Isoquinoline derivatives as protein degradation agents, E7 degradation agents, antiviral agents, tumor therapeutic agents and immunosuppressants

Abstract

The present invention relates to compounds of formula (I), in particular their use as degradation agents for the human papilloma virus E7 protein: # imgabs0 #

Description

Technical Field

[0001] The present invention relates to isoquinoline compounds and their use as antiviral agents, particularly against viruses of the Polyomaviridae, Orthomyxoviridae or Coronaviridae families, and especially against human papillomavirus (HPV). Background Art

[0002] The study of the mechanisms of action (MOA) of pathogenic viruses such as oncoviruses, zoonotic high-risk endemic and pandemic viruses, and their interactions with host cell factors not only allows one to glimpse the basic molecular pathological principles of viral infection, but also provides phenotypic mimetics for non-infectious diseases caused by somatic or germline mutations. In viral pathology, viral proteins hijack key host proteins that are also crucial for non-infectious diseases, suggesting pharmacological drug targets for comprehensive therapeutic interventions. The expression of viral proteins in host cells often leads to gain or loss of function of cellular proteins and nucleic acids, thereby distorting cellular homeostasis. Along these lines, the study of virus-host interactions has greatly advanced our current understanding (by way of example only): tumorigenesis, inflammation, innate and adaptive immune responses and immunosuppression, latency and senescence, virulence, cell signaling, RNA transcription and protein translation control, ubiquitin pathways, cell trafficking, cell-cell interactions, apoptosis and phagocytosis. As a common theme, the targeting principles of virus-host cell interactions are often conserved among distantly related pathogenic virus genera. The targeting of tumor suppressor p53, retinoblastoma protein (pRB), PTPN14, PDZ-binding proteins by different viruses are well-known examples in the art.

[0003] In addition, drug-like molecules initially discovered for virus-encoded, preferably non-structural protein targets can also be advantageously applied in the context of non-infectious diseases involving the corresponding disease pathways. Drug-like molecules initially selected from anti-infection screens can simultaneously be effective therapeutic agents in, for example, oncology and / or immunology. In summary, it is this reciprocity that is attractive for therapeutic interventions because it allows for strong targeting principles and a wider range of drugs that are less prone to resistance. Summary of the Invention

[0004] The present invention is based on these rational principles of drug discovery and has developed a class of isoquinoline molecules as candidate drugs for multifunctional degraders.

[0005] Quinoline(one)-based molecules for various uses, including cancer treatment, are disclosed in WO 2006 / 097323, WO 2010 / 055164 A2, WO 2013 / 027196 A1, EP 2 149 561 A1, US 2009 / 0068144, Rothweiler et al. (ChemMedChem 3(2008),1118-1128), US 2011 / 224208A1, US 2014 / 235593 A1, US 2013 / 315954 A1 and US 8,163,744.

[0006] It is an object of the present invention to provide compounds which are degrading agents for the E7 protein as well as proteins of other pathogenic viruses. These compounds should preferably be pharmacologically suitable molecules having drug properties capable of altering the steady-state levels of molecular disease targets. The degrader targets can also be selected from any pathogenic protein of any pathology far beyond viral protein targets. The targeting of the degrader of the molecules of the present invention can be triggered by the direct interaction of the degrader with the designated target or indirectly triggered by the interference with ectopic cellular pathways affecting the steady-state levels of the selected drug targets.

[0007] Accordingly, the present invention provides compounds of formula (I):

[0008]

[0009] wherein

[0010] R 1 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl; all of these groups may be optionally substituted; and

[0011] R 1a is a hydrogen atom or C 1-4 alkyl; or

[0012] R 1 and R 1a together are part of a heterocycloalkyl containing 5 or 6 ring atoms selected from C, N and O, which heterocycloalkyl may be unsubstituted or substituted by R 11 groups;

[0013] R 11 is C 1-4 alkyl or C 1-6 heteroalkyl;

[0014] R 2is phenyl, naphthyl, heteroaryl containing 5 or 6 ring atoms selected from C, N, O and S, or heteroaryl containing two rings, the two rings together containing 9 or 10 ring atoms selected from C, N, O and S, all of these groups may be unsubstituted or substituted by one or two R 21 groups;

[0015] R 21 is independently selected from halogen, C 1-4 alkyl and C 1-4 heteroalkyl;

[0016] R 3 is phenyl, heteroaryl containing 5 or 6 ring atoms selected from C, N, O and S, C 3-7 cycloalkyl or heterocycloalkyl containing 3 to 7 ring atoms selected from C, N, O, S, all of these groups may be unsubstituted or substituted by one or two R 31 groups;

[0017] R 31 is independently selected from halogen, C 1-4 alkyl and C 1-4 heteroalkyl;

[0018] R 4 is independently selected from halogen, OH, NH2, SH, CN, N3, NO2, C 1-4 alkyl and C 1-4 heteroalkyl; or

[0019] two R 4 groups together are a group of the formula -O-CH2-O- or -O-CH2-CH2-O-; and

[0020] n is 0, 1 or 2;

[0021] or a pharmaceutically acceptable salt thereof.

[0022] Preferably, R 4 is selected from Cl, OMe and NHAc. More preferably, R 4 is OMe.

[0023] More preferably, n is 0 or 1.

[0024] Even more preferably, n is 0.

[0025] Even more preferably, n is 1 and R 4 is OMe.

[0026] In addition, preferably, R 11 is selected from Ac, -C(=O)-NH-CH2CH3, -Me, -CHO, CH2CH2-OH and CH2CH2-OMe.

[0027] More preferably, R 1a is a hydrogen atom.

[0028] Also preferably, R 1 is phenyl, naphthyl, heteroaryl containing 5 or 6 ring atoms selected from C, N, O and S, or heteroaryl containing two rings, the two rings containing a total of 9 or 10 ring atoms selected from C, N, O and S, all of these groups being optionally substituted.

[0029] More preferably, R 1 is a group of the formula -Ar-Cy-R 5 wherein Ar is phenylene or heteroarylene containing 5 or 6 ring atoms selected from C, N and O; Cy is C 3-7 cycloalkylene or hetero-cycloalkylene containing 3, 4, 5, 6 or 7 ring atoms selected from C, N, O and S and R 5 is a hydrogen atom or C 1-4 alkyl or C 1-6 heteroalkyl.

[0030] Particularly preferably, Ar is phenylene and Cy is hetero-cycloalkylene containing 6 ring atoms selected from C, N and O and R 5 is a hydrogen atom or C 1-4 alkyl.

[0031] Even more preferably, R 1 is selected from the group consisting of:

[0032]

[0033] Also preferably, R 1 is a group of the formula -NH-CH2-CH2-N(CH3)2.

[0034] More preferably, R 2 is 1,4-phenylene carrying the R 21 group (i.e., a group of the following formula):

[0035]

[0036] Also preferably, R 21 is selected from F, Cl, Br, CF3, CH3 and OMe; particularly preferably, R 21 is the CF3 group.

[0037] More preferably, R 21 is selected from CF3, CF2CF3, CCl3 and CCl2CCl3.

[0038] More preferably, R 2 is 4-chlorophenyl.

[0039] Furthermore, preferably, R 3 is 1,4-phenylene carrying the R 31 group (i.e., the group of the following molecular formula):

[0040]

[0041] More preferably, R 31 is selected from Cl, CF3, CH3, NMe2 and OMe.

[0042] More preferably, R 31 is selected from CF3, CF2CF3, CCl3 and CCl2CCl3.

[0043] Furthermore, preferably, R 3 is 4-methylphenyl.

[0044] According to a preferred embodiment, the present invention provides a compound of formula (II):

[0045]

[0046] wherein R 21 , R 3 , R 4 and n are all defined as above, or a pharmaceutically acceptable salt thereof.

[0047] Preferably, in the compound of formula (II), n is 0 or 1; R 4 is OMe; R 21 is halogen, C 1-4 alkyl or C 1-4 heteroalkyl (especially the CF3 group); R 3 is phenyl, heteroaryl containing 5 or 6 ring atoms selected from C, N, O and S, C 3-7 cycloalkyl or heterocycloalkyl containing 3 to 7 ring atoms selected from C, N, O, S, and all these groups may be unsubstituted or substituted by one or two R 31 groups; and R 31 is independently selected from halogen, C 1-4 alkyl and C 1-4 heteroalkyl.

[0048] The most preferred compounds of the present invention are the compounds or their salts disclosed in the examples, and / or the following compounds:

[0049]

[0050]

[0051]

[0052]

[0053] , including all its pharmaceutically acceptable salt and ester forms, and including all enantiomers and racemates of these compounds and salts, preferably

[0054] rel-(3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0055] rel-(3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0056] rel-(3R,4R)-2-(4-Methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0057] rel-(3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0058] rel-(3R,4R)-7-Acetamido-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0059] rel-(3R,4R)-6,7-Dimethoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0060] rel-(3R,4R)-2-(4-Methylbenzyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0061] rel-(3R,4R)-2-(4-Methylbenzyl)-N-(3-morpholinophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0062] rel-(3R,4R)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0063] rel-(3R,4R)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0064] rel-(3R,4R)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-3-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0065] (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0066] (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0067] (3R,4R)-2-(4-Methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0068] (3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0069] (3R,4R)-7-Acetamido-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0070] (3R,4R)-6,7-Dimethoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0071] (3R,4R)-2-(4-Methylbenzyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0072] (3R,4R)-2-(4-Methylbenzyl)-N-(3-morpholinophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0073] (3R,4R)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0074] (3R,4R)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0075] (3R,4R)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-3-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0076] (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0077] (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0078] (3S,4S)-2-(4-Methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0079] (3S,4S)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0080] (3S,4S)-7-Acetamido-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0081] (3S,4S)-6,7-Dimethoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0082] (3S,4S)-2-(4-methylbenzyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0083] (3S,4S)-2-(4-methylbenzyl)-N-(3-morpholinophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0084] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0085] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and

[0086] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-3-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, especially

[0087] rel-(3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0088] rel-(3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0089] rel-(3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0090] rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0091] rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0092] (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0093] (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0094] (3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0095] (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and

[0096] (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0097] (3S,4S)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0098] (3S,4S)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0099] (3S,4S)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0100] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and

[0101] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide.

[0102] The term "rel" refers to "relative configuration". The configuration of any stereogenic (asymmetric) center relative to any other stereogenic center contained within the same molecular entity. Unlike absolute configuration, relative configuration is reflection invariant. Relative configuration, which differentiates diastereomers, can be denoted by the configuration descriptors R*,R* (or I) and R*,S* (or u), indicating that the two centers have the same or opposite configurations, respectively. For molecules with more than two asymmetric centers, the prefix rel- can be used before the enantiomeric names using R and S. If any center has a known absolute configuration, then only R* and S* can be used for relative configuration.

[0103] The term "alkyl" refers to a saturated straight-chain or branched hydrocarbon group having 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, especially 1 to 6 (e.g., 1, 2, 3, or 4) carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, n-hexyl, 2,2-dimethylbutyl, or n-octyl.

[0104] In addition, the term "alkyl" refers to a group in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl), such as 2,2,2-trichloroethyl or trifluoromethyl.

[0105] The terms "alkenyl" and "alkynyl" refer to at least partially unsaturated straight-chain or branched hydrocarbon groups having 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, especially 2 to 6 (e.g., 2, 3, or 4) carbon atoms, such as ethenyl (vinyl), propenyl (allyl), isopropenyl, butenyl, ethynyl, propynyl, butynyl, ethynyl, propargyl, isoprenyl, or hex-2-enyl. Preferably, the alkenyl has 1 or 2 (particularly preferably 1) double bonds, and the alkynyl has 1 or 2 (particularly preferably 1) triple bonds.

[0106] In addition, the terms "alkenyl" and "alkynyl" refer to a group in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl).

[0107] The term "heteroalkyl" refers to an alkyl, alkenyl, or alkynyl group in which one or more (preferably 1, 2, or 3) carbon atoms have been replaced by an oxygen, nitrogen, phosphorus, boron, selenium, silicon, or sulfur atom (preferably by an oxygen, sulfur, or nitrogen atom) or a group of the formula SO or SO2. The term "heteroalkyl" also refers to a carboxylic acid or a group derived from a carboxylic acid, such as an acyl group, acylalkyl group, alkoxycarbonyl group, acyloxy group, acyloxyalkyl group, carboxyalkylamide group, or alkoxycarbonyloxy group.

[0108] Preferably, the heteroalkyl contains 1 to 12 carbon atoms and 1 to 4 heteroatoms selected from oxygen, nitrogen, and sulfur (especially oxygen and nitrogen). Particularly preferably, the heteroalkyl contains 1 to 6 (e.g., 1, 2, 3, or 4) carbon atoms and 1, 2, or 3 (especially 1 or 2) heteroatoms selected from oxygen, nitrogen, and sulfur (especially oxygen and nitrogen). The term "C1-C6 heteroalkyl" refers to a heteroalkyl containing 1 to 6 carbon atoms and 1, 2, 3, or 4 heteroatoms selected from O, S, and / or N (especially O and / or N). The term "C1-C4 heteroalkyl" refers to a heteroalkyl containing 1 to 4 carbon atoms and 1, 2, or 3 heteroatoms selected from O, S, and / or N (especially O and / or N).

[0109] In addition, the term "heteroalkyl" refers to a group in which one or more hydrogen atoms have been replaced by a halogen atom (preferably F or Cl).

[0110] Examples of heteroalkyl groups are groups of the following formula: Ra OY a ,R a SY a ,R a SOY a ,R a SO2Y a ,R a N(R b )Y a ,R a COY a ,R a OCOY a ,R a COOY a ,R a CON(R b )Y a ,R a N(R b )COY a ,R a OCON(R b )Y a ,R a N(R b )COOY a ,R a N(R b )CON(R c )Y a ,R a OCOOY a ,R a N(R b )C(=NR d )N(R c )Y a ,R a CSY a ,R a OCSY a ,R a CSOY a ,R a CSN(R b )Y a ,R a N(R b )CSY a ,R a OCSN(R b )Y a ,R a N(R b )CSOY a ,R a N(R b )CSN(R c )Y a ,R aOCSOY a ,R a SCOY a ,R a COSY a ,R a SCON(R b )Y a ,R a N(R b )COSY a ,R a SCOOY a ,R a OCOSY a ,R a SCOSY a ,R a SCSY a ,R a CSSY a ,R a SCSN(R b )Y a ,R a N(R b )CSSY a ,R a SCSOY a ,R a OCSSY a wherein R a is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group; R b is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group; R c is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group; R d is a hydrogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group or a C2-C6 alkynyl group and Y a is a direct bond, a C1-C6 alkylene group, a C2-C6 alkenylene group or a C2-C6 alkynylene group, wherein each heteroalkyl group contains at least one carbon atom and one or more hydrogen atoms are replaced by fluorine or chlorine atoms.

[0111] Specific examples of heteroalkyl include methoxy, trifluoromethoxy, ethoxy, n-propoxy, isopropoxy, butoxy, tert-butoxy, methoxymethyl, ethoxymethyl, CH2CH2OH, CH2OH, methoxyethyl, 1-methoxyethyl, 1-ethoxyethyl, 2-methoxyethyl or 2-ethoxyethyl, methylamino, ethylamino, propylamino, isopropylamino, dimethylamino, diethylamino, isopropylethylamino, methylaminomethyl, ethylaminomethyl, diisopropylaminoethyl, thiomethyl, thioethyl, thioisopropyl, enol ether, dimethylaminomethyl, dimethylaminoethyl, acetyl (Ac, -C(=O)-CH3), propionyl, butyryloxy, acetyloxy, methoxycarbonyl, ethoxycarbonyl, propionyloxy, acetylamino or propionylamino, carboxymethyl, carboxyethyl or carboxypropyl, N-ethyl-N-methylcarbamoyl or N-methylcarbamoyl. Other examples of heteroalkyl include nitrile, isonitrile, cyanate, thiocyanate, isocyanate, isothiocyanate and alkyl nitrile groups.

[0112] The expression cycloalkyl refers to a saturated or partially unsaturated (e.g., cycloalkenyl) cyclic group that contains one or more rings (preferably 1 or 2) and contains 3 to 14 ring carbon atoms, preferably 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms. The expression cycloalkyl also refers to a group that can be substituted by one or more fluorine, chlorine, bromine or iodine atoms or by one or more OH, =O, SH, =S, NH2, =NH, N3 or NO2 groups, and thus, for example, cycloalkanones such as cyclohexanone, 2-cyclohexenone or cyclopentanone. Further specific examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, spiro[4,5]decyl, norbornyl, cyclohexyl, cyclopentenyl, cyclohexadienyl, decahydronaphthyl, bicyclo[4.3.0]nonyl, tetrahydronaphthalene, cyclopentylcyclohexyl, fluorocyclohexyl or cyclohex-2-enyl.

[0113] The expression heteroalkylcycloalkyl refers to cycloalkyl as defined above, in which one or more (preferably 1, 2, 3 or 4) ring carbon atoms have been replaced by oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atoms (preferably by oxygen, sulfur or nitrogen atoms) or by SO groups or SO2 groups. Heteroalkylcycloalkyl preferably contains one or two rings having 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms (preferably selected from C, O, N and S). The expression heteroalkylcycloalkyl also refers to a group that can be substituted by one or more fluorine, chlorine, bromine or iodine atoms or by one or more OH, =O, SH, =S, NH2, =NH, N3 or NO2 groups. Examples include piperidinyl, prolinyl, imidazolidinyl, piperazinyl, morpholinyl, hexamethylenetetraminyl, pyrrolidinyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrofuryl or 2-pyrazolinyl, as well as lactams, lactones, cyclic imides and cyclic anhydrides.

[0114] The term alkylcycloalkyl refers to a group containing both a cycloalkyl group and an alkyl, alkenyl or alkynyl group as defined above, such as alkylcycloalkyl, cycloalkylalkyl, alkylcycloalkenyl, alkenylcycloalkyl and alkynylcycloalkyl. The alkylcycloalkyl preferably contains a cycloalkyl group having one or two rings with 3 to 10 (especially 3, 4, 5, 6 or 7) ring carbon atoms, and one or two alkyl, alkenyl or alkynyl (especially alkyl) groups having 1 or 2 to 6 carbon atoms.

[0115] The expression heteroalkylcycloalkyl refers to an alkylcycloalkyl as defined above, in which one or more (preferably 1, 2, 3, 4 or 5) carbon atoms have been replaced by an oxygen, nitrogen, silicon, selenium, phosphorus or sulfur atom (preferably by an oxygen, sulfur or nitrogen atom) or an SO group or an SO2 group. The heteroalkylcycloalkyl preferably contains one or two rings having 3 to 10 (especially 3, 4, 5, 6 or 7) ring atoms, and one or two alkyl, alkenyl, alkynyl or heteroalkyl (especially alkyl or heteroalkyl) groups having 1 or 2 to 6 carbon atoms (the heteroalkyl preferably having 1, 2 or 3 heteroatoms selected from O, S and N). Examples of such groups are alkylheterocycloalkyl, alkylheterocycloalkenyl, alkenylheterocycloalkyl, alkynylheterocycloalkyl, heteroalkylcycloalkyl, heteroalkylheterocycloalkyl and heteroalkylheterocycloalkenyl, the cyclic groups being saturated or mono-, di- or tri-unsaturated.

[0116] The expression aryl refers to an aryl group containing one or more rings, the rings containing 5 or 6 to 14 ring carbon atoms, preferably 5 or 6 to 10 (especially 6) ring carbon atoms. The expression aryl also refers to a group which may be substituted by one or more fluorine, chlorine, bromine or iodine atoms or by one or more OH, SH, NH2, N3 or NO2 groups. Examples are phenyl, naphthyl, biphenyl, 2-fluorophenyl, anilino, 3-nitrophenyl or 4-hydroxyphenyl.

