropriate optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography.

[0050] Relative configuration in stereochemistry (relative stereochemistry) is the arrangement of atoms or groups of atoms described in relation to other atoms or groups of atoms in a molecule. In other words, this term describes the position of an atom or group of atoms in space relative to other atoms or groups of atoms located elsewhere in the molecule.

[0051] In stereochemistry (absolute stereochemistry), absolute configuration is the arrangement of atoms or groups of atoms described independently of any other atoms or groups of atoms in a molecule. This type of configuration is defined for chiral molecular entities and their stereochemical description (e.g., R or S).

[0052] Syn means that with respect to the orientation of the substituents on the five-membered ring to which they are attached (the four asymmetric carbon atoms), all of the substituents point in the same direction relative to the plane of the five-membered ring.

[0053] The designation (+ / -) in the formula according to the invention indicates that the compound is present as a racemic mixture.

[0054] A racemic mixture or racemic compound is defined as a mixture of compounds consisting of two molecules whose structures are like image and mirror image (= enantiomers) and are present in the mixture in equimolar amounts, i.e. in a 1:1 (50:50) ratio.

[0055] Compounds of formula (I.a') relate to compounds in which the relative stereochemistry of said compounds is specified, JPEG2025530340000005.jpg7387In formula, R 1 , R 4 , R 6 , R 7 , R 8 , and R 9 has one of the meanings defined above or below.

[0056] The compounds of formula (I.a') all have syn relative stereochemistry and are racemic mixtures of two enantiomers (all four substituents attached to the five-membered ring point in the same direction).

[0057] One preferred embodiment of the present invention is the racemic mixture of formula (I.a').

[0058] In other words, compound (I.a')((+ / -)) refers to a mixture of compounds (Ia) and (Ib) shown below, where the ratio of (Ia):(Ib) is 1:1, JPEG2025530340000006.jpg80163In formula, R 1 , R 4 , R 6 , R 7 , R 8 , and R 9 has one of the meanings defined above or below.

[0059] Compounds of formula (I) (where * indicates an asymmetric center) JPEG2025530340000007.jpg6585 represents isomers of formula (Ia), (Ib), (Ic), (Id), (Ie), (If), (Ig), (Ih), (Ii), (Ij), (Ik), (Il), (Im), (In), (Io), and (Ip), JPEG2025530340000008.jpg222111JPEG2025530340000009.jpg217110In formula, R 1 , R 4 , R 6 , R 7 , R 8 , and R 9 has one of the meanings defined above or below.

[0060] The compounds of formulae (Ia) to (Ip) are characterized by their absolute stereochemistry.

[0061] In a preferred embodiment, the compound of formula (I) is a mixture of at least two enantiomers (Ia) to (Ip), or a mixture of pharmaceutically acceptable salts thereof, wherein one enantiomer is enriched.

[0062] Preferably, the compound of formula (I) is a mixture of (Ia) and (Ib) or a mixture of pharmaceutically acceptable salts thereof, wherein the enantiomeric excess (ee) of the enantiomer of formula (Ia) is at least 20%, preferably at least 50%, particularly at least 80%, and especially at least 99%.

[0063] Preferred are compounds of formula (I) of the present invention or pharmaceutically acceptable salts thereof, wherein R 8 and R 9 Both are OCH3.

[0064] Further preferred are compounds of formula (I) of the present invention or pharmaceutically acceptable salts thereof, wherein R 6 is F and R 7 is hydrogen.

[0065] Preferred are compounds of formula (I) in which R 1 but, unsubstituted or containing 1, 2 or 3 substituents R a C1-C4 alkyl substituted with; or 1 or 2 identical or different, NR C and O, and the heterosilyl group is unsubstituted or contains one, two or three identical or different radicals R e and said heterocycloalkyl is attached to the remainder of the molecule through a carbon atom; or NR 2 R 3 And, R 2 and R 3 are each independently selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, wherein said alkyl is unsubstituted or contains 1, 2 or 3 substituents R a and said cycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents R b is replaced by; 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 heterocyclic ring, said heterocyclic ring containing one, two, or three N, NR C , O, S, SO, and SO2 as ring members, and the heterocycle is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R d is replaced by; 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 heterocyclic ring, said heterocyclic ring containing one, two or three identical or different N, NR C, O, S, SO, and SO2 as ring members, and the heterocycle is unsubstituted or contains one, two, or three identical or different radicals R f is replaced by; or R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spirocyclic system, said spirocyclic system being composed of one or two identical or different N, NR C and O, and the spirocyclic ring is unsubstituted or contains one, two or three identical or different radicals R g is replaced by NR 2 R 3 is selected from R 4 , R a , R b , R c , R d , R e , R f , and R g has one of the meanings defined above and below.

[0066] Preferred are compounds of formula (I) in which R 1 but, unsubstituted or containing 1, 2 or 3 substituents R a C1-C4 alkyl substituted with; NR 2 R 3 And, R 2 and R 3 are each independently selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, wherein said alkyl is unsubstituted or contains 1, 2 or 3 substituents R a and said cycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents R b is replaced by; or R 2 and R 3together with the nitrogen atom to which they are attached form a 3-, 4-, 5-, or 6-membered saturated or partially unsaturated heterocyclic ring, said heterocyclic ring containing one, two, or three N, NR C or O, and the heterocycle is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R d is replaced by NR 2 R 3 is selected from.

[0067] In particular, R 1 is a C3-C7 heterocycloalkyl, and the C3-C7 heterocycloalkyl is one or two identical or different NR C and O, and the heterosilyl group is unsubstituted or contains one or two identical or different radicals R e and wherein said heterocycloalkyl 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, said bicyclic ring system containing one or two identical or different N or NR C and 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]octan-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 spirocyclic ring system, said spirocyclic ring system being composed of two identical or different N, NR C and O, and preferably R 2 and R3 together with the nitrogen atom to which they are attached to form a 2-oxa-6-azaspiro[3.3]heptan-6-yl spiro compound.

[0068] More preferably, R 1 teeth, C5-C7 heterocycloalkyl, wherein the C5-C7 heterocycloalkyl is one or two NR C and S, wherein the heterosilyl group is bonded to the rest of the molecule via a carbon atom, preferably a C5-C7 heterosilyl group selected from pyrrolidinyl and piperidinyl; or NR 2 R 3 And, R 2 and R 3 are each independently selected from hydrogen, C1-C3 alkyl, and C3-C6 cycloalkyl, wherein the alkyl is unsubstituted or contains one or two substituents R a and said cycloalkyl is unsubstituted or substituted with 1 or 2 substituents, preferably 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 heterocyclic ring, said heterocyclic ring containing one or two N, NR C , SO2, and O as ring members, and R C is selected from hydrogen, C1-C4 alkyl, and the heterocycle is unsubstituted or substituted with one or two identical or different radicals 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 3together with the nitrogen atom to which they are attached form a pyrrolidine ring, a piperazine ring, an acetidine ring, or a morpholine ring, which pyrrolidine ring, piperazine ring, acetidine ring, or morpholine ring is unsubstituted or substituted with one or two substituents selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, NH2, N(C1-C2 alkyl)2, and NH(C1-C2 alkyl)carbonyloxy-C1-C2-alkyl; 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, said bicyclic ring system comprising one or two identical or different N or NR C and preferably R 2 and R 3 together with the nitrogen atom to which they are attached to form an 8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl ring system, NR 2 R 3 is selected from.

[0069] In particular, R 1 But NR 2 R 3 and R 2 and R 3 are each independently selected from hydrogen, C1-C3 alkyl, and C3-C6 cycloalkyl, and alkyl is unsubstituted or contains one or two substituents R a and cycloalkyl is unsubstituted or substituted by 1 or 2 substituents, particularly 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 heterocyclic ring, said heterocyclic ring containing one or two N, NRC and O, and 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 acetidine ring, or a morpholine ring, and the pyrrolidine ring, the piperazine ring, the acetidine ring, or the morpholine ring is unsubstituted or substituted with one or two substituents selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, and C1-C4 alkoxy.

