WO2022175384A1 - Small-molecule agents with antiviral activity against rna viruses - Google Patents

Small-molecule agents with antiviral activity against rna viruses Download PDF

Info

Publication number
WO2022175384A1
WO2022175384A1 PCT/EP2022/053938 EP2022053938W WO2022175384A1 WO 2022175384 A1 WO2022175384 A1 WO 2022175384A1 EP 2022053938 W EP2022053938 W EP 2022053938W WO 2022175384 A1 WO2022175384 A1 WO 2022175384A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
aryl
compound
haloalkyl
formula
Prior art date
Application number
PCT/EP2022/053938
Other languages
French (fr)
Inventor
José GALLEGO SALA
Ángel CANTERO CAMACHO
Álvaro SIMBA LAHUASI
Adolfo GARCÍA-SASTRE
Romel ROSALES RAMÍREZ
Kris M. WHITE
Vicente MARCHÁN SANCHO
Sergi CHUMILLAS VICEDO
Original Assignee
Fundación Universidad Católica De Valencia San Vicente Mártir
Icahn School Of Medicine At Mount Sinai
Universitat De Barcelona
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Fundación Universidad Católica De Valencia San Vicente Mártir, Icahn School Of Medicine At Mount Sinai, Universitat De Barcelona filed Critical Fundación Universidad Católica De Valencia San Vicente Mártir
Publication of WO2022175384A1 publication Critical patent/WO2022175384A1/en

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/409—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil having four such rings, e.g. porphine derivatives, bilirubin, biliverdine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4192—1,2,3-Triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C217/06—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted
    • C07C217/14—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring
    • C07C217/18—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to a carbon atom of a six-membered aromatic ring the six-membered aromatic ring or condensed ring system containing that ring being further substituted
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to compounds for use in the treatment and/or prevention of viral infections caused by RNA-viruses, including Coronaviridae, especially those caused by respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV and SARS- CoV-2).
  • RNA-viruses including Coronaviridae
  • respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV and SARS- CoV-2).
  • RNA viruses are usually single-stranded RNA (ssRNA) although retroviruses can also include DNA intermediates in their replication cycle.
  • RNA viruses are accountable for the common cold, influenza, AIDS, SARS, MERS, COVID- 19, chikungunya, Dengue fever, zika fever, yellow fever, West Nile fever, hepatitis C, hepatitis E, Ebola virus disease and rabies, among other notable human diseases.
  • the viruses of the family Coronaviridae are enveloped viruses with a positive-sense single- stranded RNA genome and a nucleocapsid of helical symmetry.
  • the name of the family is derived from the Latin corona, meaning “crown” or “halo”, which refers to the characteristic appearance pronounced of a solar corona around the virions (virus particles) when viewed under two-dimensional transmission electron microscopy, due to the surface being covered in club-shaped protein spikes.
  • SARS-CoV-2 severe acute respiratory syndrome coronavirus 2
  • Wuhan the capital of China's Hubei province
  • COVID-19 has evolved into an appalling global pandemic worldwide.
  • the first approved small-molecule antiviral drug against SARS-CoV-2 is non-specific, injectable and has limited efficacy at improving COVID-19 clinical outcome.
  • the drugs Molnupiravir and Paxlovid were approved for oral administration.
  • molnupiravir is believed to be mutagenic and thus only authorised for use in certain populations where other treatments are not feasible.
  • an urgent need for the identification of novel antivirals against SARS-CoV-2 remains.
  • WO20 15/157223 discloses the use of tamoxifen citrate and toremifene citrate for treating MERS and SARS coronavirus infections.
  • Zhao Yuguang et al. (“Toremifene interacts with and destabilizes the Ebola virus glycoprotein", Nature, Macmillan Journals Ltd., vol. 535, no. 7610, 29 June 2016, pages 169-172) reports on the mode of action of toremifene on Ebola virus.
  • US2005/096384 discloses a new class of tamoxifen analogs with estrogen receptor inhibitory activity.
  • Torriani Giulia et al. (“Identification of Clotrimazole Derivatives as Specific Inhibitors of Arenavirus Fusion", Journal of Virology, vol. 93, no. 6, 1 March 2019) reports on the antiviral activity on arenavirus of clotrimazole and TRAM-34 ((1-[(2-chlorophenyl) diphenylmethyl]-1 H-pyrazole)).
  • RNA-viruses particularly of the family Coronaviridae, even more preferably SARS-CoV-2.
  • said compounds could also be used in the treatment of other families of RNA-viruses, such as Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
  • the invention relates to a compound of formula (I) as described herein, or a salt or solvate thereof, for use in the prevention or treatment of infections caused by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV-2 and SARS- CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV).
  • the invention relates to a compound of formula (I”).
  • the present invention relates to a compound of formula (II) as described herein, or a salt, solvate or stereoisomer thereof, for use in the prevention or treatment of infections caused by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV and SARS- CoV-2) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV).
  • severe respiratory syndrome-related coronavirus such as SARS-CoV and SARS- CoV-2
  • MERS-CoV Middle East respiratory syndrome-related coronavirus
  • the invention relates to a compound of formula
  • the invention relates to a compound of formula (III) as described herein, or a salt or solvate thereof, for use in the prevention or treatment of infections caused by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV-2 and SARS-CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV).
  • severe respiratory syndrome-related coronavirus such as SARS-CoV-2 and SARS-CoV
  • MERS-CoV Middle East respiratory syndrome-related coronavirus
  • Another aspect of the invention relates to the use of a compound of formula (I), (II), or (III) as described herein, or a salt or solvate thereof, in the manufacture of a medicament for the prevention or treatment of infections caused by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV-2 and SARS-CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV).
  • severe respiratory syndrome-related coronavirus such as SARS-CoV-2 and SARS-CoV
  • MERS-CoV Middle East respiratory syndrome-related coronavirus
  • RNA-viruses preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV-2 and SARS- CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV), which comprises administering a therapeutically effective amount of a compound of formula (I), (II), or (III) as described herein, or a salt or solvate thereof.
  • severe respiratory syndrome-related coronavirus such as SARS-CoV-2 and SARS- CoV
  • MERS-CoV Middle East respiratory syndrome-related coronavirus
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), (II), or (III) as described herein, or a salt or solvate thereof, for use in the prevention or treatment of infections caused by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV-2 and SARS-CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV).
  • severe respiratory syndrome-related coronavirus such as SARS-CoV-2 and SARS-CoV
  • MERS-CoV Middle East respiratory syndrome-related coronavirus
  • the present invention relates to a combination comprising a compound of formula (I), (II) or (III) of the invention and or more additional compounds useful in the treatment of viral infections by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV-2 and SARS-CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV).
  • severe respiratory syndrome-related coronavirus such as SARS-CoV-2 and SARS-CoV
  • MERS-CoV Middle East respiratory syndrome-related coronavirus
  • Some compounds useful in said combination are nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, ribavirin, favipiravir, chloroquine, hydroxychloroquine, lopinavir, ritonavir, umifenovir and recombinant type I interferon, preferably nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, lopinavir and ritonavir.
  • the combination is synergistic. DESCRIPTION OF THE FIGURES
  • Figure 1 Results of the PK distribution study of clomiphene citrate. The lung concentrations of the cis- and trans- isomers of the drug are plotted as a function of time. 1 - Clomiphene citrate (cis); 2 - Clomiphene citrate (trans); 3 - IC90 cis-Clomiphene; 4 - IC90 Clomiphene citrate.
  • halogen refers to bromine, chlorine, iodine, or fluorine.
  • halogen refers to chlorine (Cl).
  • C 1-6 alkyl refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having between 1 and 6, preferably between 1 and 3 (“C 1-3 alkyl”), more preferably 1 or 2 (“C 1-2 alkyl”), carbon atoms and which is attached to the rest of the molecule by a single bond, including for example and in a non-limiting sense, methyl, ethyl, n-propyl, i-propyl, n- butyl, t-butyl, n-pentyl, etc.
  • alkyl refers to methyl or ethyl.
  • C 2-6 alkenyl and C 2-6 alkynyl refer to linear or branched hydrocarbon chain radicals consisting of carbon and hydrogen atoms having at least one double or triple bonds, respectively, and from 2 to 6 carbon atoms, more preferably having 2, 3 or 4 carbon atoms. In a preferred embodiment, they refer to linear hydrocarbons having a single double bond or a single triple bond, respectively, and from 2 to 6 carbon atoms, preferably 2 or 3 carbon atoms. In a preferred embodiment, C 2-6 alkynyl is ethynyl.
  • C 3-7 cycloalkyl refers to a saturated or partially saturated mono- or bicyclic aliphatic group having between 3 and 7, preferably between 3 and 6 carbon atoms (“C 3 -C 6 cycloalkyl”), which is bound to the rest of the molecule by means of a single bond, including for example and in a non-limiting sense, cyclopropyl, cyclohexyl or cyclopentyl.
  • C 1- C 6 haloalkyl refers to an alkyl group as defined above wherein at least one of the hydrogen atoms has been replaced by a halogen atom such as, for example CF 3 , CCI 3 , CHF 2 , CH 2 F, CH 2 CF 3 , CF 2 CF 3 .
  • C 6-18 uryl refers to an aromatic group having between 6 and 18, preferably between 6 and 12 carbon atoms, more preferably between 6 and 10 and even more preferable having 6 carbon atoms, comprising 1 , 2 or 3 aromatic nuclei, including for example and in a non-limiting sense, phenyl, biphenyl, naphthyl, indenyl, phenanthryl or terphenyl.
  • aryl refers to phenyl (Ph) or biphenyl.
  • (C 6- C 18 )aryl(C 1- C 6 )alkyl refers to an aryl group as defined above which is attached to the rest of the molecule through an alkyl group as defined above.
  • the (C 6- C 18 )aryl(C 1- C 6 )alkyl is (C 6- C 12 )aryl(C 1- C 3 )alkyl, and more preferably a (C 6 )aryl(C 1- C 3 )alkyl.
  • these groups include benzyl, phenylethyl, phenylpropyl, naphthylmethyl.
  • it refers to benzyl (Bn).
  • (C 6- C 18 )aryl(C 2 -C 6 )alkenyl refers to an aryl group as defined above which is attached to the rest of the molecule through an alkenyl group as defined above.
  • the (C 6- C 18 )aryl(C 2 -C 6 )alkenyl is (C 6- C 12 )aryl(C 2 -C 4 )alkenyl, and more preferably a (C 6 )aryl(C 2 -C 4 )alkenyl.
  • Examples of these groups include (C 6 )aryl(C 2 )alkenyl (styryl), (C 6 )aryl(C 2 )alkenyl, (C 10 )aryl(C 2 )alkenyl (vinylnaphthalene), (C 12 )aryl(C 2 )alkenyl (4-vinyl-1 ,T-biphenyl).
  • styryl (C 6 )aryl(C 2 )alkenyl
  • C 10 aryl(C 2 )alkenyl (vinylnaphthalene)
  • C 12 )aryl(C 2 )alkenyl (4-vinyl-1 ,T-biphenyl).
  • it refers to styryl.
  • (C 6- C 18 )aryl(C 2 -C 6 )alkynyl refers to an aryl group as defined above which is attached to the rest of the molecule through an alkynyl group as defined above.
  • the (C 6- C 18 )aryl(C 2 -C 6 )alkynyl is (C 6- C 12 )aryl(C 2 -C 4 )alkynyl, and more preferably a (C 6 )aryl(C 2 -C 4 )alkynyl.
  • Examples of these groups include (C 6 )aryl(C 2 )alkynyl (ethynylbenzene), (C 6 )aryl(C 2 )alkynyl, (C 10 )aryl(C 2 )alkynyl (ethynylnaphthalene), (C 12 )aryl(C 2 )alkynyl (4-ethynyl-1 , 1 ’-biphenyl).
  • it refers to ethynylbenzene.
  • C 6-12 haloaryl refers to an aryl group as defined above, comprising from 6 to 12 carbon atoms, wherein at least one of the hydrogen atoms has been replaced by a halogen atom such as, for example fluorobenzene or chlorobenzene.
  • heterocyclyl refers to a monocyclic or bicyclic system which can be partially or fully saturated containing 5 to 10, preferably 5 or 6, ring atoms containing one or more, specifically one, two, three, or four ring heteroatoms independently selected from N, O, and S, preferably one or two, and the remaining ring atoms being carbon.
  • heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, tetrahydropyridine, piperazine, morpholine, thiomorpholine, azepane, diazepane, tetrahydrofuran, tetrahydropyran, octahydro-pyrrolopyrazine.
  • 5- to 10-membered heteroaryl refers to a monocyclic or bicyclic system which is aromatic and contains 5 to 10, preferably 5 or 6, ring atoms containing one or more, specifically one, two, three, or four ring heteroatoms independently selected from N, O, and S, preferably one or two, and the remaining ring atoms being carbon.
  • heteroaryl examples include, but are not limited to, thiophene, furan, pyrrole, thiazole, oxazole, isothiazole, isooxazole, imidazole, pyrazole, triazole, oxadiazole, thiadiazole, tetrazole, tetrazole oxide, oxadiazolone, pyridine, pyrimidine, pyrazine, dihydroindolone, benzimidazole, isoindole, benzothiazole, benzofuran, indole, purine, quinolone, isoquinoline.
  • the aforementioned groups can be unsubstituted or can be substituted at one or more available positions with the suitable groups disclosed in each case. In a particular embodiment, it can be substituted with one, two or three, preferably with one or two, more preferably with one said suitable groups.
  • the invention also provides “salts” of the compounds described in the present description.
  • said salts can be acid addition salts, base addition salts, or metal salts, and can be synthesized from the original compounds containing a basic or acidic residue by means of conventional chemical methods known in the art.
  • Such salts are generally prepared, for example, by reacting the free acid or base forms of said compounds with a stoichiometric amount of the suitable base or acid in water or in an organic solvent or in a mixture of both.
  • said acid addition salts include inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, nitrate, phosphate, etc., organic acid addition salts such as, for example, acetate, formate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, camphorsulfonate, etc.
  • inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, nitrate, phosphate, etc.
  • organic acid addition salts such as, for example, acetate, formate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-tol
  • base addition salts include inorganic base salts such as, for example, ammonium salts, and organic base salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glutamine, basic amino acid salts, etc.
  • organic base salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glutamine, basic amino acid salts, etc.
  • metal salts include, for example, sodium, potassium, calcium, magnesium, aluminum, and lithium salts.
  • the salt is an acid addition salt.
  • the compounds of the invention can be in the form of salts, solvates or stereoisomers, preferably pharmaceutically acceptable salts, solvates or stereoisomers.
  • any salts, solvates, or stereoisomers thereof are also to be considered as excluded, unless stated otherwise.
  • pharmaceutically acceptable refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human.
  • pharmaceutically acceptable means approved by a regulatory agency of the Federal or a state government or listed in the U.S. or European Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
  • the compounds described in the present description can be obtained both as free compounds and as solvates (for example, hydrates, alcoholates, etc.), both forms being included within the scope of the present invention.
  • Solvation methods are generally known in the state of the art.
  • stereoisomer is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space, and include enantiomers and diastereomers.
  • any given compound referred to herein is intended to represent any one of a racemate, one or more enantiomeric forms and one or more diastereomeric forms. All the stereoisomers including enantiomers and diastereoisomers of the compounds referred to herein, and mixtures thereof (including racemic mixtures, enantiomerically enriched mixtures and diastereomerically enriched mixtures), are considered within the scope of the present invention. Also, the invention further contemplates any E / Z possible isomers, examples being the compounds of formula (II). In a preferred embodiment, the compound of formula (2f) is an (E)-isomer.
  • the compounds and pharmaceutical compositions of this invention can be administered to a patient using any means known in the art, including oral and parenteral routes.
  • the present invention relates to a compound of formula (I) wherein
  • - r is selected from 0, 1 and 2;
  • - s is selected from 0, 1 , 2, 3, 4 and 5;
  • - K is selected from -N-, -NR-, -CR a - and -CH 2 -, wherein R and R a are each independently selected from H, C 1-6 alkyl, -C 1-6 alkyl-OR’, C 1-6 haloalkyl, C 6-18 aryl, 5- to 10-membered heterocyclyl, -C 1-6 alkyl-(5- to 10-membered heterocyclyl), (C 6- 18 )aryl(C 1-6 )alkyl, (C 6-12 )aryl(C 2-6 )alkenyl and (C 6-12 )aryl(C 2-6 )alkynyl and wherein the C 1-6 alkyl, -C 1-6 alkyl-OR’, C 1-6 haloalkyl, C 6-18 aryl, 5- to 10-membered heterocyclyl and -C 1-6 alkyl-(5- to 10-membered heterocyclyl) can be unsubstituted or substituted
  • - M is selected from -N-, -CR 11 -, -NR 12 - and -CH 2 -, wherein R 11 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-6 alkyl)-NR 1 R 2 R 3 , and wherein R 12 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkyl-OR’, C 6-18 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, (C 6-18 )aryl(C 1-6 )alkyl, (C 6-12 )aryl(C 2-6 )alkenyl and (C 6- 12 )aryl(C 2-6 )alkynyl and wherein the C 1-6 alkyl, -C 1-6 alkyl-OR’, C 1-6 haloalkyl, C 6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-
  • - T is selected from -N-, -NH-, -CH- and -CH 2 -;
  • - L is selected from H, halogen, guanidinium, -NR 1 R 2 R 3 , C(O)NR 1 R 2 R 3 , C(O)-(CH 2 ) 1-3 - NR 1 R 2 R 3 , OR 1 , OC(O)R 1 , C(O)R 1 , C(O)OR 1 , CN, NO 2 , C 3-7 cycloalkyl, C 6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein each R 1 and R 2 are independently selected from H, C 1-6 alkyl, -C 1-6 alkyl-OR’, C 1-6 haloalkyl, C 6-18 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, (C 6-18 )aryl(C 1- 6 )alkyl, (C 6-12 )aryl(C 2-6 )alkenyl and (C 6-12 )aryl(
  • R 3 is absent, H or C 1-6 alkyl optionally substituted with at least one fluoride
  • Y 1 , Y 2 and Y 3 are each independently selected from phenyl or a 5- to 6-membered heterocyclyl each optionally substituted with X;
  • - X is selected from halogen, OR’, OC(O)R’, R' 2 , C(O)R' 2 , C(O)R’, C(O)OR’, CN, NO2, -(CH 2 ) 1-6- OR’, -(CH 2 ) 1-6- OC(O)R’, -(CH 2 ) 1-6- R' 2 , -(CH 2 ) 1-6- C(O)R' 2 , -(CH 2 ) 1-6- C(O)R’, -(CH 2 ) 1-6- C(O)OR’, -(CH 2 ) 1-6- CN, -(CH 2 ) 1-6- NO 2 , C 1-6 alkyl, C 3-7 cycloalkyl, C 1- 6 haloalkyl, C 6-18 aryl, C 6- C12 haloaryl, (C 6-18 )aryl(C 1-6 )alkyl, (C 6-12 )aryl(C 2
  • R 6 is absent, H or C 1-6 alkyl optionally substituted with at least one fluoride
  • RNA-viruses preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
  • TRAM-34 has the following molecular structure:
  • the compound of formula (I) is a compound of formula wherein X, Y 1 , Y 2 , T, M, K, L, r and s are as defined above.
  • the bond in the compound of formula (I) when K is -N- or -CH-, then the bond is a double bond, and when K is -NH- or -CH 2 -, then the bond is a single bond.
  • K is a positively charged
  • the bond K is a double bond
  • M is -NH- or -CH 2 -
  • M and K are -N-, and the bond is a double bond.
  • the bond in the compound of formula (I) when T is -N- or -CH-, then the bond is a double bond, and when T is -NH- or -CH 2 -, then the bond is a single bond.
  • At least one of Y 1 , Y 2 or Y 3 is a phenyl group.
  • X is selected from H, C 1-6 alkyl, halogen and phenyl.
  • r is 0 and represents a double bond.
  • r is 1 and represents a single bond.
  • r is 1 and one, but only one of K, M and T is N.
  • r is 1 and only one of K and M is -NR-, preferably, K is
  • r is 0, K is -N-, M is -CH- and T is -CH-.
  • M is selected from -CR 11 - or T is selected from -N- and -CH-, wherein R 11 is selected from C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-6 alkyl )-NR 1 R 2 R 3 .
  • K is -NR-, wherein R is selected from H, C 1-6 alkyl and -C 1-6 alkyl-(5- to 10- membered heterocyclyl), and wherein C 1-6 alkyl and -C 1-6 alkyl-(5- to 10-membered heterocyclyl) can be unsubstituted or substituted with R’, OR’ or NR’2, wherein each R’ is independently selected from H, C 1-6 alkyl, -C 0-6 alkyl-(guanidinium), -C 1-6 alkyl-(5- to 10-membered heterocyclyl) and C 6-18 aryl;
  • M is selected from -CH 2 - and -CR 11 -, wherein R 11 is C 1-6 alkyl;
  • T is -CH 2 -; and L is H.
  • Y 1 , Y 2 and Y 3 are preferably phenyl, each optionally substituted with X, wherein X is selected from halogen and C 6-18 aryl.
  • Y 1 and Y 2 are phenyl and Y 3 is selected from phenyl, chlorophenyl, and biphenyl.
  • K is -NR-, wherein R is selected from H, -C 1-3 alkyl and -C 1-3 alkyl-(5- to 6- membered heterocyclyl), and wherein C 1-3 alkyl and -C 1-3 alkyl-(5- to 6-membered heterocyclyl) can be unsubstituted or substituted with R’, OR’ or R' 2 , wherein each R’ is independently selected from H, -CH 3 , guanidinium, -CH 2 -guanidinium, -(CH 2 ) 2 - piperazine, and phenyl;
  • M is selected from -CH 2 - and -CR 11 -, wherein R 11 is -CH 3 ;
  • T is -CH 2 -
  • L is H.
  • 5- to 6-membered heterocyclyl is preferably selected from pyrrolidine, piperidine, and piperazine.
  • Y 1 and Y 2 are preferably phenyl and Y 3 is selected from phenyl optionally substituted with X, wherein X is selected from halogen and C 6-18 aryl.
  • Y 1 and Y 2 are phenyl and Y 3 is selected from phenyl, chlorophenyl, and biphenyl.
  • T is -CH-
  • R’ is H
  • L is selected from -NR 1 R 2 R 3 , and 5- to 10-membered heterocyclyl, wherein each R 1 and R 2 are independently selected from H, C 1-6 alkyl, and -C 1-6 alkyl-OR’; and R 3 is absent, or C 1-6 alkyl optionally substituted with at least one fluoride.
  • Y 1 and Y 2 are preferably phenyl and Y 3 is phenyl optionally substituted with X, wherein X is selected from halogen and C 6-18 aryl.
  • Y 1 and Y 2 are phenyl and Y 3 is selected from phenyl, chlorophenyl and biphenyl.
  • the compound of formula (I) comprises a piperazine, i.e., r is 1 and K is -NR-, or comprises an imidazole, i.e., r is 0 and K is -N-.
  • r is 0 or 1
  • s is 0, 1 , 2 or 3;
  • the compound of formula (I) is a compound of formula (I”) and:
  • - s is selected from 1 , 2 or 3;
  • - R is absent or is selected from H, C 1-6 alkyl and -C 1-6 alkyl-(5- to 10-membered heterocyclyl), and wherein the C 1-6 alkyl can be unsubstituted or substituted with -OR’ or -R' 2 ;
  • - L is selected from H, -NH 2 , -NR 1 R 2 R 3 , and 5- to 10-membered heterocyclyl wherein each R 1 and R 2 are independently selected from H, C 1-6 alkyl or -C 1-6 alkyl-OH, and wherein the 5- to 10-membered heterocyclyl can be unsubstituted or substituted with C 1-6 alkyl;
  • R 3 is absent, H or C 1-6 alkyl optionally substituted with at least one fluoride
  • - Y 3 is selected from phenyl, optionally substituted with X;
  • - X is selected from H, halogen or phenyl
  • - M is selected from -CH 2 - or -CH-;
  • the compound of formula (I) is a compound of formula (l vii ), and X is H, phenyl or Cl; s is 1 ; L is H; R is H; and R 11 is C 1-6 alkyl.
  • s is selected from 1 , 2, 3 and 4.
  • R is selected from H, C 1-6 alkyl and -C 1-6 alkyl-(5- to 10-membered heterocyclyl), and wherein the C 1-6 alkyl and -C 1-6 alkyl-(5- to 10- membered heterocyclyl) can be unsubstituted or substituted with NR’2.
  • R a is selected from H and C 1-6 alkyl.
  • R a is H.
  • the 5- to 10-membered heterocyclyl and the 5- to 10-membered heteroaryl in group L are selected from a N-containing 5- to 10- membered heterocyclyl and a N-containing 5- to 10-membered heteroaryl, respectively; preferably from N-containing 5- to 7-membered heterocyclyl and a N-containing 5- to 7- membered heteroaryl.
  • Suitable N-containing 5- to 7-membered heteroaryl and N-containing 5- to 10- membered heteroaryl groups in group L include, for example, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrimidine, pyrazine, indole, isoindole, benzimidazole, quinoline, isoquinoline and purine.