[0117] The term "heteroaryl" refers to an aromatic group containing one or more rings having 5 to 14 ring atoms, preferably 5 to 10 (especially 5 or 6 or 9 or 10) ring atoms, and containing one or more (preferably 1, 2, 3, 4 or 5) oxygen, nitrogen, phosphorus or sulfur ring atoms (preferably O, S or N). The term "heteroaryl" also refers to a group that can be substituted by one or more fluorine, chlorine, bromine or iodine atoms or by one or more OH, SH, NH2, N3 or NO2 groups. Examples are pyridyl (e.g., 4-pyridyl), imidazolyl (e.g., 2-imidazolyl), phenylpyrrolyl (e.g., 3-phenylpyrrolyl), thiazolyl, isothiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, oxadiazolyl, thiadiazolyl, indolyl, indazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl, isoxazolyl, indazolyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, pyridazinyl, quinolinyl, isoquinolinyl, pyrrolyl, purinyl, carbazolyl, acridinyl, pyrimidinyl, 2,3'-bifuryl, pyrazolyl (e.g., 3-pyrazolyl) and isoquinolinyl.

[0118] The term "aralkyl" refers to a group that simultaneously contains an aryl group as defined above and an alkyl, alkenyl, alkynyl and / or cycloalkyl group, such as arylalkyl, arylalkenyl, arylalkynyl, arylcycloalkyl, arylcycloalkenyl, alkylarylcycloalkyl and alkylarylcycloalkenyl. Specific examples of aralkyl are toluene, xylene, mesitylene, styrene, benzyl chloride, o-fluorotoluene, 1-indene, tetralin, dihydronaphthalene, indanone, phenylcyclopentyl, cumene, cyclohexylphenyl, fluorene and indane. Aralkyl preferably contains one or two aromatic ring systems having 6 to 10 carbon atoms (1 or 2 rings), and one or two alkyl, alkenyl and / or alkynyl groups having 1 or 2 to 6 carbon atoms, and / or one or two cycloalkyl groups having 5 or 6 ring carbon atoms.

[0119] The term "heteroaralkyl" refers to an aralkyl as defined above, in which one or more (preferably 1, 2, 3 or 4) carbon atoms have been replaced by oxygen, nitrogen, silicon, selenium, phosphorus, boron or sulfur atoms (preferably oxygen, sulfur or nitrogen), that is, a group containing an aryl or heteroaryl group, and also containing an alkyl, alkenyl, alkynyl and / or heteroalkyl and / or cycloalkyl and / or heterocycloalkyl group as defined above. Heteroaralkyl preferably contains one or two aromatic ring systems having 5 or 6 to 10 ring carbon atoms (1 or 2 rings), and one or two alkyl, alkenyl and / or alkynyl groups having 1 or 2 to 6 carbon atoms, and / or one or two cycloalkyl groups having 5 or 6 ring carbon atoms, where 1, 2, 3, 4, 5 or 6 of these carbon atoms are replaced by oxygen, sulfur or nitrogen atoms.

[0120] Examples of arylheteroalkyls include arylheterocycloalkyls, arylheterocycloalkenyls, arylalkylheterocycloalkyls, arylalkenylheterocycloalkyls, arylalkynylheterocycloalkyls, arylalkylheterocycloalkenyls, heteroarylalkyls, heteroarylalkenyls, heteroarylalkynyls, heteroarylheteroalkyls, heteroarylcycloalkyls, heteroarylcycloalkenyls, heteroarylheterocycloalkyls, heteroarylheterocycloalkenyls, heteroarylalkylcycloalkyls, heteroarylalkylheterocycloalkenyls, heteroarylheteroalkylcycloalkyls, heteroarylheteroalkylcycloalkenyls, and heteroarylheteroalkylheterocycloalkyls, and the cyclic groups are saturated or mono-, di- or tri-unsaturated. Specific examples include tetrahydroisoquinolinyl, benzoyl, 2- or 3-ethylindolyl, 4-methylpyridyl, 2-, 3- or 4-methoxyphenyl, 4-ethoxyphenyl, 2-, 3- or 4-carboxyphenylalkyl.

[0121] The term halogen or halogen atom means F, Cl, Br or I.

[0122] The expression "optionally substituted" preferably means a group in which one, two, three or more hydrogen atoms may be substituted by fluorine, chlorine, bromine or iodine atoms or by OH, =O, SH, =S, NH2, =NH, N3 or NO2 groups. This expression also means that it may be substituted by one, two, three or more (preferably unsubstituted) C1C 10 alkyl, C2C 10 alkenyl, C2C 10 alkynyl, C1C 10 heteroalkyl, C3C 18 cycloalkyl, C2C 17 heterocycloalkyl, C4C 20 alkylcycloalkyl, C2C 19 heteroalkylcycloalkyl, C6C 18 aryl, C1C 17 heteroaryl, C7C 20 arylalkyl or C2C 19 heteroarylalkyl-substituted groups. This expression also particularly means that it may be substituted by one, two, three or more (preferably unsubstituted) C1C6 alkyls, C2C6 alkenyls, C2C6 alkynyls, C1C6 heteroalkyls, C3C 10 cycloalkyl, C2C9 heterocycloalkyl, C7C 12 alkylcycloalkyl, C2C 11 heteroalkylcycloalkyl, C6C 10 aryl, C1C9 heteroaryl, C7C 12 arylalkyl or C2C 11 heteroarylalkyl-substituted groups.

[0123] If the substituent contains a ring, the ring may be bonded to each substituted group by a single bond or a double bond (especially a single bond), or if the substituted group also contains a ring, the ring of the substituent may also be cyclized to the ring of the substituted group.

[0124] Preferred substituents are F, Cl, Br, I, OH, ═O, NH2, NO2, C 1-4 alkyl (such as methyl, CF3, ethyl, tert-butyl), NMe2, NHMe, CONH2, CH2NMe2, NHSO2Me, C(CH3)2CN, COMe, OMe, SMe, COOMe, COOEt, CH2COOH, OCH2COOH, COOH, SOMe, SO2Me, cyclopropyl, SO2NH2, SO2NHMe, SO2CH2CH2OH, SF5, SO2NMe2, CHO, OCF3, SO2CF3, COMe, CH2OH, CN or CF3.

[0125] Particularly preferred substituents are F, Cl, Br, OH, NH2, CH2NH2, NO2, Me, ethyl, NMe2, CONH2, OMe, CN or CF3.

[0126] According to a preferred embodiment, all alkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aralkyl and heteroaralkyl groups described herein may be optionally substituted.

[0127] When an aryl, heteroaryl, cycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, heterocycloalkyl, aralkyl or heteroaralkyl group contains more than one ring, these rings may be bonded to each other by single or double bonds, or these rings may be annulated.

[0128] The present invention further provides a pharmaceutical composition comprising one or more compounds of formula (I) or (II) as defined herein or a pharmaceutically acceptable ester, prodrug, hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

[0129] Another aspect of the present invention is to provide a compound of formula (I) or (II) as defined herein or a pharmaceutical composition as defined herein for use in the preparation of a medicament for the treatment of one or more diseases described herein.

[0130] The compounds of the present invention are particularly suitable for use as antiviral agents, preferably as antiviral agents against the following viruses: Polyomaviridae viruses, Orthomyxoviridae viruses, especially influenza A virus, or Coronaviridae viruses, human immunodeficiency virus (HIV), Merkel cell polyomavirus (MCV, MCPyV), JC polyomavirus (JCV, JCPyV), BK polyomavirus (BKV, BKPyV), TS polyomavirus (TSV, TSPyV), H7 polyomavirus (HV7, HPyV7), Simian polyomavirus 40 (SV40), cytomegalovirus (CMV), hepatitis B virus (HEPB), hepatitis C virus (HEPC), hepatitis D virus (HEPD), human immunodeficiency virus 1 (HIV-1), human immunodeficiency virus 2 (HIV-2), human T-lymphotropic virus I (HTLV-I), human T-lymphotropic virus II (HTLV-II), Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (Herpesviridae; KSHV), especially against human papillomavirus (HPV). The compounds of the present invention have been shown to have excellent effects as antiviral agents for treating human papillomavirus (HPV) infections or for treating or preventing SARS-CoV-2 infections, especially for treating HPV-induced malignant and neoplastic diseases, especially as degraders of the E7 protein, or as antiviral agents for treating or preventing COVID-19. Accordingly, the compounds of the present invention are preferably used in a method for treating human patients suffering from a viral infection or at risk of being infected by a virus to develop a disease caused by a viral pathogen, wherein the method comprises administering an effective amount of one or more compounds of the present invention to a patient in need of such an antiviral compound.

[0131] DNA virus

[0132] HPV

[0133] DNA tumor viruses, human papillomavirus (HPV) is the causative agent of a significant proportion of cancers and precancerous lesions of the cervix, vulva, vagina, anus, penis, head and neck, as well as genital warts (Diseases associated with human papillomavirus infection Heather A. Cubie, Virology 445 (2013) 21–34; Hartwig et al., Estimation of the overall burden of cancers, precancerous lesions, and genital warts attributable to 9-valent HPV vaccine types in women and men in Europe, Infectious Agents and Cancer (2017) 12:19), and is involved in 5% of all these cancers. These include squamous cell carcinoma (SCC) and adenocarcinoma (ADC). In addition, it has been reported that HPV is present in a subset of prostate cancers (Pascale M, et al. Is human papillomavirus associated with prostate cancer survival? Dis Markers. 2013;35(6):607-13), lung cancers (Talita Helena Araujo de Oliveira Carolina Medeiros do Amaral Bianca de et al., Presence and activity of HPV in primary lung cancer, Journal of Cancer Research and Clinical Oncology, December 2018, Volume 144, Issue 12, pp 2367–2376), breast cancer (Lawson JS, et al. Human Papilloma Virus Identification in Breast Cancer Patients with Previous Cervical Neoplasia. Front Oncol. 2016 Jan 8;5:298) and Bowen's disease (Kobayashi K. et al., Identification of a human papillomavirus type 58 lineage in multiple Bowen's disease on the fingers: Case report and published work review, J Dermatol. 2018 Oct;45(10):1195-1198.doi:10.1111 / 1346-8138.14574.Epub 2018 Jul 23). Increasing evidence suggests that other HPV subtypes (such as HPV β) can induce actinic keratosis and non-melanoma skin cancer (Inhibition of TGF-β and NOTCH Signaling by Cutaneous Papillomaviruses, Meyers JM, Grace M, Uberoi A, Lambert PF, Munger K. Front Microbiol. 2018 Mar 8;9:389.doi:10.3389 / fmicb.2018.00389.eCollection 2018. Review. PMID:29568286).

[0134] Globally, the most prominent HPV cancer - cervical cancer - is the fourth most common cause of cancer-related death in women, with an estimated 527,624 new cases and 265,672 deaths in 2012. Data show that the global 5-year prevalence is 1,547,161 (rate of 59.6 / 100,000). More than 85% of cancer survivorship and 88% of deaths globally occur in countries with low to middle healthcare settings, where cervical cancer accounts for 12% of all female cancers (GLOBOCAN 2012). HPV-induced cancers are a sexually transmitted disease, and HPV is generally considered not only as a tumor-inducing pathogen but also as a pathogen for tumor progression and maintenance (zur Hausen H. Papillomaviruses in the causation of human cancers - a brief historical account. Virology 2009;384(2):260–265), which makes the tumor-maintaining HPV compounds E6 or E7 the main target for therapeutic intervention to cure the disease. Despite its important role in genital cancers, other HPV cancers, such as head and neck cancers, especially oropharyngeal cancers, are increasing rapidly, and it is expected that the number of HPV-positive oropharyngeal cancers will exceed cervical cancer within the next 15 years.

[0135] High-risk HPV infections bring about the viral oncogenes E6 and E7, and the persistent expression of their respective proteins drives tumor induction, progression, and the maintenance of the cancerous state. Loss of function, particularly loss of E7 function, leads to the reversal of the cancer phenotype in different experimental systems. The dominant and unique role of E7 in the maintenance of HPV-induced cancers has recently been confirmed by next-generation sequencing (NGS) of thousands of HPV-containing tumor genomes. In contrast to all other HPV viral factors, including E6, E7 is completely devoid of genetic variation in both pre-cancerous and cancer cases (White EA, Munger K., Crowd Control: E7 Conservation Is the Key to Cancer. Cell. 170:1057-1059(2017), Mirabello L, et al., HPV16 E7 Genetic Conservation Is Critical to Carcinogenesis, Cell 170:1164-1174(2017)). E7 has the largest number of associations with the cellular protein network (Farooq QUA, Shaukat Z, Zhou T, Aiman S, Gong W, Li C. Inferring Virus-Host relationship between HPV and its host Homo sapiens using protein interaction network. Sci Rep. 2020 May 26;10(1):8719. doi:10.1038 / s41598-020-65837-w. PMID: 32457456; PMCID: PMC7251128). Therefore, E7 is eligible as the sole non-substitutable target for therapeutic intervention. Specifically, this includes the E7 proteins listed from various high-risk HPV types, as well as the E7 proteins from disease-inducing E7 molecules defined as low-risk. The amino acid sequences can be extracted from the sequence numbers and identifiers (in parentheses) according to the Expasy ViralZone database.From Alpha - papillomavirus: P03129 (VE7_HPV16); P04020 (VE7_HPV11); P06788 (VE7_HPV18); P17387 (VE7_HPV31); P06429 (VE7_HPV33); P27230 (VE7_HPV35); P24837 (VE7_HPV39); P36829 (VE7_HPV40); P27231 (VE7_HPV42); Q705H9 (Q705H9_HPV43); Q80914 (VE7_HPV44); P21736 (VE7_HPV45); P26558 (VE7_HPV51); P36831 (VE7_HPV52); P36832 (VE7_HPV53); Q81019 (VE7_HPV54); P36833 (VE7_HPV56); P26557 (VE7_HPV58); Q81965 (Q81965_HPV59), Q80956 (VE7_HPV66); P54668 (VE7_HPV68); P50785 (VE7_HPV70); Q9IR58 (Q9IR58_HPV82); Q84292 (VE7_HPV6A); The E7 molecules of Beta - papillomavirus include P06932 (VE7_HPV05); P06430 (VE7_HPV08); Q80908 (VE7_HPV38).

[0136] Therefore, E7 - selective small - molecule drugs that cause a rapid decrease in the steady - state level of the E7 oncoprotein, thereby leading to loss of function at the protein level, have attracted great interest. Such active ingredients are called "degraders". At the molecular level, the degradation of E7 allows targeting and resolution of all pathogenic distortions caused by the expression of the E7 oncoprotein. Basically: the oncogenic dysregulation of the pRB pathway, the interference with PI3K and TGF - β cell signaling, and the direct implementation of immunosuppressive conditions in the tumor microenvironment - all of which contribute to tumor regression.

[0137] Polyomaviridae as a degrader - drug target for unmet medical needs:

[0138] Polyomavirus PyV exhibits a high degree of sequence conservation between the large / middle T antigens and the HPV oncoproteins. Similar to other viral oncoproteins, the large T antigen and the middle T antigen target cellular regulators to promote cell proliferation, immune evasion, and downregulation of apoptosis. E7 degraders can exhibit the degrader activity of the pathological large T molecule. To date, 14 different PyVs have been discovered. Multiple of these human PyV subtypes have pharmacological significance. MCPyV is the causative agent of the hitherto incurable invasive and fatal Merkel cell carcinoma. Most PyVs are opportunistic infections in the general population. However, when PyV, the pathological manifestation of whose infection is usually lytic infection, is reactivated in immunosuppressed hosts, these infections become clinically significant. These lytic reactivations can be severe or even fatal, as suggested by polyomavirus-associated nephropathy (PVAN) and progressive multifocal leukoencephalopathy (PML). For these diseases, antiviral therapy is urgently needed. The increasing use of immunosuppressive therapies will lead to more cases of polyomavirus-induced diseases and may create a market for effective therapeutic agents as a modern targeted treatment option for polyomavirus-induced pathogenicity. Currently, there is no clear treatment option. Treatment strategies proposed in the art include small molecule inhibitors targeting virus-glycan binding or T antigen function, boosting immunity when immunosuppressive regimens targeting increased antibody levels are still viable, or enhancing cell-mediated immunity in elderly patients, all options mainly targeting the inhibition of viral infection. Non-structural virulence factors such as T antigen can be targeted by the molecules of the present invention.

[0139] As an example of a disease - associated polyomavirus, Merkel cell polyomavirus (MCPyV) has been found to be the causative agent of Merkel cell carcinoma (MCC), an aggressive neuroendocrine skin cancer with a high recurrence rate, metastatic spread, and mortality. The major risk factors for MCC development include immunosuppression, ultraviolet (UV) irradiation, and advanced age. Among the currently known 14 human PyVs, MCPyV is the only virus with a causal link to human cancer. Although it is very likely that other polyomavirus subtypes are directly involved in tumor induction and maintenance, the data obtained so far do not conclusively support these conclusions. In contrast, MCPyV DNA is a) found to be clonally integrated into the tumor genomes of MCCs that continuously express LTAg and sTAg; b) LTAg isolated from tumors usually contains a truncated form of LTAg that is functionally unable to support viral replication - all of which are hallmarks of the oncogenic transformation capacity of DNA tumor viruses, as learned from high - risk HPVs. Recent studies have shown that MCPyV DNA is also present in other types of tumors and a subset of hematological malignancies (including chronic lymphocytic leukemia), which, if confirmed, would be a rather exciting prospect. The preparedness for MCC is increasing, and it is tempting to speculate that similar viruses are etiological factors in more malignancies than currently expected. Another example, BKPyV is an opportunistic pathogen. Generally, BKPyV infections are extremely common worldwide. Seroprevalence studies indicate that overall, >90% of the general adult population has anti - BKPyV IgG antibodies. BKPyV is the causative agent of BKPyV - associated nephropathy (PVAN) in renal transplant recipients and hemorrhagic cystitis in bone marrow transplant patients. The major sites of BKPyV replication are the kidney and urothelium, leading to lytic destruction of these cells. BKPyV replication has been observed under all immunosuppressive regimens. BKPyV infection is a serious complication of immunosuppression as it is considered a major cause of impaired graft function and premature transplant failure. Reducing the net state of immunosuppression is the mainstay of treatment. Unlike CMV infections, for which there is antiviral therapy, there is no direct antiviral therapy for BKV, which represents an urgent medical need for immunosuppressed patient populations, including any transplant, HIV, and elderly patients.

[0140] As another example, JC polyomavirus (JCPyV) is very similar to BKPyV at the primary amino acid sequence level, and there are no strict treatment options for it. JCPyV causes progressive multifocal leukoencephalopathy (PML), a rapidly progressive and fatal demyelinating disease. JCPyV replicates in oligodendrocytes, leading to a gradual accumulation of neurological deficits and ultimately death. JCPyV causes PML in immunocompromised patients, such as those with HIV / AIDS, hematological malignancies, and patients receiving immunomodulatory drugs (such as natalizumab, efalizumab, rituximab) for the treatment of multiple sclerosis, Crohn's disease, lymphoma, severe plaque psoriasis, and rheumatism. In addition to PML, JCPyV can also cause other neurological diseases, such as JCPyV granuloneuronal disease, JCPyV encephalopathy, and meningitis.

[0141] As another example, Trichodysplasia spinulosa polyomavirus (TSPyV). A similar conservation of the primary amino acid sequence has been observed in TSPyV, which causes the rare skin disease trichodysplasia spinulosa (TS), affecting solid organ transplant patients receiving immunosuppressive therapy. The disease is characterized by the appearance of follicular papules and keratinous spines (aciculae), mainly on the face, and there are also no strict treatment options.

[0142] As another example, Human polyomavirus 7 (HPyV7). A newly discovered subtype of HPyV7 is associated with pruritic rash and viremia in lung transplant recipients receiving immunosuppressive therapy. HPyV7 has been reported to be involved in thymic epithelial tumors. Although not yet clearly confirmed, HPyV7, as well as other recently discovered PyVs, may be associated with new pathogenicity in immunocompromised individuals.

[0143] Other viruses with similar characteristics suitable for targeting with the molecules of the present invention (exhibiting overlapping MOA against virulence and host immunosuppression) include, for example, the non-structural proteins of human immunodeficiency virus HIV, hepatitis C virus HCV, and hepatitis B virus HBV, particularly the NS1 protein of influenza A virus of highly pathogenic zoonotic influenza strains or other viruses of the family Orthomyxoviridae.