[0070] In particular, R 1 However, methyl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, N,N-diethylamino, N-isopropylamino, N-ethylamino, N,N-methyl-isopropylamino, acetidin-1-yl, morpholin-4-yl, N-cyclopentylamino, [1-(4-fluorophenyl)ethyl]amino, (cyclopropylmethyl)amino, 8-methyl-3,8-diazabicyclo[3.2.1]octan-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-ethan-1-ol-amino, azetidine-3-carbonyloxymethyl, N,N-dimethylaminomethyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, and pyrrolidin-3-yl, in particular selected from methyl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, N,N-diethylamino, N-isopropylamino, N-ethylamino, N,N-methyl-isopropylamino, acetidin-1-yl, morpholin-4-yl, N-cyclopentylamino, [1-(4-fluorophenyl)ethyl]amino, and (cyclopropylmethyl)amino.

[0071] In a first preferred embodiment, R 1is unsubstituted or contains 1, 2 or 3 substituents R a C1-C4 alkyl substituted with, in particular R 1 is selected from C1-C2 alkyl, especially R 1 is methyl.

[0072] In a second preferred embodiment, R 1 But NR 2 R 3 where R 2 and R 3 are each independently selected from hydrogen and C2-C3 alkyl, and the C2-C3 alkyl is unsubstituted or contains one or two substituents R a , preferably unsubstituted C2-C3 alkyl. In particular, R 1 is hydrogen and R 2 is unsubstituted C2-C3 alkyl, in particular R 1 is hydrogen and R 2 is selected from ethyl and isopropyl.

[0073] In a third preferred embodiment, R 1 But 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 heterocyclic ring, said heterocyclic ring containing one or two 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 acetidine ring, or a morpholine ring, and the pyrrolidine ring, the piperazine ring, the acetidine ring, or the morpholine ring is unsubstituted or substituted with one or two substituents selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, and C1-C4 alkoxy.

[0074] 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-acetidin-1-yl, 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 acetidin-1-yl or a morpholin-4-yl ring.

[0075] In a fourth preferred embodiment, R 1 is selected from C3-C7 heterocycloalkyl, and the C3-C7 heterocycloalkyl is selected from one or two identical or different NR C and O, wherein the heterosilyl group is unsubstituted or contains one, two, or three identical or different radicals R e and said heterocycloalkyl is attached to the rest of the molecule through a carbon atom. 1 is selected from C5-C7 heterocycloalkyl, and the C5-C7 heterocycloalkyl is selected from one or two of C and S, wherein the heterosilyl group is bonded to the remainder of the molecule through a carbon atom.

[0076] In a fifth preferred embodiment, R 1 But 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 is composed of one, two or three identical or different N, NR C , O, S, SO, and SO2 as ring members, and the heterocycle is unsubstituted or contains one, two, or three identical or different radicals R f is substituted with, especially R 1 But NR 2 R 3 where R2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated bicyclic ring system which contains one or two identical or different N or NR C and 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]octan-3-yl ring system.

[0077] In a sixth preferred embodiment, R 1 But 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 spirocyclic system which is composed of one, two or three identical or different N, NR C , O, S, SO, and SO2 as ring members, and the heterocycle is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R g In particular, R 1 But NR 2 R 3 where R 2 and R 3 together with the nitrogen atom to which they are attached to form saturated or partially unsaturated spiro compounds, which contain one or two identical or different N, NR C and O, and the heterocycle is unsubstituted or contains one, two or three identical or different radicals R g and preferably R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spirocyclic system, which is formed by two identical or different N, NR C and O, and in particular R2 and R 3 together with the nitrogen atom to which they are attached to form a 2-oxa-6-azaspiro[3.3]heptan-6-yl spiro compound.

[0078] In particular, R 4 is selected from Cl, CN and C3-C6 cycloalkyl. In particular, R 4 is selected from Cl, CN and cyclopropyl.

[0079] R a is, with or without, preferably selected from C1-C2 alkyl, C3-C6 cycloalkyl and phenyl, where C3-C6 cycloalkyl and phenyl are unsubstituted or substituted with one or two substituents selected from F and Cl. In particular, R a is selected from C1-C2 alkyl, C3-C6 cycloalkyl, and 4-fluorophenyl.

[0080] R b However, regardless of whether it is present or not, it is preferably selected from C1 to C2 alkyl.

[0081] R c is preferably selected from hydrogen and C1-C4 alkyl, particularly C1-C2 alkyl, especially methyl.

[0082] R d However, irrespective of whether or not it is present, it is preferably selected from C1-C4 alkyl, C1-C4 hydroxyalkyl and C1-C4 alkoxy, in particular C1-C2 alkyl and C1-C2 hydroxyalkyl.

[0083] R e with or without halogen, C1-C4 alkyl, C1-C4 haloalkyl, and NR 5a R 5b is selected from.

[0084] R fHowever, regardless of whether or not it is present, it is preferably selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0085] R g However, regardless of whether or not it is present, it is preferably selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0086] R h However, regardless of whether or not it is present, it is preferably selected from halogen, C1-C4 alkyl and C1-C4 haloalkyl.

[0087] R 5a and R 5b are, independently of each other, preferably selected from hydrogen and C1-C4 alkyl, regardless of their presence or absence.

[0088] Another preferred embodiment is a mixture of compounds of formula (I) as defined above and below, or a pharmaceutically acceptable salt thereof, which is a racemic mixture (I.a'), JPEG2025530340000010.jpg7088In formula, R 1 , R 4 , R 6 , R 7 , R 8 , and R 9 has the meaning defined above.

[0089] Another preferred embodiment is a compound of formula (I), which is a compound of formula (Ia) or an enantiomeric mixture comprising compounds of formulas (Ia) and (Ib) or pharmaceutically acceptable salts thereof, JPEG2025530340000011.jpg48127In formula, R 1 , R 4 , R 6 , R 7 , R 8 , and R 9 has the same meaning as defined above and below.

[0090] In particular, the compound of formula (I) is a mixture of (Ia) and (Ib) or a mixture of pharmaceutically acceptable salts thereof, wherein the enantiomeric excess (ee) of the enantiomer of formula (Ia) is at least 20%, preferably at least 50%, particularly at least 80%, and especially at least 99%.

[0091] In particular, the compound of formula (I) is compound (Ia) or a pharmaceutically acceptable salt thereof, JPEG2025530340000012.jpg7981In formula, R 1 , R 4 , R 6 , R 7 , R 8 , and R 9 has the meaning defined above.