  • L is selected from H, -NR 1 R 2 R 3 , C(O)NR 1 R 2 , C(O)-(CH 2 ) 1-3 - NR 1 R 2 , OR 1 , OC(O)R 1 , C(O)R 1 , C(O)OR 1 , 5- to 10-membered heterocyclyl and 5- to 10- membered heteroaryl, wherein each R 1 and R 2 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, and (C 6-12 )aryl(C 1-6 )alkyl and wherein the C 3-7 cycloalkyl, C 6-12 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R', R' 2 , C(O)R' 2 , C(O)-(CH 2 ) 1-3 -NR 1 R 2 , C(O
  • L is selected from H, -NR 1 R 2 R 3 , C(O)NR 1 R 2 , piperidine, piperazine and morpholine, wherein R 1 and R 2 are independently selected from H and C 1-6 alkyl, preferably H, and wherein the piperidine, piperazine and morpholine can be unsubstituted or substituted with -R' 2 , C(O)R' 2 , C(O)-(CH 2 ) 1-3 -NR 1 R 2 , -(CH 2 ) 1-6- R' 2 and -(CH 2 ) 1-6- C(O)R' 2 , wherein each R’ is independently selected from H and C 1-6 alkyl, preferably H, and wherein R 3 is absent or C 1-6 alkyl.
  • the compound of formula (I) is selected from In preferred embodiment, the compound of formula (I) is selected from
  • the compound of formula (I) is selected from:
  • the compound of formula (I) is selected from or a salt or solvate thereof.
  • the invention also contemplates a compound of formula (I”): wherein
  • - r is selected from 0 or 1 ;
  • - s is selected from 0, 1 , 2 or 3;
  • R is absent or is selected from H, C 1-6 alkyl and -C 1-6 alkyl-(5- to 10-membered heterocyclyl), and wherein the C 1-6 alkyl and -C 1-6 alkyl-(5- to 10-membered heterocyclyl) can be unsubstituted or substituted with R’, -OR’ or -NR’2;
  • - L is selected from H, guanidinium, -NR 1 R 2 R 3 , -C(O)NH 2 , and 5- to 10-membered heterocyclyl, wherein each R 1 and R 2 are independently selected from H, C 1-6 alkyl, - C 1-6 alkyl-OR’, and wherein the C 1-6 alkyl and 5- to 10-membered heterocyclyl can be unsubstituted or substituted with C(O)-(CH 2 ) 1-3 -R' 2 and C 1-6 alkyl;
  • R 3 is absent, H or C 1-6 alkyl optionally substituted with at least one fluoride
  • - Y 3 is selected from phenyl, optionally substituted with X;
  • - X is selected from halogen or C 6-18 aryl
  • the compound of formula (I”) is a compound of formulas (I i ) to (l v ) or (l vii ), wherein s, L, X, R and R 11 are as defined above for the compound of formula (I”).
  • the compound of formula (I”) is a compound of formula (I i ;) and X is H, phenyl, or Cl; s is 2; L is selected from -NH 2 , -NR 1 R 2 , and 5- to 10- membered heterocyclyl wherein each R 1 and R 2 are independently selected from H, C 1- 6 alkyl or -C 1-6 alkyl-OH, and wherein the 5- to 10-membered heterocyclyl can be unsubstituted or substituted with C 1-6 alkyl;.
  • the compound of formula (I”) is a compound of formula (f); X is phenyl or Cl; s is 2; and L is -NH 2 .
  • the compound of formula (I”) is a compound of formula (l ⁇ ); and X is H, phenyl or Cl; s is 0 or 1; L is H; and R is selected from H, C 1-6 alkyl-OH, C 1-6 alkyl-NH 2 , and -C 1-6 alkyl-(5- to 10-membered heterocyclyl) preferably selected from pyrrolidine, piperidine or piperazine.
  • the compound of formula (I”) is a compound of formula (I”);
  • X is H, phenyl or Cl;
  • s is 0 or 1 ;
  • L is H; and
  • R is selected from H and -C 1-6 alkyl-(5- to 10-membered heterocyclyl) preferably selected from pyrrolidine, piperidine or piperazine.
  • the compound of formula (I”) is a compound of formula (l vii ), and X is H or Cl; s is 1 ; L is H, R is H, and R 11 is C 1-6 alkyl.
  • R is absent or selected from H, methyl, C 1-6 alkyl substituted with NR’2, -C 1-6 alkyl-(pyrrolidine), -C 1-6 alkyl-(piperidine) and -C 1-6 alkyl-(piperazine), wherein each R’ is independently selected from H, and C 6-18 aryl.
  • L is selected from H, -NH 2 , -NMe 2 , -NMe 3 , -NEt 2 , -NH(C 1-6 alkyl-OH), -N(Me)(C 1-6 alkyl-OH), In yet another preferred embodiment, the compound of formula (I”) is selected from,
  • the compound of formula (I”) is selected from: or a salt or solvate thereof.
  • the present invention relates to a compound of formula (II) wherein
  • - q is selected from 1 , 2, 3 and 4;
  • R 8 is absent, H, C 1-6 alkyl or C 1-6 haloalkyl
  • R 8 is H, C 1-6 alkyl or C 1-6 haloalkyl, such as methyl, then the N atom to which it is attached has a positive charge.
  • one of R 4 and R 5 is unsubstituted C 6-12 aryl or C 6-12 aryl substituted with halogen, C 1-6 alkyl, C 1-6 haloalkyl, (C 6-12 )aryl(C 1-6 )alkyl, -OR’, -OC(O)R', -R' 2 , -C(O)R' 2 , -C(O)R’, - C(O)OR’, -CN, or -NO 2 , wherein each R’ is independently selected from H, C 1-6 alkyl, C 1- 6 haloalkyl, C 6-12 aryl and (C 6-12 )aryl(C 1-6 )alkyl.
  • R 5 is selected from unsubstituted C 6-12 aryl or C 6-12 aryl substituted with halogen, C 1-6 alkyl, C 1-6 haloalkyl, (C 6-12 )aryl(C 1-6 )alkyl, -OR’, -OC(O)R’, -R' 2 , - C(O)R' 2 , -C(O)R’, -C(O)OR’, -CN, or -NO 2 ; wherein each R’ is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-12 aryl and (C 6-12 )aryl(C 1-6 )alkyl.
  • R 5 is selected from Cl, unsubstituted C 6-12 aryl, unsubstituted 5- to 10-membered heteroaryl and C 6-12 aryl substituted with halogen, or with -OH. In a further embodiment, R 5 is selected from Cl, Ph, 4-OH-Ph, 4-CI-Ph, pyridine and thiophene.
  • each R’ is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-12 aryl and (C 6-12 )aryl(C 1-6 )alkyl;
  • R 5 is selected from unsubstituted C 6-12 aryl or C 6-12 aryl substituted with halogen, C 1-6 alkyl, C 1-6 haloalkyl, (C 6-12 )aryl(C 1-6 )alkyl, -OR’, -OC(O)R’, -R' 2 , - C(O)R' 2 , -C(O)R’, -C(O)OR’, -CN, or -NO 2 ; and unsubstituted 5- to IQ- membered heteroaryl or 5- to 10-membered heteroaryl substituted with halogen, C 1-6 alkyl, C 1-6 haloalkyl, (C 6-12 )aryl(C 1-6 )alkyl, -OR’, -OC(O)R’, -R' 2 , - C(O)R' 2 , -C(O)R’, -C(O)OR’, -CN, or -
  • R 8 is absent or C 1-6 alkyl
  • R 5 is selected from unsubstituted C 6-12 aryl or C 6-12 aryl substituted with halogen, or with -OR’, wherein R’ is selected from H, C 1-6 alkyl and (C 6-12 )aryl(C 1- 6 )alkyl;
  • the compound of formula (II) is selected from: or a salt or solvate thereof.
  • the present invention contemplates both (Z) and (E) isomers of the compounds of formula (II), including those of formula (2a) to (2w), as well as mixtures comprising both isomers.
  • the compound of formula (II) is selected from: or a salt or solvate thereof.
  • the compound of formula (II) is selected from:
  • the compound of formula (II) is: or a salt or solvate thereof.
  • the invention refers to a pharmaceutical composition comprising a compound of formula (2f), or a salt or solvate thereof, and a pharmaceutically acceptable excipient.
  • the invention refers to a compound of formula (2f), or a salt, or solvate thereof, for use in medicine.
  • the present invention relates to a compound of formula (III) wherein
  • - A is selected from -CH-, -N- and -C(OH)- when s a double bond, or is selected from -NH-, -C(O)-, -CH 2 - and -CH(OH)- when A is a single bond;
  • - B is selected from -CH- and -N- when is a double bond, and is selected from - CH 2 -, -N- and -NH- when A is a single bond;
  • - D is selected from guanidinium, -NR 2 R 3 R 4 , 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein R 2 and R 3 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-18 aryl, (C 6-18 )aryl(C 1-6 )alkyl, (C 6-12 )aryl(C 2-6 )alkenyl and (C 6- 12 )aryl(C 2-6 )alkynyl and wherein the C 6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R', R' 2 , C(O)R' 2 , C(O)R’, C(O)OR’, CN, NO2, -(CH 2 ) 1-6- OR’, -(CH 2 ) 1-6- OC(O
  • - E is selected from C 6-12 aryl and 5- to 10-membered heteroaryl; - R 4 is absent, H or C 1-6 alkyl optionally substituted with at least one fluoride;
  • R 5 is selected from halogen, OR’, OC(O)R', R' 2 , C(O)R' 2 , C(O)R’, C(O)OR’, CN, NO2, -(CH 2 ) 1-6- OR’, -(CH 2 ) 1-6- OC(O)R’, -(CH 2 ) 1-6- R' 2 , -(CH 2 ) 1-6- C(O)R' 2 , -(CH 2 ) 1-6- C(O)R', -(CH 2 ) 1-6- C(O)OR', -(CH 2 ) 1-6- CN, -(CH 2 ) 1-6- NO 2 , C 1-6 alkyl, C 3-7 cycloalkyl, C 1- 6 haloalkyl, C 6-18 aryl, C 6 -C 12 haloaryl, (C 6-18 )aryl(C 1-6 )alkyl, (C 6-12 )aryl(C
  • R 8 is absent, H or C 1-6 alkyl optionally substituted with at least one fluoride
  • - m is selected from 0 and 1 ;
  • - n is selected from 0, 1, 2, 3, 4, 5 and 6, wherein when n is 3-6 the resulting alkyl chain can contain at least one double bond;
  • each R is independently selected from H, C 1-6 alkyl, -(CH 2 ) 1-6- 0-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-18 aryl, (C 6-18 )aryl(C 1-6 )alkyl, (C 6-12 )aryl(C 2-6 )alkenyl and (C 6-12 )aryl(C 2-6 )alkynyl; represents a single or a double bond; or a salt, solvate, tautomer or stereoisomer thereof, for use in the treatment or prevention of an infection by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
  • any resonance and tautomer forms of the compounds of formula (III), as for the compounds of the invention of formula (I) and (II), are to be contemplated as part of the invention.
  • the bonds between B and the adjacent carbon (to which C is bound to) is a double bond.
  • B is selected from -CH- and -N- when is a double bond, and is selected from -CH 2 -, and -NH- when is a single bond.
  • - A is -CH- or -N- when A is a double bond, or is selected from -C(O)-, -N-, -CH 2 - and -CH(OH)- when A is a single bond;
  • - B is selected from -CH- and -N- when is a double bond, and is selected from -CH 2 -, -N- and -NH-, when A is a single bond;
  • - Y is -NH-, -CH- or -N- when is a single bond, and Y is -N- or -CH- when is a double bond.
  • - A is -CH- when is a double bond, or is selected from -C(O)-, -CH 2 - and -CH(OH)- when is a single bond;
  • - B is selected from -CH- and -N- when A is a double bond, and is selected from -CH 2 - and -NH-, when A is a single bond;
  • - Y is -NH- or -N- depending on whether is a single or a double bond, respectively.
  • B when A is -C(O)-, B is -NH- and is a single bond, or when A is -C(O)-, B is -N- and is a single bond, or when A is -C(OH)-, B is -NH- and is a double bond, or when A is -C(OH)-, B is -N- and is a double bond, or when A is -CH-, B is -CH- and is a double bond, or when A is -N-, B is -CH- and is a double bond, or when A is -CH-, B is -N- and is a double bond.
  • R5 is selected from halogen, O-C 1 -C 6 alkyl and C 1 -C 6 alkyl.
  • E is selected from C 6-10 aryl and 5- to 6- membered heteroaryl, preferably from C 6 aryl and 5- to 6-membered heteroaryl. In a preferred embodiment, E is a benzene ring.
  • the compound of formula (III) is a compound of formula (IN’) or (III”), wherein C, D, E, R, R 5 , m, n, x and z are as defined above.
  • the compound of formula (III) is a compound of formula (IN’”) or (III””), wherein C, D, R, R 5 , m, n, x and z are as defined above.
  • C is selected from -NR 1 -, -CH 2 -, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl.
  • R 1 is selected from H and C 1-6 alkyl. More preferably, R 1 is H.
  • the 5- to 10-membered heterocyclyl and the 5- to 10-membered heteroaryl in group C are selected from a N-containing 5- to 10- membered heterocyclyl and a N-containing 5- to 10-membered heteroaryl, respectively; preferably from N-containing 5- to 7-membered heterocyclyl and a N-containing 5- to 7- membered heteroaryl.
  • Suitable N-containing 5- to 7-membered heterocyclyl and N-containing 5- to IQ- membered heterocyclyl groups in radical C include, for example, pyrrolidine, piperidine, morpholine, piperazine and azepane. In a preferred embodiment, it is pyrrolidine or piperidine.
  • Suitable N-containing 5- to 7-membered heteroaryl and N-containing 5- to 10- membered heteroaryl groups in radical C include, for example, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrimidine, pyrazine, indole, isoindole, benzimidazole, quinoline, isoquinoline and purine.
  • C is selected from -NR 1 -, -CH 2 -, C 3-7 cycloalkyl, 5- to 10- membered heterocyclyl and 5- to 10-membered heteroaryl, wherein R 1 is selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-18 aryl and (C 6-18 )aryl(C 1-6 )alkyl.
  • C is selected from -NR 1 -, -CH 2 - and N-containing 5- to 7- membered heterocyclyl.
  • R 1 is H or C 1-6 alkyl, more preferably H.
  • C is selected from -NH-, -CH 2 -, pyrrolidine and piperidine.
  • C is selected from -NH-, -CH 2 - and
  • R is selected from H and C 1-6 alkyl; preferably H and Me.
  • the group is a group of the following formula: wherein
  • - o is selected from 0 and 1 ;
  • - p is selected from 0, 1 , 2, 3, 4 and 5; - R is independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-18 aryl and (C 6-18 )aryl(C 1-6 )alkyl; preferably R is selected from H and C 1-6 alkyl.
  • R 2 and R 3 are independently selected from H, C 1-6 alkyl and (C 6-12 )aryl(C 1-6 )alkyl; preferably from C 1-6 alkyl.
  • D is selected from -NR 2 R 3 , N-containing 5- to 10-membered heterocyclyl and N-containing 5- to 10-membered heteroaryl.
  • Suitable N-containing 5- to 10-membered heterocyclyl groups in radical D include, for example, pyrrolidine, piperidine, morpholine, piperazine and azepane. In a preferred embodiment, it is piperidine morpholine, piperazine .
  • Suitable N-containing 5- to 10-membered heteroaryl groups in radical D include, for example, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrimidine, pyrazine, indole, isoindole, benzimidazole, quinoline, isoquinoline and purine. In a preferred embodiment, it is benzimidazole.
  • the 5- to 10-membered heterocyclyl, N-containing 5- to 10- membered heterocyclyl, 5- to 10-membered heteroaryl and N-containing 5- to IQ- membered heteroaryl can be unsubstituted or substituted with -(CH 2 ) 1-6 -OR’, -(CH 2 ) 1-6 - OC(O)R', -(CH 2 ) 1-6- R' 2 , -(CH 2 ) 1-6- C(O)R' 2 , -(CH 2 ) 1-6- C(O)R’, -(CH 2 ) 1-6- C(O)OR’, - (CH 2 ) 1-6- CN, -(CH 2 ) 1-6- NO 2 , C 1-6 alkyl, C 1-6 haloalkyl or (C 6-12 )aryl(C 1-6 )alkyl, wherein each R’ is independently selected from H and C 1-6 alkyl.
  • each R’ is independently selected from H and C 1-6 alkyl, preferably from C 1-6 alkyl.
  • D is selected from -NR 2 R 3 , piperidine, piperazine, morpholine and benzimidazole, wherein R 2 and R 3 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-12 aryl and (C 6-12 )aryl(C 1-6 )alkyl and wherein the piperidine, piperazine, morpholine and benzoimidazole can be unsubstituted or substituted with halogen, OR’, OC(O)R’, R' 2 , C(O)R' 2 , C(O)R’, C(O)OR’, CN, NO 2 , -(CH 2 ) 1-6- OR’, - (CH 2 ) 1-6- OC(O)R’, -(CH 2 ) 1-6- R' 2 , -(CH 2 ) 1-6- COR' 2 , -(CH 2 ) 1-6- C(O)R’
  • D is selected from -NR 2 R 3 , piperidine, piperazine, morpholine and benzoimidazole, wherein R 2 and R 3 are C 1-6 alkyl and wherein the piperidine, piperazine, morpholine and benzoimidazole can be unsubstituted or substituted with -(CH 2 ) 1-6- OR’, -(CH 2 ) 1-6- OC(O)R’, -(CH 2 ) 1-6- R' 2 , -(CH 2 ) 1-6- C(O)R' 2 , - (CH 2 ) 1-6- C(O)R’, -(CH 2 ) 1-6- C(O)OR’, -(CH 2 ) 1-6- CN, -(CH 2 ) 1-6- NO 2 , C 1-6 alkyl, C 1-6 haloalkyl or (C 6-12 )aryl(C 1-6 )alkyl, wherein each R’ is independently
  • piperidine, piperazine, morpholine and benzoimidazole can be unsubstituted or substituted with -(CH 2 ) 1-6- OR’, C 1-6 alkyl and (C 6-12 )aryl(C 1-6 )alkyl, wherein each R’ is independently selected from H and C 1-6 alkyl, preferably from C 1-6 alkyl.
  • R is independently selected from H and C 1-6 alkyl, preferably from C 1-6 alkyl.
  • - C is selected from -NR 1 -, -CH 2 - and N-containing 5- to 7-membered heterocyclyl.
  • R 1 is H or C 1-6 alkyl, more preferably H;
  • R is selected from H and C 1-6 alkyl
  • - D is selected from -NR 2 R 3 , N-containing 5- to 10-membered heterocyclyl and N-containing 5- to 10-membered heteroaryl, wherein R 2 and R 3 are independently selected from H, C 1-6 alkyl and (C 6-12 )aryl(C 1-6 )alkyl and wherein the 5- to 10-membered heterocyclyl and N-containing 5- to 10-membered heteroaryl can be unsubstituted or substituted with -(CH 2 ) 1-6- OR’, -(CH 2 ) 1-6- OC(O)R’, -(CH 2 ) 1-6- R' 2 , -(CH 2 ) 1-6- C(O)R' 2 , -(CH 2 ) 1-6- C(O)R’, -(CH 2 ) 1-6- C(O)OR’, -(CH 2 ) 1-6- CN, -(CH 2 ) 1-6- NO 2 , C 1-6 alkyl, C 1-6
  • - C is selected from - NH-, -CH 2 - and pyrrolidine;
  • R is selected from H and C 1-6 alkyl
  • - D is selected from -NR 2 R 3 , piperidine, piperazine, morpholine and benzoimidazole, wherein R 2 and R 3 are C 1-6 alkyl and wherein the piperidine, piperazine, morpholine and benzoimidazole can be unsubstituted or substituted with -(CH 2 ) 1-6- OR’, -(CH 2 ) 1-6- OC(O)R’, -(CH 2 ) 1-6- R' 2 , -(CH 2 ) 1-6- C(O)R' 2 , - (CH 2 ) 1-6- C(O)R’, -(CH 2 ) 1-6- C(O)OR’, -(CH 2 ) 1-6- CN, -(CH 2 ) 1-6- NO 2 , C 1-6 alkyl, C 1-6 haloalkyl or (C 6-12 )aryl(C 1-6 )alkyl, wherein each R’ is independently selected from H
  • the piperidine, piperazine, morpholine and benzoimidazole can be unsubstituted or substituted with -(CH 2 ) 1-6- OR’, C 1- 6 alkyl and (C 6-12 )aryl(C 1-6 )alkyl, wherein each R’ is independently selected from H and C 1-6 alkyl, preferably from C 1-6 alkyl.
  • the compound of formula (III) is selected from:
  • the compound of formula (III) is selected from:
  • the invention also relates to the use of a compound of formula (I), (II), or (III) in the manufacture of a medicament for the treatment or prevention of viral infections by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV-2 and SARS-CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV).
  • severe respiratory syndrome-related coronavirus such as SARS-CoV-2 and SARS-CoV
  • MERS-CoV Middle East respiratory syndrome-related coronavirus
  • the invention also relates to a method of treating or preventing viral infections by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV-2 and SARS-CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV) in a subject, comprising administering to said subject a therapeutically effective amount of a compound of formula (I), (II) or (III).
  • RNA-viruses preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae
  • the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus
  • viruses of the family Coronaviridae is used to designate any viral species of the taxonomic family “Coronaviridae” including those of the genera “ Alphacoronavirus ", “Betacoronavirus” , “Gammacoronavirus” and “Deltacoronavirus”.
  • the viruses are selected from betacoronaviruses, in particular from the lineage “Sarbecovirus” and still more preferably from the species “Severe respiratory syndrome-related coronavirus” (such as SARS- CoV and SARS-CoV-2) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV).
  • the viral infection is an infection by influenza, HIV-1 HIV-2 or SARS-CoV-2 virus. In a preferred embodiment, the viral infection is an infection by SARS-CoV-2 virus.
  • treating means reversing, alleviating, inhibiting the progress of, the disease or condition to which such term applies, or one or more symptoms of such disease or condition, such as lowering the viral load in a patient with respect to pretreatment levels.
  • preventing and “prevention”, as used herein, means avoiding or inhibiting the onset of one or more symptoms of coronavirus infections such as fever, cough, shortness of breath, muscle pain, sputum production, diarrhea, sore throat, loss of smell, pneumonia and abdominal pain.
  • the present invention is for the treatment of an infection by RNA-viruses.
  • the compounds disclosed herein are used for the treatment and/or prevention of viral infections by “Severe respiratory syndrome-related coronavirus” and most preferably for the treatment and/or prevention of viral infections by SARS-CoV-2.
  • the viral infection is an infection by “Severe respiratory syndrome-related coronavirus” and most preferably by SARS-CoV-2.
  • the compounds for use according to the invention may be administered by any appropriate route (via), such as, oral (e.g., oral, sublingual, etc.), parenteral (e.g., subcutaneous, intramuscular, intravenous, etc.), vaginal, rectal, nasal, topical, ophtalmic, inhaled, intranasal, intratracheal, pulmonary, etc.; preferably oral, inhaled or parenteral, even more preferably by inhalation.
  • oral e.g., oral, sublingual, etc.
  • parenteral e.g., subcutaneous, intramuscular, intravenous, etc.
  • vaginal vaginal
  • rectal rectal
  • nasal topical
  • ophtalmic inhaled
  • intranasal intranasal
  • intratracheal intratracheal
  • pulmonary pulmonary
  • parenteral e.g., inhaled or parenteral, even more preferably by inhalation.
  • the compounds for use according to the invention are administered as a pharmaceutical composition, which comprises the corresponding (active) compound and one or more pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipient refers to a vehicle, diluent, or adjuvant that is administered with the active ingredient.
  • Such pharmaceutical excipients can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and similars. Water or saline aqueous solutions and aqueous dextrose and glycerol solutions, particularly for injectable solutions, are preferably used as vehicles. Suitable pharmaceutical vehicles are known by the skilled person.
  • the pharmaceutically acceptable excipient necessary to manufacture the desired pharmaceutical composition of the invention will depend, among other factors, on the elected administration route. Said pharmaceutical compositions may be manufactured according to conventional methods known by the skilled person in the art.
  • the compounds for use according to the invention may be administered in a “therapeutically effective amount”, i.e. a nontoxic but sufficient amount of the corresponding compound to provide the desired effect.
  • a “therapeutically effective amount” i.e. a nontoxic but sufficient amount of the corresponding compound to provide the desired effect.
  • the amount that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, the particular compound administered, and the like. However, an appropriate amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • the compounds for use according to the invention will typically be administered once or more times a day, for example 1 , 2, 3 or 4 times daily, with typical total daily doses depending on the particular compound and severity of the disease, and may be easily determined by the skilled practitioner.
  • typical total daily doses the compounds of the invention are in the range of from 0.1 to 2000 mg/day, preferably from 1 to 600 mg/ day, even more preferably from 1 to 100 mg/day.
  • compositions may be prepared using standard methods such as those described or referred to in the Spanish, European and US Pharmacopoeias and similar reference texts.
  • subject refers to a mammal, e.g., a human.
  • the compounds for use according to the invention may be administered as the sole active ingredient or in combination with other active ingredients.
  • the compounds are used as the sole active ingredient.
  • the compounds are used in combination with other active ingredients.
  • the invention also contemplates a composition
  • a composition comprising: a) a compound of formula (I), (II), or (III), or a salt or solvate thereof as defined above; and b) a compound selected from the group consisting of nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, ribavirin, favipiravir, chloroquine, hydroxychloroquine, lopinavir, ritonavir, umifenovir and recombinant type I interferon, preferably nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir
  • the compound of formula (I) also includes clotrimazole, TRAM-34 and salts thereof.