[0144] Coronaviruses:

[0145] Three highly pathogenic human coronaviruses (HCoV), including Severe Acute Respiratory Syndrome (SARS)-CoV, Middle East Respiratory Syndrome (MERS)-CoV, and SARS-CoV-2 emerged during the first two decades of the twenty-first century. The global epidemic of SARS-CoV in 2002–2003 first demonstrated that HCoV could pose a major threat to global public health. The mortality rate of SARS-CoV was approximately 10%, and the epidemic was contained in 2003. The mortality rate of MERS-CoV is higher than that of SARS-CoV (approximately 35%) and remains a public health concern. SARS-CoV-2 is currently in a global pandemic. Substantial efforts have been made globally to control the SARS-CoV-2 pandemic and treat patients with COVID-19, the disease caused by the virus. Vaccination is underway, but breakthrough mutations represent a global trend, and thus options for therapeutic intervention are needed.

[0146] CoVs are members of the Coronavirinae subfamily of the Coronaviridae family in the order Nidovirales. They are divided into four genera, including Alphacoronavirus (α-CoV), Betacoronavirus (β-CoV), Gammacoronavirus (γ-CoV), and Deltacoronavirus (δ-CoV). α- and β-CoVs infect only mammals, while γ- and δ-CoVs mainly infect birds, but some γ- and δ-CoVs can also infect mammals. CoVs are well-known as major causative agents in livestock, causing huge economic losses. They also infect mammalian pets, laboratory animals, and many other wild animals. All highly pathogenic HCoVs, including SARS-CoV, MERS-CoV, and SARS-CoV-2, belong to the genus Betacoronavirus and are thought to have originated initially from wild mammals, most likely bats. They are associated with severe lower respiratory tract infections, while other HCoVs, including HCoV-OC43 and HCoV-HKU1, which belong to the genus β-CoV, and HCoV-229E and HCoV-NL63, which belong to the genus α-CoV, cause relatively mild upper respiratory tract infections.

[0147] CoV is an enveloped RNA virus that contains a large (about 30 kb) capped and polyadenylated positive-sense single-stranded RNA genome. CoV particles contain at least four typical structural proteins, including N, S, M, and E proteins. The two-thirds of the 5' end of the genome encodes gene 1 proteins, and the one-third of the 3' end encodes structural and accessory proteins. The latter class of proteins is not essential for virus replication in cell culture. After entering the host cell, the CoV genomic RNA is released into the cytoplasm and two large partially overlapping precursor polyproteins are translated from gene 1. Two virus-encoded proteases process these precursor polyproteins by proteolysis to generate 16 mature proteins, designated as non-structural proteins 1 (nsp1) to nsp16 of alpha- and beta-CoVs. All these gene 1 proteins, except nsp1 and nsp2, are thought to be essential for viral RNA synthesis. Nsp1 is one of the proteins encoded by gene 1 and is only encoded in alpha- and beta-CoVs.

[0148] As an example, it can be particularly emphasized that the present invention is particularly interested in nsp1 of pathogenic CoV. Nsp1 is a major virulence factor of various CoVs. Mouse hepatitis virus (MHV) is a beta-CoV, and the expression of its nsp1 reduces cellular gene expression. MHV nsp1 acts as an interferon (IFN) antagonist and is a major virulence factor for mice. A specific amino acid region LLRKxGxKG of MHV nsp1, which is highly conserved in human pathogenic CoVs, is very important for the pathogenicity of mice. Like MHV nsp1, SARS-CoV nsp1 plays an important role in suppressing the antiviral response and thus represents an ideal animal model system for studying candidate drugs in vivo. The amino acid region of SARS-CoV nsp1 corresponding to the LLRKxGxKG region of MHV nsp1 is responsible for the pathogenicity to mice and inhibits the host antiviral signaling pathway, suggesting the importance of this region corresponding to the LLRKxGxKG region of MHV nsp1 for beta-CoV virulence. The unique but overlapping regions on nsp1 that interact with different host factors may inhibit host gene expression and the antiviral signaling pathway. The expression of SARS-CoV nsp1 and the replication of SARS-CoV enhance the signaling through the calcineurin / NFAT (nuclear factor of activated T cells) pathway, which is important for the activation of immune cells, and the expression of SARS-CoV nsp1 induces the secretion of various chemokines in human lung epithelial cells, suggesting that nsp1 may play a role in immune dysregulation.

[0149] SARS-CoV nsp1 also disrupts the nuclear-cytoplasmic transport of biomolecules. SARS-CoV nsp1 binds to the nuclear pore complex member Nup93 and replaces it from the nuclear pore complex. The expression of SARS-CoV nsp1 alters the nuclear-cytoplasmic distribution of nucleolin, an RNA-binding protein mainly present in the nucleus. These studies suggest that SARS-CoV nsp1 affects multiple steps in the expression of host genes, including antiviral genes.

[0150] Similar to the nsp1 of β-CoV, the nsp1 of α-CoV acts as an inhibitor of antiviral gene expression. HCoV-229E nsp1 is controlled by IFN-β and IFN-stimulated response elements. The Nsp1 of porcine epidemic diarrhea virus (PEDV) uses multiple mechanisms to inhibit the host innate immune response: it inhibits the production of type I IFN (a potent NF-κB antagonist that acts by inhibiting the phosphorylation and subsequent degradation of IκBα), leading to the inhibition of IFN production and the early production of pro-inflammatory cytokines, by disrupting the enhancer assembly of IRF3 and CREB-binding protein through the degradation of CREB-binding protein; it also blocks the nuclear translocation of IRF1 and reduces the number of peroxisomes to inhibit the IRF1-mediated induction of type III IFN.

[0151] A conserved region of α-CoV nsp1 (amino acids 91 - 95) is responsible for inhibiting host gene expression, as is the case for feline infectious peritonitis virus (FIPV), TGEV, PEDV, HCoV-229E, and HCoV-NL63. Further evidence shows that expression of nsp1 from TGEV, porcine respiratory coronavirus (PRCV), swine acute diarrhea syndrome coronavirus (SADS-CoV), PEDV, HCoV-229E, or HCoV-NL63 reduces IFN-related gene expression, that expression of α-CoV nsp1 significantly downregulates phosphorylation of STAT1 at residue S727 without affecting STAT1 expression levels and phosphorylation of STAT1 at S701, and that STAT1, ISG15, and IRF9 mRNAs are significantly upregulated in cells infected with an FIPV mutant carrying a deletion of amino acids 91–95 of nsp1 without severely affecting viral replication capacity. In this context, the p70 S6 kinase pathway is crucial, (Petritsch C, Beug H, Balmain A, Oft M. TGF-beta inhibits p70 S6 kinase via protein phosphatase 2A to induce G(1) arrest. Genes Dev. 2000;14(24):3093 - 3101. doi:10.1101 / gad.854200) and can be well accessed by the molecules of the present invention. These data indicate that the nsp1 protein of α-CoV also acts as a major pathogenicity determinant, like that of β-CoV.

[0152] SARS-CoV Nsp1 and SARS-CoV-2 Nsp1 inhibit cellular protein translation initiation. SARS-CoV-2 nsp1 has 84% amino acid sequence identity with SARS-CoV nsp1, indicating that the two proteins have similar biological functions. SARS-CoV-2 nsp1 binds to 40S and 80S ribosomal subunits and disrupts cap-dependent translation. Like SARS-CoV nsp1, the K164 and H165 residues near the C-terminus of SARS-CoV-2 nsp1 are important for ribosome binding and translation inhibition. In addition to inhibiting translation by binding to the 40S ribosome, SARS-CoV nsp1 also induces the degradation of endogenous host mRNAs in SARS-CoV-infected cells. The SARS-CoV nsp1-40S ribosome complex endonucleolytically cleaves the 5' region of capped non-viral mRNAs by a putative host RNase, rendering the mRNAs untranslatable. In this context, differential template-dependent cleavage of the designated RNA of SARS-CoV nsp1 is observed, for example, it induces RNA cleavage within the ribosome loading region of type I and type II picornavirus internal ribosome entry site (IRES) elements, while it does not induce RNA cleavage within the IRES elements of hepatitis C virus or cricket paralysis virus. Multiple cleavage sites in capped mRNA transcripts induced by SARS-CoV nsp1 are detected within the 30 nt range of the 5' untranslated region. Along these lines, recent studies have shown that SARS-CoV nsp1 as well as SARS-CoV-2 nsp1 inhibit the production of IFN-β, in which case SARS-CoV nsp1 inhibits the host innate immune response, including type I IFN expression, in SARS-infected cells. (Mechanism of Coronavirus Nsp1-Mediated Control of Host and Viral Gene Expression. Keishuke Nakagawa and Shinji Makino, Cells, 2021 Feb; 10(2):300; and the citations therein).

[0153] Preferably, the compounds of the present invention can be used for the treatment of HPV infection.

[0154] More preferably, the compounds of the present invention can be used for the treatment and / or prevention of neoplastic and malignant diseases, especially cervical cancer, vulvar cancer, vaginal cancer, anal cancer, penile cancer, head and neck cancer, and subsets of genital warts, non-melanoma skin cancer, lung cancer, prostate cancer and breast cancer, recurrent respiratory papillomatosis (RRP), Burkitt lymphoma, non-Hodgkin lymphoma and Bowen's disease.

[0155] The compounds of the present invention are also suitable for the prevention or treatment of infections by unicellular eukaryotic parasites, in particular Plasmodium falciparum, Plasmodium malariae and Leishmania donovani.

[0156] A therapeutically effective amount of a compound of the present invention means an amount of the compound that is effective in preventing, alleviating or ameliorating the symptoms of a disease or prolonging the survival of a subject being treated. Determination of a therapeutically effective amount is within the skill of the art.

[0157] The therapeutically effective amount or dose of a compound according to the present invention can vary within a wide range and can be determined in a manner known in the art. Such a dose can be adjusted according to the individual needs of each particular case, including the specific compound administered, the route of administration, the disorder being treated and the patient being treated.

[0158] Examples of pharmacologically acceptable salts of the compounds of formula (I) or (II) that are sufficiently basic are salts of physiologically acceptable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; or organic acids such as methanesulfonic acid, p-toluenesulfonic acid, lactic acid, acetic acid, trifluoroacetic acid, citric acid, succinic acid, fumaric acid, maleic acid and salicylic acid. In addition, compounds of formula (I) or (II) that are sufficiently acidic can form alkali metal salts or alkaline earth metal salts, such as sodium salts, potassium salts, lithium salts, calcium salts or magnesium salts; ammonium salts; or salts of organic bases, such as methylamine, dimethylamine, trimethylamine, triethylamine, ethylenediamine, ethanolamine, choline hydroxide, glucosamine, piperidine, morpholine, tris-(2-hydroxyethyl)amine, lysine or arginine salts; all of these are also further examples of salts of formula (I) or (II). The compounds of formula (I) or (II) can be solvated, especially hydrated. Hydration can occur during the preparation process or due to the hygroscopic nature of the initially anhydrous compounds of formula (I) or (II). Solvates and / or hydrates can exist, for example, in solid or liquid form.

[0159] It should be understood that certain compounds of formula (I) or (II) may have tautomeric forms (possibly only one of which is specifically mentioned or described hereinafter), different geometric isomers (which are usually represented as cis / trans isomers or more commonly as (E) and (Z) isomers) or different optical isomers resulting from one or more chiral carbon atoms (usually named according to the Cahn-Ingold-Prelog or R / S system). All these tautomeric forms, geometric or optical isomers (as well as racemates and diastereomers) and polymorphic forms are included in the present invention. Since the compounds of formula (I) or (II) may contain asymmetric C atoms, they can exist as achiral compounds, mixtures of diastereomers, mixtures of enantiomers or as optically pure compounds. The present invention includes all pure enantiomers and all pure diastereomers, as well as mixtures thereof in any mixing ratio.

[0160] The therapeutic use of the compounds of formula (I) or (II), their pharmaceutically acceptable salts, solvates and hydrates, as well as formulations and pharmaceutical compositions is also within the scope of the present invention.

[0161] The pharmaceutical compositions of the present invention comprise at least one compound of formula (I) or (II) as an active ingredient and optionally a carrier substance and / or adjuvant.

[0162] The present invention also relates to prodrugs which consist of a compound of formula (I) or (II) and at least one pharmaceutically acceptable protecting group which is cleaved under physiological conditions, said protecting groups such as alkoxy, arylalkoxy, acyl, acyloxymethyl (e.g. pivaloyloxymethyl), 2-alkyl-, 2-aryl- or 2-arylalkyl-oxycarbonyl-2-alkyleneethyl or acyloxy as defined herein, such as ethoxy, benzyloxy, acetyl or acetoxy, or, especially for the compounds of formula (I) or (II), esters of -OH: sulfate, phosphate (-OPO3 or -OCH2OPO3) or amino acids.

[0163] Preferably, the present invention also relates to prodrugs, biodegradable esters, biodegradable amides, polymorphs, tautomers, stereoisomers, metabolites, N-oxides, biodegradable carbamates, biodegradable ethers, physiologically functional derivatives, atropisomers or in vivo hydrolysable precursors, diastereomers, or mixtures of diastereomers, chemically protected forms, affinity reagents, complexes, chelates and stereoisomers of the compounds of formula (I) or (II).

[0164] As used herein, the term pharmaceutically acceptable ester particularly refers to esters that are hydrolyzed in vivo, including those that readily decompose in the human body to leave the parent compound or its salt. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic acids, alkenoic acids, cycloalkanoic acids, and alkanedioic acids, where each alkyl or alkenyl moiety advantageously has no more than 6 carbon atoms. Examples of specific esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethyl succinates.

[0165] As described above, therapeutically useful agents containing a compound of formula (I) or (II), their solvates, salts, or formulations are also included within the scope of the present invention. Generally, the compounds of formula (I) or (II) will be administered alone or in combination with any other therapeutic agent using methods known and acceptable in the art.

[0166] For oral administration, such therapeutically useful agents can be administered by one of the following routes: orally, for example, as tablets, dragees, coated tablets, pills, semi-solids, soft or hard capsules, such as soft and hard gelatin capsules, aqueous or oily solutions, emulsions, suspensions, or syrups; parenterally, including intravenous, intramuscular, and subcutaneous injection, for example, as injection solutions or suspensions; rectally as suppositories; by inhalation or insufflation, for example, as powder formulations, as microcrystals, or as sprays (e.g., liquid aerosols); transdermally, for example, through a transdermal delivery system (TDS) such as a plaster containing the active ingredient; or intranasally. For the production of these tablets, pills, semi-solids, coated tablets, dragees, and hard agents, such as gelatin capsules, the therapeutically useful product can be mixed with pharmaceutically inert, inorganic or organic excipients, such as lactose, sucrose, glucose, gelatin, malt, silica gel, starch or its derivatives, talc, stearic acid or its salts, skimmed milk powder, etc. For the production of soft capsules, excipients such as vegetable oils, petroleum, animal oils, or synthetic oils, waxes, fats, and polyols can be used. For the production of liquid solutions, emulsions, suspensions, or syrups, excipients such as water, alcohols, saline solutions, aqueous glucose solutions, polyols, glycerol, lipids, phospholipids, cyclodextrins, vegetable oils, petroleum, animal oils, or synthetic oils can be used. Lipids are particularly preferred, and phospholipids (preferably of natural origin; particularly preferably with a particle size of 300 to 350 nm) are more preferred, preferably in phosphate-buffered saline (pH = 7 to 8, preferably 7.4). For suppositories, excipients such as vegetable oils, petroleum, animal oils, or synthetic oils, waxes, fats, and polyols can be used. For aerosol formulations, compressed gases suitable for this purpose, such as oxygen, nitrogen, and carbon dioxide, can be used. The pharmaceutically useful agents can also contain additives for preservation, stabilization, such as ultraviolet stabilizers, emulsifiers, sweeteners, flavorants, salts for changing the osmotic pressure, buffers, coating additives, and antioxidants.

[0167] Generally, in the case of oral or parenteral administration to an adult with a body weight of about 80 kg, a daily dose of about 10 mg to about 10,000 mg, preferably about 20 mg to about 1,000 mg, should be appropriate, although the upper limit may be exceeded when indicated. The daily dose can be administered as a single dose or in divided doses, or for parenteral administration, it can be administered by continuous infusion or subcutaneous injection.

[0168] The present invention also provides a method for degrading E7.

[0169] In addition, the present invention provides a method for treating HPV infection in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt thereof.

[0170] In one embodiment, there is provided a method for treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or (II) or a salt thereof.

[0171] Examples of diseases (such as cancer) that can be treated using the methods of the present invention include neoplastic and malignant diseases, such as cervical cancer, vulvar cancer, vaginal cancer, anal cancer, penile cancer, head and neck cancer, and genital warts, a subset of non-melanoma skin cancer, lung cancer, prostate cancer and breast cancer, recurrent respiratory papillomatosis (RRP) and Bowen's disease.

[0172] The compounds of the present invention can be synthesized according to methods described, for example, in: Rothweiler et al. ChemMedChem 2008, 3, 1118 - 1128; WO 2006 / 097323 and WO 2008 / 034039.

[0173] According to another aspect, the present invention also relates to the use of the compounds of the present invention for the preparation of a medicament, said compounds being especially selected from (3R,4R)-N-[3-(4-methylpiperazin-1-yl)phenyl]-2-[(1-methylpiperidin-4-yl)methyl]-1-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide), (3S,4S)-N-[3-(4-methylpiperazin-1-yl)phenyl]-2-[(1-methylpiperidin-4-yl)methyl]-1-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide), (3R,4R)-N-[3-(4-methylpiperazin-1-yl)phenyl]-2-[(4-methylphenyl)methyl]-1-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide) and (3S,4S)-N-[3-(4-methylpiperazin-1-yl)phenyl]-2-[(4-methylphenyl)methyl]-1-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide), said medicament being used for the prevention or treatment of the following viral infections: Polyomaviridae viruses, Orthomyxoviridae viruses, especially influenza A virus, or Coronaviridae viruses, human immunodeficiency virus (HIV), Merkel cell polyomavirus (MCV, MCPyV), JC polyomavirus (JCV, JCPyV), BK polyomavirus (BKV, BKPyV), TS polyomavirus (TSV, TSPyV), H7 polyomavirus (HV7, HPyV7), Simian polyomavirus 40 (SV40), cytomegalovirus (CMV), hepatitis B virus (HEPB), hepatitis C virus (HEPC), hepatitis D virus (HEPD), human immunodeficiency virus 1 (HIV-1), human immunodeficiency virus 2 (HIV-2), human T-lymphotropic virus I (HTLV-I), human T-lymphotropic virus II (HTLV-II), Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (Herpesviridae; KSHV), hepatitis C virus (HCV), or hepatitis B virus (HBV), especially HPV infection or SARS-CoV-2 infection; or (especially as a degrader of the E7 protein) for the treatment of HPV-induced malignant and neoplastic diseases, especially cervical cancer, vulvar cancer, vaginal cancer, anal cancer, penile cancer, head and neck cancer, and genital warts, a subgroup of non-melanoma skin cancer, lung cancer, prostate cancer and breast cancer, recurrent respiratory papillomatosis (RRP), Burkitt lymphoma, non-Hodgkin lymphoma and Bowen's disease; or for the prevention or treatment of infections by single-celled eukaryotic parasites, especially Plasmodium falciparum, Plasmodium malariae and Leishmania donovani.