[0092] Preferred are compounds of formula (Ia), or racemic mixtures (I.a'), or enantiomeric mixtures comprising compounds of formula (Ia) and (Ib) in a ratio different from 1:1, or pharmaceutically acceptable salts thereof, wherein R 1 but, C1-C4 alkyl, wherein the alkyl is unsubstituted or has 1, 2 or 3 substituents R a C1-C4 alkyl substituted with; or C3-C7 heterocycloalkyl, wherein the C3-C7 heterocycloalkyl is one, two or three of the same or different, N, NR C , O, S, SO, and SO2 as ring members, and the heterosilyl group is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R e and said heterocycloalkyl is attached to the remainder of the molecule through a carbon atom; or NR 2 R 3 where: R 2 and R 3are each independently selected from hydrogen, C1-C4 alkyl, C3-C7 cycloalkyl, and C3-C7 heterocycloalkyl, and the C3-C7 heterocycloalkyl is selected from 1, 2 or 3 of the same or different N, NR C , O, S, SO, and SO2 as ring members, and the heterosilyl group is unsubstituted or contains 1, 2, or 3 substituents R h and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents R a and said cycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents R b is replaced by; or 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 heterocyclic ring, said heterocyclic ring containing 1, 2, or 3 identical or different N, NR C , O, S, SO, and SO2 as ring members, and the heterocycle is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R d is replaced by; or 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 heterocyclic ring, said heterocyclic ring containing one, two, or three identical or different N, NR C , O, S, SO, and SO2 as ring members, and the heterocycle is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R f is replaced by; or R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spirocyclic ring system, said spirocyclic ring system being composed of one, two or three identical or different N, NR C, O, S, SO, and SO2 as ring members, and the spirocyclic ring is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R g substituted with NR 2 R 3 Selected from; R a is halogen, OH, C3-C7 cycloalkyl, C1-C3 alkoxy, phenyl, NR 5a R 5b , C1-C4 alkylsulfonyl, and C3-C7 heterosilylalkyl, wherein the C3-C7 heterosilylalkyl is selected from the group consisting of 1, 2, or 3 of the same or different, N, NR C , O, S, SO, and SO2 as ring members, wherein the heterocycloalkyl is unsubstituted or substituted with 1, 2, or 3 substituents selected from halogen, C1-C4 alkyl, and C1-C4 haloalkyl, and the C3-C7 cycloalkyl and phenyl are unsubstituted or substituted with 1, 2, or 3 substituents selected from F, Cl, Br, and OH; R b is selected from halogen, OH and C1-C3 alkoxy; 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; R d is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, carboxy, carbonyloxy-C1-C4-alkyl, and NR 5a R 5b Selected from; R eis 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 is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, C1-C4 haloalkoxy, and NR 5a R 5b Selected from; R g is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; R h is selected from halogen, C1-C4 alkyl, C1-C4 haloalkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, and C1-C4 haloalkoxy; R 4 is selected from Cl, CN, and C3-C7 cycloalkyl; R 5a and R 5b are independently selected from hydrogen, C1-C4 alkyl, and C3-C7 cycloalkyl; R 6 is selected from hydrogen and F; R 7 is selected from hydrogen and C1-C2 alkyl; However, R 6 If H, then R 7 is a C1-C2 alkyl, and R 6 If F, then R 7 is hydrogen; R 8 is selected from OCH3 and OCD3; R 9 is selected from OCH3 and OCD3.

[0093] Preferred is R 8 and R 9 are both OCH3, or a pharmaceutically acceptable salt thereof.

[0094] Further preferred are R 6 is F and R 7 is hydrogen, or a pharmaceutically acceptable salt thereof.

[0095] Preferred are compounds of formula (Ia), (I.a') or pharmaceutically acceptable salts thereof, wherein R 1 but, C1-C4 alkyl, wherein the alkyl is unsubstituted or has 1, 2 or 3 substituents R a C1-C4 alkyl substituted with; NR 2 R 3 where: R 2 and R 3 are each independently selected from hydrogen, C1-C4 alkyl and C3-C6 cycloalkyl, wherein said alkyl is unsubstituted or contains 1, 2 or 3 substituents R a and said cycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents R b is replaced by; 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 heterocyclic ring, said heterocyclic ring containing one, two, or three N, NR C and O, wherein the heterocycle is unsubstituted or has 1, 2, 3, 4, or 5 identical or different radicals R d substituted with NR 2 R 3 is selected from.

[0096] In particular, R 1 but, C3-C7 heterocycloalkyl, wherein the C3-C7 heterocycloalkyl is one or two identical or different NR Cand O, and the heterosilyl group is unsubstituted or contains one or two identical or different radicals R e and wherein said heterocycloalkyl 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 one or two identical or different N or NR C and 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]octan-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 spirocyclic system, which is formed by two identical or different N, NR C and O, and preferably R 2 and R 3 together with the nitrogen atom to which they are attached to form a 2-oxa-6-azaspiro[3.3]heptan-6-yl spiro compound.

[0097] More preferably, R 1 but, C5-C7 heterocycloalkyl, wherein the C5-C7 heterocycloalkyl is one or two of the following: NR C and S, wherein the heterosilyl group is bonded to the rest of the molecule via a carbon atom, and preferably the C5-C7 heterosilyl group is selected from pyrrolidinyl and piperidinyl; or NR 2 R 3 wherein R2 and R 3 are each independently selected from hydrogen, C1-C3 alkyl and C3-C6 cycloalkyl, wherein the alkyl is unsubstituted or contains one or two substituents R a wherein said cycloalkyl is unsubstituted or substituted with 1 or 2 substituents, preferably 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 heterocyclic ring, said heterocyclic ring containing one or two N, NR c , SO2, and O as ring members, and R c is selected from hydrogen and C1-C4 alkyl, and the heterocycle is unsubstituted or substituted with one or two identical or different radicals 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 acetidine ring, or a morpholine ring, which pyrrolidine ring, piperazine ring, acetidine ring, or morpholine ring is unsubstituted or substituted with one or two substituents selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, C1-C4 alkoxy, NH2, N(C1-C2 alkyl)2, and NH(C1-C2 alkyl)carbonyloxy-C1-C2-alkyl; 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, said bicyclic ring system containing one or two identical or different N or NR C and preferably R 2 and R 3together with the nitrogen atom to which they are attached to form an 8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl ring system, NR 2 R 3 is selected from.

[0098] In particular, R 1 But NR 2 R 3 where R 2 and R 3 are each independently selected from hydrogen, C1-C3 alkyl, and C3-C6 cycloalkyl, wherein the alkyl is unsubstituted or contains one or two substituents R a and said cycloalkyl is unsubstituted or substituted with 1 or 2 substituents R b is substituted with, especially 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 heterocyclic ring, said heterocyclic ring containing one or two N, NR c and O, and 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 acetidine ring, or a morpholine ring, and the pyrrolidine ring, the piperazine ring, the acetidine ring, and the morpholine ring are unsubstituted or substituted with one or two substituents selected from C1-C4 alkyl, C1-C4 hydroxyalkyl, and C1-C4 alkoxy.

[0099] In particular, R 1However, methyl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, N,N-diethylamino, N-isopropylamino, N-ethylamino, N,N-methyl-isopropylamino, acetidin-1-yl, morpholin-4-yl, N-cyclopentylamino, [1-(4-fluorophenyl)ethyl]amino, (cyclopropylmethyl)amino, 8-methyl-3,8-diazabicyclo[3.2.1]octan-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-ethan-1-ol-amino, azetidine-3-carbonyloxymethyl, N,N-dimethylaminomethyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, and pyrrolidin-3-yl, in particular selected from methyl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, N,N-diethylamino, N-isopropylamino, N-ethylamino, N,N-methyl-isopropylamino, acetidin-1-yl, morpholin-4-yl, N-cyclopentylamino, [1-(4-fluorophenyl)ethyl]amino, and (cyclopropylmethyl)amino.

[0100] In a first preferred embodiment, R 1 is unsubstituted or contains 1, 2 or 3 substituents R a C1-C4 alkyl substituted with, in particular R 1 is selected from C1-C2 alkyl, especially R 1 is methyl.

[0101] In a second preferred embodiment, R 1 But NR 2 R 3 where R 2 and R 3 are each independently selected from hydrogen and C2-C3 alkyl, and the C2-C3 alkyl is unsubstituted or contains one or two substituents R a, preferably unsubstituted C2-C3 alkyl. In particular, R 1 is hydrogen and R 2 is unsubstituted C2-C3 alkyl, in particular R 1 is hydrogen and R 2 is selected from ethyl and isopropyl.

[0102] In a third preferred embodiment, R 1 But 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 heterocyclic ring, said heterocyclic ring containing one or two 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 acetidine ring, or a morpholine ring, and the pyrrolidine ring, the piperazine ring, the acetidine ring, or the morpholine ring is unsubstituted or substituted with one or two 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-acetidin-1-yl, 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 acetidin-1-yl or a morpholin-4-yl ring.