  • the compound of formula (I) is not selected from the group consisting of clotrimazole, TRAM-34 and salts thereof.
  • the invention also contemplates a composition
  • a composition comprising: a) a compound of formula (II) wherein q, R 4 , R 5 , G, R 10 , Z, and are as defined above, or a salt or solvate thereof; and b) a compound selected from the group consisting of nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, ribavirin, favipiravir, chloroquine, hydroxychloroquine, lopinavir, ritonavir, umifenovir and recombinant type I interferon, preferably nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, bo
  • Clomiphene is a mixture of two isomers: When used in combination with other active ingredients, the compound of formula (II) also includes clomiphene, tamoxifen, toremifene, droloxifene, afimoxifene, edoxifene and salts thereof, such as clomiphene citrate. In a less preferred embodiment, when used in combination with other active ingredients, the compound of formula (II) excludes clomiphene, tamoxifen, toremifene, droloxifene, afimoxifene, edoxifene and salts thereof. An example of a salt thereof is the citrate salt, for example clomiphene citrate.
  • the compounds of the invention are used in combination with one or more compounds useful in the treatment of viral infections by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially by the respiratory syndrome- related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV-2 and SARS-CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV).
  • severe respiratory syndrome-related coronavirus such as SARS-CoV-2 and SARS-CoV
  • MERS-CoV Middle East respiratory syndrome-related coronavirus
  • Some compounds that have been disclosed as potentially useful are selected from the group consisting of nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, ribavirin, favipiravir, chloroquine, hydroxychloroquine, lopinavir, ritonavir, umifenovir and recombinant type I interferon, preferably nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, lopinavir and ritonavir.
  • the combination is synergistic.
  • the invention refers to a compound of the invention of formula (I), (II) or (III) as disclosed above, in combination with one or more compounds useful in the treatment of RNA-viral infections, preferably by virus of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, such as nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, ribavirin, favipiravir, chloroquine, hydroxychloroquine, lopinavir, ritonavir, umifenovir and recombinant type I interferon, for use in the treatment or prevention of an infection by RNA-viruses, preferably of the family Coronaviridae, Ortho
  • the invention refers to a compound of the invention of formula (I), (II) or (III) as disclosed above, in combination with one or more compounds selected from nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, lopinavir and ritonavir, for use in the treatment or prevention of an infection by RNA-viruses, preferably of the family Coronaviridae.
  • said combination is synergistic.
  • the invention refers to a compound of formula (II), which also includes clomiphene, toremifene, tamoxifen, droloxifene, afimoxifene, edoxifene and salts thereof, such as clomiphene citrate, in combination with one or more compounds useful in the treatment of RNA-viral infections, preferably by virus of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, such as nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, ribavirin, favipiravir, chloroquine, hydroxychloroquine, lopinavir, r
  • the invention refers to clomiphene citrate in combination with one or more compounds useful in the treatment of RNA-viral infections, preferably by virus of the family Coronaviridae.
  • said combination is synergistic.
  • This combination is preferably administered so that the ingredients are delivered to the lungs. Therefore, in a particular embodiment said combination is to be administered orally, parenterally or by inhalation, preferably inhalation.
  • said clomiphene citrate in the combination is the cis- clomiphene. In another particular embodiment, said clomiphene citrate in the combination is the trans-clomiphene.
  • the term “combination” refers to a product comprising one or more of the defined compounds, either in a single composition or in several compositions (or units), in which case the corresponding compounds are distributed among the several compositions.
  • the combination refers to several compositions, in particular comprising one composition (or unit) per compound (compound as defined above) of the combination.
  • the expression “one or more” when characterizing the combination refers to at least one, preferably 1 , 2, 3, 4, or 5 compounds, more preferably, 1 , 2 or 3 compounds, even more preferably 1 or 2 compounds.
  • the compounds present in the combination are always administered simultaneously.
  • compositions or units When the combination is in the form of several compositions (or units), each of them having at least one of the compounds of the combination, the compositions or (units) may be administered simultaneously, sequentially or separately.
  • Simultaneous administration means that the compounds or compositions (or units) are administered at the same time.
  • Sequential administration means that the compounds or compositions (or units) are administered at different time points in a chronologically staggered manner.
  • Separate administration means that the compounds or compositions (or units) are administered at different time points independently of each other.
  • compositions which comprise the corresponding (active) compounds and a pharmaceutically acceptable excipient, as previously defined.
  • the combinations for use according to the invention will typically be administered once or more times a day, for example 1 , 2, 3 or 4 times daily, with typical total daily doses depending on the particular compound and severity of the disease, and may be easily determined by the skilled practitioner.
  • the following examples represent specific embodiments of the present invention.
  • R 5 is selected from H, halogen, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, (C 6-18 )aryl(C 1- 6 )alkyl, C 1-6 alkyl substituted with -OR’, -OC(O)R’, -R' 2 , -C(O)R' 2 , -C(O)R’, - C(O)OR’, -CN, or -NO 2 ; unsubstituted C 6-18 aryl or C 6-18 aryl substituted with halogen, C 1-6 alkyl, C 1-6 haloalkyl, (C 6-18 )aryl, (C 6-18 )aryl(C 1-6 )alkyl, C 6-12 )aryl(C 2-6 )alkenyl, (C 6- 12 )aryl(C 2-6 )alkynyl, -OR’, -OC(O)R’, -R' 2 , -OR
  • - Z is selected from -NR 6 R 7 R 8 and halogen
  • R 6 and R 7 are independently selected from H, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, (C 6-18 )aryl(C 1-6 )alkyl, C 1-6 alkyl substituted with -OR’, -OC(O)R’, -R' 2 , -C(O)R' 2 , - C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-18 aryl, (C 6-18 )aryl(C 1-6 )alkyl, (C 6-12 )aryl(C 2-6 )alkenyl and (C 6- 12 )aryl(C 2 - 6 )alkynyl; or
  • R 8 is absent, H, C 1-6 alkyl or C 1-6 haloalkyl; represents a single or a double bond;
  • - G is selected from (C 6-12 )aryl and 5- to 10-membered heteroaryl, wherein the (C 6- 12 )aryl and 5- to 10-membered heteroaryl are optionally substituted with R 9 ;
  • R 9 and R 10 are independently selected from H, halogen, C 1-6 alkyl, C 1-6 haloalkyl, (C 6- 12 )aryl, (C 6-12 )aryl(C 1-6 )alkyl, (C 6-12 )aryl(C 2-6 )alkenyl, (C 6-12 )aryl(C 2-6 )alkynyl, -OR’, - OC(O)R', -R' 2 , -C(O)R' 2 , -C(O)R’, -C(O)OR’, -CN, -NO 2, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl, wherein the rings in the (C 6-12 )aryl, (C 6
  • Embodiment 2 Compound for use according to embodiment 1 , wherein
  • - q is selected from 1 , 2, 3 and 4;
  • R 5 is selected from unsubstituted C 6-12 aryl or C 6-12 aryl substituted with halogen, C 1-6 alkyl, Ci_ 6 haloalkyl, (C 6-12 )aryl(C 1-6 )alkyl, -OR’, -OC(O)R’, -R' 2 , -C(O)R' 2 , -C(O)R’, -C(O)OR’, -CN, or -NO 2 ; and unsubstituted 5- to 10-membered heteroaryl or 5- to 10- membered heteroaryl substituted with halogen, C 1-6 alkyl, C 1-6 haloalkyl, (C 6-12 )aryl(C 1- 6 )alkyl, -OR’, -OC(O)R’, -R' 2 , -C(O)R' 2 , -C(O)R’, -C(O)OR’, -CN, or -NO
  • R 6 and R 7 are independently selected from H, unsubstituted C 1-6 alkyl, C 1-6 haloalkyl, (C 6-12 )aryl(C 1-6 )alkyl, C 1-6 alkyl substituted with -OR’, -OC(O)R’, -R' 2 , -C(O)R' 2 , - C(O)R’, -C(O)OR’, -CN, or -NO 2 ; wherein each R’ is independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-12 aryl and (C 6-12 )aryl(C 1-6 )alkyl; or
  • - R 6 and R 7 together with the nitrogen atom to which they are attached can form a 5- to 10-membered heterocyclyl group; - R 8 is absent or C 1-6 alkyl; represents a single or a double bond.
  • Embodiment 3 Compound for use according to any one of embodiments 1 or 2, wherein - q is selected from 1, 2, 3 and 4;
  • - R 5 is selected from unsubstituted C 6-12 aryl or C 6-12 aryl substituted with halogen, or with -OR’, wherein R’ is selected from H, C 1-6 alkyl and (C 6-12 )aryl(C 1-6 )alkyl; - R 6 and R 7 are independently selected from H, unsubstituted C 1-6 alkyl or C 1-6 alkyl substituted with -OR’, wherein R’ is selected from H, C 1-6 alkyl and (C 6-12 )aryl(C 1- 6 )alkyl; and
  • Embodiment 4 Compound for use according to any one of embodiments 1 to 3, wherein the compound of formula (I) is selected from:
  • Embodiment 5 Compound of formula or a salt or solvate thereof.
  • Embodiment 6. A compound of formula (II) wherein
  • - K is selected from -N-, -NR-, -CR a - and -CH 2 -, wherein R and R a are each independently selected from H, C 1-6 alkyl, -C 1-6 alkyl-OR’, C 1-6 haloalkyl, C 6 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, (C 6-18 )aryl(C 1-6 )alkyl, (C 6-12 )aryl(C 2-6 )alkenyl and (C 6-12 )aryl(C 2-6 )alkynyl and wherein the C 3-7 cycloalkyl, C 6- 18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R’, R' 2 , C(O)R' 2 , C(O)- (CH 2 ) 1-3 -NR
  • - M is selected from -N-, -CR 11 -, -NR 12 - and -CH 2 -, wherein R 11 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -(C 1-6 alkyl)-NR 1 R 2 R 3 , and wherein R 12 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, -C 1-6 alkyl-OR’, C 6-18 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, (C 6-18 )aryl(C 1-6 )alkyl, (C 6-12 )aryl(C 2-6 )alkenyl and (C 6- 12 )aryl(C 2-6 )alkynyl and wherein the C 3-7 cycloalkyl, C 6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with
  • - T is selected from -N-, -NH-, -CR b - and -CH 2 -, wherein R b is selected from H, C 1-6 alkyl, -C 1-6 alkyl-OR’, C 1-6 haloalkyl, C 6-18 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, (C 6-18 )aryl(C 1-6 )alkyl, (C 6-12 )aryl(C 2-6 )alkenyl and (C 6- 12 )aryl(C 2-6 )alkynyl and wherein the C 3-7 cycloalkyl, C 6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R’, R' 2 , C(O)R' 2 , C(O)-(CH 2 ) 1-3 -NR 1 R 2
  • - L is selected from H, halogen, guanidinium, -NR 1 R 2 R 3 , C(O)NR 1 R 2 R 3 , C(O)-(CH 2 ) 1-3 - NR 1 R 2 R 3 , OR 1 , OC(O)R 1 , C(O)R 1 , C(O)OR 1 , CN, NO 2 , C 3-7 cycloalkyl, C 6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein each R 1 and R 2 are independently selected from H, C 1-6 alkyl, -C 1-6 alkyl-OR’, C 1-6 haloalkyl, C 6-18 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, (C 6-18 )aryl(C 1- 6 )alkyl, (C 6-12 )aryl(C 2-6 )alkenyl and (C 6-12 )aryl(
  • R 3 is absent, H or C 1-6 alkyl optionally substituted with at least one fluoride
  • Y 1 , Y 2 and Y 3 are each independently selected from phenyl or a 5- to 6-membered heterocyclyl, each optionally substituted with X;
  • - X is selected from halogen, OR’, OC(O)R', R' 2 , C(O)R' 2 , C(O)R', C(O)OR', CN, NO 2 , -(CH 2 ) 1-6- OR’, -(CH 2 ) 1-6- OC(O)R’, -(CH 2 ) 1-6- R' 2 , -(CH 2 ) 1-6- C(O)R' 2 , -(CH 2 ) 1-6- C(O)R’, -(CH 2 ) 1-6- C(O)OR', -(CH 2 ) 1-6- CN, -(CH 2 ) 1-6- NO 2 , C 1-6 alkyl, C 3-7 cycloalkyl, C 1- 6 haloalkyl, C 6- i b aryl, C 6- C 12 haloaryl, (C 6-18 )aryl(C 1-6 )alkyl, (C 6-12 )
  • RNA-viruses preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
  • Embodiment 7 Compound for use according to embodiment 6, wherein the compound of formula (II) is a compound of formulas (ll') to (II vi ) wherein s, X, L and R are as defined in embodiment 1.
  • Embodiment 8 Compound for use according to any one of embodiments 6 or 7, wherein L is selected from H, NR 1 R 2 , C(O)NR 1 R 2 , C(O)-(CH 2 ) 1-3 -NR 1 R 2 , N-containing 5- to IQ- membered heterocyclyl and N-containing 5- to 10-membered heteroaryl, wherein each R 1 and R 2 are independently selected from H and C 1-6 alkyl and wherein the N-containing 5- to 10-membered heterocyclyl and the N-containing 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R’, R' 2 , C(O)R' 2 , C(O)- (CH 2 ) 1-3 -NR 1 R 2 , C(O)R', C(O)OR', CN, NO 2, C 1-6 alkyl, C 1-6 haloalkyl, -(CH 2 ) 1-6- OR’,
  • Embodiment 9 Compound for use according to any one of embodiments 6 to 8, wherein the compound of formula (II) is selected from:
  • Embodiment 10 A compound of formula (III) wherein
  • - A is selected from -CH-, -N-, and -C(OH)- when is a double bond, or is selected from -NH-, -C(O)-, -CH 2 - and -CH(OH)- when s a single bond;
  • - B is selected from -CH- and -N- when is a double bond, and is selected from - CH 2 -, -N- and -NH- when is a single bond;
  • - C is selected from -NR 1 -, C 1-6 alkyl, C 3-7 cycloalkyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein R 1 is selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-18 aryl and (C 6-18 )aryl(C 1-6 )alkyl;
  • - D is selected from guanidinium, -NR 2 R 3 R 4 , 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein R 2 and R 3 are independently selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 6-18 aryl, (C 6-18 )aryl(C 1-6 )alkyl, (C 6-12 )aryl(C 2-6 )alkenyl and (C 6- 12 )aryl(C 2-6 )alkynyl and wherein the C 6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R', R' 2 , C(O)R' 2 , C(O)R’, C(O)OR’, CN, NO2, -(CH 2 ) 1-6- OR', -(CH 2 ) 1-6- OC(O
  • - E is selected from C 6-12 aryl and 5- to 10-membered heteroaryl
  • R 4 is absent, H or C 1-6 alkyl optionally substituted with at least one fluoride
  • - Rs is selected from halogen, OR’, OC(O)R', R' 2 , C(O)R' 2 , C(O)R’, C(O)OR’, CN, NO2, -(CH 2 ) 1-6- OR’, -(CH 2 ) 1-6- OC(O)R’, -(CH 2 ) 1-6- R' 2 , -(CH 2 ) 1-6- C(O)R' 2 , -(CH 2 ) 1-6- C(O)R’, -(CH 2 ) 1-6- C(O)OR’, -(CH 2 ) 1-6- CN, -(CH 2 ) 1-6- NO 2 , C 1-6 alkyl, C 3-7 cycloalkyl, C 1- 6 haloalkyl, C 6-18 aryl, C 6- C12 haloaryl, (C 6-18 )aryl(C 1-6 )alkyl, (C 6-12 )aryl(C 2-6
  • R 8 is absent, H or C 1-6 alkyl optionally substituted with at least one fluoride
  • - m is selected from 0 and 1 ;
  • - n is selected from 0, 1, 2, 3, 4, 5 and 6, wherein when n is 3-6 the resulting alkyl chain can contain at least one double bond;
  • each R is independently selected from H, C 1-6 alkyl, -(CH 2 ) 1-6- 0-C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-18 aryl, (C 6-18 )aryl(C 1-6 )alkyl, (C 6-12 )aryl(C 2-6 )alkenyl and
  • RNA-viruses preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
  • Embodiment 11 Compound for use according to embodiment 10, wherein the compound of formula (III) is a compound of formula (IN’) or (III”)
  • Embodiment 12 Compound for use according to any one of embodiments 10 or 11, wherein o is selected from 0 and 1 ; - p is selected from 0, 1 , 2, 3, 4 and 5;
  • R is independently selected from H, C 1-6 alkyl, C 3-7 cycloalkyl, C 1-6 haloalkyl, C 6-12 aryl and (C 6-12 )aryl(C 1-6 )alkyl; preferably R is selected from H and C 1-6 alkyl.
  • Embodiment 13 Compound for use according to any one of embodiments 10 to 12, wherein the compound of formula (III) is selected from: or a salt, solvate or stereoisomer thereof.
  • Embodiment 14 Compound for use according to any one of embodiments 1 to 4 and 6 to 13 wherein the infection by viruses is selected from infections by respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” and “Middle East respiratory syndrome-related coronavirus”.
  • Embodiment 15 Compound for use according to embodiment 14, wherein the respiratory syndrome-related coronavirus is selected from the group consisting of SARS-CoV-2, SARS-CoV and MERS-CoV, preferably SARS-CoV-2.
  • Compounds 1 a and 1 b were acquired from BOC Sciences. Compounds 1 c and 1 d were obtained from MCule. Compounds 1 i, 1k and 11 were purchased from Emolecules.
  • the crude was diluted with 10 mL of DCM and 0.75 mL of triethylamine (5.44 mmol) and 300 mg (0.96 mmol) of 2-chlorotrityl chloride were added sequentially, and the resulting solution was stirred overnight.
  • the crude mixture was partitioned between DCM (10 mL) and H 2 O (10 mL) and the aqueous phase extracted with DCM (3x10 mL). The combined organic phases were dried over anhydrous Na 2 SO 4 , filtered and evaporated to dryness.
  • Precursor compounds 1ax and 1aq’ (1aq’ being the trifluoroacetamide precursor of 1aq) were isolated by column chromatography (silica gel, 0-10% MeOH in DCM) obtaining 190 mg (36%) of 1ax and 29 mg (2%) of 1aq’.
  • Compound 1aq’ has the following molecular structure:
  • mice 24 female swiss albino mice were dosed PO with 4 mg/Kg of clomiphene citrate once per day during 7 consecutive days. Three additional animals were used as a control group. The concentration of the two diastereomers of clomiphene citrate was measured in plasma and lungs at eight time points after the last dose (30 min, 1 , 2, 4, 6, 8, 12 and 24 hours) using three animals per time point and liquid chromatography coupled to mass spectrometry methodology. Tmax, cmax, AUC, MRT and lung:plasma ratios were determined with Phoenix WinNonlin pharmacokinetics software.
  • Percent infection was quantified as ((Infected cells/Total cells) - Background) x 100 and the DMSO control was then set to 100% infection for analysis.
  • the IC50 and IC90 for each experiment were determined using the Prism (Graph Pad Software) software. Cytotoxicity was also performed using the MTT assay (Roche), according to the manufacturer’s instructions. Cytotoxicity was performed in uninfected VeroE6 cells with same compound dilutions and concurrent with viral replication assay. All assays were performed in biologically independent triplicates.
  • the tables below show the antiviral activity (anti SARS-CoV-2) and cytotoxicity of representative compounds of the invention by indication of the IC50, IC90, CC50, CC10 and Selectivity Index (SI) parameters.
  • Table 9 Results from the Viral growth and Cytotoxicity assays in the presence of compound 2b. Table 10. Results from the Viral growth and Cytotoxicity assays in the presence of compound 2c.
  • Table 20 Results from the Viral growth and Cytotoxicity assays in the presence of compound 1d.
  • Table 21 Results from the Viral growth and Cytotoxicity assays for the Hela-ACE2 cell line in the presence of compounds of the invention.
  • Comparative compounds The following table shows IC50, CC50 and SI values for the corresponding depicted comparative compounds, which are not part of the present invention.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Virology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to the use of small organic compounds, or a salt or solvate thereof, for the treatment and/or prevention of viral infections by RNA-viruses, preferably from the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, such as SARS-CoV-2.

Description

SMALL-MOLECULE AGENTS WITH ANTIVIRAL ACTIVITY AGAINST RNA
VIRUSES
FIELD OF THE INVENTION
The present invention relates to compounds for use in the treatment and/or prevention of viral infections caused by RNA-viruses, including Coronaviridae, especially those caused by respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV and SARS- CoV-2).
BACKGROUND The genetic material of RNA viruses is usually single-stranded RNA (ssRNA) although retroviruses can also include DNA intermediates in their replication cycle. RNA viruses are accountable for the common cold, influenza, AIDS, SARS, MERS, COVID- 19, chikungunya, Dengue fever, zika fever, yellow fever, West Nile fever, hepatitis C, hepatitis E, Ebola virus disease and rabies, among other notable human diseases. The viruses of the family Coronaviridae are enveloped viruses with a positive-sense single- stranded RNA genome and a nucleocapsid of helical symmetry. The name of the family is derived from the Latin corona, meaning "crown" or "halo", which refers to the characteristic appearance reminiscent of a solar corona around the virions (virus particles) when viewed under two-dimensional transmission electron microscopy, due to the surface being covered in club-shaped protein spikes.
In December 2019 a new infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first identified in Wuhan, the capital of China's Hubei province, and has since spread globally, resulting in the ongoing 2019- 2021 coronavirus pandemic. The disease has been given the name Coronavirus disease 2019 orCOVID-19. COVID-19 has evolved into an appalling global pandemic worldwide.
The etiological agent of this severe respiratory syndrome was named SARS-CoV- 2 due to its genetic similarity to the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) that caused the 2003 epidemic outbreak in different areas of Southeast Asia. SARS-CoV-2 replicates efficiently in asymptomatic patients, which are responsible for the spread of the virus worldwide, given that high replication levels are not necessarily associated with clinical manifestations of the disease that may restrict infected patient mobility. While silent or causing mild symptoms in a majority of cases, SARS-CoV-2 may lead to COVID-19, which is primarily but not exclusively characterized by severe pneumonia that may lead to death in a fraction of the population, most notably the elderly.
Common symptoms include fever and cough and loss of taste or smell, which may be accompanied by other such as muscle pain, diarrhoea or sore throat. While the majority of cases result in these mild symptoms, some patients progress to hypoxia, bilateral pneumonia and multi-organ failure.
Early immunological studies as well as prior experience with SARS-CoV has led to an enormous number of prophylactic vaccines being developed against SARS-CoV-2. Given the severity and wide impact of the disease, numerous efforts are being put into the development of such vaccines and while in early January 2021 there were 63 candidate vaccines in clinical development and 173 in pre-clinical development, at the time of writing 9 vaccines have already been approved for full use, 114 are in clinical trials (37 in phase 3) and 75 in preclinical trials. While this is certainly the best approach to contain future outbreaks, it is clear that additional strategies need to be in place for patients that already acquired the infection. Antiviral treatment may contribute to infection resolution and better prognosis of hospitalized patients. Eventually, antivirals may also be considered under certain circumstances as prophylactic treatment option for the containment of specific outbreaks. Moreover, durable antivirals may also serve to contain likely future coronavirus outbreaks.
The first approved small-molecule antiviral drug against SARS-CoV-2, remdesivir, is non-specific, injectable and has limited efficacy at improving COVID-19 clinical outcome. During 2021 and in the early 2022, the drugs Molnupiravir and Paxlovid were approved for oral administration. However, molnupiravir is believed to be mutagenic and thus only authorised for use in certain populations where other treatments are not feasible. In addition, with the constant outbreak of new variants, an urgent need for the identification of novel antivirals against SARS-CoV-2 remains.
WO20 15/157223 discloses the use of tamoxifen citrate and toremifene citrate for treating MERS and SARS coronavirus infections.
Calderone Alba et al. ("Selective Estrogen Receptor Modulators in COVID-19: A Possible Therapeutic Option?", Frontiers in Pharmacology, vol. 11 , 15 July 2020) analyses the role of estrogen receptor in COVID-19 diseases and stipulates that selective estrogen receptor modulators (SERMs) may be useful in treating COVID-19.
Zhao Yuguang et al. ("Toremifene interacts with and destabilizes the Ebola virus glycoprotein", Nature, Macmillan Journals Ltd., vol. 535, no. 7610, 29 June 2016, pages 169-172) reports on the mode of action of toremifene on Ebola virus.
Xiong Hua-Long et al. ("Several FDA-Approved Drugs Effectively Inhibit SARS- CoV-2 Infection in vitro", Frontiers in Pharmacology, vol. 11 , 5 February 2021 ) discloses that FDA approved drugs against SARS-CoV-2 infections, Tamoxifen citrate, tamoxifen, clomiphene citrate and toremifene citrate, were found to be effective against SARS-CoV- 2. This document is silent with regards to clomiphene isomers, whereas Nelson, E. A., et al. (“Clomiphene and its isomers block Ebola virus particle entry and infection with similar potency: potential therapeutic implications. Viruses 8 (8), 2016, 206) discloses that clomiphene and its isomers have similar potency.