[0174] According to another aspect, the present invention relates to a method for treating or preventing viral infections by viruses of the Polyomaviridae family, Orthomyxoviridae family, in particular influenza A virus, or Coronaviridae family, human immunodeficiency virus (HIV), Merkel cell polyomavirus (MCV, MCPyV), JC polyomavirus (JCV, JCPyV), BK polyomavirus (BKV, BKPyV), TS polyomavirus (TSV, TSPyV), H7 polyomavirus (HV7, HPyV7), Simian polyomavirus 40 (SV40), cytomegalovirus (CMV), hepatitis B virus (HEPB), hepatitis C virus (HEPC), hepatitis D virus (HEPD), human immunodeficiency virus 1 (HIV-1), human immunodeficiency virus 2 (HIV-2), human T-lymphotropic virus I (HTLV-I), human T-lymphotropic virus II (HTLV-II), Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (Herpesviridae; KSHV), hepatitis C virus (HCV), or hepatitis B virus (HBV), in particular HPV infection or SARS-CoV-2 infection; or (in particular as a degrader of the E7 protein) for the treatment and prevention of HPV-induced malignant and neoplastic diseases, in particular cervical cancer, vulvar cancer, vaginal cancer, anal cancer, penile cancer, head and neck cancer, and genital warts, a subgroup of non-melanoma skin cancer, lung cancer, prostate cancer and breast cancer, recurrent respiratory papillomatosis (RRP), Burkitt lymphoma, non-Hodgkin lymphoma and Bowen's disease; or a method for preventing or treating infections by single-celled eukaryotic parasites, in particular Plasmodium falciparum, Plasmodium malariae and Leishmania donovani, wherein an effective amount of a compound of the present invention, in particular a compound selected from (3R,4R)-N-[3-(4-methylpiperazin-1-yl)phenyl]-2-[(1-methylpiperidin-4-yl)methyl]-1-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide), (3S,4S)-N-[3-(4-methylpiperazin-1-yl)phenyl]-2-[(1-methylpiperidin-4-yl)methyl]-1-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide), (3R,4R)-N-[3-(4-methylpiperazin-1-yl)phenyl]-2-[(4-methylphenyl)methyl]-1-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide) and (3S,4S)-N-[3-(4-methylpiperazin-1-yl)phenyl]-2-[(4-methylphenyl)methyl]-1-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide), is administered to a patient in need thereof.

[0175] According to another aspect, the present invention relates to a pharmaceutical composition comprising an antagonist or agonist of a signaling molecule and a compound of the present invention, preferably a compound selected from the following group:

[0176] rel-(3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0177] rel-(3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0178] rel-(3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0179] rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0180] rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0181] (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0182] (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0183] (3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0184] (3R,4R)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and

[0185] (3R,4R)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0186] (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0187] (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0188] (3S,4S)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0189] (3S,4S)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and

[0190] (3S,4S)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;

[0191] or a combination of its pharmaceutically acceptable hydrates, solvates or salts, optionally in combination with a pharmaceutically acceptable carrier. The signaling molecule is preferably a receptor molecule or one or more of its downstream targets, such as EGFR, Ras, phosphatidylinositol-4,5-bisphosphate 3-kinase alpha 85 kDa regulatory subunit or 110 kDa catalytic subunit (PI3K), phosphatase and tensin homolog (PTEN), protein kinase B (PKB, Akt), p70-S6 kinase 1, mammalian target of rapamycin (mTOR1), FK506-binding protein (FKBP12), mTOR complex 1 (mTORC1), TGFbeta pathway signaling, and / or NOTCH signaling. Particularly preferred signaling molecules are estrogen steroid receptor molecules or signaling molecule antagonists or agonists selected from the group consisting of (as mTOR, Pi3 and Akt agonists / antagonists): mTOR inhibitor-8 (CAS No.: 2489196-70-3), mTOR inhibitor-3 (CAS No.: 1207358-59-5), mTOR inhibitor-1 (CAS No.: 468747-17-3), mTOR inhibitor-2 (CAS No.: 2219323-96-1), HDACs / mTOR inhibitor 1 (CAS No.: 2271413-06-8), PI3K / mTOR inhibitor-3 (CAS No.: 1363338-53-7), PI3K / mTOR inhibitor-2 (CAS No.: 1848242-58-9), PI3K / mTOR inhibitor-1 (CAS No.: 1949802-49-6), MTI-31 (CAS No.: 1567915-38-1), Sapanisertib (CAS No.: 1224844-38-5), WAY-600 (CAS No.: 1062159-35-6), Onatasertib (CAS No.: 1228013-30-6), MHY1485 (CAS No.: 326914-06-1), PI3Kα / mTOR-IN-1 (CAS No.: 1013098-90-2), PF-04979064 (CAS No.: 1220699-06-8), 3BDO (CAS No.: 890405-51-3), Dihydromyricetin,CAS No.: 27200-12-0), Rapalink-1 (CAS No.: 1887095-82-0), AD80 (CAS No.: 1384071-99-1), DS-7423 (CAS No.: 1222104-37-1), ETP-46464 (CAS No.: 1345675-02-6), Torin 2 (CAS No.: 1223001-51-1), PF-04691502 (CAS No.: 1013101-36-4), TFEB activator 1 (CAS No.: 39777-61-2), Vistusertib (CAS No.: 1009298-59-2), MHY-1685 (CAS No.: 27406-31-1), MCX 28 (CAS No.: 1414453-58-9), CZ415 (CAS No.: 1429639-50-8), XL388 (CAS No.: 1251156-08-7), GNE-317 (CAS No.: 1394076-92-6), NSC781406 (CAS No.: 1676893-24-5), GDC-0349 (CAS No.: 1207360-89-1), Gedatolisib (CAS No.: 1197160-78-3), Compound 401 (CAS No.: 168425-64-7), Temsirolimus (CAS No.: 162635-04-3), 28-Epiphyllanthocin (CAS No.: 253431-35-5), GNE-477 (CAS No.: 1032754-81-6), Ridaforolimus (CAS No.: 572924-54-0), GNE-493 (CAS No.: 1033735-94-2), Bimiralisib (CAS No.: 1225037-39-7), (+)-Usnic acid (CAS No.: 7562-61-0), PP121 (CAS No.: 1092788-83-4), 42-(2-Tetrazolyl)rapamycin (CAS No.: 221877-56-1), AZD-8055 (CAS No.: 1009298-09-2), Torin 1 (CAS No.: 1222998-36-8), PKI-402 (CAS No.: 1173204-81-3), PKI-402 (CAS No.: 1173204-81-3), Chrysophanol,CAS No.: 481-74-3), VS-5584 (CAS No.: 1246560-33-7), Dactolisib (CAS No.: 915019-65-7), PI3K-IN-22 (CAS No.: 1202884-94-3), Torkinib (CAS No.: 1092351-67-1), Zeylenone (CAS No.: 193410-84-3), CC-115 (CAS No.: 1300118-55-1), Rapamycin (CAS No.: 53123-88-9), Salidroside (CAS No.: 10338-51-9), PQR626 (CAS No.: 1927857-98-4), Dactolisib Tosylate (CAS No.: 1028385-32-1), LAT1-IN-1 (CAS No.: 20448-79-7), GSK1059615 (CAS No.: 958852-01-2), Rubioncolin C (CAS No.: 132242-52-5), KU-57788 (CAS No.: 503468-95-9), Apitolisib (CAS No.: 1032754-93-0), Everolimus (CAS No.: 159351-69-6), WYE-687 (CAS No.: 1062161-90-3), SF2523 (CAS No.: 1174428-47-7), WYE-132 (CAS No.: 1144068-46-1), Lupiwighteone,CAS No.: 104691-86-3), OSI-027 (CAS No.: 936890-98-1), JR-AB2-011 (CAS No.: 2411853-34-2), SAR405 (CAS No.: 1523406-39-4), WYE-687 dihydrochloride (CAS No.: 1702364-87-1), PI3Ka-IN-5 (CAS No.: 2237953-19-2), PQR530 (CAS No.: 1927857-61-1), PKI-179 (CAS No.: 1197160-28-3), WYE-354 (CAS No.: 1062169-56-5), BGT226 malate (CAS No.: 1245537-68-1), AKT-IN-10 (CAS No.: 2709045-56-5), BGT226 (CAS No.: 915020-55-2), AKT-IN-9 (CAS No.: 2709045-53-2), PI-103 (CAS No.: 371935-74-9), Voxtalisib (CAS No.: 934493-76-2), ETP-45658 (CAS No.: 1198357-79-7), PF-06843195 (CAS No.: 2067281-51-8), (32-carbonyl)-RMC-5552 (CAS No.: 2382768-55-8), BC-LI-0186 (CAS No.: 695207-56-8); and (as PDK, PDK1, AKT inhibitors) P7 (CAS No.: 1001409-50-2), BX-320 (CAS No.: 702676-93-5), BX-517 (CAS No.: 850717-64-5), BX517 (CAS No.: 850717-64-5), BX795 (CAS No.: 702675-74-9), BX-912 (CAS No.: 702674-56-4), JX06 (CAS No.: 729-46-4), Paris saponin I (Polyphyllin I,CAS No.: 50773-41-6), PS10 (CAS No.: 1564265-82-2), PS210 (CAS No.: 1221962-86-2), PS423 (CAS No.: 1221964-37-9), PDK1-IN-RS2 (CAS No.: 1643958-89-7), GSK2334470 (CAS No.: 1227911-45-6), PF-AKT400 (CAS No.: 1004990-28-6), Capivasertib (CAS No.: 1143532-39-1), Afuresertib (CAS No.: 1047644-62-1), Borussertib (CAS No.: 1800070-77-2), GSK-690693 (CAS No.: 937174-76-0), AKT-IN-10 (CAS No.: 2709045-56-5), AKT-IN-9 (CAS No.: 2709045-53-2), AKT-IN-3 (CAS No.: 2374740-21-1), Vevorisertib (CAS No.: 1416775-46-6), FPA-124 (CAS No.: 902779-59-3), CCT128930 (CAS No.: 885499-61-6), AT13148 (CAS No.: 1056901-62-2), anti-CTLA-4 antibody, especially ipilimumab; anti-PD-1 antibody, especially nivolumab, pembrolizumab or tislelizumab; and / or anti-PD-L1 antibody, especially atezolizumab, durvalumab or avelumab.,

[0192] According to a particularly preferred embodiment, the present invention also relates to a pharmaceutical composition comprising a combination of an anti-CTLA-4 antibody (especially ipilimumab); an anti-PD-1 antibody (especially nivolumab, pembrolizumab or tislelizumab); and / or an anti-PD-L1 antibody (especially atezolizumab, durvalumab or avelumab) and a compound of the present invention, the compound of the present invention preferably

[0193] (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0194] (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0195] (3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0196] (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and

[0197] (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0198] (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0199] (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0200] (3S,4S)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0201] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and

[0202] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide;

[0203] or a pharmaceutically acceptable hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

[0204] The present invention will be further illustrated by examples and drawings, but is not limited thereto. BRIEF DESCRIPTION OF THE DRAWINGS

[0205] The present invention is further described by examples and drawings, but is not limited thereto.

[0206] Figure 1: Cellular fluorescence (CF) analysis for detecting the expression level of E7 protein in the presence of the compounds of the present invention for screening E7 degraders. Reduction of the steady-state level of E7 protein in CaSki cells in the presence of a) cycloheximide (CHX) as a non-specific positive control for 100% degradation or b) the OC246 compound for 2.5 hours was analyzed by flow cytometry using an intracellular antibody labeling procedure with an anti-HPV E7 monoclonal antibody. The E7 signal intensity obtained from the FL1 histogram was used to analyze the E7 intensity of untreated (right histogram) or treated (left histogram) cells on a logarithmic scale. The FL1 single histogram represents the change in the mean fluorescence intensity (MFI) channel as described in Methods 1-4. This reading can be used for medium- to high-throughput screening of compound libraries.

[0207] Figure 2: Compounds of the present invention induce cell cycle arrest and ultimately apoptosis, analyzed by flow cytometry and propidium iodide DNA staining of HPV-containing CaSki tumor cells. Logarithmic scale histograms are shown. A) Untreated cells showed a conventional cell cycle distribution into G1 (left peak) and G2 / M phases (right peak). B) Cells treated with OC246 showed a sub-G1 content at 24 hours and C) after 48 hours, indicating DNA degradation as a measure of apoptosis induction.

[0208] Figure 3: Steady state levels were evaluated by western blotting with an E7-specific antibody for A) HPV 16 E7 in CaSki cells incubated with VSP035 (VS035) for the indicated time points. β-actin staining served as a loading control. B) Comparing E7 staining of different markers of signal transduction, indicating a sharp increase in the tumor suppressors PTPN14 (known to be a direct downstream target of E7 degradation activity) and TP53 (known to be an indirect target of E7 regulated via E6 / p53), in the presence of VSP035 for the indicated period, there was no change in the steady state protein levels of Akt or phosphorylated Akt (T473), IRF3 or phosphorylated IRF3 (S386), NLRX1 and STING (stimulator of interferon genes), non-glycosylated PDL-1 decreased, and the multiple band pattern indicated different glycosylation states, with the lowest band being the non-glycosylated nascent form, showing a time-dependent decrease in abundance in the presence of VSP035. This indicates that the known targets of E7 respond to the degradation of E7 by VSP035, and the tumor suppressors are reactivated, which is very important for efficacy and is associated with the apoptosis pattern detected in Figures 2B and C. Figure 3C shows different exposures of E7 staining after cells were treated with VSP035 for the indicated period and the compound was washed out, and the remaining 6-hour and 24-hour recovery periods, indicating that the compound is very stable after entering the cells; Figure 3D: Comparing the effects induced by OC974 and its enantiomers VSP034 and VSP035 and the mTOR1 inhibitor rapamycin and the mTOR1 / 2 inhibitor Torin 1 on various signal transduction markers. The compounds of the present invention showed similar downstream regulation, with a weaker effect on translation initiation than the mTOR1 inhibitor rapamycin, but a stronger E7 degradation effect, and still had a strong regulation on the phosphorylation of p70 S6 kinase (T389), and the pattern obtained by the mTOR1 / 2 inhibitor was overlapping but different because the mTOR2 selectivity pattern was not reflected; Figure 3E: Evaluating the effects of various inhibitors on the E7 steady state level of VSP025 and comparing with inhibitors of the MAP kinase and PI3K / mTOR kinase signal transduction pathways, while the MAPK pathway showed only a minor effect on the PI3K / mTOR kinase signal transduction, confirming the interactions observed in Figures 3C and D. The inhibitors were PD184352 (CI-1040) for the MEK kinase, CGP57380 for the MNK kinase, AT13148 for Akt1 and p70S6 kinase, and Torin 1 and Torin 2 for the mTOR1 and mTOR2 kinases. Again, VSP035 was the strongest E7 degrader, but was generally weaker in the regulation of translation initiation and stronger in the inhibition of p70S6 kinase phosphorylation, suggesting an effective combination for inhibiting HPV E7.

[0209] Figure 4: To evaluate the effect of PI3 kinase pathway inhibitors on the steady-state level of E7. Growing CaSki (HPV+) cells were incubated with medium (1), 100 nM rapamycin (2), 10 μM Akt1 VIII inhibitor (3), 2 μM GSK3 IX inhibitor + 10 μM Akt1 VIII (4), 2 μM GSK3 IX inhibitor (5), 0.5 μM PI103 + 0.1 μM Wortmanin PI3KCA inhibitor (6) for 4 hours; the extracts of CaSki (HPV+) cells were analyzed by Western blotting using HPV16E, pan-S6 ribosomal protein, anti-phospho-specific S6 ribosomal protein serine 235 / 236, anti-phospho-specific Akt1 serine 473, and pan-Akt1 specific monoclonal antibodies. This Western blotting experiment showed that the presence of rapamycin, PI3KCA, and Akt1 inhibitors led to a significant decrease in the steady-state level of E7 protein in CaSki cells.

[0210] Figure 5 : To compare cancer cells containing HPV with HPV-negative cancer cells. CaSki (HPV+) cells and osteosarcoma cells (U2Os, HPV-) were incubated with medium (1), 10 μM OC246 (2), or 100 nM rapamycin (3) and 10 μM OC246 and 100 nM rapamycin (4) for 4 hours; stained with P70-S6K (T389); pan-Akt, Akt (p473); pS6 S235 / 23 and HPV 16E7 antibodies, and the extracts of both types of cells were analyzed by Western blotting. This test showed that OC246 did not inhibit the signal transduction of phosphorylated Akt S473 because this site was stably phosphorylated in CaSki cells containing HPV E7 and dominant-active PIK3CA-E545K (p110α), and also in PIK3CA WT U2OS cells. In addition, in p70 S6 kinase, phospho-p70-S6K T389 was dephosphorylated in response to E7 degradation and was much less dephosphorylated in cells without HPV E7 protein.

[0211] Figure 6 : The compounds of the present invention regulate the tumor immune inhibitor PDL-1. The extracts of CaSki (HPV+) cells were analyzed by Western blotting and stained with PDL-1 monoclonal antibody (GLY-PDL-1 represents the glycosylated population of PDL-1). 1.5x10 5CaSki cells (showing high levels of PDL-1 expression) were seeded in 2 ml of rpmi 1640 + 10% fcs in a 6-well plate and incubated at 37 °C to allow cell growth. 24 hours after seeding, the cells were treated with vsp035, cycloheximide (CHX) and / or the MG132 proteasome inhibitor as indicated. Cells were harvested for WB analysis. Results showed a dose-dependent strong modulation of post-translational modification bands pointing to faster migration, with more expression at 8 hours than at 4 hours. The abundance of the faster migrating band was regulated by the proteasome inhibitor MG132, and the protein was unstable in the presence of CHX. This indicates that E7 stabilizes PDL-1, while the E7 degrader VSP035 reverses these effects, making it an effective PDL-1 destabilizer.

[0212] Figure 7 : The compounds of the present invention induce the degradation of HPV E7 from HPV+ SiHa tumor cells, which causes the stabilization of the protein level of the well-known E7 target tumor suppressor retinoblastoma protein (a transcriptional repressor, and it is well known in the art that E7 alters its homeostasis). After SiHa (HPV+) cells were incubated with medium (0), or 10 μM OC246 for 12 hours and 24 hours, the extracts were analyzed by Western blotting; the blot membranes were stained with monoclonal antibodies against HPV 16E7, actin, and the retinoblastoma protein pRb1; as the E7 signal decreased, an increase in the Rb protein signal could be detected.

[0213] Figure 8 : The abundance of HPV16E7 after incubation with CHX (cycloheximide), OC974, and various chemotherapeutic drugs for 4, 8, and 12 hours, respectively. Extracts from CaSki (HPV+) cells were analyzed by Western blotting and stained with monoclonal antibodies specific for HPV 16E7 and p53 (DO1): medium (lanes 1, 14), CHX_cycloheximide (lanes 2, 3, 4), OC974 (5, 6, 7), CDDP_cisplatin (8, 9, 10), DOX_doxorubicin (11, 12, 13). This indicates that the E7 degradation observed with the compounds of the present invention is not a non-specific effect also observed with standard-of-care chemotherapy, but an inherent property of these compounds. Given that E7 is strongly considered to be a pathogenic oncogene in HPV-induced malignancies, it has strong advantages as a tumor therapeutic agent for HPV+ tumors.

[0214] Figure 9: The antiviral activity of VSP035 as a single agent or in combination with various pharmacological drugs at different concentrations against SARS-CoV-2 is shown by the bars from left to right. Y-axis % inhibition. Due to the lethal concentration for Vero E6 cells, dose-dependence is only visible at non-lethal doses (median of multiple experiments n4 is shown); concentrations (from left to right) of compounds and their respective test concentrations (in μM) are as follows, "constant" refers to the same concentration for the series (X-axis, series number).

[0215] Figure 10 : VS035 has been confirmed to have potent antiviral activity as a single agent, and many very active synergistic VSP035 drug combinations have been confirmed to be dose-dependent.

[0216] (1) VSP035 (10, 5, 2.5, 1.25, 0.625);

[0217] (2) Rapamycin (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0218] (3) VSP035 (constant 10), Rapamycin (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0219] (4) VSP035 (10, 5, 2.5, 1.25, 0.625), Rapamycin (constant 0.0625);

[0220] (5) CI-1040 (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0221] (6) VSP035 (constant 10), CI-1040 (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0222] (7) CGP57380 (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0223] (8) VSP035 (constant 10), CGP57380 (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0224] (9) VSP035 (10, 5, 2.5, 1.25, 0.625), CGP57380 (constant 0.250);

[0225] (10) Torin-1 (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0226] (11) VSP035 (constant 10), Torin-1 (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0227] (12) VSP035 (10, 5, 2.5, 1.25, 0.625), Torin-1 (constant 0.0625);

[0228] These data indicate that the moderate SARS-COV2 antiviral activity observed with VSP035 monotherapy was significantly increased in combination studies with various inhibitors, especially with mTOR1 inhibitors, resulting in a potent dose-dependent inhibition of the SARS-COV2 virus.