[0103] In a fourth preferred embodiment, R 1 is selected from C3-C7 heterocycloalkyl, and the C3-C7 heterocycloalkyl is selected from one or two identical or different NR Cand O, wherein the heterosilyl group is unsubstituted or contains one, two, or three identical or different radicals R e and said heterocycloalkyl is attached to the rest of the molecule through a carbon atom. 1 is selected from C5-C7 heterocycloalkyl, and the C5-C7 heterocycloalkyl is selected from one or two of C and S, wherein the heterosilyl group is bonded to the remainder of the molecule through a carbon atom.

[0104] In a fifth preferred embodiment, R 1 But 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 is composed of one, two or three identical or different N, NR C , O, S, SO, and SO2 as ring members, and the heterocycle is unsubstituted or contains one, two, or three identical or different radicals R f is substituted with, especially R 1 But 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 one or two identical or different 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]octan-3-yl ring system.

[0105] In a sixth preferred embodiment, R 1 But NR2 R 3 where R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spirocyclic system which is composed of one, two or three identical or different N, NR C , O, S, SO, and SO2 as ring members, and the heterocycle is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R g In particular, R 1 But NR 2 R 3 where R 2 and R 3 together with the nitrogen atom to which they are attached to form saturated or partially unsaturated spiro compounds, which contain one or two identical or different N, NR C and O, and the heterocycle is unsubstituted or contains one, two or three identical or different radicals R g and preferably R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spirocyclic system, which is formed by two identical or different N, NR C and O, and in particular R 2 and R 3 together with the nitrogen atom to which they are attached to form a 2-oxa-6-azaspiro[3.3]heptan-6-yl spiro compound.

[0106] In particular, R 4 is selected from Cl, CN and C3-C6 cycloalkyl. In particular, R 4 is selected from Cl, CN and cyclopropyl.

[0107] Another particular embodiment is a compound of formula (IA): JPEG2025530340000013.jpg7686In formula, R 1 and R 4 is selected from the definitions shown in one row in Table 1: Table 1: JPEG2025530340000014.jpg208146JPEG2025530340000015.jpg213145JPEG2025530340000016.jpg57145

[0108] Another particular embodiment is a compound of formula (IA.a'), JPEG2025530340000017.jpg76104In formula, R 1 and R 4 has one of the meanings selected from the definitions shown in row 1 in Table 1 above.

[0109] Another particular embodiment is a compound of formula (IA.a) JPEG2025530340000018.jpg7883In formula, R 1 and R 4 has one of the meanings selected from the definitions shown in row 1 in Table 1 above.

[0110] Another particular embodiment is an enantiomeric mixture comprising a compound of formula (I), a compound of formula (IA.a) and (IA.b) or a pharmaceutically acceptable salt thereof, JPEG2025530340000019.jpg48135In formula, R 1 and R 4 has one of the meanings selected from the definitions shown in row 1 in Table 1 above.

[0111] In particular, the compound of formula (I) is a mixture of formulae (I-Aa) and (IA.b), in which the enantiomeric excess (ee) of the enantiomer of formula (IA.a) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%, and R 1 and R 4has one of the meanings selected from the definitions shown in row 1 in Table 1 above.

[0112] Another particular embodiment is a compound selected from A, B, C, D, E, F, G, H, I, J, K, L, M, N, O, P, Q, R, S, T, U, V, and W, and mixtures of each of compounds A through W with their respective enantiomers, or mixtures thereof. JPEG2025530340000020.jpg209126JPEG2025530340000021.jpg219127JPEG2025530340000022.jpg219129

[0113] Preferred are compounds of formula (A) or enantiomeric mixtures comprising compounds of formula (A) and their enantiomers, especially those in which the enantiomeric excess (ee) of the enantiomer of formula (A) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0114] Preferred are compounds of formula (B) or enantiomeric mixtures comprising compounds of formula (B) and their enantiomers, especially those in which the enantiomeric excess (ee) of the enantiomer of formula (B) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0115] Preferred are compounds of formula (C) or enantiomeric mixtures comprising compounds of formula (C) and their enantiomers, especially those in which the enantiomeric excess (ee) of the enantiomer of formula (C) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0116] Preferred are compounds of formula (D) or enantiomeric mixtures comprising compounds of formula (D) and their enantiomers, especially those in which the enantiomeric excess (ee) of the enantiomer of formula (D) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0117] Preferred are compounds of formula (E) or enantiomeric mixtures comprising compounds of formula (E) and their enantiomers, in particular those in which the enantiomeric excess (ee) of the enantiomer of formula (E) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0118] Preferred are compounds of formula (F) or enantiomeric mixtures comprising compounds of formula (F) and its enantiomers, in particular those in which the enantiomeric excess (ee) of the enantiomer of formula (F) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0119] Preferred are compounds of formula (G) or enantiomeric mixtures comprising compounds of formula (G) and its enantiomers, in particular those in which the enantiomeric excess (ee) of the enantiomer of formula (G) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0120] Preferred are compounds of formula (H) or enantiomeric mixtures comprising compounds of formula (H) and its enantiomers, especially those in which the enantiomeric excess (ee) of the enantiomer of formula (H) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0121] Preferred are compounds of formula (I) or enantiomeric mixtures comprising compounds of formula (I) and their enantiomers, in particular those in which the enantiomeric excess (ee) of the enantiomer of formula (I) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0122] Preferred are compounds of formula (J) or enantiomeric mixtures comprising compounds of formula (J) and their enantiomers, especially those in which the enantiomeric excess (ee) of the enantiomer of formula (J) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0123] Preferred are compounds of formula (K) or enantiomeric mixtures comprising compounds of formula (K) and its enantiomers, in particular those in which the enantiomeric excess (ee) of the enantiomer of formula (K) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0124] Preferred are compounds of formula (L) or enantiomeric mixtures comprising compounds of formula (L) and their enantiomers, in particular those in which the enantiomeric excess (ee) of the enantiomer of formula (L) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0125] Preferred are compounds of formula (M) or enantiomeric mixtures comprising compounds of formula (M) and its enantiomers, in particular those in which the enantiomeric excess (ee) of the enantiomer of formula (M) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0126] Preferred are compounds of formula (N) or enantiomeric mixtures comprising compounds of formula (N) and their enantiomers, in particular those in which the enantiomeric excess (ee) of the enantiomer of formula (N) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0127] Preferred are compounds of formula (O) or enantiomeric mixtures comprising compounds of formula (O) and their enantiomers, especially those in which the enantiomeric excess (ee) of the enantiomer of formula (O) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0128] Preferred are compounds of formula (Q) or enantiomeric mixtures comprising compounds of formula (Q) and its enantiomers, in particular those in which the enantiomeric excess (ee) of the enantiomer of formula (Q) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0129] Preferred are compounds of formula (R) or enantiomeric mixtures comprising compounds of formula (R) and their enantiomers, especially those in which the enantiomeric excess (ee) of the enantiomer of formula (R) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0130] Preferred are compounds of formula (S) or enantiomeric mixtures comprising compounds of formula (S) and its enantiomers, especially those in which the enantiomeric excess (ee) of the enantiomer of formula (S) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0131] Preferred are compounds of formula (T) or enantiomeric mixtures comprising compounds of formula (T) and their enantiomers, in particular those in which the enantiomeric excess (ee) of the enantiomer of formula (T) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0132] Preferred are compounds of formula (U) or enantiomeric mixtures comprising compounds of formula (U) and its enantiomers, in particular those in which the enantiomeric excess (ee) of the enantiomer of formula (U) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0133] Preferred are compounds of formula (V) or enantiomeric mixtures comprising compounds of formula (V) and their enantiomers, in particular those in which the enantiomeric excess (ee) of the enantiomer of formula (V) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0134] Preferably, the enantiomeric excess (ee) of the compound of formula (W), or of the enantiomeric mixture comprising the compound of formula (W) and its enantiomer, in particular of the enantiomer of formula (W), is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%.