Martin William R. et al. ("Repurposing of FDA-Approved Toremifene to Treat COVID-19 by Blocking the Spike Glycoprotein and NSP14 of SARS-CoV-2", Journal Of Proteome Research, vol. 19, no. 11 , 10 September 2020, pages 4670-4677) studies the in silica docking of toremifene on the spike protein of SARS-CoV-2 and suggests this compound as a promising candidate for COVID-19. It also refers to previous results of toremifene on MERS, SARS-CoV-1 and Ebola and of tamoxifen on MERS and SARS- CoV-1.
Jeon Sangeun et al. ("Identification of Antiviral Drug Candidates against SARS- CoV-2 from FDA-Approved Drugs", Antimicrobial Agents and Chemotherapy, vol. 64, no. 7, 4 May 2020, pages e00819-20) investigates the antiviral activity towards SARS-CoV- 2 of clomiphene citrate, droloxifene and toremifene citrate. This document is silent with regards to clomiphene isomers.
Capuzzi Stephen J. et al. ("Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors", Journal of Medicinal Chemistry, vol. 61 , no. 8, 26 April 2018, pages 3582-3594) discloses that afimoxifene and endoxifen exhibit inhibitory activity against Ebola.
US2005/096384 discloses a new class of tamoxifen analogs with estrogen receptor inhibitory activity.
R. Jeffrey Baumann et al. ("Clomiphene Analogs with Activity In Vitro and In Vivo against Human Breast Cancer Cells", Biochemical Pharmacology, vol. 55, no. 6, 1 March 1998, pages 841-851 ) describes clomiphene analogs with antiproliferative activity. This document does not refer to the clomiphene isomers (zuclomiphene and enclomiphene) nor does it relate to antiviral compounds.
Torriani Giulia et al. ("Identification of Clotrimazole Derivatives as Specific Inhibitors of Arenavirus Fusion", Journal of Virology, vol. 93, no. 6, 1 March 2019) reports on the antiviral activity on arenavirus of clotrimazole and TRAM-34 ((1-[(2-chlorophenyl) diphenylmethyl]-1 H-pyrazole)).
Karunakaran Kalyani B. et al. ("Potentially repurposable drugs for COVID-19 identified from SARS-CoV-2 Host Protein Interactome", 28 May 2020 & supplementary material), Gao Kaifu et al. ("Repositioning of 8565 Existing DrugsforCOVID-19", Journal of Physical Chemistry Letters, vol. 11 , no. 13, 2 July 2020, pages 5373-5382) and Samant Lalit R. et al. ("Comparative Docking analysis of rational drugs against COVID- 19 Main Protease", 1 January 2020) report computer modelling studies of various compounds including clotrimazole on binding affinity towards SARS-CoV proteins.
US2014/005196 discloses N-trityl amine derivatives as inhibitors of apolipoprotein E for treating Alzheimer's disease. JP2013032299 discloses N-trityl amine derivatives of formula as melanin production suppressor. Given the urgency of the matter, a large effort has been done in drug repurposing, with a long list of repurposing candidates currently under clinical evaluation. In addition to evaluating repurposed drugs, it is of capital importance to discover new antivirals, which could allow the identification of clinical candidates. This should be the way to arrive in a medium-to-long term to efficient drugs for COVID-19 treatment, and potentially also for other coronaviruses infections that could emerge.
SUMMARY OF THE INVENTION
The inventors have surprisingly found that certain organic compounds are useful in the treatment and/or prevention of viral infections caused by RNA-viruses, particularly of the family Coronaviridae, even more preferably SARS-CoV-2. However, said compounds could also be used in the treatment of other families of RNA-viruses, such as Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
Thus, in a first aspect, the invention relates to a compound of formula (I) as described herein, or a salt or solvate thereof, for use in the prevention or treatment of infections caused by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV-2 and SARS- CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV). In another aspect, the invention relates to a compound of formula (I”).
In a further aspect, the present invention relates to a compound of formula (II) as described herein, or a salt, solvate or stereoisomer thereof, for use in the prevention or treatment of infections caused by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV and SARS- CoV-2) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV).
In a further aspect, the invention relates to a compound of formula
Figure imgf000006_0001
In another aspect, the invention relates to a compound of formula (III) as described herein, or a salt or solvate thereof, for use in the prevention or treatment of infections caused by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV-2 and SARS-CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV).
Another aspect of the invention relates to the use of a compound of formula (I), (II), or (III) as described herein, or a salt or solvate thereof, in the manufacture of a medicament for the prevention or treatment of infections caused by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV-2 and SARS-CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV).
Another aspect of the invention relates to a method of preventing or treating infections caused by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV-2 and SARS- CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV), which comprises administering a therapeutically effective amount of a compound of formula (I), (II), or (III) as described herein, or a salt or solvate thereof. In an additional aspect, the invention relates to a pharmaceutical composition comprising a compound of formula (I), (II), or (III) as described herein, or a salt or solvate thereof, for use in the prevention or treatment of infections caused by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus" (such as SARS-CoV-2 and SARS-CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV).
In another aspect, the present invention relates to a combination comprising a compound of formula (I), (II) or (III) of the invention and or more additional compounds useful in the treatment of viral infections by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV-2 and SARS-CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV). Some compounds useful in said combination are nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, ribavirin, favipiravir, chloroquine, hydroxychloroquine, lopinavir, ritonavir, umifenovir and recombinant type I interferon, preferably nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, lopinavir and ritonavir. Preferably, the combination is synergistic. DESCRIPTION OF THE FIGURES
Figure 1. Results of the PK distribution study of clomiphene citrate. The lung concentrations of the cis- and trans- isomers of the drug are plotted as a function of time. 1 - Clomiphene citrate (cis); 2 - Clomiphene citrate (trans); 3 - IC90 cis-Clomiphene; 4 - IC90 Clomiphene citrate.
DESCRIPTION OF THE INVENTION
Definitions
The term “halogen” refers to bromine, chlorine, iodine, or fluorine. Preferably, halogen refers to chlorine (Cl).
The term “C1-6 alkyl” refers to a linear or branched hydrocarbon chain radical consisting of carbon and hydrogen atoms, containing no unsaturation, having between 1 and 6, preferably between 1 and 3 (“C1-3 alkyl”), more preferably 1 or 2 (“C1-2 alkyl”), carbon atoms and which is attached to the rest of the molecule by a single bond, including for example and in a non-limiting sense, methyl, ethyl, n-propyl, i-propyl, n- butyl, t-butyl, n-pentyl, etc. Preferably, “alkyl” refers to methyl or ethyl.
The terms "C2-6 alkenyl" and "C2-6 alkynyl" refer to linear or branched hydrocarbon chain radicals consisting of carbon and hydrogen atoms having at least one double or triple bonds, respectively, and from 2 to 6 carbon atoms, more preferably having 2, 3 or 4 carbon atoms. In a preferred embodiment, they refer to linear hydrocarbons having a single double bond or a single triple bond, respectively, and from 2 to 6 carbon atoms, preferably 2 or 3 carbon atoms. In a preferred embodiment, C2-6 alkynyl is ethynyl.
The term “C3-7 cycloalkyl” refers to a saturated or partially saturated mono- or bicyclic aliphatic group having between 3 and 7, preferably between 3 and 6 carbon atoms (“C3-C6 cycloalkyl”), which is bound to the rest of the molecule by means of a single bond, including for example and in a non-limiting sense, cyclopropyl, cyclohexyl or cyclopentyl.
The term “C1-C6 haloalkyl” refers to an alkyl group as defined above wherein at least one of the hydrogen atoms has been replaced by a halogen atom such as, for example CF3, CCI3, CHF2, CH2F, CH2CF3, CF2CF3.
The term “C6-18 uryl” refers to an aromatic group having between 6 and 18, preferably between 6 and 12 carbon atoms, more preferably between 6 and 10 and even more preferable having 6 carbon atoms, comprising 1 , 2 or 3 aromatic nuclei, including for example and in a non-limiting sense, phenyl, biphenyl, naphthyl, indenyl, phenanthryl or terphenyl. Preferably, aryl refers to phenyl (Ph) or biphenyl.
The term “(C6-C18)aryl(C1-C6)alkyl” refers to an aryl group as defined above which is attached to the rest of the molecule through an alkyl group as defined above. Preferably, the (C6-C18)aryl(C1-C6)alkyl is (C6-C12)aryl(C1-C3)alkyl, and more preferably a (C6)aryl(C1-C3)alkyl. Examples of these groups include benzyl, phenylethyl, phenylpropyl, naphthylmethyl. Preferably, it refers to benzyl (Bn).
The term “(C6-C18)aryl(C2-C6)alkenyl” refers to an aryl group as defined above which is attached to the rest of the molecule through an alkenyl group as defined above. Preferably, the (C6-C18)aryl(C2-C6)alkenyl is (C6-C12)aryl(C2-C4)alkenyl, and more preferably a (C6)aryl(C2-C4)alkenyl. Examples of these groups include (C6)aryl(C2)alkenyl (styryl), (C6)aryl(C2)alkenyl, (C10)aryl(C2)alkenyl (vinylnaphthalene), (C12)aryl(C2)alkenyl (4-vinyl-1 ,T-biphenyl). Preferably, it refers to styryl.
The term “(C6-C18)aryl(C2-C6)alkynyl” refers to an aryl group as defined above which is attached to the rest of the molecule through an alkynyl group as defined above. Preferably, the (C6-C18)aryl(C2-C6)alkynyl is (C6-C12)aryl(C2-C4)alkynyl, and more preferably a (C6)aryl(C2-C4)alkynyl. Examples of these groups include (C6)aryl(C2)alkynyl (ethynylbenzene), (C6)aryl(C2)alkynyl, (C10)aryl(C2)alkynyl (ethynylnaphthalene), (C12)aryl(C2)alkynyl (4-ethynyl-1 , 1 ’-biphenyl). Preferably, it refers to ethynylbenzene.
The term “C6-12 haloaryl” refers to an aryl group as defined above, comprising from 6 to 12 carbon atoms, wherein at least one of the hydrogen atoms has been replaced by a halogen atom such as, for example fluorobenzene or chlorobenzene.
The term “5- to 10-membered heterocyclyl” refers to a monocyclic or bicyclic system which can be partially or fully saturated containing 5 to 10, preferably 5 or 6, ring atoms containing one or more, specifically one, two, three, or four ring heteroatoms independently selected from N, O, and S, preferably one or two, and the remaining ring atoms being carbon. Examples of heterocyclyl groups include, but are not limited to, pyrrolidine, piperidine, tetrahydropyridine, piperazine, morpholine, thiomorpholine, azepane, diazepane, tetrahydrofuran, tetrahydropyran, octahydro-pyrrolopyrazine.
The term “5- to 10-membered heteroaryl” refers to a monocyclic or bicyclic system which is aromatic and contains 5 to 10, preferably 5 or 6, ring atoms containing one or more, specifically one, two, three, or four ring heteroatoms independently selected from N, O, and S, preferably one or two, and the remaining ring atoms being carbon. Examples of such heteroaryl include, but are not limited to, thiophene, furan, pyrrole, thiazole, oxazole, isothiazole, isooxazole, imidazole, pyrazole, triazole, oxadiazole, thiadiazole, tetrazole, tetrazole oxide, oxadiazolone, pyridine, pyrimidine, pyrazine, dihydroindolone, benzimidazole, isoindole, benzothiazole, benzofuran, indole, purine, quinolone, isoquinoline.
The aforementioned groups can be unsubstituted or can be substituted at one or more available positions with the suitable groups disclosed in each case. In a particular embodiment, it can be substituted with one, two or three, preferably with one or two, more preferably with one said suitable groups.
The invention also provides “salts” of the compounds described in the present description. By way of illustration, said salts can be acid addition salts, base addition salts, or metal salts, and can be synthesized from the original compounds containing a basic or acidic residue by means of conventional chemical methods known in the art. Such salts are generally prepared, for example, by reacting the free acid or base forms of said compounds with a stoichiometric amount of the suitable base or acid in water or in an organic solvent or in a mixture of both. Illustrative examples of said acid addition salts include inorganic acid addition salts such as, for example, hydrochloride, hydrobromide, hydroiodide, sulfate, perchlorate, nitrate, phosphate, etc., organic acid addition salts such as, for example, acetate, formate, maleate, fumarate, citrate, oxalate, succinate, tartrate, malate, mandelate, methanesulfonate, p-toluenesulfonate, camphorsulfonate, etc. Illustrative examples of base addition salts include inorganic base salts such as, for example, ammonium salts, and organic base salts such as, for example, ethylenediamine, ethanolamine, N,N-dialkylenethanolamine, triethanolamine, glutamine, basic amino acid salts, etc. Illustrative examples of metal salts include, for example, sodium, potassium, calcium, magnesium, aluminum, and lithium salts. In a particular embodiment, the salt is an acid addition salt.
The compounds of the invention can be in the form of salts, solvates or stereoisomers, preferably pharmaceutically acceptable salts, solvates or stereoisomers. Similarly, when a particular compound, or group of compounds, is excluded from the claims, any salts, solvates, or stereoisomers thereof are also to be considered as excluded, unless stated otherwise.
The term “pharmaceutically acceptable” refers to molecular entities and compositions that are physiologically tolerable and do not typically produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a human. Preferably, as used herein, the term “pharmaceutically acceptable” means approved by a regulatory agency of the Federal or a state government or listed in the U.S. or European Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.
Likewise, the compounds described in the present description can be obtained both as free compounds and as solvates (for example, hydrates, alcoholates, etc.), both forms being included within the scope of the present invention. Solvation methods are generally known in the state of the art.
As used herein, the term "stereoisomer" is a general term for all isomers of individual molecules that differ only in the orientation of their atoms in space, and include enantiomers and diastereomers.
When the compounds of the invention have chiral centers (for example as in formula (III) herein), they can exist in different stereoisomeric forms, such as enantiomeric or diastereomeric forms. Thus, any given compound referred to herein is intended to represent any one of a racemate, one or more enantiomeric forms and one or more diastereomeric forms. All the stereoisomers including enantiomers and diastereoisomers of the compounds referred to herein, and mixtures thereof (including racemic mixtures, enantiomerically enriched mixtures and diastereomerically enriched mixtures), are considered within the scope of the present invention. Also, the invention further contemplates any E / Z possible isomers, examples being the compounds of formula (II). In a preferred embodiment, the compound of formula (2f) is an (E)-isomer.
The compounds and pharmaceutical compositions of this invention can be administered to a patient using any means known in the art, including oral and parenteral routes.
Compounds of formula (I)
In an aspect, the present invention relates to a compound of formula (I)
Figure imgf000011_0001
wherein
- r is selected from 0, 1 and 2;
- s is selected from 0, 1 , 2, 3, 4 and 5;
- K is selected from -N-, -NR-, -CRa- and -CH2-, wherein R and Ra are each independently selected from H, C1-6 alkyl, -C1-6 alkyl-OR’, C1-6 haloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl, -C1-6 alkyl-(5- to 10-membered heterocyclyl), (C6- 18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl and wherein the C1-6 alkyl, -C1-6 alkyl-OR’, C1-6 haloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl and -C1-6 alkyl-(5- to 10-membered heterocyclyl) can be unsubstituted or substituted with R’, halogen, OR’, OC(O)R' R'2 , C(O)R'2 , C(O)-(CH2)1-3-NR1R2, C(O)R’, C(O)OR’, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1- 6- NR'2, -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, -(CH2)1- 6- NO2, C3-7 cycloalkyl, C6-18 aryl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, -Co-6 alkyl-(guanidinium), -C1-6 alkyl-(5- to 10-membered heterocyclyl), -C1-6 alkyl-(5- to 10-membered heterocyclyl substituted with -Co-6 alkyl- guanidinium), and C6-18 aryl;
- M is selected from -N-, -CR11-, -NR12- and -CH2-, wherein R11 is selected from H, C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkyl)-NR1R2R3, and wherein R12 is selected from H, C1-6 alkyl, C1-6 haloalkyl, -C1-6 alkyl-OR’, C6-18 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl and wherein the C1-6 alkyl, -C1-6 alkyl-OR’, C1-6 haloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R’, R'2 , C(O)R'2 , C(O)- (CH2)1-3-NR1R2, C(O)R', C(O)OR', CN, NO2, C1-6 alkyl, C1-6 haloalkyl, -(CH2)1-6-OR’, - (CH2)1-6-OC(O)R’, -(CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6- C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6- NO2, C3-7 cycloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2- 6)alkynyl;
- T is selected from -N-, -NH-, -CH- and -CH2-;
- L is selected from H, halogen, guanidinium, -NR1R2R3, C(O)NR1R2R3, C(O)-(CH2)1-3- NR1R2R3, OR1, OC(O)R1, C(O)R1, C(O)OR1, CN, NO2, C3-7 cycloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein each R1 and R2 are independently selected from H, C1-6 alkyl, -C1-6 alkyl-OR’, C1-6 haloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, (C6-18)aryl(C1- 6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl and wherein the C1-6 alkyl, - C1-6 alkyl-OR’, C1-6 haloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10- membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R', R'2 , C(O)R'2 , C(O)-(CH2)1-3-R'2 , C(O)R’, C(O)OR’, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1-6- R'2 , -(CH2)1-6-C(O)R'2 , - (CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6- NO2, C3-7 cycloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2- 6)alkenyl and (C6-12)aryl(C2-6)alkynyl;
- R3 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
- Y1, Y2 and Y3 are each independently selected from phenyl or a 5- to 6-membered heterocyclyl each optionally substituted with X;
- X is selected from halogen, OR’, OC(O)R’, R'2 , C(O)R'2 , C(O)R’, C(O)OR’, CN, NO2, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6- C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6-NO2, C1-6 alkyl, C3-7 cycloalkyl, C1- 6 haloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl or (C6-12)aryl(C2-6)alkynyl, -NR4R5R6, 5- to 10-membered heterocyclyl and 5- to 10- membered heteroaryl, wherein R4 and R5 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl and wherein the C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R’, R'2 , C(O)R'2 , C(O)R’, C(O)OR’, CN, NO2, -(CH2)1-6-OR’, -(CH2)1-6- OC(O)R’, -(CH2)1-6- R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, - (CH2)1-6-CN, -(CH2)1-6- N02, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl;
- R6 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
- ^ represents a single or a double bond; or a salt or solvate thereof, with the proviso that the compound of formula (I) is not selected from the group consisting of clotrimazole, TRAM-34 and salts thereof, for use in the treatment or prevention of an infection by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
TRAM-34 has the following molecular structure:
Figure imgf000013_0001
According to a particular embodiment, the compound of formula (I) is a compound of formula
Figure imgf000013_0002
wherein X, Y1, Y2, T, M, K, L, r and s are as defined above.
According to a particular embodiment, in the compound of formula (I) when K is -N- or -CH-, then the bond
Figure imgf000013_0003
is a double bond, and when K is -NH- or -CH2-, then the bond is a single bond.
Figure imgf000013_0004
According to a particular embodiment, in the compound of formula (I) when K is -NR- and the bond
Figure imgf000013_0005
K is a double bond, then K is a positively charged
-NR-.
According to a particular embodiment, in the compound of formula (I) when M is -N- or -CH-, then the bond K is a double bond, and when M is -NH- or -CH2-, then the bond is a single bond.
According to a particular embodiment, in the compound of formula (I) M and K are -N-, and the bond is a double bond.
According to a particular embodiment, in the compound of formula (I) when T is -N- or -CH-, then the bond is a double bond, and when T is -NH- or -CH2-, then the bond is a single bond.
Figure imgf000014_0001
According to a particular embodiment, in the compound of formula (I), at least one of Y1, Y2 or Y3 is a phenyl group. Preferably, Y1 = Y2 = phenyl, even more preferably Y1 = Y2 = Y3 = phenyl.
In another particular embodiment, X is selected from H, C1-6 alkyl, halogen and phenyl.
In an embodiment, r is 0 and represents a double bond.
Figure imgf000014_0002
In an embodiment, r is 1 and
Figure imgf000014_0003
represents a single bond.
In an embodiment, r is 1 and one, but only one of K, M and T is N.
In a particular embodiment, r is 1 and only one of K and M is -NR-, preferably, K is
-NR-.
In another particular embodiment, r is 0, K is -N-, M is -CH- and T is -CH-. According to a particular embodiment, in the compound of formula (I), if s is 0, then M is selected from -CR11- or T is selected from -N- and -CH-, wherein R11 is selected from C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkyl )-NR1R2R3.
According to a preferred embodiment, in the compound of formula (I): r is 1 ; s is 0 or 1 ;
K is -NR-, wherein R is selected from H, C1-6 alkyl and -C1-6 alkyl-(5- to 10- membered heterocyclyl), and wherein C1-6 alkyl and -C1-6 alkyl-(5- to 10-membered heterocyclyl) can be unsubstituted or substituted with R’, OR’ or NR’2, wherein each R’ is independently selected from H, C1-6 alkyl, -C0-6 alkyl-(guanidinium), -C1-6 alkyl-(5- to 10-membered heterocyclyl) and C6-18 aryl;
M is selected from -CH2- and -CR11-, wherein R11 is C1-6 alkyl;
T is -CH2-; and L is H.
In the latter preferred embodiment, Y1, Y2 and Y3 are preferably phenyl, each optionally substituted with X, wherein X is selected from halogen and C6-18 aryl. In a more preferred embodiment, Y1 and Y2 are phenyl and Y3 is selected from phenyl, chlorophenyl, and biphenyl.
According to a more preferred embodiment, in the compound of formula (I): r is 1 ; s is 0 or 1;
K is -NR-, wherein R is selected from H, -C1-3 alkyl and -C1-3 alkyl-(5- to 6- membered heterocyclyl), and wherein C1-3 alkyl and -C1-3 alkyl-(5- to 6-membered heterocyclyl) can be unsubstituted or substituted with R’, OR’ or R'2 , wherein each R’ is independently selected from H, -CH3, guanidinium, -CH2-guanidinium, -(CH2)2- piperazine, and phenyl;
M is selected from -CH2- and -CR11-, wherein R11 is -CH3;
T is -CH2-; and
L is H. In the latter more preferred embodiment, 5- to 6-membered heterocyclyl is preferably selected from pyrrolidine, piperidine, and piperazine. Also in the latter more preferred embodiment, Y1 and Y2 are preferably phenyl and Y3 is selected from phenyl optionally substituted with X, wherein X is selected from halogen and C6-18 aryl. In a more preferred embodiment, Y1 and Y2 are phenyl and Y3 is selected from phenyl, chlorophenyl, and biphenyl.
According to a preferred embodiment, in the compound of formula (I): r is 0; s is 0, 2 or 3;
K is -N-; M is -CH-;
T is -CH-;
R’ is H;
L is selected from -NR1R2R3, and 5- to 10-membered heterocyclyl, wherein each R1 and R2 are independently selected from H, C1-6 alkyl, and -C1-6 alkyl-OR’; and R3 is absent, or C1-6 alkyl optionally substituted with at least one fluoride.
In the latter preferred embodiment, Y1 and Y2 are preferably phenyl and Y3 is phenyl optionally substituted with X, wherein X is selected from halogen and C6-18 aryl. In a more preferred embodiment, Y1 and Y2 are phenyl and Y3 is selected from phenyl, chlorophenyl and biphenyl. According to a preferred embodiment, in the compound of formula (I): r is 0; s is 0, 2 or 3;
K is -N-;
M is -CH-;
T is -CH-; R’ is H;
L is selected from -NR1R2R3, pyrrolidine and piperazine, the piperazine being optionally substituted with C1-6 alkyl, wherein each R1 and R2 are independently selected from H, -C2 alkyl, and -C2 alkyl-OR’; and
R3 is absent.
In the latter preferred embodiment, Y1 and Y2 are preferably phenyl and Y3 is phenyl optionally substituted with X, wherein X is selected from halogen and C6-18 aryl. In a more preferred embodiment, Y1 and Y2 are phenyl and Y3 is selected from phenyl, chlorophenyl and biphenyl.
In a preferred embodiment, the compound of formula (I) comprises a piperazine, i.e., r is 1 and K is -NR-, or comprises an imidazole, i.e., r is 0 and K is -N-. Thus, in a preferred embodiment, which is compatible with any of the above, in the compound of formula (I): r is 0 or 1 ; s is 0, 1 , 2 or 3;
K is -N- or -NR-, wherein R is selected from H, C1-6 alkyl and -C1-6 alkyl-(5- to 10- membered heterocyclyl), and wherein C1-6 alkyl and -C1-6 alkyl-(5- to 10-membered heterocyclyl) can be unsubstituted or substituted with R’, OR’ or NR’2, wherein each R’ is independently selected from H, C1-6 alkyl, -C0-6 alkyl-(guanidinium), -C1-6 alkyl-(5- to 10-membered heterocyclyl), and C6-18 aryl;
M is -CH-, -CH2- and -CR11-, wherein R11 is C1-6 alkyl;
T is -CH2-;
R’ is H;
L is selected from H, -NR1R2R3, and 5- to 10-membered heterocyclyl, wherein each R1 and R2 are independently selected from H, C1-6 alkyl, and -C1-6 alkyl-OR’; and
R3 is absent, or C1-6 alkyl optionally substituted with at least one fluoride.