[0229] Figure 11 Titration of VS977, VS978, VS035, and OC969 in CaSki cells for 6 hours is shown.

[0230] Figure 12 Analysis of the steady-state levels of compounds VS035, VS977, VS978, and OC969 is shown, compared to the method in Figure 3. Example

[0231] Example 1 (Synthesis of OC974):

[0232] trans-2-[(1-Methylpiperidin-4-yl)methyl]-1-oxo-3-[4-(trifluoromethyl)phenyl]-3,4-dihydroisoquinoline-4-carboxylic acid (Acid 1): trans-2-[(1-Methylpiperidin-4-yl)methyl]-1-oxo-3-[4-(trifluoromethyl)phenyl]-3,4-dihydroisoquinoline-4-carboxylic acid (Acid 1):

[0233]

[0234] 1-(1-Methylpiperidin-4-yl)methanamine (622 mg, 3.57 mmol) was added to a 10 mL solution of 4-trifluoromethylbenzaldehyde (527 mg, 3.75 mmol) in CH2Cl2 (peptide grade). The mixture was stirred in a round-bottom flask at room temperature for 1 h. Then phthalic acid (578.8 mg, 3.57 mmol) was added and the reaction mixture turned orange, and the mixture was stirred under reflux for 1 h. After the mixture was cooled to room temperature, the formed precipitate was separated by filtration and washed several times with CH2Cl2. The resulting white solid (0.557 g, 1.249 mmol) was a cis / trans mixture (1:2 ratio) of the desired product. Then, the isomer mixture was refluxed with 40 mL of acetic acid for 20 h. After evaporation of the solvent, the yellow residue was washed with 20 mL of Et2O to give a white solid (0.45 g, 28% yield). Molecular weight 446.47. [M+]=446.

[0235] Molecular formula: C 24 H 25 Composition of F3N2O3: C (64.57%), H (5.64%), F (12.77%), N (6.27%), O (10.75%)

[0236] (3R,4R)- and (3S,4S)-N-[3-(4-Methylpiperazin-1-yl)phenyl]-2-[(1-methylpiperidin-4-yl)methyl]-1-oxo-3-[4-(trifluoromethyl)phenyl]-3,4-dihydroisoquinoline-4-carboxamide (OC974): VSP034 (3R,4R)-; VSP035 (3S,4S)

[0237]

[0238] The complexing agent 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide·HCl (EDCI, 881.8 mg, 4.6 mmol) was added to a solution of acid 1 (1 g, 2.3 mmol) in 10 mL of dry N,N-dimethylformamide (DMF). The mixture was stirred in a round-bottom flask at room temperature for 10 min.

[0239] Then 3-(4-Methylpiperazin-1-yl)aniline (880 mg, 4.6 mmol) was added and the mixture was stirred at 50 °C overnight. Then, EtOAc (60 mL) was added and the organic layer was washed twice with 40 mL of brine, dried over MgSO4 and the solvent was removed under vacuum. Finally, the crude product was purified by silica gel chromatography using EtOAc / hexane 4:1 as the eluent to give the desired product as a white solid (450 mg, 32% yield); molecular weight 619.733; [M+]=619.0

[0240] C 35 H 40 Composition: C (67.83%), H (6.51%), F (9.2%), N (11.3%), O (5.16%) consisting of C, H, F3N5O2

[0241] Example 2A (Synthesis of Other Compounds):

[0242] The following compounds are prepared according to the above process or according to the processes described, for example, in Rothweiler et al. ChemMedChem 2008, 3, 1118 - 1128; WO 2006 / 097323 and WO 2008 / 034039, using suitable starting materials:

[0243]

[0244]

[0245]

[0246]

[0247]

[0248]

[0249]

[0250] Example 2B: Synthesis of Stereoisomers of the Compounds of the Invention

[0251]

[0252] Possible stereoisomers of OC246

[0253] According to the present invention, the preferred stereoisomers of OC 246 are (3R,4R)-N-[3-(4-methylpiperazin-1-yl)phenyl]-2-[(4-methylphenyl)methyl]-1-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide) and (3S,4S)-N-[3-(4-methylpiperazin-1-yl)phenyl]-2-[(4-methylphenyl)methyl]-1-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide

[0254]

[0255] Possible stereoisomers of OC974

[0256] According to the present invention, the preferred stereoisomers of OC 974 are VSP0034 UB-17964, (3R,4R)-N-[3-(4-methylpiperazin-1-yl)phenyl]-2-[(1-methylpiperidin-4-yl)methyl]-1-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide); and VSP0035 UB-17971, (3S,4S)-N-[3-(4-methylpiperazin-1-yl)phenyl]-2-[(1-methylpiperidin-4-yl)methyl]-1-oxo-3-[4-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroisoquinoline-4-carboxamide

[0257] Example 3: Biological Assay

[0258] Cell fluorescence (CF) analysis can be used to detect the expression levels of E7 protein in different HPV cancer isolates and to analyze the cell cycle status of designated cells.

[0259] Method 1 : Preparation of samples for cell fluorescence analysis - intracellular antibody labeling

[0260] For intracellular antibody labeling, 0.5 x 106 cells are washed once with 1 ml of ice-cold PBS. The cells are centrifuged at 350 x g for 5 minutes at 4°C, then fixed in 1% paraformaldehyde (1 ml / 106 cells) for 20 minutes at 4°C. The cells are washed with 1 ml of ice-cold PBS and centrifuged at 350 x g for 5 minutes at 4°C. To permeabilize the cells, ice-cold 100% methanol (1 ml / 106 cells) is added to the cells, incubated at 4°C for 20 minutes, and then centrifuged at 350 x g for 5 minutes at 4°C. The cells are washed with 1 ml of ice-cold PBS and centrifuged at 350 x g for 5 minutes at 4°C, and then resuspended in PBS (ice-cold) containing 0.1% saponin + 2% FBS. The cells are placed at room temperature for 20 - 30 minutes to reduce background signal, and then centrifuged at 350 x g for 5 minutes at 4°C. The primary antibody (mAb_HPV 16E7-1 (VS13004); concentration 1 μg / μl) is diluted in 0.1% saponin + 2% FBS (diluted 0.25 μg / 50 μl incubation buffer (5 ng / μl) per 1 x 106 cells). The cells are incubated with the primary antibody at room temperature for 30 minutes, washed with 0.1% saponin + 2% FBS, and centrifuged at 350 x g for 5 minutes at 4°C. The secondary antibody (FITC-conjugated goat anti-mouse IgG1-IgM, BD, catalog number 555988) is diluted in 0.1% saponin + 2% FBS (dilution 1:50). The cells are incubated with the secondary antibody at room temperature for 30 minutes, washed once with 0.1% saponin + 2% FBS, washed once with PBS, and centrifuged at 350 x g for 5 minutes at 4°C.

[0261] Method 2 : Cell fluorescence (CF) cell cycle analysis by propidium iodide staining

[0262] Propidium iodide (PI) DNA staining was performed to facilitate cell cycle analysis. For PI-DNA staining, the fixed cells and the cells finally stained with antibodies were resuspended in 450 μl PBS (per 106 cells) and incubated with 100 μg / ml RNase (stock solution 1 mg / ml, in PBS) at 37 °C for 10 minutes. Then the cells were incubated with 5 μg / 106 cells of PI (stock solution 1 mg / ml, in PBS) at room temperature for 10 minutes. The samples were stored at 4 °C until CF analysis was performed.

[0263] Method 3 : Cell fluorescence analysis (CF)

[0264] The cells were resuspended in 700 μl PBS and then CF analysis was performed using a Beckman Coulter FC 500MPL (excitation laser 488 nm). Data analysis was performed, with acquisition using MXP and data analysis (including MFI calculation) using CXP in the Beckman Coulter software package. Detection of HPV-E7 protein expression was based on morphological back-gating of the FL1 histogram (log scale), as well as gating for the dot plot FS (forward scatter) log / SS (side scatter) log and for the histogram SSlog.

[0265] Method 4 : E7 degrader assay

[0266] To determine the E7 protein expression level and to study the extent of reduction in the steady-state level of E7 protein in E7-expressing cells in the presence of various compounds, FC analysis was performed using an intracellular antibody labeling procedure with an HPV E7 monoclonal antibody. The E7 signal intensity was analyzed from the resulting FL1 histogram (log plot). The FL1 single histogram represents the change in the mean fluorescence intensity (MFI) channel of cells treated with the selected compound compared to cells incubated without the primary antibody but with the secondary antibody (which allows testing for autofluorescence), with non-compound-treated cells as the control. The acquisition parameters were set to zero for cells stained without the primary antibody. The reduction in the mean fluorescence intensity channel corresponds to the reduction in HPV16 E7 protein expression. The degradation of E7 in cells was calculated as the percentage (%) reduction in MFI (x - Me) using the following formula:

[0267] i) Relative degradation:

[0268] %D rel = (T - C) / T * 100;

[0269] ii) Adjusted degradation:

[0270] %D ad =(T - C) / (T - CHX)*100;

[0271] Drel = relative degradation,

[0272] Dad = adjusted degradation, assuming CHX %Drel = 100;

[0273] T = MFI of untreated cells;

[0274] C = MFI of cells treated with the compound;

[0275] CH = MFI of cells treated with cycloheximide (CHX);

[0276] To compare i)% relative degradation (Drel) within one experiment, it is sufficient. To compare ii) between two or more experiments, use adjusted degradation (Dad) and set the CHX steady state to 100% degradation parameter.

[0277] Method 5 : Cell extracts and Western blot were used for E7 protein detection

[0278] Reagents for extract preparation and Western blot:

[0279] Extraction buffer: 2.5x (Tris 0.25M pH6.8, glycerol 50%, SDS10%), gel: 4 - 12% gradient gel ( 4 - 12% Bis - Tris Plus Gel). MES buffer: 50mM MES, 50mM Tris Base, 0.1% SDS, 1mM EDTA, pH 7.3, blotting membrane: nitrocellulose 0.2μm (Whatman Protran#10401394), 3MM filter paper (e.g., Whatman 3MM Chr, #3030917). Western detection reagents: WB wash buffer 1X (TBET): 20mM Tris, 150mM NaCl, 0.125% Tween20, pH 7.8; non - fat milk powder (fat content less than 0.15%). Phosphate - buffered saline (PBS) 1X: Prepared as 1L, add 8g sodium chloride (NaCl), 0.2g potassium chloride (KCl), 1.44g disodium hydrogen phosphate (Na2HPO4) and 0.24g potassium dihydrogen phosphate (KH2PO4) to 1L dH2O, adjust pH to 7.2.

[0280] Cell extract preparation:

[0281] A) For natural cell pellets or cell pellets fixed in methanol or ethanol, add the extraction buffer as for cells in cell culture and proceed as described below. Paraffin-embedded cells fixed in formaldehyde must be rehydrated as described in the IHC procedures in the art and then proceed accordingly.

[0282] B) For cells in cell culture, use the following procedure to prepare total cell extracts. Freshly seeded cells are grown for 24 hours to obtain 65–75% confluence (equivalent to plating approximately 2x10 6 cells / 10 cm cell culture dish) for CaSki cells. The cell culture dish containing the medium is removed and placed on ice for 5 minutes.

[0283] The medium is aspirated from the culture and the dish is kept on ice. The cells are washed twice with ice-cold PBS 1x. All remaining liquid is aspirated.

[0284] The plate is placed at room temperature and 500 μl of extraction buffer (2.5x) preheated to 96 °C is added to immediately lyse the cells. The recommended volumes are as follows. The lysed cells are scraped from the dish and transferred to a microcentrifuge tube and then sonicated for 2 x 10 seconds to completely lyse the cells at room temperature. The sample is heated at 96 °C for 10 minutes and centrifuged at 12,000 g for 5 minutes at room temperature.

[0285] The supernatant is transferred to a new tube and DTT is added to a final concentration of 100 mM. Before loading on the gel, the sample is heated at 96 °C for 10 minutes. 10 - 20 μl is loaded onto an SDS-PAGE gel. The extract can be stored at -20 °C.

[0286] Western blot:

[0287] Endogenous E7 protein is a rigid, tightly folded molecule that binds only transiently to the hydrophilic membrane during Western blotting, especially when using the semi-dry method. Therefore, for Western blotting, a buffer system containing 40% (v / v) methanol is used. These buffers tend to be unstable, so freshly prepared solutions need to be used. The E7 antibody is used for TBET, pH 7.8. Under these conditions, the Western blot transfer of most other proteins is not complete. If different proteins on the same gel are stained, the gel is separated before blotting, with 40% methanol used in the transfer buffer for E7, while a transfer buffer containing 20% methanol is used for most other markers. To achieve optimal retention of the transferred E7 protein on the membrane, it must be allowed to air dry completely after transfer (at least 2 hours, preferably overnight). A 0.2 μm nitrocellulose is used as the blotting membrane. To prepare 50 ml of transfer buffer, mix 2.5 ml of MES buffer 20x, 27.5 ml of ultrapure water, and 20 ml of methanol before transfer (final methanol concentration 40% (v / v)). A bottom stack is formed by soaking filter paper in the transfer buffer, the membrane is wetted in ultrapure water, the gel is transferred to the membrane, and the upper stack is placed. Transfer at 0.8 mA / cm 2 for 1 hour. After transfer, the membrane is blotted dry between two layers of dry 3MM filter paper and transferred to two new 3MM filter papers, wrapped in aluminum foil, and dried overnight at room temperature.

[0288] Western blot detection:

[0289] All incubations are carried out at room temperature. Blocking buffer: 2% solution (w / v) of non-fat milk powder in WB wash buffer 1X. Non-fat milk powder (fat content less than 0.15%).

[0290] Blocking:

[0291] After overnight drying at RT (room temperature), the blotting membrane is wetted in WB wash buffer 1x for 5 minutes. Ensure that the membrane is thoroughly rehydrated - do not rehydrate in a solution containing milk powder or similar blocking proteins. Block the membrane with a large volume of WB blocking buffer for 30 minutes while gently stirring. Ensure that a sufficient volume of buffer is used to completely cover the membrane. Discard the blocking buffer.

[0292] Primary antibody:

[0293] The primary antibody mAb_HPV 16E7-1 (VS13004) is diluted 1:1000 in WB blocking buffer. Incubate with gentle shaking for 2 hours. Discard the antibody solution. Wash the membrane twice with a large volume of WB blocking buffer. Incubate 3 times in WB blocking buffer for 10 minutes each while gently shaking.

[0294] Secondary antibody:

[0295] The anti-mouse HRP secondary antibody was diluted in WB blocking buffer according to the instructions (for example, CST anti-mouse IgG HRP conjugated antibody, #7076, 1:3000). Incubate with gentle shaking for 1 hour. Wash the membrane twice with a large volume of WB blocking buffer. Incubate 3 times in WB blocking buffer for 10 minutes each time with gentle shaking. Wash the membrane twice with a large volume of PBS1x. Incubate in PBS1x for 10 minutes with gentle shaking. These membranes were developed using a standard chemiluminescence (ECL) detection system and imaged using a Licor or Viber device.

[0296] Method 6 : The inhibition of the molecule of the present invention on SARS-CoV-2 replication was analyzed and measured by RNA qPCR analysis.

[0297] Vero E6 cells were pre-incubated with the compound at a concentration of 7.5 μM. These cells were infected with the SARS-2 coronavirus (COVID19) derived from patients. The cell supernatant was collected 3 days after infection and centrifuged at 2000 rpm for 5 minutes to remove detached cells. Viral RNA was extracted using the MagNA Pure 24 system (Roche, Germany). The SARS-CoV-2 RNA genome was quantified using the TIB MOLBIOL LightMix Assay SARS-CoV-2 RdRP RTqPCR detection kit and the RNA Process Control PCR Kit (Roche). The PCR reaction was performed using a BRAND LHS laboratory robot to ensure quality. Amplification was performed using a LightCycler 480II (Roche). The method used was as Figure 10 shown.

[0298] Method 7 : The inhibition of the molecule of the present invention on SARS-CoV-2 replication was analyzed and measured by the ARS-CoV-2 / VeroE6-EGFP HTS antiviral test (384-well) and the SARS-CoV-2 / Huh7-EGFP HTS antiviral test (96-well);

[0299] Based on https: / / doi.org / 10.1016 / j.jviromet.2005.05.010 (Development of a homogeneous screening assay for automated detection of antiviral agents active against severe acute respiratory syndrome-associated coronavirus, Tania Ivens c et al, Journal of Virological Methods ,Volume 129, Issue 1 , October 2005, Pages 56 - 63)

[0300] A) Antiviral test setup and workflow

[0301] - First, add 30 μL of the assay solution to columns 23 - 24 (i.e., cell control) of the assay-ready plate provided by the partner.

[0302] - Then, add 30 μL of the cell suspension to all columns 1 - 24.

[0303] - Then transfer the plate to the robot / isolator system.

[0304] - Add 30 μL of 2x virus dilution (MOI to be determined) to columns 1 - 22 using a non-contact liquid dispenser.

[0305] - The final test volume is 60 μL plus the volume of the pre-plated compound.

[0306] - The percentage of DMSO remains < 1%.

[0307] - Incubate the plate at 37 °C for 5 days.

[0308] - Perform standard full-well fluorescence plate reading (self-optimized protocol, approximately 6 minutes per 384-well plate, 4 readings / well).

[0309] - Perform high-content imaging reading (auto-focus for each well, no binning, 1 channel, 5x objective, approximately 25 minutes per 384-well plate).

[0310] B) Details of the screening test:

[0311] ○ Fluorescent EGFP reporter gene VeroE6 cells.

[0312] ○ SARS-CoV-2 isolate BetaCov / Belgium / GHB-03021 / 2020.

[0313] - Plate reading: After 5 days.

[0314] ○ Microplate reader full-well fluorescence measurement: 4 readings / well, average readings provided as raw data.

[0315] ○ Full-well high-content imaging (5x objective): The raw data provided includes

[0316] ■ Count of bright objects (proportional to the cell number).

[0317] ■ Count of the surface covered by fluorescent cells.

[0318] ■ Calculated value of the intensity of the surface covered by fluorescent cells.

[0319] Table 1: Study and evaluation of commercially available substances alone or in combination

[0320]

[0321] Test 1 : Testing of E7 degrading agents using FC

[0322] 1x10 6 Freshly inoculated CaSki cells (ATCC CRL-7915) were grown overnight at 37 °C and 5% CO2 in RPMI 1640, 10% FCS medium in a 10 cm diameter cell culture dish, and then incubated at 37 °C and 5% CO2 for 4 hours in the presence of 10 μM cycloheximide (CHX) and 10 μM OC246 or in the presence of only the medium. Subsequently, E7 protein was evaluated by intracellular HPV16 E7 antibody labeling method using flow cytometry. The overlay of individual FL1 histograms obtained from the medium and OC246-treated samples is shown in Figure 1. The left histogram in overlay A) was treated with CHX, and the more right histogram was the medium (CH 1.71; T 8.06; %D rel 78.78, %D ab 100)% ) — In overlay B), the left histogram was treated with OC246, and the right histogram was the medium (C OC246 4.53; T 8.06; %D rel 43.79, %D ab 55.59). The values of MFI and D are shown in parentheses. Figure 1 shows a representative histogram of the E7 degrading agent test.

[0323] Test 2 : Drug screening using E7 degrading agent test.

[0324] The degrading agent test was used to screen a series of compounds for E7 degrading activity. The corresponding %D values are listed in Table 2 below. ad Summary Table 2 of the values.

[0325] Table 2

[0326] Compound <![CDATA[%D ad > SD Compound <![CDATA[%D ad > SD OC244 0 0 OC250 19 1.52 OC245 0 0 OC251 1 0.08 OC246 56 4.48 OC252 0 0 OC247 6 0.48 OC253 0 0 OC974 68 5.44 OC254 16 1.28 OC975 67 5.36 OC255 2 0.16 OC976 54 4.32 OC256 8 0.64 OC973 20 1.6 OC257 12 0.96 OC972 32 2.56 OC258 0 0 OC971 26 2.08 OC377 35 2.8 OC970 20 1.6 OC378 48 3.84 OC969 66 5.28 OC379 26 2.08 OC968 37 2.96 OC380 3 0.24 OC967 22 1.76 OC381 41 3.28

[0327] Test 3: Cell Cycle Analysis of Various Compounds of the Invention

[0328] CaSki cells were incubated with various compounds, and the cell cycle distribution of the cells was evaluated using propidium iodide staining.