[0135] In one embodiment, R 1 is NH2, R 4 is Cl, R 6 F, R 7 is hydrogen, R 8 is OCH3, R 9 is OCH3, and R 1 is N(CH3)2, R 4 is Cl, R 6 F, R 7 is hydrogen, R 8 is OCH3, R 9 Compounds in which is OCH3 are excluded from the present invention.

[0136] virus The present invention provides compounds of formula (I) as defined herein and pharmaceutically acceptable salts thereof ("compounds of the invention") for use in the treatment or prevention of a disease caused by or associated with a viral infection.

[0137] In the sense of the present invention, the term "diseases caused by viral infection", also called "primary diseases", relates to diseases that result directly from a viral infection or that are a manifestation of a series of consecutive diseases (hereinafter referred to as associated diseases).

[0138] In the context of the present invention, the term "diseases associated with viral infections", also called "secondary diseases", primarily refers to diseases in which additional pathogens, such as bacteria, allergens, disinfectants, or viruses different from those of the initial viral infection, attack an organism in which a primary disease ("initial viral infection") has already developed. Diseases associated with viral infections (secondary diseases) often occur when the primary disease weakens the immune system or damages the pathogen's barrier to entry. In some diseases, the treatment of the secondary disease may be the most urgent therapeutic issue, as is the case with AIDS. Secondly, the term "secondary diseases" refers to subsequent diseases resulting from a primary disease. These include, for example, cardiac diseases and neurological complications, as defined below.

[0139] Preferably, the present invention provides compounds of formula (I) as defined herein and pharmaceutically acceptable salts thereof for use in the treatment or prevention of a disease caused by or 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). This is in particular for use in the treatment or prevention of 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).

[0140] Positive-strand RNA viruses ((+)ssRNA viruses) are a group of related viruses that have a positive-stranded, single-stranded genome made of ribonucleic acid. This positive-strand genome can function as messenger RNA (mRNA) and can be directly translated into viral proteins by host cell ribosomes. Positive-strand RNA viruses encode an RNA-dependent RNA polymerase (RdRp), which is used during genome replication to synthesize a negative-strand antigenome. This antigenome is then used as a template to create a new positive-strand viral genome.

[0141] In particular, the (+)ssRNA virus is a member of a family selected from the families Togaviridae, Flaviviridae, Coronaviridae, and Retroviridae.

[0142] The Togaviridae family is a family of enveloped, positive-stranded RNA viruses. It currently includes two genera of enveloped viruses with positive-stranded, single-stranded RNA. The Togaviridae family includes virus species in the genera Alphavirus and Rubella virus. Alphaviruses transmit disease to humans and animals via insects. Rubella virus is transmitted exclusively between humans via the respiratory system.

[0143] The Flaviviridae family is a family of enveloped, positive-stranded RNA viruses that primarily infect mammals and birds. They are spread primarily by arthropods (primarily ticks and mosquitoes). The Flaviviridae family 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.

[0144] Coronavirus is the general name for the Coronaviridae and Orthocoronavirus families, also called the Coronavirinae subfamily. The Coronaviridae family is a family of enveloped, positive-stranded RNA viruses. Coronaviruses cause disease in mammals and birds. In humans, the viruses cause respiratory infections.

[0145] The Coronaviridae family includes virus species of the genera Alphacoronavirus, Betacoronavirus and Torovirus. Preferably, the Coronaviridae family is selected from SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-NL63, HCoVC43, and HKU1.

[0146] Four human coronaviruses cause mild illness, typically similar to the common cold, while three are known to cause more severe illness and can be fatal: SARS-CoV-1, which causes SARS; MERS-CoV, which causes MERS; and SARS-CoV-2, which causes COVID-19.

[0147] Severe acute respiratory syndrome coronavirus 1 (SARS-CoV-1 or SARS-CoV) is a type of coronavirus that causes severe acute respiratory syndrome (SARS). It often causes severe illness, characterized by initial systemic symptoms of myalgia, headache, and fever, followed by respiratory symptoms, primarily cough, dyspnea, and pneumonia, over 2–14 days. Another common finding in SARS patients is a decreased number of circulating lymphocytes in the blood. SARS-CoV is a member of the Betacoronavirus genus and the Envecovirus subgenus.

[0148] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a type of coronavirus that causes the respiratory illness COVID-19. SARS-CoV-2 is a virus of the severe acute respiratory syndrome-related coronavirus (SARSr-CoV) species, related to the SARS-CoV-1 virus. SARS-CoV-2 is a member of the Betacoronavirus genus and the Envecovirus subgenus.

[0149] Middle East respiratory syndrome-related coronavirus (MERS-CoV) is the virus that causes Middle East respiratory syndrome (MERS). It is a type of coronavirus that infects humans, bats, and camels. This species is a member of the genus Betacoronavirus and the subgenus Merbecovirus.

[0150] Human coronavirus 229E (HCoV-229E) is a type of coronavirus that infects humans and bats. It is a type of virus that causes the common cold. HCoV-229E is a member of the Alphacoronavirus genus and the Dubinacovirus subgenus.

[0151] Human coronavirus NL63 (HCoV-NL63) is a type of coronavirus, specifically a Cetrachovirus, of the alphacoronavirus genus. This virus is present worldwide and is associated with a number of common illnesses and conditions, including mild to moderate upper respiratory tract infections, severe lower respiratory tract infections, croup, and bronchiolitis.

[0152] Human coronavirus OC43 (HCoV-OC43) is a member of the Betacoronavirus genus that infects humans and cattle. OC43 is one of seven coronaviruses known to infect humans. It is a type of virus that causes the common cold. It is a member of the Betacoronavirus genus and the Envecovirus subgenus.

[0153] Human coronavirus HKU1 (HCoV-HKU1) is a type of coronavirus in humans and animals. It causes an upper respiratory tract illness similar to the common cold, but can progress to pneumonia and bronchiolitis. HCoV-HKU1 is a member of the Betacoronavirus genus and the Envecovirus subgenus.

[0154] The Retroviridae family is a family of enveloped, positive-stranded RNA viruses. The Retroviridae family includes, among others, the genera Deltoretrovirus and Lentivirus. Lentiviruses cause chronic and fatal diseases in humans and other mammalian species, characterized by long latency periods. This genus includes the human immunodeficiency virus (HIV), which causes AIDS.

[0155] Negative-strand RNA viruses ((-)ssRNA viruses) are a group of related viruses with negative, single-stranded genomes made of ribonucleic acid. They have a genome that serves as the complementary strand to which messenger RNA (mRNA) is synthesized by the viral enzyme RNA-dependent RNA polymerase (RdRp). During viral genome replication, RdRp synthesizes a positive-strand antigenome and uses it as a template to create the genome negative-strand RNA. Negative-strand RNA viruses share several other common features, and most contain a viral envelope surrounding a capsid that encases the viral genome. The genomes of (-)ssRNA viruses are usually linear, and their genomes are commonly segmented.

[0156] Preferably, the (-)ssRNA virus is a member of a family selected from the families Arenaviridae, Bornaviridae, Bunyviridae, Filoviridae, Othymyxoviridae, Paramyxoviridae, Pneumoviridae, and Rhabdoviridae, in particular Filoviridae.

[0157] Preferably, the Filoviridae family is selected from Bundibugyo Ebolavirus, Reston Ebolavirus, Sudan Ebolavirus, Tai Forest Ebolavirus, Zaire Ebolavirus, and Bombali Ebolavirus.