Preferably, the compound of formula (I) is a compound of formula (I”),
Figure imgf000016_0001
wherein
- r is selected from 0 or 1 ;
- s is selected from 0, 1 , 2 or 3;
- R is absent or is selected from H, C1-6 alkyl and -C1-6 alkyl-(5- to 10-membered heterocyclyl), and wherein the C1-6 alkyl and -C1-6 alkyl-(5- to 10-membered heterocyclyl) can be unsubstituted or substituted with R’, -OR’ or -R'2 ;
- R’ is each independently selected from H, C1-6 alkyl, -C0-6 alkyl-(guanidinium), -C1-6 alkyl-(5- to 10-membered heterocyclyl), -C1-6 alkyl-(5- to 10-membered heterocyclyl substituted with -C0-6 alkyl-guanidinium) and C6-18 aryl;
- M is selected from -CH2-, -N- and -CR11-, wherein R11 is selected from H, C1-6 alkyl and -(C3 alkyl)-NH2;
- L is selected from H, guanidinium, -NR1R2R3, -C(O)NH2, and 5- to 10-membered heterocyclyl, wherein each R1 and R2 are independently selected from H, C1-6 alkyl, - C1-6 alkyl-OR’, and wherein the C1-6 alkyl and 5- to 10-membered heterocyclyl can be unsubstituted or substituted with C(O)-(CH2)1-3-R'2 and C1-6 alkyl;
- R3 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
- Y3 is selected from phenyl, optionally substituted with X;
- X is selected from halogen or C6-18 aryl;
- ^ represents a single or a double bond; or a salt or solvate thereof, with the proviso that the compound of formula (I”) is not 1-(triphenylmethyl)imidazole, clotrimazole, and salts thereof.
Preferably, the compound of formula (I) is a compound of formula (I”) and:
- r is selected from 0 or 1 ;
- s is selected from 1 , 2 or 3;
- R is absent or is selected from H, C1-6 alkyl and -C1-6 alkyl-(5- to 10-membered heterocyclyl), and wherein the C1-6 alkyl can be unsubstituted or substituted with -OR’ or -R'2 ;
- R’ is H;
- M is selected from -CH2- or -CR11-, wherein R11 is selected from H or C1-6 alkyl;
- L is selected from H, -NH2, -NR1R2R3, and 5- to 10-membered heterocyclyl wherein each R1 and R2 are independently selected from H, C1-6 alkyl or -C1-6 alkyl-OH, and wherein the 5- to 10-membered heterocyclyl can be unsubstituted or substituted with C1-6 alkyl;
- R3 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
- Y3 is selected from phenyl, optionally substituted with X;
- X is selected from H, halogen or phenyl;
- represents a single or a double bond;
Figure imgf000017_0001
or a salt or solvate thereof, with the proviso that the compound of formula (I”) is not 1-(triphenylmethyl)imidazole, clotrimazole, and salts thereof.
Preferably, the compound of formula (I) is a compound of formula (I”) and:
- r is selected from 0 or 1 ;
- s is selected from 1 , 2 or 3;
- R is absent or is selected from H, C1-6 alkyl and -C1-6 alkyl-(5- to 10-membered heterocyclyl);
- M is selected from -CH2- or -CH-;
- L is selected from H or -NH2;
- Y3 is selected from phenyl, optionally substituted with X;
- X is selected from H, phenyl or halogen, the halogen being preferably Cl;
- represents a single or a double bond; or a salt or solvate thereof, with the proviso that the compound of formula (I”) is not 1-(triphenylmethyl)imidazole, clotrimazole, and salts thereof.
More preferably, the compound of formula (I) is a compound of formulas (I') to (lvii)
Figure imgf000018_0001
wherein s, L, X, R and R11 are as defined above.
The compounds of formula (Ii) (Iii and (lvii) are particularly preferred, with (Ii) and (I") being mostly preferred.
In a particular embodiment, the compound of formula (I) is a compound of formula (Ii;) and X is H, phenyl or Cl; s is selected from 1 , 2 or 3; L is selected from -NH2, -NR1R2, and 5- to 10-membered heterocyclyl wherein each R1 and R2 are independently selected from H, C1-6 alkyl or -C1-6 alkyl-OH, and wherein the 5- to 10-membered heterocyclyl can be unsubstituted or substituted with C1-6 alkyl;. Preferably, when the compound of formula (I) is a compound of formula (Ii;) X is H, phenyl or Cl; s is selected from 2 or 3; and L is -NH2.
In another particular embodiment, the compound of formula (I) is a compound of formula (Iii); and X is H, phenyl or Cl; s is 0 or 1 ; L is H; and R is selected from H, C1-6 alkyl, C1-6 alkyl-OH, C1-6 alkyl-NH2, and -C1-6 alkyl-(5- to 10-membered heterocyclyl) preferably selected from pyrrolidine, piperidine or piperazine. Preferably, when the compound of formula (I) is a compound of formula (Iii); X is H, phenyl or Cl; s is 0 or 1 ; L is H; and R is selected from H, C1-6 alkyl, and -C1-6 alkyl-(5- to 10-membered heterocyclyl) preferably selected from pyrrolidine, piperidine or piperazine.
In another particular embodiment, the compound of formula (I) is a compound of formula (lvii), and X is H, phenyl or Cl; s is 1 ; L is H; R is H; and R11 is C1-6 alkyl.
Just as those disclosed above, the following particular and preferred embodiments also apply to the compounds of formula (I), and (Ii) to (lvii).
In an embodiment, s is selected from 1 , 2, 3 and 4.
In a particular embodiment, R is selected from H, C1-6 alkyl and -C1-6 alkyl-(5- to 10-membered heterocyclyl), and wherein the C1-6 alkyl and -C1-6 alkyl-(5- to 10- membered heterocyclyl) can be unsubstituted or substituted with NR’2.
In a preferred embodiment, R is H, methyl, C1-6 alkyl substituted with NR’2, -C1-6 alkyl-(pyrrolidine), -C1-6 alkyl-(piperidine) and -C1-6 alkyl-(piperazine), wherein each R’ is independently selected from H and C6-18 aryl. In a most preferred embodiment of the latter, r is 1.
In a particular embodiment, Ra is selected from H and C1-6 alkyl.
In a preferred embodiment, Ra is H.
According to a particular embodiment, the 5- to 10-membered heterocyclyl and the 5- to 10-membered heteroaryl in group L are selected from a N-containing 5- to 10- membered heterocyclyl and a N-containing 5- to 10-membered heteroaryl, respectively; preferably from N-containing 5- to 7-membered heterocyclyl and a N-containing 5- to 7- membered heteroaryl.
Suitable N-containing 5- to 7-membered heterocyclyl and N-containing 5- to 10- membered heterocyclyl groups in group L include, for example, pyrrolidine, piperidine, morpholine, piperazine and azepane. In a preferred embodiment, it is pyrrolidine. Suitable N-containing 5- to 7-membered heteroaryl and N-containing 5- to 10- membered heteroaryl groups in group L include, for example, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrimidine, pyrazine, indole, isoindole, benzimidazole, quinoline, isoquinoline and purine.
In an embodiment, L is selected from H, -NR1R2R3, C(O)NR1R2, C(O)-(CH2)1-3- NR1R2, OR1, OC(O)R1, C(O)R1, C(O)OR1, 5- to 10-membered heterocyclyl and 5- to 10- membered heteroaryl, wherein each R1 and R2 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, and (C6-12)aryl(C1-6)alkyl and wherein the C3-7 cycloalkyl, C6-12 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R', R'2 , C(O)R'2 , C(O)-(CH2)1-3-NR1R2, C(O)R’, C(O)OR’, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, - (CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, - (CH2)1-6-NO2, C3-7 cycloalkyl, C6-12 aryl or (C6-12)aryl(C1-6)alkyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl and (C6-12)aryl(C1-6)alkyl and wherein R3 is absent or C1-6 alkyl.
In a further embodiment, L is selected from H, -NR1R2R3, C(O)NR1R2, C(O)-(CH2)1- 3-NR1R2, N-containing 5- to 10-membered heterocyclyl and N-containing 5- to 10- membered heteroaryl, wherein each R1 and R2 are independently selected from H and C1-6 alkyl and wherein the N-containing 5- to 10-membered heterocyclyl and the N- containing 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R’, R'2 , C(O)R'2 , C(O)-(CH2)1-3-NR1R2, C(O)R’, C(O)OR’, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1-6-R'2 , -(CH2)1-6- C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6- NO2, C3-7 cycloalkyl, C6-12 aryl or (C6-12)aryl(C1-6)alkyl, wherein each R’ is independently selected from H and C1-6 alkyl and wherein R3 is absent or C1-6 alkyl.
In a particular embodiment, L is selected from H, -NR1R2R3, C(O)NR1R2, C(O)- (CH2)1-3-NR1R2, piperidine, piperazine and morpholine, wherein R1 and R2 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1- 6)alkyl and wherein the piperidine, piperazine and morpholine can be unsubstituted or substituted with halogen, OR’, OC(O)R’, R'2 , C(O)R'2 , C(O)-(CH2)1-3-NR1R2, C(O)R’, C(O)OR’, CN, NO2, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6-NO2, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl or (C6-12)aryl(C1-6)alkyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1- 6)alkyl and wherein R3 is absent or C1-6 alkyl. In a further embodiment, L is selected from H, -NR1R2R3, C(O)NR1R2, piperidine, piperazine and morpholine, wherein R1 and R2 are independently selected from H and C1-6 alkyl, preferably H, and wherein the piperidine, piperazine and morpholine can be unsubstituted or substituted with -R'2 , C(O)R'2 , C(O)-(CH2)1-3-NR1R2, -(CH2)1-6-R'2 and -(CH2)1-6-C(O)R'2 , wherein each R’ is independently selected from H and C1-6 alkyl, preferably H, and wherein R3 is absent or C1-6 alkyl.
In a particular embodiment, L is selected from H, -NH2, -NMe2, -NMe3, -NEt2, -
NH(C1-6 alkyl-OH), -N(Me)(C1-6 alkyl-OH), guanidinium, -C(O)NH2, In a preferred
Figure imgf000021_0002
embodiment of the latter, r is 0.
In an embodiment, the compound of formula (I) is selected from
Figure imgf000021_0001
Figure imgf000022_0001
Figure imgf000023_0001
In preferred embodiment, the compound of formula (I) is selected from
Figure imgf000024_0001
(1 at) (1au) (1az) or a salt or solvate thereof.
In most preferred embodiment, the compound of formula (I) is selected from
Figure imgf000024_0002
Figure imgf000025_0001
or a salt or solvate thereof.
In another preferred embodiment, the compound of formula (I) is selected from
Figure imgf000025_0002
or a salt or solvate thereof.
In a further aspect, the invention also contemplates a compound of formula (I”): wherein
Figure imgf000025_0003
- r is selected from 0 or 1 ;
- s is selected from 0, 1 , 2 or 3;
- R is absent or is selected from H, C1-6 alkyl and -C1-6 alkyl-(5- to 10-membered heterocyclyl), and wherein the C1-6 alkyl and -C1-6 alkyl-(5- to 10-membered heterocyclyl) can be unsubstituted or substituted with R’, -OR’ or -NR’2;
- R’ is each independently selected from H, C1-6 alkyl, -C0-6 alkyl-(guanidinium), -C1-6 alkyl-(5- to 10-membered heterocyclyl), -C1-6 alkyl-(5- to 10-membered heterocyclyl substituted with -C0-6 alkyl-guanidinium), and C6-18 aryl; - M is selected from -CH2-, -N- and -CR11-, wherein R11 is selected from H, C1-6 alkyl and -(C3 alkyl)-NH2;
- L is selected from H, guanidinium, -NR1R2R3, -C(O)NH2, and 5- to 10-membered heterocyclyl, wherein each R1 and R2 are independently selected from H, C1-6 alkyl, - C1-6 alkyl-OR’, and wherein the C1-6 alkyl and 5- to 10-membered heterocyclyl can be unsubstituted or substituted with C(O)-(CH2)1-3-R'2 and C1-6 alkyl;
- R3 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
- Y3 is selected from phenyl, optionally substituted with X;
- X is selected from halogen or C6-18 aryl;
- represents a single or a double bond;
Figure imgf000026_0003
or a salt or solvate thereof, with the proviso that the compound of formula (I”) is not selected from the group consisting of
Figure imgf000026_0002
The person skilled in the art will readily understand that all of the above particular and preferred embodiments are also applicable to this aspect.
In a preferred embodiment, the compound of formula (I”) is a compound of formulas (Ii) to (lv) or (lvii),
Figure imgf000026_0001
Figure imgf000027_0001
wherein s, L, X, R and R11 are as defined above for the compound of formula (I”).
The compounds of formula (Ii), (I") and (lvii) are particularly preferred, with (Ii) and (I”) being mostly preferred.
In a particular embodiment, the compound of formula (I”) is a compound of formula (Ii;) and X is H, phenyl, or Cl; s is 2; L is selected from -NH2, -NR1R2, and 5- to 10- membered heterocyclyl wherein each R1 and R2 are independently selected from H, C1- 6 alkyl or -C1-6 alkyl-OH, and wherein the 5- to 10-membered heterocyclyl can be unsubstituted or substituted with C1-6 alkyl;. Preferably, when the compound of formula (I”) is a compound of formula (f); X is phenyl or Cl; s is 2; and L is -NH2.
In another particular embodiment, the compound of formula (I”) is a compound of formula (l·); and X is H, phenyl or Cl; s is 0 or 1; L is H; and R is selected from H, C1-6 alkyl-OH, C1-6 alkyl-NH2, and -C1-6 alkyl-(5- to 10-membered heterocyclyl) preferably selected from pyrrolidine, piperidine or piperazine. Preferably, when the compound of formula (I”) is a compound of formula (I”); X is H, phenyl or Cl; s is 0 or 1 ; L is H; and R is selected from H and -C1-6 alkyl-(5- to 10-membered heterocyclyl) preferably selected from pyrrolidine, piperidine or piperazine.
In another particular embodiment, the compound of formula (I”) is a compound of formula (lvii), and X is H or Cl; s is 1 ; L is H, R is H, and R11 is C1-6 alkyl.
In another preferred embodiment, in the compound of formula (I”), R is absent or selected from H, methyl, C1-6 alkyl substituted with NR’2, -C1-6 alkyl-(pyrrolidine), -C1-6 alkyl-(piperidine) and -C1-6 alkyl-(piperazine), wherein each R’ is independently selected from H, and C6-18 aryl. In another preferred embodiment, in the compound of formula (I”), L is selected from H, -NH2, -NMe2, -NMe3, -NEt2, -NH(C1-6 alkyl-OH), -N(Me)(C1-6 alkyl-OH),
Figure imgf000027_0002
In yet another preferred embodiment, the compound of formula (I”) is selected from,
Figure imgf000028_0001
Figure imgf000029_0001
Figure imgf000030_0001
or a salt or solvate thereof.
In yet another preferred embodiment, the compound of formula (I”) is selected from:
Figure imgf000030_0002
or a salt or solvate thereof.
In most preferred embodiment, the compound of formula (I”) is selected from
Figure imgf000031_0002
or a salt or solvate thereof.
Compounds of formula (II)
In an aspect, the present invention relates to a compound of formula (II) wherein
Figure imgf000031_0001
- q is selected from 1 , 2, 3 and 4;
- R4 is selected from H; =0; OR’; halogen; unsubstituted C1-6 alkyl; C1-6 haloalkyl; (C6- 18)aryl(C1-6)alkyl; C1-6 alkyl substituted with -OR’, OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; unsubstituted C6-18 aryl or C6-18 aryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl, (C6-18)aryl(C1-6)alkyl, C6-12)aryl(C2-6)alkenyl, (C6- 12)aryl(C2-6)alkynyl, -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or - NO2; and unsubstituted 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl, or 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, -OR’, - OC(O)R', -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR', -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1- 6)alkyl;
- R5 is selected from H; halogen; unsubstituted C1-6 alkyl, C1-6 haloalkyl; (C6-18)aryl(C1- 6)alkyl; C1-6 alkyl substituted with -OR’, -OC(O)R', -R'2 , -C(O)R'2 , -C(O)R’, - C(O)OR’, -CN, or -NO2; unsubstituted C6-18 aryl or C6-18 aryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl, (C6-18)aryl(C1-6)alkyl, C6-12)aryl(C2-6)alkenyl, (C6- 12)aryl(C2-6)alkynyl, -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or - NO2; and unsubstituted 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, -OR’, - OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1- 6)alkyl;
- Z is selected from -NR6R7R8 and halogen;
- R6 and R7 are independently selected from H, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , - C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl; or
- R6 and R7, together with the nitrogen atom to which they are attached can form a 5- to 7-membered heterocyclyl group;
- R6, R7 and R8 together with the nitrogen atom to which they are attached can form a guanidinium group; or
- R8 is absent, H, C1-6 alkyl or C1-6 haloalkyl;
- represents a single or a double bond;
- G is selected from (C6-12)aryl and 5- to 10-membered heteroaryl, wherein the (C6- 12)aryl and 5- to 10-membered heteroaryl are optionally substituted with R9;
- R9 and R10 are independently selected from H, halogen, C1-6 alkyl, C1-6 haloalkyl, (C6- 12)aryl, (C6-12)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl, (C6-12)aryl(C2-6)alkynyl, -OR’, - OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, -NO2, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl, wherein the rings in the (C6-12)aryl, (C6-12)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl, (C6-12)aryl(C2-6)alkynyl, 5- to 10- membered heteroaryl or 5- to 10-membered heterocyclyl are optionally substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, -OR’, -OC(O)R’, -R'2 , - C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1-6)alkyl; or a salt or solvate thereof, with the proviso that the compound of formula (II) is not selected from the group consisting of clomiphene, tamoxifen, toremifene, droloxifene, afimoxifene, edoxifene and salts thereof, such as clomiphene citrate, for use in the treatment or prevention of an infection by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
In formula (II), represents a single bond when R4 is a keto group (=0).
Figure imgf000033_0002
Therefore, in formula (II) represents double bond except when R4 is =0.
Figure imgf000033_0001
In the compounds of formula (II), R8 is absent, H, C1-6 alkyl or C1-6 haloalkyl, wherein C1-6 haloalkyl is preferably selected from a C1-6 alkyl comprising from one to three Cl or F atoms. In an embodiment, R8 is absent, H, C1-6 alkyl or C1-2 alkyl substituted with from one to three Cl or F atoms, preferably -CH2F or -CHF2. In an embodiment, R8 is absent or methyl. In a further embodiment, R8 is absent.
When R8 is H, C1-6 alkyl or C1-6 haloalkyl, such as methyl, then the N atom to which it is attached has a positive charge.
In an embodiment, q is selected from 1 , 2 and 3. Preferably, q is 2.
According to a preferred embodiment, one of R4 and R5 is selected from unsubstituted C6-12 aryl or C6-12 aryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-i2)aryl(C1-6)alkyl, -OR’, -OC(O)R', -R'2 , -C(O)R'2 , -C(O)R', -C(O)OR', -CN, or-NO2; and unsubstituted 5- to 10-membered heteroaryl or 5- to 10-membered heteroaryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl(Ci^)alkyl, -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R', -C(O)OR', -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl. Preferably, one of R4 and R5 is unsubstituted C6-12 aryl or C6-12 aryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl(C1-6)alkyl, -OR’, -OC(O)R', -R'2 , -C(O)R'2 , -C(O)R’, - C(O)OR’, -CN, or -NO2, wherein each R’ is independently selected from H, C1-6 alkyl, C1- 6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl.
In a particular embodiment, R’ is selected from H and C1-6 alkyl. Preferably, R’ is H.
In an embodiment, in the compound of formula (II)
R4 is selected from H, =0, OR’, halogen, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl, (C6-12)aryl(C1-6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R’, - R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6- 12)aryl(C1-6)alkyl; and
R5 is selected from unsubstituted C6-12 aryl or C6-12 aryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl(C1-6)alkyl, -OR’, -OC(O)R’, -R'2 , - C(O)R'2 , -C(O)R’, -C(O)OR', -CN, or -NO2; and unsubstituted 5- to 10- membered heteroaryl or 5- to 10-membered heteroaryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl(C1-6)alkyl, -OR’, -OC(O)R’, -R'2 , - C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl.
In a further embodiment, in the compound of formula (II)
R4 is selected from H, =0, OR’, halogen, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl, (C6-12)aryl(C1-6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R’, - R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR', -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6- 12)aryl(C1-6)alkyl; and
R5 is selected from unsubstituted C6-12 aryl or C6-12 aryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl(C1-6)alkyl, -OR’, -OC(O)R’, -R'2 , - C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl.
In another embodiment:
R4 is selected from H, =0, halogen, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6- 12)aryl, (C6-12)aryl(C1-6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R’, -R'2 , - C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl;
R5 is selected from unsubstituted C6-12 aryl or C6-12 aryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl(C1-6)alkyl, -OR’, -OC(O)R’, -R'2 , - C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; and unsubstituted 5- to 10- membered heteroaryl or 5- to 10-membered heteroaryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl(C1-6)alkyl, -OR’, -OC(O)R’, -R'2 , - C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl.
In a further embodiment:
R4 is selected from H, halogen, =0, unsubstituted C1-6 alkyl and C1-6 alkyl substituted with -OR’, wherein R’ is selected from H, C1-6 alkyl and (C6-12)aryl(C1- 6)alkyl;
R5 is selected from unsubstituted C6-12 aryl or C6-12 aryl substituted with halogen, or with -OR’, wherein R’ is selected from H, C1-6 alkyl and (C6-12)aryl(C1- 6)alkyl. In a particular embodiment, R4 is selected from H, Cl, =0, Ph, unsubstituted C1-6 alkyl and C1-6 alkyl substituted with -OH. In a further embodiment, R4 is selected from H, Cl, =0, Ph, Et, and -CH2CH2OH.
In an embodiment, R5 is selected from Cl, unsubstituted C6-12 aryl, unsubstituted 5- to 10-membered heteroaryl and C6-12 aryl substituted with halogen, or with -OH. In a further embodiment, R5 is selected from Cl, Ph, 4-OH-Ph, 4-CI-Ph, pyridine and thiophene.
In a particular embodiment, when R6 and R7, together with the nitrogen atom to which they are attached, form a 5- to 7-membered heterocyclyl group, the 5- to 7- membered heterocyclyl group can be selected from pyrrolidine, piperidine, morpholine, piperazine and azepane. In a preferred embodiment of the former, R8 is absent.
In a particular embodiment, G is selected from (C6-12)aryl and 5- to 10-membered heteroaryl, wherein the (C6-12)aryl and 5- to 10-membered heteroaryl are substituted with one, two or three R9. Preferably, G is selected from (C6-12)aryl and 5- to 10-membered heteroaryl, wherein the (C6-12)aryl and 5- to 10-membered heteroaryl are substituted with one R9, preferably in para position.
In a particular embodiment, G is selected from (C6-12)aryl, wherein the (C6-12)aryl is optionally substituted with one, two or three R9. Preferably, G is substituted with one R9, preferably in para position.
In a particular embodiment, when R9 is not H, then it is 1 , 2 or 3 substituents, preferably 1. In a preferred embodiment, when R9 is not H, then it is in para-, meta- or ortho- positions.
In a particular embodiment: q is selected from 1, 2, 3 and 4;
R4 is selected from H, =0, halogen, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6- 12)aryl, (C6-12)aryl(C1-6)alkyl and C1-6 alkyl substituted with -OR’, -OC(O)R’, -R'2 ,
-C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl;
R5 is selected from unsubstituted C6-12 aryl or C6-12 aryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl(C1-6)alkyl, -OR’, -OC(O)R’, -R'2 , - C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; and unsubstituted 5- to IQ- membered heteroaryl or 5- to 10-membered heteroaryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl(C1-6)alkyl, -OR’, -OC(O)R’, -R'2 , - C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl;
- Z is -NR6R7R8;
R6 and R7 are independently selected from H, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl(C1-6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl, (C6-12)aryl(C1-6)alkyl and (C6- 12)aryl(C2-6)alkynyl; or
R6 and R7, together with the nitrogen atom to which they are attached, form a 5- to 10-membered heterocyclyl group;
- R6, R7 and R8 together with the nitrogen atom to which they are attached, form a guanidinium group; or
R8 is absent or C1-6 alkyl;
... represents a single or a double bond;
- R9 is H, halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl, (C6-12)aryl(C1-6)alkyl, (C6- 12)aryl(C2-6)alkynyl, -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2.
In a further embodiment: q is selected from 1 , 2, 3 and 4;
R4 is selected from H, halogen, =0, unsubstituted C1-6 alkyl and C1-6 alkyl substituted with -OR’, wherein R’ is selected from H, C1-6 alkyl and (C6-12)aryl(C1- 6)alkyl;
R5 is selected from unsubstituted C6-12 aryl or C6-12 aryl substituted with halogen, or with -OR’, wherein R’ is selected from H, C1-6 alkyl and (C6-12)aryl(C1- 6)alkyl;
R6 and R7 are independently selected from H, unsubstituted C1-6 alkyl or C1-6 alkyl substituted with -OR’, wherein R’ is selected from H, C1-6 alkyl and (C6- 12)aryl(C1-6)alkyl; and
... represents a single or a double bond.
In an embodiment, the compound of formula (II) is selected from:
Figure imgf000037_0001
or a salt or solvate thereof. Unless stated otherwise, the present invention contemplates both (Z) and (E) isomers of the compounds of formula (II), including those of formula (2a) to (2w), as well as mixtures comprising both isomers.
In a preferred embodiment, the compound of formula (II) is selected from:
Figure imgf000039_0001
or a salt or solvate thereof.
In a more preferred embodiment, the compound of formula (II) is selected from:
Figure imgf000039_0002
(2a’) (2b’) (2c’) or a salt or solvate thereof.
In a most preferred embodiment, the compound of formula (II) is:
Figure imgf000040_0001
or a salt or solvate thereof.