[0329] To analyze the cytostatic and cytotoxic effects of OC compounds, the cell cycle profile was analyzed in vitro using flow cytometry as a readout after 48 hours of incubation. For this purpose, cell cycle analysis was performed on selected OC E7 degrader compounds in CaSki cells. Using a 6-well plate, 1.5 x 10 5 cells were seeded per well and grown overnight at 37 °C and 5% CO2. Subsequently, the cells were treated with 10 μl of a DMSO solution of the OC compound (concentrations are shown in Table 2). To analyze the cell cycle behavior, the cells were analyzed by flow cytometry (FC) in the presence of propidium iodide (PI-). Briefly, the cells were detached by trypsinization, and all supernatants were included in the analysis, fixed with 70% ice-cold ethanol and stored at 4 °C until FC analysis with PI- staining (1 mg / ml). At least 7000 events were collected for each sample.

[0330] To further analyze apoptosis, a washout experiment was performed where cells expressing E7 were incubated with the compounds of the invention for a short time, then the cells were washed 3 times with fresh medium and incubated for a further period, and the FC-PI profile was evaluated. Figure 2 shows the cell cycle distribution of FC PI-stained CaSki cells after 4 hours of growth, washout and further growth in the presence of 50 μM of the compound OC246 of the invention, compared to the medium control (a), after further growth for 24 hours (b) and after further growth for 48 hours (c). The X-axis is the PI-FL3 signal intensity in logarithmic scale, and the Y-axis is the number of events. The median G1 content of the cells, the right peak G2 / M content and the left peak sub-G1 population were used as a measure of apoptosis.

[0331] Conclusion : As determined by the sub-G1 content observed after 48 hours, OC246 and OC974 are potent apoptosis inducers in cervical cancer cells. The other compounds did not induce substantial apoptosis under the experimental conditions used. The 48-hour incubation time was chosen instead of the 72 or 94 hours commonly used for such experiments, allowing us to argue that the almost complete apoptosis induction effect (89.4 / 82.9%) observed for OC246 / OC974 is a first-cycle event.

[0332] Table 3: Changes in cell cycle distribution induced by OC compounds (%)

[0333] Compound G1 / 5 μM G1 / 10 μM G2 / 5 μM G2 / 10 μM A* / 5 μM A* / 10 μM Untreated 53.3 53.3 15.6 15.6 15.0 15.0 OC246 48.0 1.5 15.7 0.2 19.6 89.4 OC974 49.6 8.7 9.9 0.8 19.5 81.8 OC975 49.9 51.4 10.4 10.5 13.9 11.8 OC976 58.8 53.2 9.3 16.9 11.4 12.8 OC972 53.2 48.4 16.9 15.9 12.8 13.5 OC973 52.1 52.6 17.6 11.5 11.1 13.0 OC968 52.7 48.0 18.0 19.7 11.9 11.6

[0334] * Apoptosis measured from the total sub-G1 content in logarithmic form

[0335] Test 4: The E7 degrader VSP035 shows first order kinetics of E7 protein destabilization and subsequent modulation of HPV E7 loss on the mTOR and pi3K signaling pathways.

[0336] HPV 16 E7 protein degradation time course of VSP035. Seed 2 x 10 5 CaSki cells into 2 ml of RPMI 1640 + 10% fcs in a 6-well plate and incubate at 37 °C for 1 day. Subsequently, treat with 10 μM VSP035 for the indicated times. β-actin was used as an internal loading control. Even with short-term treatment, Vsp035 induced a stable reduction in E7, an effect that persisted over the 24-hour observation period. ( Figure 3a ))

[0337] Figure 3b ) Time course of example VSP035.

[0338] Seed 1 x 10 6 CaSki cells into 12 ml of RPMI 1640 + 10% FCS in each 10-cm culture dish and incubate at 37 °C for 2 days. The cells were then treated with 10 μm VSP035 for the indicated times and lysed for WB analysis. β-actin was used as an internal loading control.

[0339] For E7, VSP035 treatment showed a steady decline over time; the longer the cell treatment time, the greater the decline. p(S473)Akt, Sting, and Irf-3 did not appear to be affected by VSP035.

[0340] The 24-hour time point showed the greatest reduction in E7, which was consistent with the increase in Ptpn14 and p53. Ptpn14 is a known E7 substrate. PD-L1 is regulated by E7 and thus by VSP035.

[0341] Figure 3c Example. The persistent, potent degradation effect of VSP035 on the HPV 16 E7 steady-state protein level.

[0342] Seed 1.5 x 10 4 CaSki cells into 2 ml of RPMI 1640 + 10% FCS in each well of a 6-well plate and incubate at 37 °C for 2 days; then treat with 10 μm VSP035 for the indicated time periods and harvest at 6 hours or 24 hours after the 0 h or 24 h time points. The medium containing VSP035 was removed by washing twice with RPMI 1640 + 10% fcs and changed to RPM 1640 + 10% fcs without the VSP035 compound for the remaining time before harvest.

[0343] Figure 3d )Example The effects of E7 degraders (OC974, VSP034, VSP035) on E7 steady-state levels and activation of cellular signaling molecules compared to mTor inhibitors (rapamycin, Torin 1).

[0344] Cell signaling in CaSki cells treated with HPV 16 E7 degraders, MAPK, and mTOR inhibitors. mRNA translation can be stimulated by mTORC1 through its downstream substrates, S6 kinase, and 4E-BP1 / eIF4E [Choo, 2008]. In addition to the latter, which has been studied in multiple cell lines, several key signaling molecules were further analyzed in more detail. To better understand the mechanism of action of Valdospan compounds (OC974, VSP034, and VSP035) and to distinguish these small molecules from commonly used mTOR inhibitors, CaSki cells were treated with multiple inhibitors, including: CGP 57380, an MNK1 inhibitor; rapamycin and Torin 2 as mTOR inhibitors; Torin 1, an mTORC1 / 2 inhibitor; PD184352, a MEK inhibitor; and MKK2 and AT13148 as multi-AGC kinase inhibitors. The expression and phosphorylation of key molecules in major cell signaling pathways were studied, and the unique but overlapping functions of the molecules of the present invention were shown.

[0345] A. Seed 8x10 5 CaSki cells in 12 ml of RPMI 1640 + 10% FCS in a 10 cm culture dish and incubate at 37 °C for 2 days. Subsequently, treat the cells with 10 μM VSP034, 10 μM VSP035, 10 μM OC974, 250 nM Torin 1, and 100 nM rapamycin for 6 hours, scrape the cells into 400 μl of lysis buffer, and analyze by WB.

[0346] B. Seed 1x10 6 CaSki cells in 12 ml of RPMI 1640 + 10% FCS in a 10 cm culture dish and incubate at 37 °C for 2 days. After treating with 10 μM and 5 μM VSP035, 10 μM CGP-57380, 100 nM rapamycin, 250 nM Torin 1, 100 nM Torin 2, 100 nM PD184352, and 100 nM AT13148 for 6 hours, scrape the cells in 400 μl of lysis buffer and analyze by WB. β-Actin and vinculin are used as internal loading controls.

[0347] Figure 3eExample. Effects of various inhibitors on signaling molecules in Caski cells compared to the molecules of the present invention.

[0348] 1x10 6 CaSki cells were seeded in 12 ml of RPMI 1640 + 10% FCS in a 10 cm culture dish and left static at 37 °C for 2 days. After treatment with 10 μm and 5 μm VSP035, 10 μm CGP-57380, 100 nM rapamycin, 250 nM Torin 1, 100 nM Torin 2, 100 nM pd184352, and 100 nM at13148 for 6 hours, the cells were scraped into 400 μl of lysis buffer and analyzed by WB. β-actin was used as an internal loading control. VSP035 always induced the strongest reduction of the HPV 16 E7 protein, followed by Torin 1, Torin 2, GP-57380, and rapamycin. Except that Torin 1 caused greater inhibition of E7 than other inhibitors but not VSP035, Torin 1 and Torin 2 also showed similar effects on all other investigated cellular signaling molecules.

[0349] VSP035 led to dose-dependent hypophosphorylation of 4E-BP1. Rapamycin also showed hypophosphorylation of total 4E-BP1; but overall, the phosphorylation of p-4E-BP1 (Thr37 / 46) increased. Exeot applied to Torin1 and Torin 2, and all other compounds allowed Thr46 phosphorylation. After incubation with Torin 1 and Torin 2, only hypophosphorylated 4E-BP1 was present, without Thr37 / 46 or Ser65 phosphorylation. Phosphorylation of Ser65 on 4E-BP1 was reduced or completely inhibited by all compounds. Thus, a clear distinction of downstream effects can be made compared to general TOR kinase inhibition.

[0350] After the induction of Thr37 and Thr46 phosphorylation, Thr70 phosphorylation was described as an ectopic of Ser65 phosphorylation. Besides mTOR, other kinases can also phosphorylate 4E-BP1 [as reviewed by Qin, 2016]. This is consistent with VSP035 regulating and preventing eIF4E from releasing 4E-BP1, thereby inhibiting cap-dependent translation.

[0351] Phosphorylation of 4E-BP1 at Ser65 and of p70S6 kinase at Thr389 showed the same trend, i.e., they were inhibited or strongly reduced by (in increasing order) 10 μM VSP035, Torin 1, Torin 2, rapamycin, 5 μM VSP035, and CGP 57380.

[0352] The important phosphorylation of AKT at Ser473 is inhibited only by Torin 1 and Torin 2, but not by VSP035 and rapamycin.

[0353] Test 5 :

[0354] Growing CaSki (HPV+) cells were incubated with medium (1), 100 nM rapamycin (2), 10 μM Akt1 VIII inhibitor (3), 2 μM GSK3 IX inhibitor + 10 μM Akt1 VIII inhibitor (4), 2 μM GSK3IX inhibitor (5), 0.5 μM PI103 + 0.1 μM wortmannin PI3KCA inhibitor (6) for 4 hours, stained with HPV16E7 (VS13004) pan S6 ribosomal protein, anti-phospho-specific S6 ribosomal protein serine 235 / 236, anti-phospho-specific Akt1 serine 473, and pan-Akt1 specific monoclonal antibodies, and Western blot analysis was performed on cell extracts. This test showed that the presence of rapamycin, PI3KCA, and Akt1 inhibitors led to the degradation of E7 protein in CaSki cells ( Figure 4 ).

[0355] Test 6 :

[0356] CaSki (HPV+) and osteosarcoma cells (U2Os, HPV-) were incubated with medium (1), 10 μM OC246 (2), or 100 nM rapamycin (3), and 10 μM OC246 and 100 nM rapamycin (4) for 4 hours, stained with P70-S6K (T389); pan-Akt, Akt (p473); pS6 S235 / 236, and HPV16E7 antibodies, and Western blot analysis was performed on cell extracts. This test showed that OC246 did not inhibit the phosphorylation-Akt S473 signal transduction because this site was stably phosphorylated in CaSki cells containing HPV E7 and dominant active PIK3CA-E545K (p110α), and also in PIK3CAWT U2OS cells. In addition, in the p70S6 kinase, phospho-p70-S6K T389 was dephosphorylated in response to E7 degradation ( Figure 5 ).

[0357] Test 7:

[0358] VSP035 regulates the tumor immune inhibitor PDL-1

[0359] Western blot analysis of extracts from CaSki (HPV+) cells was performed, staining with a monoclonal antibody against PDL-1 (gly-PDL-1 represents the glycosylated population of PDL-1). 1.5 x 10 5 CaSki cells (a cell line showing high levels of PDL-1 expression) were seeded into 2 ml of RPMI 1640 + 10% FCS in 6-well plates and incubated at 37 °C to allow cell growth. Twenty-four hours after seeding, the cells were treated with VSP035, cycloheximide (CHX) and / or the proteasome inhibitor MG132 as indicated. Cells were harvested for BY WB analysis. Results showed a strong modulation of the faster migrating post-translationally modified band in a dose-dependent manner, with more expression of the band after 8 hours compared to the 4-hour time point. In particular, the abundance of the faster migrating band was regulated by the proteasome inhibitor MG132, and the protein was unstable in the presence of CHX. This indicates that E7 stabilizes PDL-1, while the E7 degrader VSP035 reverses these effects, making it an effective pdl-1 destabilizer ( Figure 6 ).

[0360] Test 8:

[0361] (D) Western blot analysis of cell extracts was performed after SiHa (HPV+) cells were incubated with vehicle (0), or 10 μM OC246 for 12 hours and 24 hours; the blot was stained with monoclonal antibodies against HPV16 E7, actin and the retinoblastoma protein pRb1; an increase in the Rb protein signal could be detected as the E7 signal decreased ( Figure 7 ).

[0362] Test 9:

[0363] HPV16 E7 abundance after incubation with CHX (cycloheximide) OC974 and various chemotherapeutic drugs for 4, 8 and 12 hours, respectively.

[0364] Western blot analysis of extracts from CaSki (HPV+) cells was performed, staining with monoclonal antibodies specific for HPV16 E7 and p53 (DO1): vehicle (lanes 1, 14), CHX_cycloheximide, (lanes 2, 3, 4), OC974 (5, 6, 7), CDDP_cisplatin (8, 9, 10), DOX_doxorubicin (11, 12, 13)( Figure 8 ).

[0365] Test 10:

[0366] HPV16 E7 abundance after incubation with OC246 and various chemotherapeutic drugs for 4, 8, and 12 hours. Western blot analysis of extracts from CaSki (HPV+) cells was performed and stained with monoclonal antibodies specific for HPV16 E7 and p53 (DO1): medium (lanes 1, 14), vincristine (lanes 2, 3, 4), AKT1 VIII inhibitor (5, 6, 7), etoposide (8, 9, 10), OC246 (11, 12, 13).

[0367] Test 11:

[0368] Growing CaSki (HPV+) cells were incubated with medium (1), 10 μM OC246 (2), 30 μM LLnL (MG101) (3), 10 μM OC246 + 30 μM LLnL (MG101) (proteasome inhibitor) (4), 10 μM G5 (DUB, deubiquitinase inhibitor) (5), 10 μM OC246 + 10 μM G5 (DUB, deubiquitinase inhibitor) (6), medium (7), 10 μM OC246 + 0.5 μM PI103 + 0.1 μM wortmannin PI3KCA inhibitor together for 4 hours; Western blot analysis of cell extracts was performed and stained with a monoclonal antibody specific for HPV16 E7 (VS13004).

[0369] Table 4: Antibodies used in WB experiments

[0370]

[0371]

[0372] Test 12: Antitumor efficacy of OC246 and OC974 against a CaSki high-risk HPV16 human cervical cancer xenograft model

[0373] OC246 and OC974 degraders represent a new class of anticancer drug compounds. OC246 and OC974 are highly stable small molecules that cause degradation of intracellular HPV E7 protein, thereby inhibiting tumor cell proliferation.

[0374] The aim of this study was to evaluate the in vivo efficacy of OC246 and OC974 in a human cervical cancer (CaSki) xenograft model in nude mice. OC246 and OC974 were administered orally at 2 mg / kg / dose once daily for a total of four times, with a three-day break, for a total of three cycles. Cisplatin (CDDP) was used as a reference compound and administered intravenously at 6 mg / kg three times a week (q7dx3).

[0375] The study summarized in Table 3 showed that the growth of CaSki human cervical cancer (evaluated on day 44, one week after the final treatment) was inhibited by treatment with OC246 and OC974 (tumor growth inhibition rate (%TGI) was 66.6% and 63.9%, respectively), with similar anti-tumor efficacy to treatment with CDDP at the maximum tolerated dose (79.2% TGI).

[0376] Neither OC246 nor OC974 caused a decrease in body weight (BW) compared to the starting level on day 44 ( +5.5% and +1.1%, respectively), in contrast, a significant BW loss (-10.2%) occurred in the CDDP group. The control group did not show weight loss (BW +4.9%).

[0377] In summary, these results indicate that OC246 and OC974 have anti-tumor activity against CaSki cervical cancer xenografts expressing human HPV16E6 and HPV16E7 oncoproteins at well-tolerated doses, and the CaSki cells acquired a PIK3CA-E545K (phosphatidylinositol-3 kinase 110-kDa catalytic subunit (p110α)) functional mutation. In addition, these findings further support the in vivo efficacy of OC246 and OC974 in experimental tumor models after repeated oral treatment.

[0378] Table 5

[0379]

[0380]

[0381] Test 13 : Pharmacokinetics of OC246:

[0382] The pharmacokinetics of OC246 were evaluated after a single oral (p.o.) administration to female NMRI mice. The compound OC246 was suspended in Lipoid S100 and Myritol 318 at 50 mg / kg. The oral dose was 50 mg / kg, the final concentration was 10 mg / ml, and the dosing volume was 5.0 ml / kg. Blood samples were collected from three mice at time points of 0.25, 0.5, 1, 2, 4, 6, 8, 16, and 24 hours after dosing and analyzed by HPLC and mass spectrometry bioanalytical methods. The main pharmacokinetic parameters are summarized in Table 4.

[0383] Table 5:

[0384]

[0385] obs: Observed; tmax: Cmax time point; tlast: Time of the last quantifiable concentration; Cmax: Observed maximum concentration; Clast: Last quantifiable concentration; SE: Standard error; AUClast: Area under the concentration-time curve (AUC) calculated using the trapezoidal rule between the time of dosing and the last measurement time point where the concentration is above the lower limit of quantification; AUCinf(obs): AUC calculated using the trapezoidal rule from 0 hours to infinity; AUC%extrapol: Percentage of AUCinf(obs) extrapolated from tlast to infinity; Rsq: Goodness of fit used to determine λz in the terminal elimination phase; λz (Lambda_z): Terminal elimination rate constant (at least three of the last measured concentrations); t1 / 2: Apparent terminal elimination half-life; CLobs: Observed total (systemic) body clearance; Vz_obs: Apparent volume of distribution based on AUClast and λz.

[0386] Test 14 Pharmacokinetic analysis of the OC974 trans enantiomers VSP034 and VSP035 after oral liposomal formulation.

[0387] After a single oral gavage dose of 100 mg / kg to 6 female Sprague-Dawley rats weighing 250 g (±25 g), the pharmacokinetic parameters of VSP034 and VSP035 encapsulated as liposomal formulations were evaluated. These animals were randomly divided into two experimental groups (Group 1 and Group 2), with each group consisting of 3 rats. VSP034 was administered to the rats in Group 1, and VSP035 was administered to the rats in Group 2. Blood was collected at baseline and at 15 minutes, 30 minutes, 1, 2, 4, 6, 8, and 24 hours after oral gavage. The rats were sacrificed 24 hours after dosing. Blood was collected from the tail vein at each time point, except for the last collection (24 hours), which was performed by intracardiac puncture at the time of sacrifice under isoflurane anesthesia. The animals were weighed immediately before dosing to assess the appropriate dose and were carefully monitored throughout the experiment. They were housed under standard housing conditions that met the legal requirements for the proper housing of rodents for no more than the maximum experimental endpoint. Access to water and food was allowed ad libitum. After administration of the liposomal formulation, all rats were in good condition and showed no signs of distress or abnormal behavior. The humane endpoint was not reached. Pharmacokinetic analysis was performed using the Microsoft Excel add-in PK Solver. The pharmacokinetic parameters of the two compounds were compared using the Student's t-test for unpaired data with the software GraphPad Prism ver. 8.0. A p-value < 0.05 was considered statistically significant.

[0388] Analytical method: Compound analysis was performed according to the bioanalytical method in Test 13. In this study, Carbamazepine was used as the internal standard.

[0389] Pharmacokinetic analysis: The pharmacokinetic analysis of VSP034 and VSP035 was performed using the Excel add-in 2.0 PK Solver. The results were fitted according to the non-compartmental model after extravascular administration. Concentration-time curves of VSP034 and VSP035.