[0158] As defined above, positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA) account for the majority of known viruses, including many pathogens and less clinically serious pathogens such as the rhinovirus that causes the common cold. Thus, in one embodiment, the disease is a disease associated with positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA).

[0159] In a preferred embodiment, the compound of formula (I) is for use in the treatment or prevention of a disease caused by a viral infection, in particular for use in the treatment or prevention of a disease selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA), especially when said disease is selected from dengue fever, MERS, COVID-19, SARS, Ebola, AIDS, and Zika.

[0160] In a preferred embodiment, the compounds of formula (I) are for use in the treatment or prevention of diseases associated with viral infections.

[0161] Diseases associated with positive-strand single-stranded RNA virus infections and negative-strand single-stranded RNA virus infections include various complications, including respiratory distress, pulmonary fibrosis, pneumonia, cytokine storm, acute liver injury, septic shock, acute kidney injury, pancreatic injury, peripheral nervous system complications (e.g., taste disorders, olfactory disorders, and visual impairments), muscle pain, myocardial inflammation, venous thrombosis, reduced coronary artery blood flow, cardiogenic shock, heart failure, impaired consciousness, brain inflammation, inflammation and swelling of the brain and blood vessels, acute cerebrovascular complications (e.g., stroke, seizures, and slurred speech), arrhythmia, myocarditis, thrombotic events, rhabdomyolysis, neurocognitive disorders, and sensory and motor disorders. The present invention encompasses complications caused by SARS-CoV-2 infection.

[0162] In one embodiment, the disease is pulmonary inflammation. Suitably, the pulmonary inflammation is caused by a pathogen infection, a bacterial infection, a fungal infection, or a viral infection, particularly a (+)ssRNA viral infection. More suitably, the pulmonary inflammation is caused by a disease selected from the group consisting of pneumonia, acute respiratory distress syndrome (ARDS), CORD, asthma, idiopathic pulmonary fibrosis, allergic rhinitis, rhinitis, and sinusitis. More suitably, the pulmonary inflammation is caused by CORD, asthma, or idiopathic pulmonary fibrosis. Even more suitably, the pulmonary inflammation is caused by CORD. Even more suitably, the pulmonary inflammation is caused by asthma. Even more suitably, the pulmonary inflammation is caused by idiopathic pulmonary fibrosis.

[0163] In one embodiment, the compounds of the invention are used to treat hyperinflammation associated with a positive single-stranded RNA virus infection, such as a coronavirus infection, e.g., the compounds of the invention reduce hyperinflammation associated with a coronavirus infection.

[0164] As used herein, the phrase "pharmaceutically acceptable" is used to refer to compounds, materials, compositions, and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings or animals without undue toxicity, irritation, allergic response, or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0165] The phrase "therapeutically effective" refers to the amount of each agent that can achieve the goal of ameliorating disease severity and frequency while avoiding the adverse side effects typically associated with alternative therapies. For example, an effective anti-cancer agent may prolong survival or improve quality of life of a patient, inhibit the rapid cell proliferation associated with a neoplasm, or cause regression of the neoplasm.

[0166] As used herein, the terms "treat," "treating," and "treatment" refer to any type of intervention or process performed on a subject, or by administration of an active agent to a subject, to reverse, alleviate, ameliorate, inhibit, or slow or prevent the progression, onset, severity, or recurrence of symptoms, complications, conditions, or biochemical manifestations associated with a disease. In contrast, "prophylaxis" or "prevention" refers to administration to a subject not having a disease to prevent the onset of the disease.

[0167] The term "cell" as used herein is meant to refer to an in vitro, ex vivo, or in vivo cell. In the sense of the present invention, an ex vivo cell may be part of a tissue sample excised from an organism, such as a mammal. In the sense of the present invention, an in vitro cell may be a cell in cell culture. In the sense of the present invention, an in vivo cell is a cell living in an organism, such as a mammal.

[0168] The term "patient" includes humans and animals receiving either therapeutic or prophylactic treatment.

[0169] The term "subject" includes any human or animal. For example, the methods and compositions disclosed herein can be used to treat a subject with cancer.

[0170] (Non-human) animals include all vertebrates, including mammals and non-mammals, for example, cows, sheep, pigs, goats, horses, poultry, dogs, cats, non-human primates, rodents, etc. In one embodiment, the subject is a human subject.

[0171] As used herein, the phrase "pharmaceutically acceptable carrier" means a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid diluent, solvent, excipient, manufacturing aid, etc. (e.g., lubricant), or encapsulating material, that is involved in carrying or transporting a compound of interest from one organ or part of the body to another. Any carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation.

[0172] Suitable other ingredients are the above-mentioned carriers and further additives including adjuvants, preservatives, fillers, flow regulators, disintegrating agents, wetting agents, emulsifiers, suspending agents, sweeteners, flavoring agents, bittering agents, perfumes, antibacterial agents, antifungal agents, lubricants, dispensing agents, etc. Suitable additives are selected depending on the mode of administration and the nature of the dosage form, and are not harmful to the patient.

[0173] The term "pharmaceutical composition" means a composition comprising a compound of the present invention in combination with at least one additional compound selected from the following: a) at least one further pharmaceutically active substance, and b) at least one additional pharmaceutically acceptable carrier and / or excipient

[0174] For use in therapy, the compounds of formula (I) are usually 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.

[0175] The compounds of the invention may be administered in any convenient way, for example orally, parenterally, bucally, sublingually, nasally, rectally, intrathecally or transdermally, or by inhalation (e.g., topically to the lung by inhalation), and the pharmaceutical compositions adapted accordingly.

[0176] Compounds of formula (I) that are active when given orally can be formulated as liquids or solids, for example syrups, suspensions, emulsions, tablets, capsules, or troches.

[0177] Liquid formulations will usually consist of a suspension or solution of the active ingredient in a suitable liquid carrier, such as an aqueous solvent like water, ethanol, glycerin, or a non-aqueous solvent like polyethylene glycol or oil, etc. The formulation may also contain a suspending agent, a preservative, a flavoring, and / or a coloring agent.

[0178] A composition in the form of a tablet may be prepared using any suitable pharmaceutical carrier routinely used for preparing solid formulations, such as magnesium stearate, starch, lactose, sucrose, and cellulose.

[0179] A composition in capsule form can be prepared using conventional encapsulation procedures, for example, pellets 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 aqueous gums, cellulose, silicates, or oils, and then the dispersion or suspension can be filled into soft gelatin capsules.

[0180] A typical parenteral composition will consist of a solution or suspension of the active ingredient in a sterile aqueous carrier or parenterally acceptable oil (such as polyethylene glycol, polyvinylpyrrolidone, lecithin, peanut oil, sesame oil, etc.) Alternatively, the solution can be optimized and reconstituted with a suitable solvent just prior to administration.

[0181] Compositions for nasal administration or inhalation (e.g., for topical administration to the lungs by inhalation) can be conveniently formulated as aerosols, drops, gels, or powders. Aerosol formulations typically consist of a solution or fine suspension of the active ingredient in a pharmaceutically acceptable aqueous or non-aqueous solvent, usually provided in a sterile, single- or multi-dose form in a sealed container, which may be in the form of a cartridge or refill for use in a nebulizer device. Alternatively, the sealed container may be a disposable administration device, such as a single-dose nasal inhaler or an aerosol dispenser equipped with a metering valve suitable for delivering the aerosol to the nasal passages or bronchi. When the dosage form comprises an aerosol dispenser, it contains a compressed gas (e.g., air) or an organic propellant, such as a fluorochlorohydrocarbon or hydrofluorocarbon. The aerosol dosage form can also take the form of a pump-atomizer.

[0182] Local administration to the lung may also be achieved by use of a dry powder formulation comprising a compound of the invention in finely divided form, optionally together with one or more carriers or other excipients, which is typically delivered using a dry powder inhaler (DPI).