In a further aspect, the present invention is directed to a compound of formula (2f)
Figure imgf000040_0002
or a salt or solvate thereof. This compound of formula (2f) can also be identified as N-methylclomiphene. In a preferred embodiment, the compound of formula (2f) is the isomer of formula (2f).
In another aspect, the invention refers to a pharmaceutical composition comprising a compound of formula (2f), or a salt or solvate thereof, and a pharmaceutically acceptable excipient. In another aspect, the invention refers to a compound of formula (2f), or a salt, or solvate thereof, for use in medicine. Compounds of formula (III)
In a further aspect, the present invention relates to a compound of formula (III)
Figure imgf000041_0001
wherein
- A is selected from -CH-, -N- and -C(OH)- when s a double bond, or is selected
Figure imgf000041_0002
from -NH-, -C(O)-, -CH2- and -CH(OH)- when A is a single bond;
Figure imgf000041_0003
- B is selected from -CH- and -N- when
Figure imgf000041_0004
is a double bond, and is selected from - CH2-, -N- and -NH- when A
Figure imgf000041_0007
is a single bond; - Y is selected from -NH- and -CH2- when s a single bond, or is selected from -N-
Figure imgf000041_0005
and -CH- when double bond;
Figure imgf000041_0006
provided that when B is -NH-, then Y is -N- or -CH-, when B is -N-, then Y is -N-, -NH- or -CH-, and when B is -CH-, then Y = -N- or -CH-;
- C is selected from -NR1-, C1-6 alkyl, C3-7 cycloalkyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein R1 is selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1-6)alkyl;
- D is selected from guanidinium, -NR2R3R4, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein R2 and R3 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl and wherein the C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R', R'2 , C(O)R'2 , C(O)R’, C(O)OR’, CN, NO2, -(CH2)1-6-OR’, -(CH2)1-6- OC(O)R’, -(CH2)1-6- R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, - (CH2)1-6-CN, -(CH2)1-6- NO2, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl;
- E is selected from C6-12 aryl and 5- to 10-membered heteroaryl; - R4 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
- R5 is selected from halogen, OR’, OC(O)R', R'2 , C(O)R'2 , C(O)R’, C(O)OR’, CN, NO2, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6- C(O)R', -(CH2)1-6-C(O)OR', -(CH2)1-6-CN, -(CH2)1-6-NO2, C1-6 alkyl, C3-7 cycloalkyl, C1- 6 haloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl or (C6-12)aryl(C2-6)alkynyl, -NR6R7R8, 5- to 10-membered heterocyclyl and 5- to 10- membered heteroaryl, wherein R6 and R7 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl and wherein the C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R', R'2 , C(O)R'2 , C(O)R’, C(O)OR’, CN, NO2, -(CH2)1-6-OR’, -(CH2)1-6- OC(O)R’, -(CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, - (CH2)1-6-CN, -(CH2)1-6- NO2, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl;
- R8 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
- m is selected from 0 and 1 ;
- n is selected from 0, 1, 2, 3, 4, 5 and 6, wherein when n is 3-6 the resulting alkyl chain can contain at least one double bond;
- x is 0 or 1;
- z is 0, 1, 2, 3 or 4;
- each R is independently selected from H, C1-6 alkyl, -(CH2)1-6-0-C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl; represents a single or a double bond;
Figure imgf000042_0001
or a salt, solvate, tautomer or stereoisomer thereof, for use in the treatment or prevention of an infection by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
In the present invention, any resonance and tautomer forms of the compounds of formula (III), as for the compounds of the invention of formula (I) and (II), are to be contemplated as part of the invention. In this context, and as an example, in the compounds of formula (III), if B is -N- and is single bond, then the bond between B
Figure imgf000042_0002
and the adjacent carbon (to which C is bound to) is a double bond.
According to a particular embodiment, in the compound of formula (III), B is selected from -CH- and -N- when is a double bond, and is selected from -CH2-,
Figure imgf000042_0003
and -NH- when is a single bond.
Figure imgf000043_0014
According to a particular embodiment, in the compound of formula (III), when B is -NH-, then Y is -N- or -CH-, and when Y is -N-, then B is -CH-, -CH2- or -NH-.
According to a further embodiment, in the compound of formula (III), when B is - NH-, then Y is -N-, and when Y is -N-, then B is -CH-, -CH2- or -NH-.
According to a particular embodiment, in the compound of formula (III):
- A is -CH- or -N- when A
Figure imgf000043_0013
is a double bond, or is selected from -C(O)-, -N-, -CH2- and -CH(OH)- when A
Figure imgf000043_0012
is a single bond; and/or
- B is selected from -CH- and -N- when is a double bond, and is selected from -CH2-, -N- and -NH-, when A is a single bond; and/or
Figure imgf000043_0011
- Y is -NH-, -CH- or -N- when is a single bond, and Y is -N- or -CH- when
Figure imgf000043_0010
Figure imgf000043_0015
is a double bond.
According to a particular embodiment, in the compound of formula (III):
- A is -CH- when
Figure imgf000043_0009
is a double bond, or is selected from -C(O)-, -CH2- and -CH(OH)- when
Figure imgf000043_0008
is a single bond; and/or
- B is selected from -CH- and -N- when A is a double bond, and is selected
Figure imgf000043_0007
from -CH2- and -NH-, when A
Figure imgf000043_0006
is a single bond; and/or
- Y is -NH- or -N- depending on whether is a single or a double bond,
Figure imgf000043_0005
respectively. According to a particular embodiment, in the compound of formula (III): when A is -C(O)-, B is -NH- and is a single bond, or
Figure imgf000043_0001
when A is -C(O)-, B is -N- and is a single bond, or when A is -C(OH)-, B is -NH- and is a double bond, or when A is -C(OH)-, B is -N- and
Figure imgf000043_0002
is a double bond, or when A is -CH-, B is -CH- and
Figure imgf000043_0003
is a double bond, or when A is -N-, B is -CH- and is a double bond, or when A is -CH-, B is -N- and is a double bond.
Figure imgf000043_0004
According to a particular embodiment, in the compound of formula (III), R5 is selected from halogen, O-C1-C6 alkyl and C1-C6 alkyl. According to a particular embodiment, E is selected from C6-10 aryl and 5- to 6- membered heteroaryl, preferably from C6 aryl and 5- to 6-membered heteroaryl. In a preferred embodiment, E is a benzene ring.
In a particular embodiment, the compound of formula (III) is a compound of formula (IN’) or (III”),
Figure imgf000044_0001
wherein C, D, E, R, R5, m, n, x and z are as defined above.
Preferably, the compound of formula (III) is a compound of formula (IN’”) or (III””),
Figure imgf000044_0002
wherein C, D, R, R5, m, n, x and z are as defined above.
The following particular and preferred embodiments apply to the compounds of formula (III), (III’), (III”), (III’”), and (III””).
In an embodiment, C is selected from -NR1-, -CH2-, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl.
In a further embodiment, R1 is selected from H and C1-6 alkyl. More preferably, R1 is H.
According to a particular embodiment, the 5- to 10-membered heterocyclyl and the 5- to 10-membered heteroaryl in group C are selected from a N-containing 5- to 10- membered heterocyclyl and a N-containing 5- to 10-membered heteroaryl, respectively; preferably from N-containing 5- to 7-membered heterocyclyl and a N-containing 5- to 7- membered heteroaryl.
Suitable N-containing 5- to 7-membered heterocyclyl and N-containing 5- to IQ- membered heterocyclyl groups in radical C include, for example, pyrrolidine, piperidine, morpholine, piperazine and azepane. In a preferred embodiment, it is pyrrolidine or piperidine.
Suitable N-containing 5- to 7-membered heteroaryl and N-containing 5- to 10- membered heteroaryl groups in radical C include, for example, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrimidine, pyrazine, indole, isoindole, benzimidazole, quinoline, isoquinoline and purine.
In an embodiment, C is selected from -NR1-, -CH2-, C3-7 cycloalkyl, 5- to 10- membered heterocyclyl and 5- to 10-membered heteroaryl, wherein R1 is selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1-6)alkyl.
In an embodiment, C is selected from -NR1-, -CH2- and N-containing 5- to 7- membered heterocyclyl. Preferably, wherein R1 is H or C1-6 alkyl, more preferably H.
In a particular embodiment, C is selected from -NH-, -CH2-, pyrrolidine and piperidine.
In a further embodiment, C is selected from -NH-, -CH2- and
Figure imgf000045_0002
Figure imgf000045_0001
In a particular embodiment, R is selected from H and C1-6 alkyl; preferably H and Me.
In a particular embodiment, the group is a group of the following formula: wherein
Figure imgf000045_0003
- o is selected from 0 and 1 ;
- p is selected from 0, 1 , 2, 3, 4 and 5; - R is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1-6)alkyl; preferably R is selected from H and C1-6 alkyl.
In a particular embodiment, R2 and R3 are independently selected from H, C1-6 alkyl and (C6-12)aryl(C1-6)alkyl; preferably from C1-6 alkyl.
According to a particular embodiment, D is selected from -NR2R3, N-containing 5- to 10-membered heterocyclyl and N-containing 5- to 10-membered heteroaryl.
Suitable N-containing 5- to 10-membered heterocyclyl groups in radical D include, for example, pyrrolidine, piperidine, morpholine, piperazine and azepane. In a preferred embodiment, it is piperidine morpholine, piperazine .
Suitable N-containing 5- to 10-membered heteroaryl groups in radical D include, for example, pyrrole, imidazole, pyrazole, oxazole, isoxazole, thiazole, isothiazole, pyridine, pyrimidine, pyrazine, indole, isoindole, benzimidazole, quinoline, isoquinoline and purine. In a preferred embodiment, it is benzimidazole.
In an embodiment, the 5- to 10-membered heterocyclyl, N-containing 5- to 10- membered heterocyclyl, 5- to 10-membered heteroaryl and N-containing 5- to IQ- membered heteroaryl can be unsubstituted or substituted with -(CH2)1-6-OR’, -(CH2)1-6- OC(O)R', -(CH2)1-6- R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, - (CH2)1-6-CN, -(CH2)1-6- NO2, C1-6 alkyl, C1-6 haloalkyl or (C6-12)aryl(C1-6)alkyl, wherein each R’ is independently selected from H and C1-6 alkyl. More preferably, it can be unsubstituted or substituted with -(CH2)1-6-OR’, C1-6 alkyl and (C6-12)aryl(C1-6)alkyl, wherein each R’ is independently selected from H and C1-6 alkyl, preferably from C1-6 alkyl.
In a particular embodiment, D is selected from -NR2R3, piperidine, piperazine, morpholine and benzimidazole, wherein R2 and R3 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl and wherein the piperidine, piperazine, morpholine and benzoimidazole can be unsubstituted or substituted with halogen, OR’, OC(O)R’, R'2 , C(O)R'2 , C(O)R’, C(O)OR’, CN, NO2, -(CH2)1-6-OR’, - (CH2)1-6-OC(O)R’, -(CH2)1-6- R'2 , -(CH2)1-6-COR'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6-NO2, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl or (Ce- 12)aryl(C1-6)alkyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl.
In a further embodiment, D is selected from -NR2R3, piperidine, piperazine, morpholine and benzoimidazole, wherein R2 and R3 are C1-6 alkyl and wherein the piperidine, piperazine, morpholine and benzoimidazole can be unsubstituted or substituted with -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , - (CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6- NO2, C1-6 alkyl, C1-6 haloalkyl or (C6-12)aryl(C1-6)alkyl, wherein each R’ is independently selected from H and C1-6 alkyl. Preferably, wherein the piperidine, piperazine, morpholine and benzoimidazole can be unsubstituted or substituted with -(CH2)1-6-OR’, C1-6 alkyl and (C6-12)aryl(C1-6)alkyl, wherein each R’ is independently selected from H and C1-6 alkyl, preferably from C1-6 alkyl.
Figure imgf000046_0001
In an embodiment, in the compounds of formula (III), (IN’) or (III”):
- C is selected from -NR1-, -CH2- and N-containing 5- to 7-membered heterocyclyl. Preferably, wherein R1 is H or C1-6 alkyl, more preferably H;
Figure imgf000047_0001
- R is selected from H and C1-6 alkyl; and
- D is selected from -NR2R3, N-containing 5- to 10-membered heterocyclyl and N-containing 5- to 10-membered heteroaryl, wherein R2 and R3 are independently selected from H, C1-6 alkyl and (C6-12)aryl(C1-6)alkyl and wherein the 5- to 10-membered heterocyclyl and N-containing 5- to 10-membered heteroaryl can be unsubstituted or substituted with -(CH2)1-6-OR’, -(CH2)1-6- OC(O)R’, -(CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6- C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6- NO2, C1-6 alkyl, C1-6 haloalkyl or (C6-12)aryl(C1- 6)alkyl, wherein each R’ is independently selected from H and C1-6 alkyl, preferably from C1-6 alkyl.
In a further embodiment, in the compounds of formula (III), (III·) or (III”):
- C is selected from - NH-, -CH2- and pyrrolidine;
Figure imgf000047_0002
- R is selected from H and C1-6 alkyl; and
- D is selected from -NR2R3, piperidine, piperazine, morpholine and benzoimidazole, wherein R2 and R3 are C1-6 alkyl and wherein the piperidine, piperazine, morpholine and benzoimidazole can be unsubstituted or substituted with -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , - (CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6-NO2, C1-6 alkyl, C1-6 haloalkyl or (C6-12)aryl(C1-6)alkyl, wherein each R’ is independently selected from H and C1-6 alkyl. Preferably, wherein the piperidine, piperazine, morpholine and benzoimidazole can be unsubstituted or substituted with -(CH2)1-6-OR’, C1- 6 alkyl and (C6-12)aryl(C1-6)alkyl, wherein each R’ is independently selected from H and C1-6 alkyl, preferably from C1-6 alkyl.
In an embodiment, the compound of formula (III) is selected from:
Figure imgf000048_0001
Figure imgf000049_0001
or a salt, solvate or stereoisomer thereof.
In a preferred embodiment the compound of formula (III) is selected from:
Figure imgf000049_0002
Figure imgf000050_0001
or a salt, solvate or stereoisomer thereof.
Uses of the compounds of formula (I) (II) and (III)
The invention also relates to the use of a compound of formula (I), (II), or (III) in the manufacture of a medicament for the treatment or prevention of viral infections by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus" (such as SARS-CoV-2 and SARS-CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV).
The invention also relates to a method of treating or preventing viral infections by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially caused by the respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” (such as SARS-CoV-2 and SARS-CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV) in a subject, comprising administering to said subject a therapeutically effective amount of a compound of formula (I), (II) or (III).
The term “viruses of the family Coronaviridae”, as used herein, is used to designate any viral species of the taxonomic family “Coronaviridae” including those of the genera “ Alphacoronavirus ", “Betacoronavirus” , “Gammacoronavirus" and “Deltacoronavirus”.
In a preferred embodiment of the present invention, the viruses are selected from betacoronaviruses, in particular from the lineage “Sarbecovirus” and still more preferably from the species “Severe respiratory syndrome-related coronavirus” (such as SARS- CoV and SARS-CoV-2) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV).
In a particular embodiment, the viral infection is an infection by influenza, HIV-1 HIV-2 or SARS-CoV-2 virus. In a preferred embodiment, the viral infection is an infection by SARS-CoV-2 virus.
The terms "treating" and “treatment”, as used herein, means reversing, alleviating, inhibiting the progress of, the disease or condition to which such term applies, or one or more symptoms of such disease or condition, such as lowering the viral load in a patient with respect to pretreatment levels.
The terms “preventing” and “prevention”, as used herein, means avoiding or inhibiting the onset of one or more symptoms of coronavirus infections such as fever, cough, shortness of breath, muscle pain, sputum production, diarrhea, sore throat, loss of smell, pneumonia and abdominal pain.
In a preferred embodiment, the present invention is for the treatment of an infection by RNA-viruses.
Preferably, the compounds disclosed herein, are used for the treatment and/or prevention of viral infections by “Severe respiratory syndrome-related coronavirus” and most preferably for the treatment and/or prevention of viral infections by SARS-CoV-2.
In another particular embodiment, the viral infection is an infection by “Severe respiratory syndrome-related coronavirus” and most preferably by SARS-CoV-2.
The compounds for use according to the invention may be administered by any appropriate route (via), such as, oral (e.g., oral, sublingual, etc.), parenteral (e.g., subcutaneous, intramuscular, intravenous, etc.), vaginal, rectal, nasal, topical, ophtalmic, inhaled, intranasal, intratracheal, pulmonary, etc.; preferably oral, inhaled or parenteral, even more preferably by inhalation.
In particular, the compounds for use according to the invention are administered as a pharmaceutical composition, which comprises the corresponding (active) compound and one or more pharmaceutically acceptable excipients.
The term “pharmaceutically acceptable excipient” refers to a vehicle, diluent, or adjuvant that is administered with the active ingredient. Such pharmaceutical excipients can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, and similars. Water or saline aqueous solutions and aqueous dextrose and glycerol solutions, particularly for injectable solutions, are preferably used as vehicles. Suitable pharmaceutical vehicles are known by the skilled person. The pharmaceutically acceptable excipient necessary to manufacture the desired pharmaceutical composition of the invention will depend, among other factors, on the elected administration route. Said pharmaceutical compositions may be manufactured according to conventional methods known by the skilled person in the art.
The compounds for use according to the invention may be administered in a “therapeutically effective amount”, i.e. a nontoxic but sufficient amount of the corresponding compound to provide the desired effect. The amount that is “effective” will vary from subject to subject, depending on the age and general condition of the individual, the particular compound administered, and the like. However, an appropriate amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
The compounds for use according to the invention will typically be administered once or more times a day, for example 1 , 2, 3 or 4 times daily, with typical total daily doses depending on the particular compound and severity of the disease, and may be easily determined by the skilled practitioner.
By way of example, typical total daily doses the compounds of the invention are in the range of from 0.1 to 2000 mg/day, preferably from 1 to 600 mg/ day, even more preferably from 1 to 100 mg/day.
The pharmaceutical compositions may be prepared using standard methods such as those described or referred to in the Spanish, European and US Pharmacopoeias and similar reference texts.
The term “subject” refers to a mammal, e.g., a human.
Combination of the compounds of formula (I), (II) and (III) with further active ingredients
The compounds for use according to the invention may be administered as the sole active ingredient or in combination with other active ingredients. In a particular embodiment, the compounds are used as the sole active ingredient. In another particular embodiment, the compounds are used in combination with other active ingredients.
Therefore, in a further aspect, the invention also contemplates a composition comprising: a) a compound of formula (I), (II), or (III), or a salt or solvate thereof as defined above; and b) a compound selected from the group consisting of nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, ribavirin, favipiravir, chloroquine, hydroxychloroquine, lopinavir, ritonavir, umifenovir and recombinant type I interferon, preferably nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, lopinavir and ritonavir.
All of the particular and preferred embodiments disclosed above for the compounds of formula (I), (II) and (III) are applicable to this aspect. Preferably, this combination is synergistic, thus producing an antiviral activity that is greater than the sum of the antiviral activities of each individual compound. In a particular embodiment of the above combination, the compound of formula (I) also includes clotrimazole, TRAM-34 and salts thereof. In another particular embodiment of this combination, the compound of formula (I) is not selected from the group consisting of clotrimazole, TRAM-34 and salts thereof.
In a particular embodiment, the invention also contemplates a composition comprising: a) a compound of formula (II)
Figure imgf000053_0001
wherein q, R4, R5, G, R10, Z, and are as defined above, or a salt or solvate
Figure imgf000053_0002
thereof; and b) a compound selected from the group consisting of nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, ribavirin, favipiravir, chloroquine, hydroxychloroquine, lopinavir, ritonavir, umifenovir and recombinant type I interferon, preferably nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, lopinavir and ritonavir.
Clomiphene is a mixture of two isomers: When used in combination with other active ingredients, the compound of formula (II) also includes clomiphene, tamoxifen, toremifene, droloxifene, afimoxifene, edoxifene and salts thereof, such as clomiphene citrate. In a less preferred embodiment, when used in combination with other active ingredients, the compound of formula (II) excludes clomiphene, tamoxifen, toremifene, droloxifene, afimoxifene, edoxifene and salts thereof. An example of a salt thereof is the citrate salt, for example clomiphene citrate.
In a particular embodiment, the compounds of the invention are used in combination with one or more compounds useful in the treatment of viral infections by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, especially by the respiratory syndrome- related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus" (such as SARS-CoV-2 and SARS-CoV) and “Middle East respiratory syndrome-related coronavirus” (MERS-CoV). Some compounds that have been disclosed as potentially useful are selected from the group consisting of nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, ribavirin, favipiravir, chloroquine, hydroxychloroquine, lopinavir, ritonavir, umifenovir and recombinant type I interferon, preferably nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, lopinavir and ritonavir. Preferably, the combination is synergistic.
Therefore, in a particular embodiment, the invention refers to a compound of the invention of formula (I), (II) or (III) as disclosed above, in combination with one or more compounds useful in the treatment of RNA-viral infections, preferably by virus of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, such as nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, ribavirin, favipiravir, chloroquine, hydroxychloroquine, lopinavir, ritonavir, umifenovir and recombinant type I interferon, for use in the treatment or prevention of an infection by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
More preferably, the invention refers to a compound of the invention of formula (I), (II) or (III) as disclosed above, in combination with one or more compounds selected from nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, lopinavir and ritonavir, for use in the treatment or prevention of an infection by RNA-viruses, preferably of the family Coronaviridae.
In a particular embodiment, said combination is synergistic.
In a particular embodiment, the invention refers to a compound of formula (II), which also includes clomiphene, toremifene, tamoxifen, droloxifene, afimoxifene, edoxifene and salts thereof, such as clomiphene citrate, in combination with one or more compounds useful in the treatment of RNA-viral infections, preferably by virus of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae, such as nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, ribavirin, favipiravir, chloroquine, hydroxychloroquine, lopinavir, ritonavir, umifenovir and recombinant type I interferon, for use in the treatment or prevention of an infection by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae. In an embodiment, the invention refers to clomiphene citrate in combination with one or more compounds useful in the treatment of RNA-viral infections, preferably by virus of the family Coronaviridae. Preferably, said combination is synergistic. This combination is preferably administered so that the ingredients are delivered to the lungs. Therefore, in a particular embodiment said combination is to be administered orally, parenterally or by inhalation, preferably inhalation.
In a particular embodiment, said clomiphene citrate in the combination is the cis- clomiphene. In another particular embodiment, said clomiphene citrate in the combination is the trans-clomiphene.
The term “combination” refers to a product comprising one or more of the defined compounds, either in a single composition or in several compositions (or units), in which case the corresponding compounds are distributed among the several compositions. Preferably, the combination refers to several compositions, in particular comprising one composition (or unit) per compound (compound as defined above) of the combination. The expression “one or more” when characterizing the combination refers to at least one, preferably 1 , 2, 3, 4, or 5 compounds, more preferably, 1 , 2 or 3 compounds, even more preferably 1 or 2 compounds.
When the combination is in the form of a single composition, the compounds present in the combination are always administered simultaneously.
When the combination is in the form of several compositions (or units), each of them having at least one of the compounds of the combination, the compositions or (units) may be administered simultaneously, sequentially or separately.
Simultaneous administration means that the compounds or compositions (or units) are administered at the same time.
Sequential administration means that the compounds or compositions (or units) are administered at different time points in a chronologically staggered manner.
Separate administration means that the compounds or compositions (or units) are administered at different time points independently of each other.
In particular, the combinations for use according to the invention are administered as pharmaceutical compositions, which comprise the corresponding (active) compounds and a pharmaceutically acceptable excipient, as previously defined.
The combinations for use according to the invention will typically be administered once or more times a day, for example 1 , 2, 3 or 4 times daily, with typical total daily doses depending on the particular compound and severity of the disease, and may be easily determined by the skilled practitioner. The following examples represent specific embodiments of the present invention.
They do not intend to limit in any way the scope of the invention defined in the present description.
Particular embodiments The following are particular embodiments of the invention:
Embodiment 1. A compound of formula (I)
Figure imgf000056_0001
wherein - q is selected from 1, 2, 3 and 4;
- R4 is selected from H, =0, OR’, halogen, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6- 18)aryl(C1-6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; unsubstituted C6-18 aryl or C6-18 aryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl, (C6- 12)aryl(C2-6)alkynyl, -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or - NO2; and unsubstituted 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, -OR’, - OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1- 6)alkyl;
- R5 is selected from H, halogen, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1- 6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, - C(O)OR’, -CN, or -NO2; unsubstituted C6-18 aryl or C6-18 aryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl, (C6-18)aryl(C1-6)alkyl, C6-12)aryl(C2-6)alkenyl, (C6- 12)aryl(C2-6)alkynyl, -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or - NO2; and unsubstituted 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, -OR’, - OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1- 6)alkyl;
- Z is selected from -NR6R7R8 and halogen;
- R6 and R7 are independently selected from H, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , - C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl; or
- R6 and R7, together with the nitrogen atom to which they are attached can form a 5- to 7-membered heterocyclyl group; or
- R6, R7 and R8 together with the nitrogen atom to which they are attached can form a guanidinium group; or
- R8 is absent, H, C1-6 alkyl or C1-6 haloalkyl; represents a single or a double bond;
Figure imgf000057_0001
- G is selected from (C6-12)aryl and 5- to 10-membered heteroaryl, wherein the (C6- 12)aryl and 5- to 10-membered heteroaryl are optionally substituted with R9; - R9 and R10 are independently selected from H, halogen, C1-6 alkyl, C1-6 haloalkyl, (C6- 12)aryl, (C6-12)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl, (C6-12)aryl(C2-6)alkynyl, -OR’, - OC(O)R', -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, -NO2, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl, wherein the rings in the (C6-12)aryl, (C6-12)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl, (C6-12)aryl(C2-6)alkynyl, 5- to 10- membered heteroaryl or 5- to 10-membered heterocyclyl are optionally substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, -OR’, -OC(O)R’, -R'2 , - C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1-6)alkyl; or a salt or solvate thereof, with the proviso that the compound of formula (I) is not selected from clomiphene citrate and tamoxifen, for use in the treatment or prevention of an infection by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and
Togaviridae.