[0390] Major pharmacokinetic parameters (half-life, t 1 / 2 ; time to reach maximum plasma concentration, T max ; maximum plasma concentration, C max ; AUC extrapolated to infinity, AUC 0-inf ; mean residence time, MRT; apparent volume of distribution at the terminal phase, V z / F; and apparent oral clearance (CL / F) were calculated using standard formulas based on the coefficients and exponents of the best fit. The results for each rat and the mean, standard deviation (SD), and median for each study group are reported in Tables 6 and 7 below.

[0391] Table 6. Pharmacokinetic parameters of VSP034.

[0392]

[0393]

[0394] Table 7. Pharmacokinetic parameters of VSP035

[0395]

[0396] Statistical analysis was performed using the Student's t-test for unpaired data to compare the pharmacokinetic parameters of the two compounds. t1 / 2, Tmax, and MRT did not show significant differences. The AUC of VSP035 was significantly higher than that of VSP034 (4-fold), and Cmax showed a related increasing trend, although statistical significance could not be achieved. Accordingly, Vz / F and CL / F of VSP035 were significantly lower than those of VSP034.

[0397] Test 15 Monolayer Assay Using Sulforhodamine B (SRB) Staining :

[0398] After treatment with various OC compounds at different concentrations, monolayer-grown various cell cultures were harvested from exponentially growing cultures. For this purpose, 10,000 to 30,000 cells were seeded into 96-well flat-bottom microtiter plates according to the cell line. After a 24-hour recovery period to allow the cells to resume exponential growth, the supernatant was discarded and the liquid handling robotic system ( Starlet, Hamilton) was added with 100 μl of medium (8 control wells / plate) or medium containing the test compound, and treated continuously for 72 hours. The compound was applied at 9 concentrations and 8 wells / concentration. At least three independent experiments were conducted. For SRB staining, the cells were fixed with SRB01 (Table 5) at 4 °C for 1 hour (final concentration of TCA = 10%), and washed 5 times with H2O using a plate washer (Hydroflex, ) and then stained with 100 μl of SRB02 at room temperature for 10 minutes, followed by washing 4 times with SRB03, and finally oscillated with 100 μl of the developing solution SRB04 for 5 minutes. The optical density was evaluated at 540 nm using a plate reader (Sunrise, ).

[0399] The concentration required for the half-maximal response of the compound to cell growth inhibition (EC50) was calculated by non-linear regression (log[inhibitor concentration] versus response (% T / C)), using the analysis software GraphPad Prism 5 (GraphPad Software Inc., CA) applicable to Windows, version 5.01.

[0400] Table 8: SRB test solutions

[0401] SRB Test Solution SRB01 <![CDATA[Fixative: Trichloroacetic acid (TCA) 50% w / v in dH2O]]> SRB02 Staining Solution: Sulforhodamine B (SRB) 0.4% w / v in SRB03 Wash Solution; SRB03 <![CDATA[Wash solution: 1% acetic acid in dH2O]]> SRB04 Development Solution: Tris-Base 10 mM

[0402] Table 9 : EC50 measurement values of cervical cancer cells in the presence of OC246

[0403] The EC50 of OC246 on cervical cancer cell lines Hela (ATCC CCL-2), SiHa (ATCC HTB-35), and CaSki (ATCC CRM-CRL-1550) expressing HPV E7 was evaluated in the SRB test and compared with peripheral blood mononuclear cells (PBMC). The results showed that compared with > 10 -4 of PBMC cells, the IC50 activity was in the low μM range.

[0404] Table 9:

[0405] Cell HPV EC50 CaSki HPV16 <![CDATA[2.89x10 -6 > SiHa HPV16 <![CDATA[3.53x10 -6 > Hela HPV18 <![CDATA[2.68x10 -6 > PBMC - <![CDATA[> 10 -4 >

[0406] Table 10:

[0407] The SRB assay of Caski cells was used to determine the EC50 of each compound of the present invention, showing its potent anti-tumor activity ("0" indicates no activity detected at the tested concentration). The EC50 was calculated by Graphpad fit (Y = 100 / (1 + 10^((LogEC50 - X)*HillSlope))).

[0408] Table 10

[0409]

[0410]

[0411] Test CoV2

[0412] Test 16 The antiviral activity of the molecules of the present invention is exemplified by their SARV-CoV-2 antiviral activity.

[0413] The SARV-CoV-2 antiviral activities of VSP034 and VSP035 (n3; the number of times this test was repeated under each condition). The results of DMSO (1), 7.5 μM VSP034 (2), and 7.5 μM VSP035 (3) are shown, with the y-axis on a logarithmic scale. The SARV-CoV-2 antiviral activities of 7.5 μM VSP034 and VSP035 were determined by PCR, showing a one-order-of-magnitude reduction in viral load.( Figure 9 )

[0414] Test 17

[0415] The inhibition of the compounds of the present invention on the SARV-CoV-2 virus activity was evaluated in %, and a non-toxic compound concentration of 1.25 μM was used. The results showed strong antiviral activity of various compounds (n4). The SARS-CoV-2 / VeroE6-EGFP HTS antiviral test (384-well) was used (Table 11);

[0416] Table 11:

[0417]

[0418]

[0419] Test 18

[0420] The antiviral activity of VSP035 alone or in combination with various pharmacological drugs at different concentrations against SARS-CoV-2 is shown by the bars from left to right. Y-axis % inhibition. Due to the lethal concentration for Vero E6 cells, dose-dependence is only visible at non-lethal doses (median of multiple experiments n4 is shown); concentrations (left to right) of compounds and their respective test concentrations (in μM) are, "constant" refers to the same concentration for the series (X-axis, number of the series):( Figure 10 )

[0421] VS035 has potent antiviral activity as a single agent, and many very active synergistic VSP035 drug combinations have been shown to be dose-dependent.

[0422] (1) VSP035 (10, 5, 2.5, 1.25, 0.625);

[0423] (2) Rapamycin (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0424] (3) VSP035 (constant 10), Rapamycin (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0425] (4) VSP035 (10, 5, 2.5, 1.25, 0.625), Rapamycin (constant 0.0625);

[0426] (5) CI-1040 (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0427] (6) VSP035 (constant 10), CI-1040 (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0428] (7) CGP57380 (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0429] (8) VSP035 (constant 10), CGP57380 (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0430] (9) VSP035 (10, 5, 2.5, 1.25, 0.625), CGP57380 (constant 0.250);

[0431] (10) Torin-1 (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0432] (11) VSP035 (constant 10), Torin-1 (0.250, 0.125, 0.0625, 0.03125, 0.15625);

[0433] (12) VSP035 (10, 5, 2.5, 1.25, 0.625), Torin-1 (constant 0.0625);

[0434] Test 19 : SARS-CoV-2 antiviral activity of VSP035 in Huh7 cells

[0435] The antiviral activity of the single compound of VSP035 against SARV-CoV-2 was determined by the SARS-CoV-2 / Huh7-EGFP HTS antiviral assay (96-well) (n4). This assay tested the antiviral activity of the representative compound VSP035 at a sub-lethal dose of 10 μM (n4), showing an inhibition rate of 72 ± 7.7%. The results showed that VS035 had strong SARS-CoV-2 antiviral activity in the liver epithelial tumor cell line Huh7.

[0436] Test 20 : Steady-state levels of compounds VS035, VS977, VS978, and OC969

[0437] Figure 11 The steady-state level analysis of compounds VS035, VS977, VS978, and OC969 is shown and compared with the method in Figure 3. Incubated with the compounds of the present invention for 6 hours. The MG-132 proteasome inhibitor was used as a control. 0.1% DMSO was used as a vehicle control. Figure 11 A shows the Western blot evaluation of the compounds of the present invention at various concentrations in the figure; Figure 11 B shows quantification of the Western blot exemplified in Figure 11 A using Vilber Bio 1D to quantify the bioluminescence signal of the Western blot; Figure 11 C is Figure 11 A summary table of the results obtained in B.

[0438] Test 21 : SRB assay was performed on CaSki cells as described in Test 15 to determine the EC50 of compounds VS035, VS977, VS978, and OCS969

[0439] In this Test 21, SRB assays were performed on CaSki cells as described in Test 15 to determine the EC50 of the compounds of the invention VS035, VS977, VS978 and OCS969, which showed potent anti-tumor activity. The EC50 was calculated by Graphpad fitting (Y = 100 / (1+10^((LogEC50-X)*HillSlope))). As seen in the degradation experiments, VS977 showed the most significant effect ( Figure 12 ).

[0440] Accordingly, the present invention discloses the following preferred embodiments:

[0441] 1. Compounds of formula (I):

[0442]

[0443] wherein

[0444] R 1 is alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, heterocycloalkyl, alkylcycloalkyl, heteroalkylcycloalkyl, aryl, heteroaryl, arylalkyl or heteroarylalkyl; all of these groups may optionally be substituted; and

[0445] R 1a is a hydrogen atom or C 1-4 alkyl; or

[0446] R 1 and R 1a together are part of a heterocycloalkyl containing 5 or 6 ring atoms selected from C, N and O, the heterocycloalkyl of which may be unsubstituted or substituted by R 11 groups;

[0447] R 11 is C 1-4 alkyl or C 1-6 heteroalkyl;

[0448] R 2 is phenyl, naphthyl, heteroaryl containing 5 or 6 ring atoms selected from C, N, O and S, or heteroaryl containing two rings, the two rings together containing 9 or 10 ring atoms selected from C, N, O and S, all of these groups may be unsubstituted or substituted by one or two R 21 groups;

[0449] R 21 is independently selected from halogen, C 1-4 alkyl and C 1-4 heteroalkyl;

[0450] R 3 is phenyl, heteroaryl containing 5 or 6 ring atoms selected from C, N, O and S, C3-7 A cycloalkyl group or a heteroalkyl group containing 3 to 7 ring atoms selected from C, N, O, and S, all of these groups may be unsubstituted or substituted by one or two R 31 groups;

[0451] R 31 is independently selected from halogen, C 1-4 alkyl, and C 1-4 heteroalkyl;

[0452] R 4 is independently selected from halogen, OH, NH2, SH, CN, N3, NO2, C 1-4 alkyl, and C 1-4 heteroalkyl; or

[0453] two R 4 groups together form a group of the formula -O-CH2-O- or -O-CH2-CH2-O-; and

[0454] n is 0, 1, or 2;

[0455] or a pharmaceutically acceptable salt thereof,

[0456] is preferably used as an antiviral agent, more preferably as an antiviral agent against viruses of the family Polyomaviridae, Orthomyxoviridae, or Coronaviridae, even more preferably for the treatment of human papillomavirus (HPV) infection or for the treatment or prevention of SARS-CoV-2 infection, especially for the treatment of HPV-induced malignant and neoplastic diseases or for the treatment or prevention of COVID-19.

[0457] 2. The compound according to embodiment 1, wherein R 4 is selected from Cl, OMe, and NHAc; especially wherein R 4 is OMe.

[0458] 3. The compound according to embodiment 1 or 2, wherein n is 0 or 1; especially wherein n is 0 or wherein n is 1 and R 4 is OMe.

[0459] 4. The compound according to any one of the preceding embodiments, wherein R 1a is a hydrogen atom.

[0460] 5. The compound according to any one of the preceding embodiments, wherein R 1 is phenyl, naphthyl, heteroaryl containing 5 or 6 ring atoms selected from C, N, O, and S, or heteroaryl containing two rings, the two rings together containing 9 or 10 ring atoms selected from C, N, O, and S, all of these groups may be optionally substituted.

[0461] 6. The compound according to any one of the preceding embodiments, wherein R1 is a group of the formula -Ar-Cy-R 5 wherein Ar is a phenylene or a heteroarylene containing 5 or 6 ring atoms selected from C, N and O; Cy is a C 3-7 cycloalkylene or a heterocycloalkylene containing 3, 4, 5, 6 or 7 ring atoms selected from C, N, O and S and R 5 is a hydrogen atom or a C 1-4 alkyl or a C 1-6 heteroalkyl.

[0462] 7. The compound according to embodiment 6, wherein Ar is a phenylene and Cy is a heterocycloalkylene containing 6 ring atoms selected from C, N and O and R 5 is a hydrogen atom or a C 1-4 alkyl.

[0463] 8. The compound according to any one of the preceding embodiments, wherein R 1 is selected from the group consisting of:

[0464]

[0465] 9. The compound according to any one of embodiments 1-4, wherein R 1 is a group of the formula -NH-CH2-CH2-N(CH3)2.

[0466] 10. The compound according to any one of the preceding embodiments, wherein R 2 is a 1,4-phenylene carrying one R 21 group.

[0467] 11. The compound according to any one of the preceding embodiments, wherein R 21 is selected from F, Cl, Br, CF3, CH3 and OMe.

[0468] 12. The compound according to any one of the preceding embodiments, wherein R 21 is a CF3 group.

[0469] 13. The compound according to any one of the preceding embodiments, wherein R 3 is a 1,4-phenylene carrying one R 31 group.

[0470] 14. The compound according to any one of the preceding embodiments, wherein R 31 is selected from Cl, CF3, CH3, NMe2 and OMe.

[0471] 15. The compound according to any one of the preceding embodiments, wherein R 2 is 4-chlorophenyl and R 3 is 4-methylphenyl.

[0472] 16. A compound according to any preceding embodiment, having the formula (II):

[0473]

[0474] wherein R 21 , R 3 , R 4 and n are as defined in any preceding embodiment, or a pharmaceutically acceptable salt thereof.

[0475] 17. A compound according to embodiment 16, wherein n is 0 or 1; R 4 is OMe; R 21 is halogen, C 1-4 alkyl or C 1-4 heteroalkyl (especially a CF3 group); R 3 is phenyl, a heteroaryl containing 5 or 6 ring atoms selected from C, N, O and S, C 3-7 cycloalkyl or a heterocycloalkyl containing 3 - 7 ring atoms selected from C, N, O and S, all of which groups may be unsubstituted or substituted by one or two R 31 groups; and R 31 are independently selected from halogen, C 1-4 alkyl and C 1-4 heteroalkyl.

[0476] 18. A pharmaceutical composition comprising a compound according to any preceding embodiment or a pharmaceutically acceptable hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

[0477] 19. A compound or pharmaceutical composition according to any preceding embodiment for the treatment of infections by viruses of the family Polyomaviridae, Orthomyxoviridae, especially influenza A virus, or Coronaviridae, human immunodeficiency virus (HIV), Merkel cell polyomavirus (MCV, MCPyV), JC polyomavirus (JCV, JCPyV), BK polyomavirus (BKV, BKPyV), TS polyomavirus (TSV, TSPyV), H7 polyomavirus (HV7, HPyV7), Simian polyomavirus 40 (SV40), cytomegalovirus (CMV), hepatitis B virus (HEPB), hepatitis C virus (HEPC), hepatitis D virus (HEPD), human immunodeficiency virus 1 (HIV - 1), human immunodeficiency virus 2 (HIV - 2), human T - cell lymphotropic virus I (HTLV - I), human T - cell lymphotropic virus II (HTLV - II), Epstein - Barr virus (EBV), Kaposi's sarcoma - associated herpesvirus (Herpesviridae; KSHV), especially HPV infection or SARS - CoV - 2 infection.

[0478] 20. A compound or pharmaceutical composition according to any one of embodiments 1-19 for the treatment of HPV-induced malignant and neoplastic diseases, particularly cervical cancer, vulvar cancer, vaginal cancer, anal cancer, penile cancer, head and neck cancer, and condyloma acuminata, subsets of non-melanoma skin cancer, lung cancer, prostate cancer and breast cancer, recurrent respiratory papillomatosis (RRP), Burkitt lymphoma, non-Hodgkin lymphoma and Bowen's disease; or for the prevention or treatment of infections by unicellular eukaryotic parasites, particularly Plasmodium falciparum, Plasmodium malariae and Leishmania donovani.

[0479] 21. A pharmaceutical composition comprising a combination of a signal transduction molecule antagonist or agonist and a compound according to any one of embodiments 1-20 or a pharmaceutically acceptable hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier, said compound being preferably selected from

[0480] rel-(3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0481] rel-(3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0482] rel-(3R,4R)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0483] rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0484] rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0485] (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0486] (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0487] (3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0488] (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and

[0489] (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0490] (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0491] (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0492] (3S,4S)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0493] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and

[0494] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide.

[0495] 22. The pharmaceutical composition according to embodiment 21, wherein the signaling molecule is a receptor molecule or one or two of its downstream targets, such as EGFR, Ras, phosphatidylinositol-4,5-bisphosphate 3-kinase alpha 85 kDa regulatory subunit or 110 kDa catalytic subunit (PI3K), phosphatase and tensin homolog (PTEN), protein kinase B (PKB, Akt), p70-S6 kinase 1, mammalian target of rapamycin (mTOR1), FK506-binding protein (FKBP12), mTOR complex 1 (mTORC1), TGFβ pathway signaling, and / or NOTCH signaling.

[0496] 23. The pharmaceutical composition according to embodiment 21, wherein the signaling molecule is a steroid receptor molecule of estrogen or a signaling molecule antagonist or agonist selected from the group consisting of: mTOR inhibitor-8 (CAS No.: 2489196-70-3), mTOR inhibitor-3 (CAS No.: 1207358-59-5), mTOR inhibitor-1 (CAS No.: 468747-17-3), mTOR inhibitor-2 (CAS No.: 2219323-96-1), HDACs / mTOR inhibitor 1 (CAS No.: 2271413-06-8), PI3K / mTOR inhibitor-3 (CAS No.: 1363338-53-7), PI3K / mTOR inhibitor-2 (CAS No.: 1848242-58-9), PI3K / mTOR inhibitor-1 (CAS No.: 1949802-49-6), MTI-31 (CAS No.: 1567915-38-1), sapacitabine (CAS No.: 1224844-38-5), WAY-600 (CAS No.: 1062159-35-6), Onatasertib (CAS No.: 1228013-30-6), MHY1485 (CAS No.: 326914-06-1), PI3Kα / mTOR-IN-1 (CAS No.: 1013098-90-2), PF-04979064 (CAS No.: 1220699-06-8), 3BDO (CAS No.: 890405-51-3), dihydromyricetin (CAS No.: 27200-12-0), RapaLink-1 (CAS No.: 1887095-82-0), AD80 (CAS No.: 1384071-99-1), DS-7423 (CAS No.: 1222104-37-1), ETP-46464 (CAS No.: 1345675-02-6), Torin 2 (CAS No.: 1223001-51-1), PF-04691502 (CAS No.: 1013101-36-4), TFEB activator 1 (CAS No.: 39777-61-2), vistusertib (CAS No.: 1009298-59-2), MHY-1685 (CAS No.: 27406-31-1), MCX28 (CAS No.: 1414453-58-9), CZ415 (CAS No.: 1429639-50-8), XL388 (CAS No.: 1251156-08-7), GNE-317 (CAS No.: 1394076-92-6), NSC781406 (CAS No.: 1676893-24-5), GDC-0349 (CAS No.: 1207360-89-1),Gedatolisib (CAS No.: 1197160-78-3), Compound 401 (CAS No.: 168425-64-7), Temsirolimus (CAS No.: 162635-04-3), 28-Epiphyllocladinol (CAS No.: 253431-35-5), GNE-477 (CAS No.: 1032754-81-6), Ridaforolimus (CAS No.: 572924-54-0), GNE-493 (CAS No.: 1033735-94-2), Bimiralisib (CAS No.: 1225037-39-7), (+)-Usnic acid (CAS No.: 7562-61-0), PP121 (CAS No.: 1092788-83-4), 42-(2-Tetrazolyl)rapamycin (CAS No.: 221877-56-1), AZD-8055 (CAS No.: 1009298-09-2), Torin 1 (CAS No.: 1222998-36-8), PKI-402 (CAS No.: 1173204-81-3), PKI-402 (CAS No.: 1173204-81-3), Chrysophanol (CAS No.: 481-74-3), VS-5584 (CAS No.: 1246560-33-7), Dactolisib (CAS No.: 915019-65-7), PI3K-IN-22 (CAS No.: 1202884-94-3), Torkinib (CAS No.: 1092351-67-1), Zingiberenone (CAS No.: 193410-84-3), CC-115 (CAS No.: 1300118-55-1), Rapamycin (CAS No.: 53123-88-9), Salidroside (CAS No.: 10338-51-9), PQR626 (CAS No.: 1927857-98-4), Dactolisib Tosylate (CAS No.: 1028385-32-1), LAT1-IN-1 (CAS No.: 20448-79-7), GSK1059615 (CAS No.: 958852-01-2), Rubioncoclathrin (CAS No.: 132242-52-5), KU-57788 (CAS No.: 503468-95-9), Apitolisib (CAS No.: 1032754-93-0), Everolimus (CAS No.: 159351-69-6), WYE-687 (CAS No.: 1062161-90-3), SF2523 (CAS No.: 1174428-47-7), WYE-132 (CAS No.: 1144068-46-1), Lupiwighteone (CAS No.: 104691-86-3),OSI-027 (CAS No.: 936890-98-1), JR-AB2-011 (CAS No.: 2411853-34-2), SAR405 (CAS No.: 1523406-39-4), WYE-687 dihydrochloride (CAS No.: 1702364-87-1), PI3Ka-IN-5 (CAS No.: 2237953-19-2), PQR530 (CAS No.: 1927857-61-1), PKI-179 (CAS No.: 1197160-28-3), WYE-354 (CAS No.: 1062169-56-5), BGT226 malate (CAS No.: 1245537-68-1), AKT-IN-10 (CAS No.: 2709045-56-5), BGT226 (CAS No.: 915020-55-2), AKT-IN-9 (CAS No.: 2709045-53-2), PI-103 (CAS No.: 371935-74-9), Voxtalisib (CAS No.: 934493-76-2), ETP-45658 (CAS No.: 1198357-79-7), PF-06843195 (CAS No.: 2067281-51-8), (32-carbonyl)-RMC-5552 (CAS No.: 2382768-55-8), BC-LI-0186 (CAS No.: 695207-56-8), P7 (CAS No.: 1001409-50-2), BX-320 (CAS No.: 702676-93-5), BX-517 (CAS No.: 850717-64-5), BX517 (CAS No.: 850717-64-5), BX795 (CAS No.: 702675-74-9), BX-912 (CAS No.: 702674-56-4), JX06 (CAS No.: 729-46-4), Paris saponin I (CAS No.: 50773-41-6), PS10 (CAS No.: 1564265-82-2), PS210 (CAS No.: 1221962-86-2), PS423 (CAS No.: 1221964-37-9), PDK1-IN-RS2 (CAS No.: 1643958-89-7), GSK2334470 (CAS No.: 1227911-45-6), PF-AKT400 (CAS No.: 1004990-28-6), Capivasertib (CAS No.: 1143532-39-1), Afuresertib (CAS No.: 1047644-62-1), Borussertib (CAS No.: 1800070-77-2),GSK-690693 (CAS No.: 937174-76-0), AKT-IN-10 (CAS No.: 2709045-56-5), AKT-IN-9 (CAS No.: 2709045-53-2), AKT-IN-3 (CAS No.: 2374740-21-1), Vevorisertib (CAS No.: 1416775-46-6), FPA-124 (CAS No.: 902779-59-3), CCT128930 (CAS No.: 885499-61-6), AT13148 (CAS No.: 1056901-62-2), anti-CTLA-4 antibody, especially ipilimumab; anti-PD-1 antibody, especially nivolumab, pembrolizumab or tislelizumab; and / or anti-PD-L1 antibody, especially atezolizumab, durvalumab or avelumab.,