[0183] Compositions suitable for buccal or sublingual administration include tablets, lozenges and pastilles, wherein the active ingredient is formulated with a carrier such as sugar and acacia, tragacanth, or gelatin and glycerin.

[0184] Compositions for rectal administration are conveniently in the form of suppositories containing a conventional suppository base such as cocoa butter.

[0185] 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.

[0186] In one embodiment of the present invention, the compound of formula (I) is used in combination with an additional therapeutic agent. When the compound of formula (I) is used in combination with another therapeutic agent, the compounds of formula (I) may be administered sequentially or simultaneously by any convenient route. Alternatively, the compounds may be administered separately.

[0187] The present invention will be further described with reference to the following examples, without the scope being limited to the specific embodiments described. The present invention includes all combinations of the described features and particularly preferred features, which are not mutually exclusive. [Brief explanation of the drawings]

[0188] Figure 1: Dual reporter assay mRNAs. Firefly luciferase (F Luc) is translated by the eIF4F complex, while Renilla luciferase (R Luc) is translated independently of the complex.

[0189] Figure 2: Sequence of the 5'UTR of the viral mRNA.

[0190] Figure 3: Dual-luciferase assay for cap-dependent translation initiation. A. Plasmid map of the dual-luciferase assay system. B. Dual-luciferase assay for cap-dependent translation initiation was performed in HeLa cells transfected with a dual-luciferase reporter gene based on pFR_HCV_xb. Cells were treated with compounds 1, 2, 3, and 4 (100 nM) in serum-free DMEM for 24 hours. After incubation, dual-luciferase reporter assays were performed according to the manufacturer's instructions, and luminescence was measured using a multiplate reader. Data were normalized to cells transfected with the indicated mutants and exposed to DMSO for 24 hours. DMSO-treated cells were set to 1. Bars represent the mean ± SEM of three independent experiments. Dot plots indicate the values ​​for each experiment (EV corresponds to the empty vector). [Example]

[0191] Compounds 1, 2, 3, and 4 can be prepared analogously to PCT / EP 2022 / 025396. Compound 1: JPEG2025530340000023.jpg5864 Compound 2: JPEG2025530340000024.jpg5973 Compound 3: JPEG2025530340000025.jpg5566 Compound 4: JPEG2025530340000026.jpg5360

Claims

1. 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prophylaxis of a disease caused by or associated with a viral infection, During the ceremony, R 1 but, C 1 ~C 4 alkyl, wherein the alkyl is unsubstituted or contains 1, 2 or 3 substituents R a Replaced by C 1 ~C 4 Alkyl; C 3 ~C 7 Heterosilyl alkyl, wherein said C 3 ~C 7 Heterosilyl alkyl is one, two or three of the same or different N, NR C , O, S, SO, and SO 2 and wherein the heterosilyl group is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R e and the heterocycloalkyl is attached to the remainder of the molecule through a carbon atom, 3 ~C 7 heterocycloalkyl; and NR 2 R 3 And, R 2 and R 3 are, independently of each other, hydrogen, C 1 ~C 4 Alkyl, C 3 ~C 7 Cycloalkyl, and C 3 ~C 7 heterocycloalkyl, wherein C 3 ~C 7 Heterosilyl alkyl is one, two or three of the same or different N, NR C , O, S, SO, and SO 2 and wherein said heterosilyl group is unsubstituted or contains one, two or three substituents R h and said alkyl is unsubstituted or substituted with 1, 2 or 3 substituents R a and said cycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents R b is replaced by; 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 heterocyclic ring, said heterocyclic ring containing 1, 2, or 3 identical or different N, NR C , O, S, SO, and SO 2 and the heterocycle is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R d is replaced by; 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 heterocyclic ring, said heterocyclic ring containing one, two, or three identical or different N, NR C , O, S, SO, and SO 2 and the heterocycle is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R f is replaced by; R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spirocyclic ring system, said spirocyclic ring system being composed of one, two or three identical or different N, NR C , O, S, SO, and SO 2 and the spirocyclic ring is unsubstituted or contains 1, 2, 3, 4 or 5 identical or different radicals R g substituted with NR 2 R 3 Selected from: R a But halogens, OH, C 3 ~C 7 Cycloalkyl, C 1 ~C 3 Alkoxy, phenyl, NR 5a R 5b , C 1 ~C 4 Alkylsulfonyl, and C 3 ~C 7 heterocycloalkyl, wherein C 3 ~C 7 Heterosilyl alkyl is one, two or three of the same or different N, NR C , O, S, SO, and SO 2 and wherein said heterosilyl alkyl is unsubstituted or contains 1, 2 or 3 heteroatoms or heteroatom-containing groups selected from the group consisting of halogen, C 1 ~C 4 Alkyl, and C 1 ~C 4 haloalkyl; 3 ~C 7 cycloalkyl and phenyl are unsubstituted or substituted with 1, 2 or 3 substituents selected from F, Cl, Br, and OH; R b But halogens, OH and C 1 ~C 3 alkoxy; R C But hydrogen, C 1 ~C 4 Alkyl, C 3 ~C 7 Cycloalkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Cyanoalkyl, carbonyloxy-C 1 ~C 4 -alkyl, and C 1 ~C 4 hydroxyalkyl; R d But halogen, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Hydroxyalkyl, C 1 ~C 4 Alkoxy, C 1 ~C 4 Haloalkoxy, carboxy, carbonyloxy-C 1 ~C 4 -alkyl, and NR 5a R 5b Selected from: R e But halogen, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Hydroxyalkyl, C 1 ~C 4 Alkoxy, carbonyloxy-C 1 ~C 4 Alkyl, and C 1 ~C 4 haloalkoxy; R f But halogen, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Hydroxyalkyl, C 1 ~C 4 Alkoxy, C 1 ~C 4 Haloalkoxy and NR 5a R 5b Selected from: R g But halogen, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Hydroxyalkyl, C 1 ~C 4 Alkoxy, and C 1 ~C 4 haloalkoxy; R h But halogen, C 1 ~C 4 Alkyl, C 1 ~C 4 Haloalkyl, C 1 ~C 4 Hydroxyalkyl, C 1 ~C 4 Alkoxy, and C 1 ~C 4 haloalkoxy; R 4 However, Cl, CN and C 3 ~C 7 cycloalkyl; R 5a and R 5b are, independently of each other, hydrogen, C 1 ~C 4 Alkyl and C 3 ~C 7 cycloalkyl; R 6 is selected from hydrogen and F; R 7 But hydrogen and C 1 ~C 2 alkyl; However, R 6 If H, then R 7 is C 1 ~C 2 alkyl, and R 6 If F, then R 7 is hydrogen; R 8 But OCH 3 and OCD 3 Selected from: R 9 But OCH 3 and OCD 3 is selected from The compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein the disease is selected from viral infections caused by positive single-stranded RNA viruses ((+)ssRNA) and negative single-stranded RNA viruses ((-)ssRNA).

2. A compound of formula (I) for use in the treatment or prevention of a disease caused by or associated with a viral infection according to claim 1, wherein said compound (I) is a mixture of (Ia) and (Ib), or a mixture of pharmaceutically acceptable salts thereof, and the enantiomeric excess (ee) of the enantiomer of formula (Ia) is at least 20%, preferably at least 50%, in particular at least 80%, especially at least 99%, In the formula, R 1 , R 4 , R 6 , R 7 , R 8 , and R 9 has the same meaning as defined in claim 1.

3. R 6 is F and R 7 10. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease caused by or associated with a viral infection according to any of the preceding claims, wherein is hydrogen.