Embodiment 2. Compound for use according to embodiment 1 , wherein
- q is selected from 1 , 2, 3 and 4;
- R4 is selected from H, =0, halogen, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6- 12)aryl(C1-6)alkyl and C1-6 alkyl substituted with -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , - C(O)R’, -C(O)OR’, -CN, or -NO2, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl;
- R5 is selected from unsubstituted C6-12 aryl or C6-12 aryl substituted with halogen, C1-6 alkyl, Ci_6 haloalkyl, (C6-12)aryl(C1-6)alkyl, -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; and unsubstituted 5- to 10-membered heteroaryl or 5- to 10- membered heteroaryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl(C1- 6)alkyl, -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6- 12)aryl(C1-6)alkyl;
- R6 and R7 are independently selected from H, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl(C1-6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , - C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl; or
- R6 and R7, together with the nitrogen atom to which they are attached can form a 5- to 10-membered heterocyclyl group; - R8 is absent or C1-6 alkyl; represents a single or a double bond.
Figure imgf000059_0002
Embodiment 3. Compound for use according to any one of embodiments 1 or 2, wherein - q is selected from 1, 2, 3 and 4;
- R4 is selected from H, halogen, =0, unsubstituted C1-6 alkyl and C1-6 alkyl substituted with -OR’, wherein R’ is selected from H, C1-6 alkyl and (C6-12)aryl(C1-6)alkyl;
- R5 is selected from unsubstituted C6-12 aryl or C6-12 aryl substituted with halogen, or with -OR’, wherein R’ is selected from H, C1-6 alkyl and (C6-12)aryl(C1-6)alkyl; - R6 and R7 are independently selected from H, unsubstituted C1-6 alkyl or C1-6 alkyl substituted with -OR’, wherein R’ is selected from H, C1-6 alkyl and (C6-12)aryl(C1- 6)alkyl; and
- represents a single or a double bond. Embodiment 4. Compound for use according to any one of embodiments 1 to 3, wherein the compound of formula (I) is selected from:
Figure imgf000059_0001
Figure imgf000060_0001
Figure imgf000061_0001
Embodiment 5. Compound of formula
Figure imgf000061_0002
or a salt or solvate thereof. Embodiment 6. A compound of formula (II) wherein
Figure imgf000061_0003
- r is selected from 0, 1 and 2; - s is selected from 0, 1, 2, 3, 4 and 5;
- K is selected from -N-, -NR-, -CRa- and -CH2-, wherein R and Ra are each independently selected from H, C1-6 alkyl, -C1-6 alkyl-OR’, C1-6 haloalkyl, C6 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl and wherein the C3-7 cycloalkyl, C6- 18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R’, R'2 , C(O)R'2 , C(O)- (CH2)1-3-NR1R2, C(O)R’, C(O)OR’, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, -(CH2)1-6-OR’, - (CH2)1-6-OC(O)R’, -(CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6- C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6- NO2, C3-7 cycloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2- 6)alkynyl;
- M is selected from -N-, -CR11-, -NR12- and -CH2-, wherein R11 is selected from H, C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkyl)-NR1R2R3, and wherein R12 is selected from H, C1-6 alkyl, C1-6 haloalkyl, -C1-6 alkyl-OR’, C6-18 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl and wherein the C3-7 cycloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R’, R'2 , C(O)R'2 , C(O)-(CH2)1-3-NR1R2, C(O)R’, C(O)OR’, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1-6- R'2 , - (CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6-NO2, C3-7 cycloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1- 6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl;
- T is selected from -N-, -NH-, -CRb- and -CH2-, wherein Rb is selected from H, C1-6 alkyl, -C1-6 alkyl-OR’, C1-6 haloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl and wherein the C3-7 cycloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R’, R'2 , C(O)R'2 , C(O)-(CH2)1-3-NR1R2, C(O)R’, C(O)OR’, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1-6- R'2 , - (CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6-NO2, C3-7 cycloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1- 6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl;
- L is selected from H, halogen, guanidinium, -NR1R2R3, C(O)NR1R2R3, C(O)-(CH2)1-3- NR1R2R3, OR1, OC(O)R1, C(O)R1, C(O)OR1, CN, NO2, C3-7 cycloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein each R1 and R2 are independently selected from H, C1-6 alkyl, -C1-6 alkyl-OR’, C1-6 haloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, (C6-18)aryl(C1- 6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl, and wherein the C3-7 cycloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R’, NR’2, C(O)R'2 , C(O)-(CH2)1-3-NR1R2, C(O)R', C(O)OR’, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R', -(CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6- C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6- NO2, C3-7 cycloalkyl, C6-18 aryl, (C6- 18)aryl(C1-6)alkyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl;
- R3 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
- Y1, Y2 and Y3 are each independently selected from phenyl or a 5- to 6-membered heterocyclyl, each optionally substituted with X;
- X is selected from halogen, OR’, OC(O)R', R'2 , C(O)R'2 , C(O)R', C(O)OR', CN, NO2, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6- C(O)R’, -(CH2)1-6-C(O)OR', -(CH2)1-6-CN, -(CH2)1-6-NO2, C1-6 alkyl, C3-7 cycloalkyl, C1- 6 haloalkyl, C6-ib aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl or (C6-12)aryl(C2-6)alkynyl, -NR4R5R6, 5- to 10-membered heterocyclyl and 5- to 10- membered heteroaryl, wherein R4 and R5 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-ib aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl and wherein the C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R', R'2 , C(O)R'2 , C(O)R’, C(O)OR', CN, NO2, -(CH2)1-6-OR’, -(CH2)1-6- OC(O)R’, -(CH2)1-6- R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, - (CH2)1-6-CN, -(CH2)1-6- NO2, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl;
- R6 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride; represents a single or a double bond;
Figure imgf000063_0001
or a salt or solvate thereof, for use in the treatment or prevention of an infection by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
Embodiment 7. Compound for use according to embodiment 6, wherein the compound of formula (II) is a compound of formulas (ll') to (IIvi)
Figure imgf000064_0001
wherein s, X, L and R are as defined in embodiment 1.
Embodiment 8. Compound for use according to any one of embodiments 6 or 7, wherein L is selected from H, NR1R2, C(O)NR1R2, C(O)-(CH2)1-3-NR1R2, N-containing 5- to IQ- membered heterocyclyl and N-containing 5- to 10-membered heteroaryl, wherein each R1 and R2 are independently selected from H and C1-6 alkyl and wherein the N-containing 5- to 10-membered heterocyclyl and the N-containing 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R’, R'2 , C(O)R'2 , C(O)- (CH2)1-3-NR1R2, C(O)R', C(O)OR', CN, NO2, C1-6 alkyl, C1-6 haloalkyl, -(CH2)1-6-OR’, - (CH2)1-6-OC(O)R’, -(CH2)1-6- R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-
C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6-NO2, C3-7 cycloalkyl, C6-12 aryl or (C6-12)aryl(C1-6)alkyl, wherein each R’ is independently selected from H and C1-6 alkyl.
Embodiment 9. Compound for use according to any one of embodiments 6 to 8, wherein the compound of formula (II) is selected from:
Figure imgf000064_0002
Figure imgf000065_0001
or a salt or solvate thereof.
Embodiment 10. A compound of formula (III)
Figure imgf000065_0002
wherein
- A is selected from -CH-, -N-, and -C(OH)- when
Figure imgf000065_0005
is a double bond, or is selected from -NH-, -C(O)-, -CH2- and -CH(OH)- when
Figure imgf000065_0003
s a single bond;
- B is selected from -CH- and -N- when is a double bond, and is selected from - CH2-, -N- and -NH- when is a single bond;
Figure imgf000065_0004
- Y is selected from -NH- and -CH2- when is a single bond, or is selected from -N- and -CH- when is a double bond;
Figure imgf000066_0001
provided that when B is -NH-, then Y is -N- or -CH-, when B is -N-, then Y is -N-, -NH- or -CH-, and when B is -CH-, then Y = -N- or -CH-;
- C is selected from -NR1-, C1-6 alkyl, C3-7 cycloalkyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein R1 is selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1-6)alkyl;
- D is selected from guanidinium, -NR2R3R4, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein R2 and R3 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl and wherein the C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R', R'2 , C(O)R'2 , C(O)R’, C(O)OR’, CN, NO2, -(CH2)1-6-OR', -(CH2)1-6- OC(O)R’, -(CH2)1-6- R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, - (CH2)1-6-CN, -(CH2)1-6-N02, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl;
- E is selected from C6-12 aryl and 5- to 10-membered heteroaryl;
- R4 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
- Rs is selected from halogen, OR’, OC(O)R', R'2 , C(O)R'2 , C(O)R’, C(O)OR’, CN, NO2, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6- C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6-NO2, C1-6 alkyl, C3-7 cycloalkyl, C1- 6 haloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl or (C6-12)aryl(C2-6)alkynyl, -NR6R7R8, 5- to 10-membered heterocyclyl and 5- to 10- membered heteroaryl, wherein R6 and R7 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl and wherein the C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R', R'2 , C(O)R'2 , C(O)R’, C(O)OR’, CN, NO2, -(CH2)1-6-OR’, -(CH2)1-6- OC(O)R’, -(CH2)1-6- R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, - (CH2)1-6-CN, -(CH2)1-6-N02, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl;
- R8 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
- m is selected from 0 and 1 ; - n is selected from 0, 1, 2, 3, 4, 5 and 6, wherein when n is 3-6 the resulting alkyl chain can contain at least one double bond;
- x is 0 or 1;
- z is 0, 1, 2, 3 or 4;
- each R is independently selected from H, C1-6 alkyl, -(CH2)1-6-0-C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and
(C6-12)aryl(C2-6)alkynyl;
- represents a single or a double bond;
Figure imgf000067_0003
or a salt, solvate, tautomer or stereoisomer thereof, for use in the treatment or prevention of an infection by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
Embodiment 11. Compound for use according to embodiment 10, wherein the compound of formula (III) is a compound of formula (IN’) or (III”)
Figure imgf000067_0001
(III’) (III”) wherein C, D, E, R, R5, m, n, x and z are as defined in embodiment 10.
Embodiment 12. Compound for use according to any one of embodiments 10 or 11,
Figure imgf000067_0002
wherein o is selected from 0 and 1 ; - p is selected from 0, 1 , 2, 3, 4 and 5;
- R is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl; preferably R is selected from H and C1-6 alkyl. Embodiment 13. Compound for use according to any one of embodiments 10 to 12, wherein the compound of formula (III) is selected from:
Figure imgf000068_0001
or a salt, solvate or stereoisomer thereof.
Embodiment 14. Compound for use according to any one of embodiments 1 to 4 and 6 to 13 wherein the infection by viruses is selected from infections by respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” and “Middle East respiratory syndrome-related coronavirus”.
Embodiment 15. Compound for use according to embodiment 14, wherein the respiratory syndrome-related coronavirus is selected from the group consisting of SARS-CoV-2, SARS-CoV and MERS-CoV, preferably SARS-CoV-2.
Examples
Compounds: Compounds 2a-2e, 2g, 2x and 2y were purchased from Toronto Research Chemicals. N-methylclomiphene (compound of formula (2f)) was prepared as described below.
Compounds 3a-3h and 3q were purchased from SIA Enamine.
Compounds 1 a and 1 b were acquired from BOC Sciences. Compounds 1 c and 1 d were obtained from MCule. Compounds 1 i, 1k and 11 were purchased from Emolecules.
All compounds were dissolved in DMSO at a concentration of 5 mM. Synthesis of N-methylclomiphene (compound of formula (2f))
Methyl trifluoromethanesulfonate (314 μL , 5.04 mmol) and N,N-diisopropylethylamine (878 μL , 5.04 mmol) were added to a solution of Clomiphene citrate (60 mg, 0.10 mmol) in ACN (6 mL). The mixture was stirred overnight at 50 °C protected from light. The crude product was evaporated under reduced pressure and purified by semi preparative RP HPLC (gradient from 10-100% B in 30 min; A, 0.1 % HCOOH in H20; B, 0.1 % HCOOH in ACN; flow rate, 3 mL/min; Rt = 17 min). LRMS (ESI-TOF) (m/z): [M]+ Calcd for C27H31CINO, 420.21 ; found, 420.10; 1H NMR (400 MHz, CD3CN) δ (ppm): 8.62 (1 H, s), 7.43-7.30 (6H, m), 7.26-7.21 (3H, m), 7.13 (1 H, m), 7.01-6.95 (3H, m), 6.72 (1 H, m), 4.40 (0.8H, m), 4.27 (1.2H, m), 3.66 (0.8H, m), 3.58 (1.2H, m), 3.42 (1.6H, q, J = 7.2 Hz), 3.35
(2.4H, q, J = 7.2 Hz), 3.02 (1 2H, s), 2.96 (1 8H, s), 1 .33 (2.4H, s), 1.27 (3.6H, s).
Synthesis of compounds of formula (I)
The following are synthesis details of representative compounds disclosed herein.
Synthesis of compounds 1ap and 1aq
Synthesis of trifluoroacetamide precursors 1ax and 1aq’
To a cold (ice bath) solution of 500 mg (2.72 mmol) of histamine dihydrochloride and 1.13 mL of triethylamine (8.16 mmol) in 10 mL of MeOH, 388 μL_ of ethyl trifluoroacetate (3.26 mmol) were added dropwise, and the reaction mixture was stirred at RT for 3.5 h.
Then, the crude was diluted with 10 mL of DCM and 0.75 mL of triethylamine (5.44 mmol) and 300 mg (0.96 mmol) of 2-chlorotrityl chloride were added sequentially, and the resulting solution was stirred overnight. The crude mixture was partitioned between DCM (10 mL) and H2O (10 mL) and the aqueous phase extracted with DCM (3x10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated to dryness. Precursor compounds 1ax and 1aq’ (1aq’ being the trifluoroacetamide precursor of 1aq) were isolated by column chromatography (silica gel, 0-10% MeOH in DCM) obtaining 190 mg (36%) of 1ax and 29 mg (2%) of 1aq’. Compound 1aq’ has the following molecular structure:
Figure imgf000070_0001
Characterization of 1ax: Rf: 0.6 (10% MeOH in DCM). 1H NMR (400 MHz, CDCI3) δ (ppm) 7.42 (m, 2H), 7.35 (m, 7H), 7.26 (m, 1 H), 7.16 (m, 4H), 6.93 (dd, J = 8.0, 1.7 Hz, 1 H), 6.55 (s, 1 H), 3.63 (t, J = 6.1 Hz, 2H), 2.76 (m, 2H).
Characterization of 1aq’: Rf: 0.2 (10% MeOH in DCM). 1H NMR (400 MHz, CDCI3) δ (ppm) 7.49 (s, 1 H), 7.41 (t, J = 6.0 Hz, 5H), 7.34 (dd, J = 7.7, 1.6 Hz, 1 H), 7.28 (m, 8H), 6.78 (s, 1 H), 2.85 (t, J = 6.7 Hz, 2H), 2.39 (t, J = 6.7 Hz, 2H). LRMS (ESI-TOF) m/z
484.22 [M+H]+ Calcd for C28H32N3, 483.92.
Synthesis of 1aq
29 mg (0.06 mmol) of the trifluoroacetamide precursor compound 1 aq’ were dissolved in 2 mL of a 1 :1 (v/v) mixture of THF and MeOH. Then, after addition of 1 mL of NaOH 1
M, the reaction crude was stirred for 2 h at RT. After evaporation under reduce pressure, 10 mL of water were added and the the aqueous phase was extracted with DCM (3x10 mL). The combined organic phases were dried over anhydrous Na2S04, filtered and evaporated to dryness. The product was isolated by column chromatography (silica gel, 0-10% MeOH in DCM), obtaining 20 mg of white solid (yield: 85%).
Characterization: Rf: 0.4 (10% MeOH in DCM). 1H NMR (400 MHz, CDCI3) δ (ppm) 7.54 (s, 1 H), 7.40 (m, 6H), 7.14 (m, 8H), 6.81 (s, 1 H), 2.86 (t, J = 6.6 Hz, 2H), 2.40 (t, J = 6.6 Hz, 2H). LRMS (ESI-TOF) m/z 388.18 [M+H]+ Calcd for C28H32N3, 387.91 . Synthesis of 1 ap
Compound 1 ap was synthesized from 1 ax (180 mg) following the same procedure as for 1aq. The product was isolated by column chromatography (silica gel, 0-40% MeOH in DCM), obtaining 13 mg of a white solid (yield: 9%).
Characterization: Rf: 0.2 (10% MeOH in DCM). 1H NMR (400 MHz, CDCI3) δ (ppm) 7.41 (dd, J = 7.8, 1.5 Hz, 1 H), 7.35 (m, 7H), 7.25 (m, 2H), 7.17 (m, 4H), 6.94 (dd, J = 7.9, 1.7 Hz, 1 H), 6.51 (s, 1 H), 2.95 (t, J = 6.5 Hz, 2H), 2.65 (t, J = 6.5 Hz, 2H). LRMS (ESI-TOF) m/z 388.18 [M+H]+ Calcd for C28H32N3, 387.91 .
Synthesis of compounds 1ar, 1as, 1at, 1au and 1av Synthesis of precursor of formula (1a’)
Figure imgf000071_0001
2 g (10.9 mmol) of histamine dihydrochloride and 4 g (33.6 mmol) of KBr were dissolved in 15 mL of a 1.5 M H2SO4 solution at RT and the mixture was stirred for 10 min at -10°C. After careful dropwise addition of 0.7 mL of a saturated NaNO2 solution, the reaction mixture became brown and it was stirred for additional 30 min at -10 °C. Then, the reaction mixture was stirred for 3 h at RT and became colorless. The solution was cooled with an ice bath and basified until pH 10 with a saturated NaOH solution and then extracted with DCM (3x1 OmL). The combined organic layers were treated with 1 .2 mL of 4 N HCI in dioxane solution, dried over anhydrous Na2SO4 and evaporated to dryness. 1 17 g (yield: 53%) of an amorphous grey solid were obtained which was a mixture of the hydrochloride salt of the chloride and bromide derivatives in a 1 :4 ratio, respectively, as inferred by ESI MS analysis (m/z 131 and 177, respectively). The compound was used without further purification in the next step.
Characterization (1a'-Br): 1H NMR (400 MHz, CD3OD) δ (ppm): 8.82 (s, 1 H), 7.42 (s, 1 H), 3.66 (t, J = 6.7 Hz, 2H), 3.27 (t, J = 6.7 Hz, 2H).
Synthesis of precursor of formula (1a”)
Figure imgf000072_0001
600 mg of the precursor 1a' (3 mmol) were dissolved in 30 mL of DCM (previously neutralized through basic alumina) and 3 mL (17.2 mmol) of DIPEA were added. The reaction mixture was stirred for approximately 5 min and then 1.4 g (5.0 mmol) of trityl chloride were added, and the resulting reaction mixture was stirred overnight at RT. After evaporation under reduced pressure, the product was isolated by column chromatography (silica gel, starting from hexanes to DCM and then 0-0.5% of MeOH in DCM) obtaining 959 mg of a white solid (yield: 78 %) containing a mixture of chlorinated/brominated compounds (1 :2 ratio).
Characterization (1a”CI + 1a”Br): Rf (DCM): 0.3. 1H NMR (400 MHz, CDCI3) δ (ppm): 7.38 (s, 1 H), 7.32 (m, 13H), 7.15 (m, 9H), 6.65 (s, 1 H), 3.77 (t, J = 7.1 Hz, 1 H), 3.63 (t, J = 7.1 Hz, 2H), 3.08 (t, J = 7.1 Hz, 2H), 2.99 (t, J = 7.1 Hz, 1 H). LRMS (ESI-TOF) m/z 373.08 [M+H]+ (1a”-CI) Calcd for C24H21CIN2, 373.14; m/z 416.90 [M+H]+ (1a”-Br) Calcd for C24H21BrN2, 417.09. Synthesis of 1ar
To a solution of 25 mg of 1a” (0.06 mmol) and 10 mg (0.06 mmol) of Kl in ACN (2 ml_), 23 mI_ (0.3 mmol) of N,N-diethylamine were added. The reaction mixture was stirred overnight at 60 °C. After evaporation under reduced pressure, the product was isolated by column chromatography (silica gel, 0-1.5% of MeOH in DCM) obtaining 16 mg of an amorphous orange solid (yield: 65%).
Characterization Rf (10% MeOH/DCM): 0.4. 1H NMR (400 MHz, CDCI3) δ (ppm) 7.37 (s, 1 H), 7.34 (m, 8H), 7.11 (m, 7H), 6.74 (s, 1 H), 3.57 (m, 2H), 3.26 (m, 4H), 3.15 (q, J = 7.4 Hz, 2H), 1.44 (t, J = 7.3 Hz, 6H). LRMS (ESI-TOF) m/z410.12 [M+H]+ Calcd for C28H32N3, 410.26.
Synthesis of 1as
To a solution of 25 mg of 1a” (0.06 mmol) and 10 mg (0.06 mmol) of Kl in ACN (2 ml_), 25 mI_ (0.3 mmol) of pyrrolidine were added. The reaction mixture was stirred overnight at 60°C. After evaporation under reduced pressure, the product was isolated by column chromatography (silica gel, 0-1.5% of MeOH in DCM) obtaining 20 mg pale orange solid (yield: 82%).
Characterization: Rf (DCM): 0.4. 1H NMR (400 MHz, CDCI3) δ (ppm): 7.37 (s, 1 H), 7.33 (m, 9H), 7.11 (m, 6H), 6.75 (s, 1 H), 3.51 (m, 2H), 3.34 (m, 4H), 3.18 (t, J = 7.6 Hz, 2H), 2.15 (q, J= 3.6 Hz, 4H). LRMS (ESI-TOF) m/z 408.16 [M+H]+ Calcd for C28H30N3, 408.24.
Synthesis of 1at
To a solution of 50 mg (0.12 mmol) of 1a” and 25 mg (0.12 mmol) of Kl in ACN (4 mL), 67 μL (0.6 mmol) of 1-methylpiperazine were added, and the reaction mixture was stirred overnight at 70 °C. The crude mixture was partitioned between H2O (10 mL) and DCM (10 mL), and the aqueous phase extracted with DCM (3x10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated to dryness. The product was isolated by column chromatography (silica gel, 0-10% of MeOH in DCM) obtaining 30 mg of a pale orange solid (yield: 57%). Characterization: Rf (10% MeOH/DCM): 0.1. 1H NMR (400 MHz, CDCI3) δ (ppm) 7.32 (m, 10H), 7.12 (m, 6H), 6.58 (s, 1 H), 2.59 (m, 12H), 2.30 (s, 3H). LRMS (ESI-TOF) m/z 437.21 [M+H]+ Calcd for C29H33N4, 437.27.
Synthesis of 1au To a solution of 20 mg of 1a” (0.05 mmol) and 8 mg (0.05 mmol) of Kl in ACN (2 mL), 30 mI_ (0.5 mmol) of ethanolamine were added, and the reaction mixture was stirred for 48 h at 60 °C. The crude mixture was partitioned between H2O (10 mL) and DCM (10 ml_), and the aqueous phase extracted with DCM (3x10 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated to dryness. The product was purified via column chromatography (silica gel, 0-5% of MeOH in DCM) obtaining 7 mg of a pale pink solid (yield: 37%).
Characterization: Rf (10% MeOH/DCM): 0.1. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 7.41 (m, 9H), 7.34 (s, 1 H), 7.09 (m, 7H), 6.79 (s, 1 H), 3.63 (s, 2H), 3.17 (t, J = 7.5 Hz, 2H), 3.01 (t, J= 5.3 Hz, 2H), 2.80 (t, J= 7.6 Hz, 2H). LRMS (ESI-TOF) m/z 398.16 [M+H]+ Calcd for C26H28N3O, 398.22.
Synthesis of 1av
To a solution of 25 mg (0.06 mmol) of 1a” and 10 mg (0.06) of Kl in ACN (4 mL) of ACN, 29 μL (0.3 mmol) of diethanolamine were added and the resulting mixture was stirred overnight at 70°C. The crude mixture was partitioned between H2O (10 mL) and DCM (10 mL), and the aqueous phase extracted with DCM (3x10 mL). The combined organic phases were dried over anhydrous Na2S04, filtered and evaporated to dryness. The product was isolated by column chromatography (silica gel, 0-10% of MeOH in DCM) obtaining 12 mg of a pale orange solid (yield: 45%).
Characterization. Rf (10% MeOH/DCM): 0.3. 1H NMR (400 MHz, CDCI3) δ (ppm): 7.45 (s, 1 H), 7.32 (m, 9H), 7.13 (m, 6H), 6.57 (s, 1 H), 3.58 (s, 4H), 2.76 (m, 8H). LRMS (ESI- TOF) m/z 442.14 [M+H]+442.31 Calcd for C28H32N3O2, 442.25.