[0497] 24. Compounds selected from

[0498] rel-(3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0499] rel-(3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0500] rel-(3R,4R)-2-(4-Methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0501] rel-(3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0502] rel-(3R,4R)-7-Acetamido-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0503] rel-(3R,4R)-6,7-dimethoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0504] rel-(3R,4R)-2-(4-methylbenzyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0505] rel-(3R,4R)-2-(4-methylbenzyl)-N-(3-morpholinophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0506] rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0507] rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0508] rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-3-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, including all pharmaceutically acceptable salts and ester forms thereof, and including all enantiomers and racemates of these compounds and salts, preferably

[0509] (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0510] (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0511] (3R,4R)-2-(4-Methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0512] (3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0513] (3R,4R)-7-Acetamido-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0514] (3R,4R)-6,7-Dimethoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0515] (3R,4R)-2-(4-Methylbenzyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0516] (3R,4R)-2-(4-Methylbenzyl)-N-(3-morpholinophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0517] (3R,4R)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0518] (3R,4R)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0519] (3R,4R)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-3-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0520] (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0521] (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0522] (3S,4S)-2-(4-Methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0523] (3S,4S)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0524] (3S,4S)-7-Acetamido-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0525] (3S,4S)-6,7-Dimethoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0526] (3S,4S)-2-(4-Methylbenzyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0527] (3S,4S)-2-(4-Methylbenzyl)-N-(3-morpholinophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0528] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0529] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and

[0530] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-3-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, especially

[0531] rel-(3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0532] rel-(3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0533] rel-(3R,4R)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0534] rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0535] rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0536] (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0537] (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0538] (3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0539] (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and

[0540] (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0541] (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0542] (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0543] (3S,4S)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0544] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and

[0545] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, including all pharmaceutically acceptable salt and ester forms thereof;

[0546] It is preferably used for the treatment of HPV infection or for the prevention or treatment of SARS-CoV-2 infection, especially for the treatment of HPV-induced malignant and neoplastic diseases, especially as an E7 protein degrader, or for the prevention or treatment of COVID-19.

[0547] 25. Use of a compound according to any one of embodiments 1-17 for the preparation of a medicament for the treatment or prevention of the following viral infections, said viral infections being polyomavirus, orthomyxovirus, especially infection with influenza A virus, or coronaviridae, human immunodeficiency virus (HIV), Merkel cell polyomavirus (MCV, MCPyV), JC polyomavirus (JCV, JCPyV), BK polyomavirus (BKV, BKPyV), TS polyomavirus (TSV, TSPyV), H7 polyomavirus (HV7, HPyV7), Simian polyomavirus 40 (SV40), cytomegalovirus (CMV), hepatitis B virus (HEPB), hepatitis C virus (HEPC), hepatitis D virus (HEPD), human immunodeficiency virus 1 (HIV-1), human immunodeficiency virus 2 (HIV-2), human T-lymphotropic virus I (HTLV-I), human T-lymphotropic virus II (HTLV-II), Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (herpesviridae; KSHV), hepatitis C virus (HCV), or hepatitis B virus (HBV) infection, especially HPV infection or SARS-CoV-2 infection; or for the treatment of HPV-induced malignant and neoplastic diseases, especially cervical cancer, vulvar cancer, vaginal cancer, anal cancer, penile cancer, head and neck cancer, and condyloma acuminata, a subgroup of non-melanoma skin cancer, lung cancer, prostate cancer and breast cancer, recurrent respiratory papillomatosis (RRP), Burkitt lymphoma, non-Hodgkin lymphoma and Bowen's disease; or for the prevention or treatment of single-celled eukaryotic parasites, especially Plasmodium falciparum, Plasmodium malariae and Leishmania donovani infections.

[0548] 26. A method for treating or preventing a viral infection, said viral infection being a polyomavirus, an orthomyxovirus, particularly an infection with an influenza A virus, or a coronaviral virus, human immunodeficiency virus (HIV), Merkel cell polyomavirus (MCV, MCPyV), JC polyomavirus (JCV, JCPyV), BK polyomavirus (BKV, BKPyV), TS polyomavirus (TSV, TSPyV), H7 polyomavirus (HV7, HPyV7), Simian polyomavirus 40 (SV40), cytomegalovirus (CMV), hepatitis B virus (HEPB), hepatitis C virus (HEPC), hepatitis D virus (HEPD), human immunodeficiency virus 1 (HIV-1), human immunodeficiency virus 2 (HIV-2), human T-lymphotropic virus I (HTLV-I), human T-lymphotropic virus II (HTLV-II), Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (Herpesviridae; KSHV), hepatitis C virus (HCV), or hepatitis B virus (HBV) infection, particularly an HPV infection or an SARS-CoV-2 infection; or for treating or preventing HPV-induced malignant and neoplastic diseases, particularly cervical cancer, vulvar cancer, vaginal cancer, anal cancer, penile cancer, head and neck cancer, and condyloma acuminata, a subgroup of non-melanoma skin cancer, lung cancer, prostate cancer and breast cancer, recurrent respiratory papillomatosis (RRP), Burkitt lymphoma, non-Hodgkin lymphoma and Bowen's disease; or for preventing or treating an infection with a unicellular eukaryotic parasite, particularly Plasmodium falciparum, Plasmodium malariae and Leishmania donovani, wherein an effective amount of a compound according to any one of embodiments 1-17 is administered to a patient in need thereof.

[0549] 27. A pharmaceutical composition comprising an anti-CTLA-4 antibody, particularly ipilimumab; an anti-PD-1 antibody, particularly nivolumab, pembrolizumab or tislelizumab; and / or an anti-PD-L1 antibody, particularly atezolizumab, durvalumab or avelumab, in combination with a compound according to embodiment 24 or a pharmaceutically acceptable hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier, said compound preferably

[0550] (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0551] (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0552] (3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0553] (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and

[0554] (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0555] (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0556] (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0557] (3S,4S)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide,

[0558] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and

[0559] (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide.

Claims

1. A compound selected from the following group, or a pharmaceutically acceptable hydrate, solvate or salt thereof: rel-(3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide.

2. A pharmaceutical composition comprising the compound according to any one of the preceding claims or a pharmaceutically acceptable hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

3. Use of the compound of claim 1 or the pharmaceutical composition of claim 2 for the treatment of HPV infection or for the prevention or treatment of SARS-CoV-2 infection.

4. Use of the compound of claim 1 or the pharmaceutical composition of claim 2 for the treatment of HPV-induced malignant and neoplastic diseases, in particular as a degrader of protein E7, or for the prevention or treatment of COVID-19.

5. A pharmaceutical composition comprising a combination of a signal transduction molecule antagonist or agonist and a compound selected from the group consisting of compounds or pharmaceutically acceptable hydrates, solvates or salts thereof, optionally in combination with a pharmaceutically acceptable carrier, rel-(3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and (3S,4S)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide; Preferably, the signal transduction molecule is a receptor molecule or one or more of its downstream targets, for example, EGFR, Ras, phosphatidylinositol-4,5-bisphosphate 3-kinase alpha 85 kDa regulatory subunit or 110 kDa catalytic subunit (PI3K), phosphatase and tensin homolog (PTEN), protein kinase B (PKB, Akt), p70-S6 kinase 1, mammalian target of rapamycin (mTOR1), FK506-binding protein (FKBP12), mTOR complex 1 (mTORC1), TGFbeta pathway signal transduction molecules, and / or NOTCH signal transduction molecules, particularly the signal transduction molecule is a steroid receptor molecule such as estrogen or a signal transduction molecule antagonist or agonist selected from the group consisting of: mTOR inhibitor-8 (CAS No.: 2489196-70-3), mTOR inhibitor-3 (CAS No.: 1207358-59-5), mTOR inhibitor-1 (CAS No.: 468747-17-3), mTOR inhibitor-2 (CAS No.: 2219323-96-1), HDACs / mTOR inhibitor 1 (CAS No.: 2271413-06-8), PI3K / mTOR inhibitor-3 (CAS No.: 1363338-53-7), PI3K / mTOR inhibitor-2 (CAS No.: 1848242-58-9), PI3K / mTOR inhibitor-1 (CAS No.: 1949802-49-6), MTI-31 (CAS No.: 1567915-38-1), sapacitabine (CAS No.: 1224844-38-5), WAY-600 (CAS No.: 1062159-35-6), Onatasertib (CAS No.: 1228013-30-6), MHY1485 (CAS No.: 326914-06-1), PI3Kα / mTOR-IN-1 (CAS No.: 1013098-90-2), PF-04979064 (CAS No.: 1220699-06-8), 3BDO (CAS No.: 890405-51-3), dihydromyricetin (CAS No.: 27200-12-0), RapaLink-1 (CAS No.: 1887095-82-0), AD80 (CAS No.: 1384071-99-1), DS-7423 (CAS No.: 1222104-37-1), ETP-46464 (CAS No.: 1345675-02-6), Torin 2 (CAS No.: 1223001-51-1), PF-04691502 (CAS No.: 1013101-36-4), TFEB activator 1 (CAS No.: 39777-61-2), vistusertib (CAS No.: 1009298-59-2),MHY-1685 (CAS No.: 27406-31-1), MCX 28 (CAS No.: 1414453-58-9), CZ415 (CAS No.: 1429639-50-8), XL388 (CAS No.: 1251156-08-7), GNE-317 (CAS No.: 1394076-92-6), NSC781406 (CAS No.: 1676893-24-5), GDC-0349 (CAS No.: 1207360-89-1), Gedatolisib (CAS No.: 1197160-78-3), Compound 401 (CAS No.: 168425-64-7), Temsirolimus (CAS No.: 162635-04-3), 28-Epiphyllocladinol (CAS No.: 253431-35-5), GNE-477 (CAS No.: 1032754-81-6), Ridaforolimus (CAS No.: 572924-54-0), GNE-493 (CAS No.: 1033735-94-2), Bimiralisib (CAS No.: 1225037-39-7), (+)-Usnic acid (CAS No.: 7562-61-0), PP121 (CAS No.: 1092788-83-4), 42-(2-Tetrazolyl)rapamycin (CAS No.: 221877-56-1), AZD-8055 (CAS No.: 1009298-09-2), Torin 1 (CAS No.: 1222998-36-8), PKI-402 (CAS No.: 1173204-81-3), PKI-402 (CAS No.: 1173204-81-3), Chrysophanol (CAS No.: 481-74-3), VS-5584 (CAS No.: 1246560-33-7), Dactolisib (CAS No.: 915019-65-7), PI3K-IN-22 (CAS No.: 1202884-94-3), Torkinib (CAS No.: 1092351-67-1), Wighteone (CAS No.: 193410-84-3), CC-115 (CAS No.: 1300118-55-1), Rapamycin (CAS No.: 53123-88-9), Salidroside (CAS No.: 10338-51-9), PQR626 (CAS No.: 1927857-98-4), Dactolisib tosylate (CAS No.: 1028385-32-1), LAT1-IN-1 (CAS No.: 20448-79-7), GSK1059615 (CAS No.: 958852-01-2), Rubioncoclathrin (CAS No.: 132242-52-5),KU-57788 (CAS No.: 503468-95-9), Apitolisib (CAS No.: 1032754-93-0), Everolimus (CAS No.: 159351-69-6), WYE-687 (CAS No.: 1062161-90-3), SF2523 (CAS No.: 1174428-47-7), WYE-132 (CAS No.: 1144068-46-1), Lupanine wightone (CAS No.: 104691-86-3), OSI-027 (CAS No.: 936890-98-1), JR-AB2-011 (CAS No.: 2411853-34-2), SAR405 (CAS No.: 1523406-39-4), WYE-687 dihydrochloride (CAS No.: 1702364-87-1), PI3Ka-IN-5 (CAS No.: 2237953-19-2), PQR530 (CAS No.: 1927857-61-1), PKI-179 (CAS No.: 1197160-28-3), WYE-354 (CAS No.: 1062169-56-5), BGT226 malate (CAS No.: 1245537-68-1), AKT-IN-10 (CAS No.: 2709045-56-5), BGT226 (CAS No.: 915020-55-2), AKT-IN-9 (CAS No.: 2709045-53-2), PI-103 (CAS No.: 371935-74-9), Voxtalisib (CAS No.: 934493-76-2), ETP-45658 (CAS No.: 1198357-79-7), PF-06843195 (CAS No.: 2067281-51-8), (32-carbonyl)-RMC-5552 (CAS No.: 2382768-55-8), BC-LI-0186 (CAS No.: 695207-56-8), P7 (CAS No.: 1001409-50-2), BX-320 (CAS No.: 702676-93-5), BX-517 (CAS No.: 850717-64-5), BX517 (CAS No.: 850717-64-5), BX795 (CAS No.: 702675-74-9), BX-912 (CAS No.: 702674-56-4), JX06 (CAS No.: 729-46-4), Paris saponin I (CAS No.: 50773-41-6), PS10 (CAS No.: 1564265-82-2), PS210 (CAS No.: 1221962-86-2), PS423 (CAS No.: 1221964-37-9),PDK1-IN-RS2 (CAS No.: 1643958-89-7), GSK2334470 (CAS No.: 1227911-45-6), PF-AKT400 (CAS No.: 1004990-28-6), Capivasertib (CAS No.: 1143532-39-1), Afuresertib (CAS No.: 1047644-62-1), Borussertib (CAS No.: 1800070-77-2), GSK-690693 (CAS No.: 937174-76-0), AKT-IN-10 (CAS No.: 2709045-56-5), AKT-IN-9 (CAS No.: 2709045-53-2), AKT-IN-3 (CAS No.: 2374740-21-1), Vevorisertib (CAS No.: 1416775-46-6), FPA-124 (CAS No.: 902779-59-3), CCT128930 (CAS No.: 885499-61-6), AT13148 (CAS No.: 1056901-62-2), anti-CTLA-4 antibody, especially ipilimumab; anti-PD-1 antibody, especially nivolumab, pembrolizumab or tislelizumab; and / or anti-PD-L1 antibody, especially atezolizumab, durvalumab or avelumab., 6. Use of a compound, said compound being selected from the group consisting of rel-(3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-2-(4-Methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-7-Acetamido-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-6,7-Dimethoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-2-(4-Methylbenzyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-2-(4-Methylbenzyl)-N-(3-morpholinophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-3-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, including all its pharmaceutically acceptable salt and ester forms, and including all enantiomers and racemates of these compounds and salts, preferably (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-2-(4-Methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-7-Acetamido-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-6,7-Dimethoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-2-(4-Methylbenzyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-2-(4-Methylbenzyl)-N-(3-morpholinophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-3-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-2-(4-Methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(6-(trifluoromethyl)pyridin-3-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-Acetamido-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-6,7-Dimethoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-2-(4-Methylbenzyl)-N-(4-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-2-(4-Methylbenzyl)-N-(3-morpholinophenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-N-(3-(4-Methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-3-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, especially rel-(3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, rel-(3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-7-methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-7-methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide; Preferably used as an antiviral agent, more preferably as an antiviral agent against the following viruses: Polyomaviridae viruses, Orthomyxoviridae viruses, especially influenza A virus, or Coronaviridae viruses, human immunodeficiency virus (HIV), Merkel cell polyomavirus (MCV, MCPyV), JC polyomavirus (JCV, JCPyV), BK polyomavirus (BKV, BKPyV), TS polyomavirus (TSV, TSPyV), H7 polyomavirus (HV7, HPyV7), Simian polyomavirus 40 (SV40), cytomegalovirus (CMV), hepatitis B virus (HEPB), hepatitis C virus (HEPC), hepatitis D virus (HEPD), human immunodeficiency virus 1 (HIV-1), human immunodeficiency virus 2 (HIV-2), human T-lymphotropic virus I (HTLV-I), human T-lymphotropic virus II (HTLV-II), Epstein - Barr virus (EBV), Kaposi's sarcoma - associated herpesvirus (Herpesviridae; KSHV), Even more preferably for the treatment of human papillomavirus (HPV) infection or for the treatment or prevention of SARS-CoV-2 infection, especially for the treatment of HPV-induced malignant and neoplastic diseases, especially as a degrader of the E7 protein, or for the treatment or prevention of COVID-19.

7. A pharmaceutical composition comprising a combination of an antibody and a compound, the antibody being an anti-CTLA-4 antibody, especially ipilimumab; an anti-PD-1 antibody, especially nivolumab, pembrolizumab or tislelizumab; and / or an anti-PD-L1 antibody, especially atezolizumab, durvalumab or avelizumab; the compound being selected from the following group (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and (3R,4R)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-Methoxy-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-7-Methoxy-2-(4-methylbenzyl)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-2-((1-methylpiperidin-4-yl)methyl)-1-oxo-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide, and (3S,4S)-N-(3-(4-methylpiperazin-1-yl)phenyl)-1-oxo-2-(pyridin-4-ylmethyl)-3-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxamide; or a pharmaceutically acceptable hydrate, solvate or salt thereof, optionally in combination with a pharmaceutically acceptable carrier.

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