4. 10. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease caused by or associated with a viral infection according to any of the preceding claims, In the formula, R 1 but, unsubstituted or containing 1, 2 or 3 substituents R a C replaced with 1 ~C 4 alkyl; or 1 or 2 identical or different, NR C and O, and the heterosilyl group is unsubstituted or contains one, two or three identical or different radicals R e and the heterocycloalkyl is attached to the remainder of the molecule through a carbon atom, 3 ~C 7 heterocycloalkyl; or NR 2 R 3 And, R 2 and R 3 are, independently of each other, hydrogen, C 1 ~C 4 Alkyl and C 3 ~C 6 cycloalkyl, wherein said alkyl is unsubstituted or has one, two or three substituents R a and said cycloalkyl is unsubstituted or substituted with 1, 2 or 3 substituents R b is replaced by; 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 heterocyclic ring, said heterocyclic ring containing one, two, or three N, NR C , O, S, SO, and SO 2 and the heterocycle is unsubstituted or contains 1, 2, 3, 4, or 5 identical or different radicals R d is replaced by; 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 heterocyclic ring, said heterocyclic ring containing one, two or three identical or different N, NR C , O, S, SO, and SO 2 and the heterocycle is unsubstituted or contains one, two or three identical or different radicals R f is replaced by; or R 2 and R 3 together with the nitrogen atom to which they are attached form a saturated or partially unsaturated spirocyclic system, said spirocyclic system being composed of one or two identical or different N, NR C and O, and the spirocyclic ring is unsubstituted or contains one, two or three identical or different radicals R g is replaced by NR 2 R 3 is selected from 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, A compound of formula (I) or a pharmaceutically acceptable salt thereof.

5. 10. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease caused by or associated with a viral infection according to any of the preceding claims, R １ But NR 2 R 3 And, R 2 and R 3 are, independently of each other, hydrogen, C 1 ~C 3 Alkyl, and C 3 ~C 6 cycloalkyl, wherein alkyl is unsubstituted or is selected from one or two substituents R a and cycloalkyl is unsubstituted or substituted with 1 or 2 substituents R b and preferably R 2 and R 3 are independently hydrogen, unsubstituted C 2 ~C 3 Alkyl and unsubstituted C 3 ~C 6 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 heterocyclic ring, said heterocyclic ring containing one or two N, NR C , SO 2 and O, and R C But hydrogen and C 1 ~C 4 alkyl, wherein the heterocycle is unsubstituted or contains 1 or 2, C 1 ~C 4 Alkyl, C 1 ~C 4 Hydroxyalkyl, C 1 ~C 4 Alkoxy, NH 2 , N(C 1 ~C 2 alkyl) 2 , NH(C 1 ~C 2 alkyl), and carbonyloxy-C 1 ~C 4 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 acetidine ring, or a morpholine ring, and the pyrrolidine ring, the piperazine ring, the acetidine ring, or the morpholine ring is unsubstituted or contains one or two 1 ~C 4 Alkyl, C 1 ~C 4 Hydroxyalkyl, C 1 ~C 4 Alkoxy, NH 2 , N(C 1 ~C 2 alkyl) 2 , NH(C 1 ~C 2 alkyl), and carbonyloxy-C 1 ~C 4 substituted with a substituent selected from alkyl, NR 2 R 3 ;or C 3 ~C 7 Heterosilyl alkyl, wherein said C 3 ~C 7 Heterosilyl is one or two identical or different NR C and O, and the heterosilyl group is unsubstituted or contains one or two identical or different radicals R e and the heterocycloalkyl is attached to the remainder of the molecule through a carbon atom, 3 ~C 7 heterocycloalkyl; 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, said bicyclic ring system containing one or two identical or different N or NR C and preferably R 2 and R 3 together with the nitrogen atom to which they are attached form a 8-methyl-3,8-diazabicyclo[3.2.1]octan-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 spirocyclic ring system, said spirocyclic ring system being composed of two identical or different N, NR C and O, and preferably R 2 and R 3 together with the nitrogen atom to which they are attached to form a 2-oxa-6-azaspiro[3.3]heptan-6-yl spiro compound, or a pharmaceutically acceptable salt thereof.

6. R １ But NR C and S, and C, which contains one or two heteroatoms or heteroatom-containing groups as ring members and is bonded to the rest of the molecule through a carbon atom. 5 ~C 7 heterocycloalkyl, preferably R １ is selected from pyrrolidinyl and piperidinyl, for use in the treatment or prevention of a disease caused by or associated with a viral infection according to claims 1 to 4,

7. R １ However, methyl, 4-methyl-piperazin-1-yl, pyrrolidin-1-yl, N,N-diethylamino, N-isopropylamino, N-ethylamino, N,N-methyl-isopropylamino, acetidin-1-yl, morpholin-4-yl, N-cyclopentylamino, [1-(4-fluorophenyl)ethyl]amino, (cyclopropylmethyl)amino, 8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl, 1-methylpiperidin-4-yl, thiomorpholin-4-yl-1,1-dioxide, 3 10. A compound of formula (I) or a pharmaceutically acceptable salt thereof for use in the treatment or prevention of a disease caused by or associated with a viral infection according to any of the preceding claims, wherein the compound is selected from -(dimethylamino)azetidin-l-yl, 4-(dimethylamino)piperidin-1-yl, N-ethan-1-ol-amino, azetidine-3-carbonyloxymethyl, N,N-dimethylamino-methyl, 2-oxa-6-azaspiro[3.3]heptan-6-yl, and pyrrolidin-3-yl.

8. A compound of formula (I) 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 and W, and mixtures of each of compounds A to W with its respective enantiomer, or mixtures selected from two or more compounds A to W and their enantiomers, for use in the treatment or prevention of a disease caused by or associated with a viral infection according to any of the preceding claims.

9. A compound of formula (I) for use in the treatment or prevention of a disease caused by or associated with a viral infection according to any of the preceding claims, wherein the (+)ssRNA virus is a member of a family selected from the families Togaviridae, Flaviviridae, Coronaviridae, and Retroviridae.

10. A compound of formula (I) for use in the treatment or prevention of a disease caused by or associated with a viral infection according to claims 1 to 8, wherein the (-)ssRNA virus is a member of a family selected from the families Arenaviridae, Bornaviridae, Bunyviridae, Filoviridae, Othymyxoviridae, Paramyxoviridae, Pneumoviridae and Rhabdoviridae, in particular Filoviridae.

11. 10. A compound of formula (I) for use in the treatment or prevention of a disease caused by or associated with a viral infection according to any one of claims 1 to 9, wherein the Flaviviridae family is selected from dengue virus, Japanese encephalitis, Kyasanur Forest disease, Powassan virus, West Nile virus, yellow fever virus, and Zika virus.

12. A compound of formula (I) for use in the treatment or prevention of a disease caused by or associated with a viral infection according to any one of claims 1 to 9, wherein the Coronaviridae family is selected from SARS-CoV, SARS-CoV-2, MERS-CoV, HCoV-229E, HCoV-NL63, HCoVC43, and HKU1.

13. A compound of formula (I) for use in the treatment or prevention of a disease caused by or associated with a viral infection according to any one of claims 1 to 9, wherein the Retroviridae family is selected from HIV-1 and HIV-2.

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

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

16. 10. A compound of formula (I) for use in the treatment or prevention of a disease caused by or associated with a viral infection according to any of the preceding claims, wherein the associated disease is selected from lung inflammation, dyspnea, pulmonary fibrosis, pneumonia, cytokine storm, acute liver injury, septic shock, acute kidney injury, pancreatic injury, peripheral nervous system complications (such as taste disorders, smell disorders, visual disorders), muscle pain, myocardial inflammation, venous thrombosis, reduced coronary blood flow, cardiogenic shock, heart failure, impaired consciousness, brain inflammation, inflammation and swelling of the brain and blood vessels, acute cerebrovascular complications (such as stroke, seizures, slurred speech), arrhythmia, myocarditis, thrombotic events, rhabdomyolysis, neurocognitive disorders, and sensory and motor disorders.

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

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

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

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

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