Synthesis of 1x
To a solution of 100 mg (0.32 mmol) of 2-chlorotrityl chloride in DCM (4 mL), 115 mg (3.2 mmol) of 2-methylpiperazine were added and the reaction mixture was stirred for 3 h at RT. After addition of DCM (10 mL), the organic phase was washed with 10 mL of a 1 M aqueous solution of Na2CO3 and with 10 mL of H2O, and the resulting aqueous phase extracted with DCM (3x10 mL). The combined organic phases were dried over anhydrous Na2S04, filtered and evaporated to dryness. The product was isolated by column chromatography (silica gel, 0-5% MeOH in DCM) obtaining 8 mg of a pale yellow solid (yield: 8%).
Characterization: Rf: 0.5 (10% MeOH in DCM). 1H NMR (400 MHz, CDCI3) δ (ppm) 7.36 (m, 1 H), 7.28 (d, J = 6.5 Hz, 3H), 7.21 (t, J = 7.2 Hz, 1 H), 7.15 (m, 2H), 7.07 (d, J = 6.7 Hz, 2H), 6.95 (m, 3H), 6.84 (d, J = 9.0 Hz, 2H), 3.51 (m, 2H), 3.05 (m, 3H), 2.73 (m, 1 H), 2.38 (m, 1 H), 1.15 (d, J = 6.3 Hz, 3H). LRMS (ESI-TOF) m/z 377.19 [M+H]+ Calcd for C24H26CIN2, 377.18.
Synthesis of 1v To a solution of 100 mg (0.36 mmol) of trityl chloride in DCM (4 ml_), 123 mg (1 .08 mmol) of 2,6-dimethylpiperazine were added and the reaction mixture was stirred for 3 h at RT. After addition of DCM (10 ml_), the organic phase was washed with 10 mL of a 1 M aqueous solution of Na2CO3 and with 10 mL of H2O, and the resulting aqueous phase extracted with DCM (3x10 mL). The combined organic phases were dried over anhydrous Na2S04, filtered and evaporated to dryness. The product was isolated by column chromatography (silica gel, 0-3.5% MeOH in DCM), obtaining 90 mg of white solid product (yield: 78%).
Characterization. Rf: 0.5 (10% MeOH in DCM). 1H NMR (400 MHz, CDCI3) δ (ppm): 7.46 (s, 5H), 7.25 (t, J = 8.0 Hz, 7H), 7.14 (t, J = 7.2 Hz, 3H), 3.23 (m, 2H), 3.01 (m, 2H), 1 .08 (m, 2H), 0.96 (d, J = 6.3 Hz, 6H). LRMS (ESI-TOF) m/z 357.32 [M+H]+ Calcd for C25H29N2, 357.23.
Synthesis of 1ac
To a solution of 100 mg (0.36 mmol) of trityl chloride in DCM (4 mL), 185 μL (1.08 mmol) of 1-(2-dimethylaminoethyl)-piperazine were added, and the reaction mixture was stirred overnight at RT. After addition of DCM (10 mL), the organic phase was washed with 10 mL of a 1 M aqueous solution of Na2CO3 and with 10 mL of H2O, and the resulting aqueous phase extracted with DCM (3x10 mL). The combined organic phases were dried over anhydrous Na2S04, filtered and evaporated to dryness. The product was isolated by chromatography column (silica gel, 0-3.5% of MeOH in DCM) obtaining 122 mg of a yellow solid (yield: 77%).
Characterization: Rf (10% MeOH/DCM): 0.4. 1H NMR (400 MHz, CDCI3) δ (ppm) 7.49 (s, 5H), 7.25 (m, 7H), 7.14 (m, 3H), 2.55 (m, 12H), 2.23 (s, 6H). LRMS (ESI-TOF) m/z 400.39 [M+H]+ Calcd for C27H34N3, 400.27.
Synthesis of 1ad
Compound 1ad was synthesized following the same procedure as for 1ac but using 202 mg (1.08 mmol) of 1-(2-pyrrolidinoethyl)-piperazine as piperazine reagent. The product was isolated by column chromatography (silica gel, 0-5% of MeOH in DCM) obtaining 110 mg of a pale yellow (yield: 72%). Characterization: Rf (10% MeOH/DCM): 0.3. 1H NMR (400 MHz, CDCI3) δ (ppm) 7.39 (s, 5H), 7.15 (m, 7H), 7.04 (m, 3H), 2.46 (m, 15H), 1.67 (s, 5H). LRMS (ESI-TOF) m/z 426.38 Calcd for C29H36N3, 426.29. Synthesis of 1ae
To a solution of 50 mg (0.18 mmol) of trityl chloride in DCM (2 ml_), 106 mg (0.56 mmol) of 1-(1-piperidin-yl-ethyl)-piperazine were added, and the reaction mixture was stirred overnight at RT. Then, the organic phase was washed with water (10 mL) and the aqueous phase extracted with DCM (3x1 OmL). The combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated to dryness. The product was isolated by column chromatography (silica gel, 0-5% MeOH in DCM) obtaining 58 mg of a white solid (yield: 74%).
Characterization: Rf (10% MeOH in DCM): 0.3. 1H NMR (400 MHz, CDCI3) δ (ppm) 7.48 (s, 5H), 7.24 (m, 7H), 7.13 (m, 3H), 2.50 (m, 14H), 1.58 (m, 6H), 1.42 (m, 2H). LRMS (ESI-TOF) m/z 440.18 [M+H]+ Calcd for C30H37N3, 440.31.
Synthesis of 1af
To a solution of 50 mg (0.18 mmol) of trityl chloride in DCM (2 mL), 64 mg (0.36 mmol) of 1 -piridin-4-yl-piperazine were added. The resulting mixture was stirred overnight at RT. After evaporation under reduced pressure, the product was isolated by column chromatography (silica gel, 0-1 % MeOH in DCM) obtaining 60 mg of a yellow solid (yield 79%).
Characterization: Rf (10% MeOH in DCM): 0.7. 1H NMR (400 MHz, CDCI3) δ (ppm) 8.48 (m, 2H), 7.48 (s, 6H), 7.25 (t, J = 7.6 Hz, 6H), 7.21 (m, 2H), 7.15 (t, J = 7.3 Hz, 3H), 3.52 (s, 2H), 2.82 (m, 6H), 2.06 (s, 2H). LRMS (ESI-TOF) m/z 420.30 [M+H]+ Calcd for C29H30N3, 420.24.
Synthesis of 1aq
To a solution of 50 mg (0.18 mmol) of trityl chloride in DCM (4 ml_), 82 mg (0.54 mmol) of tert-butyl N-[2-(piperazin-1-yl)ethyl]carbamate were added. The resulting mixture was stirred overnight at RT. After evaporation under reduced pressure, the product was isolated by column chromatography (silica gel, 0-1 % MeOH in DCM) obtaining 67 mg of a white solid (yield: 79%).
Characterization: Rf (10% MeOH in DCM): 0.8. 1H NMR (400 MHz, CDCI3) δ (ppm) 7.48 (s, 6H), 7.27 (t, J = 7.9 Hz, 7H), 7.16 (t, J = 7.1 Hz, 3H), 2.69 (m, 12H), 1.42 (s, 9H). LRMS (ESI-TOF) m/z 472.48 [M+H]+ Calcd for C30H38N3O, 472.30.
Synthesis of compounds 1aab, 1az, 1ak, 1 al and 1am
Figure imgf000077_0001
To a solution of 2 g (11 mmol) of benzophenone in anhydrous THF (10 ml_), 26 mL of biphenyl magnesium bromide 0.5 M in THF (13 mmol) were added and the colorless solution changed to pink. The reaction mixture was stirred overnight and then was quenched by adding 50 mL of 10% aqueous HCI. The mixture was transferred to a separatory funnel and extracted with hexanes (3x50 mL). The combined organic phases were dried over anhydrous Na2S04, filtered and evaporated to dryness. The product was isolated by column chromatography (silica gel, 0-35% of DCM in hexanes) obtaining 1.9 g of a white solid (yield: 51%). Characterization: Rf (50% DCM/Hexanes): 0.2. 1H NMR (400 MHz, CDCI3) δ (ppm) 7.61 (d, J = 7.0 Hz, 2H), 7.56 (d, J = 8.7 Hz, 2H), 7.45 (m, 2H), 7.34 (m, 13H). LRMS (ESI- TOF) m/z 336.24 [M+H]+ Calcd for C25H2IO, 337.16.
Synthesis of 1aab First, 650 mg (3.53 mmol) of histamine hydrochloride were dissolved in 4 mL of MeOH and 1 mL of triethylamine were added. The resulting solution was stirred 10 min at 0 °C, followed by the addition of 450 μL (3.8 mmol) of ethyl trifluoroacetate. The resulting mixture was stirred for 3 h at RT. At same time, 400 mg (1.2 mmol) of 1 az’ were dissolved in 4 mL of DCM and 500 μL (2.5 mmol) of SOCI2 were added, and the resulting reaction mixture was stirred for 3 h at RT. 3 h later, both crudes were evaporated to dryness and re-dissolved in DCM (4 mL each). To the histamine-containing solution, 1 mL of triethylamine were added and, immediately, the biphenyl-containing solution was added. The resulting reaction mixture was stirred overnight at RT. After evaporation to dryness, the product was isolated by column chromatography (silica gel, 0-10% of MeOH in DCM) obtaining 389 mg of a white solid (yield: 62%).
Characterization: Rf (10% MeOH / DCM): 0.8. 1H NMR (400 MHz, CDCI3) δ (ppm) 8.44 (s, 1 H), 7.59 (m, 4H), 7.45 (m, 2H), 7.37 (m, 7H), 7.18 (m, 6H), 6.67 (s, 1 H), 3.65 (q, J = 5.6 Hz, 2H), 2.78 (t, J = 6.0 Hz, 2H). LRMS (ESI-TOF) m/z 526.18 [M+H]+ Calcd for C32H27F3O, 526.21.
Synthesis of 1az
To a solution of 380 mg (0.7 mmol) of 1aab in 4 mL of a 1 :1 (v/v) mixture of THF and MeOH, 10 mL of 1 M NaOH solution were added. After stirring for 2h at RT, the reaction mixture was extracted with DCM (3x10 mL), and the combined organic phases were dried over anhydrous Na2SO4, filtered and evaporated to dryness. The product was isolated by column chromatography (silica gel, 0-10% of MeOH in DCM) obtaining 270mg of an amorphous white solid (yield: 90%).
Characterization: Rf (20% MeOH/DCM): 0.5. 1H NMR (400 MHz, CDCI3) δ (ppm) 7.73 (m, 4H), 7.56 (m, 11 H), 7.34 (m, 6H), 6.80 (s, 1 H), 3.22 (t, J = 6.5 Hz, 2H), 2.90 (t, J = 6.5 Hz, 2H). LRMS (ESI-TOF) m/z 430.12 [M+H]+ Calcd for C30H28N3, 430.23.
Synthesis of 1ak
To a solution of 50 mg (0.15 mmol) of 1az’ in 3 mL of DCM, 119 μL (1.5 mmol) of SOCI2 were added. The mixture was stirred for 1 h or until the white vapors disappeared, then several evaporations with DCM were carried out. Finally, the crude was dissolved with 4 mL of DCM and 140 mg (1 .4 mmol) of 2-methylpiperazine were added, and the reaction mixture was refluxed overnight. The product was isolated by column chromatography (silica gel, 0-2.5% of MeOH in DCM) obtaining 21 mg of a white solid (yield: 33%). Characterization: Rf (10% MeOH/DCM): 0.3. 1H NMR (400 MHz, CDCI3) δ (ppm) 7.54 (m, 10H), 7.41 (m, 2H), 7.31 (m, 6H), 7.18 (t, J = 9.1 Hz, 2H), 3.23 (m, 2H), 3.03 (m, 3H), 2.50 (m, 1 H), 1.27 (s, 1 H), 1 .01 (d, J = 6.3 Hz, 3H). LRMS (ESI-TOF) m/z 419.98 [M+H]+ Calcd for C30H31N2, 419.25.
Synthesis of 1al
To a solution of 100 mg (0.3 mmol) of 1az’ in 4 mL of DCM, 66 μL (0.9 mmol) of SOCI2 were added. The mixture was stirred for 1 h or until the white vapors disappeared, then several evaporations with DCM were carried out. Finally, the crude was dissolved with 4 mL of DCM and 320 μL (1.8 mmol) of 1-(2-pyrrolidin-1-yl-ethyl)piperazine were added, and the reaction mixture was stirred overnight. The product was isolated by column chromatography (silica gel, 0-3% of MeOH in DCM) obtaining 84 mg of an amorphous yellow solid (yield: 56%).
Characterization: Rf (10% MeOH/DCM): 0.6. 1H NMR (400 MHz, CDCI3) δ (ppm) 7.52 (m, 10H), 7.41 (dd, J = 8.4, 6.9 Hz, 2H), 7.28 (m, 5H), 7.16 (t, J = 7.3 Hz, 2H), 2.67 (m, 14H), 1.81 (d, J = 3.1 Hz, 6H). LRMS (ESI-TOF) m/z 502.40 [M+H]+ Calcd for C35H40N3, 502.32.
Synthesis of 1am
To a solution of 100 mg (0.3 mmol) of 1az’ in 4 mL of DCM, 120 mI_ (1 .5 mmol) of SOCI2 were added. The mixture was stirred for 1 h or until the white vapors disappeared, then several evaporations with DCM were carried out. Finally, the crude was dissolved with 4 mL of DCM and 300 mg (3 mmol) of 1-(2-piperidin-1-yl-ethyl)-piperazine were added, and the reaction mixture was stirred overnight. The product was isolated by column chromatography (silica gel, 0-5% of MeOH in DCM) obtaining 109 mg of an amorphous yellow solid (yield: 71%).
Characterization: Rf (10% MeOH/DCM): 0.6. 1H NMR (400 MHz, CDCI3) δ (ppm) 7.52 (m, 10H), 7.30 (t, J = 7.6 Hz, 2H), 7.18 (m, 5H), 7.05 (t, J = 7.2 Hz, 2H), 2.58 (m, 15H), 1.62 (m, 6H), 1.33 (m, 2H). LRMS (ESI-TOF) m/z 516.42 [M+H]+ Calcd for C36H41N3, 516.34.
Tissue distribution study of clomiphene citrate.
24 female swiss albino mice were dosed PO with 4 mg/Kg of clomiphene citrate once per day during 7 consecutive days. Three additional animals were used as a control group. The concentration of the two diastereomers of clomiphene citrate was measured in plasma and lungs at eight time points after the last dose (30 min, 1 , 2, 4, 6, 8, 12 and 24 hours) using three animals per time point and liquid chromatography coupled to mass spectrometry methodology. Tmax, cmax, AUC, MRT and lung:plasma ratios were determined with Phoenix WinNonlin pharmacokinetics software.
Viral growth and cytotoxicity assays in the presence of inhibitors 2,000 Vero E6, hACE2-293T or Hela-ACE2 cells were seeded into 96-well plates in DMEM (10% FBS) and incubated for 24 h at 37 °C, 5% CO2. Two hours before infection, the medium was replaced with 100 μL of DMEM (2% FBS) containing the compound of interest at concentrations 50% greater than those indicated, including a DMSO control. Plates were then transferred into the BSL3 facility and 100 PFU (MOI = 0.025) was added in 50 μL of DMEM (2% FBS), bringing the final compound concentration to those indicated. Plates were then incubated for 48 h at 37 °C. After infection, supernatants were removed and cells were fixed with 4% formaldehyde for 24 hours prior to being removed from the BSL3 facility. The cells were then immunostained for the viral NP protein (an in-house mAb 1C7, provided by Dr. Thomas Moran, Thomas.Moran@mssm.edu) with a DAPI counterstain. Infected cells (488 nM) and total cells (DAPI) were quantified using the Celigo (Nexcelcom) imaging cytometer. Infectivity was measured by the accumulation of viral NP protein in the nucleus of the Vero E6 cells (fluorescence accumulation). Percent infection was quantified as ((Infected cells/Total cells) - Background) x 100 and the DMSO control was then set to 100% infection for analysis. The IC50 and IC90 for each experiment were determined using the Prism (Graph Pad Software) software. Cytotoxicity was also performed using the MTT assay (Roche), according to the manufacturer’s instructions. Cytotoxicity was performed in uninfected VeroE6 cells with same compound dilutions and concurrent with viral replication assay. All assays were performed in biologically independent triplicates.
Results
The tables below show the antiviral activity (anti SARS-CoV-2) and cytotoxicity of representative compounds of the invention by indication of the IC50, IC90, CC50, CC10 and Selectivity Index (SI) parameters.
Table 1. Results from the Viral growth and Cytotoxicity assays in the presence of compound 3a.
Figure imgf000080_0001
Table 2. Results from the Viral growth and Cytotoxicity assays in the presence of compound 3b
Figure imgf000080_0002
Table 3. Results from the Viral growth and Cytotoxicity assays in the presence of compound 3c.
Figure imgf000080_0003
Table 4. Results from the Viral growth and Cytotoxicity assays in the presence of compound 3e.
Figure imgf000081_0001
Table 5. Results from the Viral growth and Cytotoxicity assays in the presence of compound 3f.
Figure imgf000081_0002
Table 6. Results from the Viral growth and Cytotoxicity assays in the presence of compound 3h.
Figure imgf000081_0003
Table 7. Results from the Viral growth and Cytotoxicity assays in the presence of compound 3q.
Figure imgf000081_0004
Table 8. Results from the Viral growth and Cytotoxicity assays in the presence of compound 2a.
Figure imgf000081_0005
Table 9. Results from the Viral growth and Cytotoxicity assays in the presence of compound 2b.
Figure imgf000081_0006
Table 10. Results from the Viral growth and Cytotoxicity assays in the presence of compound 2c.
Figure imgf000082_0001
Table 11. Results from the Viral growth and Cytotoxicity assays in the presence of compound 2d.
Figure imgf000082_0002
Table 12. Results from the Viral growth and Cytotoxicity assays in the presence of compound 2e.
Figure imgf000082_0003
Table 13. Results from the Viral growth and Cytotoxicity assays in the presence of compound 2f.
Figure imgf000082_0004
Table 14. Results from the Viral growth and Cytotoxicity assays in the presence of compound 2g.
Figure imgf000082_0005
Table 15. Results from the Viral growth and Cytotoxicity assays in the presence of compound 2h
Figure imgf000082_0006
Table 16. Results from the Viral growth and Cytotoxicity assays in the presence of compound 2j.
Figure imgf000083_0001
Table 17. Results from the Viral growth and Cytotoxicity assays in the presence of compound 1a.
Figure imgf000083_0002
Table 18. Results from the Viral growth and Cytotoxicity assays in the presence of compound 1b
Figure imgf000083_0003
Table 19. Results from the Viral growth and Cytotoxicity assays in the presence of compound 1c.
Figure imgf000083_0004
Table 20. Results from the Viral growth and Cytotoxicity assays in the presence of compound 1d.
Figure imgf000083_0005
Table 21. Results from the Viral growth and Cytotoxicity assays for the Hela-ACE2 cell line in the presence of compounds of the invention.
Figure imgf000084_0001
Comparative compounds The following table shows IC50, CC50 and SI values for the corresponding depicted comparative compounds, which are not part of the present invention.
Table 22. Results from the Viral growth and Cytotoxicity assays for the Hela-ACE2 cell line in the presence of comparative compounds.
Figure imgf000084_0002
Figure imgf000085_0001
Pharmacokinetic results
A pharmacokinetic distribution study of clomiphene citrate in mice was conducted, dosing the animals PO once per day at 4 mg/Kg in order to resemble routine clinical conditions in humans (this dose corresponds to 240 mg per day for a 60 Kg individual). In this study, the cis- and trans- isomers of clomiphene citrate (zuclomiphene and enclomiphene, respectively) were specifically monitored. The results indicated that the lung to plasma concentration ratio was 44.5 for the cis-isomer and 29.6 for the trans-isomer, that is, both isomers reached concentrations in lungs that were 44.5 or 29.6 times above those detected in plasma. In addition, the study also indicated that the cmax, tmax, AUC and MRT of cis-clomiphene were significantly higher than those of trans-clomiphene. Importantly, the concentration in lungs of the cis-isomer of clomiphene citrate was above the IC90 values of both clomiphene citrate and cis-clomiphene for approximately 10 hours (Figure 1). This result indicated that the compound exerts antiviral action in lungs at routine clinical doses.

Claims

1. A compound of formula (I)
Figure imgf000086_0001
wherein
- r is selected from 0, 1 and 2;
- s is selected from 0, 1 , 2, 3, 4 and 5;
- K is selected from -N-, -NR-, -CRa- and -CH2-, wherein R and Ra are each independently selected from H, C1-6 alkyl, -C1-6 alkyl-OR’, C1-6 haloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl, -C1-6 alkyl-(5- to 10-membered heterocyclyl), (C6- 18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl and wherein the C1-6 alkyl, -C1-6 alkyl-OR’, C1-6 haloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl and -C1-6 alkyl-(5- to 10-membered heterocyclyl) can be unsubstituted or substituted with R’, halogen, OR’, OC(O)R', R'2 , C(O)R'2 , C(O)-(CH2)1-3-NR1R2, C(O)R’, C(O)OR’, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1- 6-NR 2, -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, -(CH2)1- 6-NO2, C3-7 cycloalkyl, C6-18 aryl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, -C0-6 alkyl-(guanidinium), -C1-6 alkyl-(5- to 10-membered heterocyclyl), -C1-6 alkyl-(5- to 10-membered heterocyclyl substituted with -C0-6 alkyl- guanidinium), and C6-18 aryl;
- M is selected from -N-, -CR11-, -NR12- and -CH2-, wherein R11 is selected from H, C1-6 alkyl, C1-6 haloalkyl, -(C1-6 alkyl)-NR1R2R3, and wherein R12 is selected from H, C1-6 alkyl, C1-6 haloalkyl, -C1-6 alkyl-OR’, C6-18 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl and wherein the C1-6 alkyl, -C1-6 alkyl-OR’, C1-6 haloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R’, NR’2, C(O)R'2 , C(O)- (CH2)1-3-NR1R2, C(O)R’, C(O)OR’, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, -(CH2)1-6-OR’, - (CH2)1-6-OC(O)R’, -(CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-
C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6- NO2, C3-7 cycloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2- 6)alkynyl;
- T is selected from -N-, -NH-, -CH- and -CH2-;
- L is selected from H, halogen, guanidinium, -NR1R2R3, C(O)NR1R2R3, C(O)-(CH2)1-3- NR1R2R3, OR1, OC(O)R1, C(O)R1, C(O)OR1, CN, NO2, C3-7 cycloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein each R1 and R2 are independently selected from H, C1-6 alkyl, -C1-6 alkyl-OR’, C1-6 haloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl, 5- to 10-membered heteroaryl, (C6-18)aryl(C1- 6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl and wherein the C1-6 alkyl, - C1-6 alkyl-OR’, C1-6 haloalkyl, C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10- membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R’, R'2 , C(O)R'2 , C(O)-(CH2)1-3-R'2 , C(O)R’, C(O)OR’, CN, NO2, C1-6 alkyl, C1-6 haloalkyl, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1-6- R'2 , -(CH2)1-6-C(O)R'2 , - (CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6- NO2, C3-7 cycloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2- 6)alkenyl and (C6-12)aryl(C2-6)alkynyl;
- R3 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
- Y1, Y2 and Y3 are each independently selected from phenyl or a 5- to 6-membered heterocyclyl, each optionally substituted with X;
- X is selected from halogen, OR’, OC(O)R’, R'2 , C(O)R'2 , C(O)R’, C(O)OR’, CN, NO2, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6- C(O)R’, -(CH2)1-6-C(O)OR’, -(CH2)1-6-CN, -(CH2)1-6-NO2, C1-6 alkyl, C3-7 cycloalkyl, C1- 6 haloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl or (C6-12)aryl(C2-6)alkynyl, -NR4R5R6, 5- to 10-membered heterocyclyl and 5- to 10- membered heteroaryl, wherein R4 and R5 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl and wherein the C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R’, R'2 , C(O)R'2 , C(O)R’, C(O)OR’, CN, NO2, -(CH2)1-6-OR’, -(CH2)1-6- OC(O)R’, -(CH2)1-6- R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, - (CH2)1-6-CN, -(CH2)1-6- N02, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl;
- R6 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
Figure imgf000088_0003
represents a single or a double bond; or a salt or solvate thereof, with the proviso that the compound of formula (I) is not selected from the group consisting of 1-(triphenylmethyl)imidazole, clotrimazole, TRAM-34 and salts thereof, for use in the treatment or prevention of an infection by RNA-viruses, selected from the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
2. Compound for use according to claim 1, wherein the compound of formula (I) is a compound of formula
Figure imgf000088_0001
wherein X, Y1, Y2, T, M, K, L, r and s are as defined in claim 1.
3. Compound for use according to any one of claims 1 or 2, wherein the compound of formula (I) is a compound of formula (I”), wherein
Figure imgf000088_0002
- r is selected from 0 or 1 ;
- s is selected from 0, 1 , 2 or 3;
- R is absent or is selected from H, C1-6 alkyl and -C1-6 alkyl-(5- to 10-membered heterocyclyl), and wherein the C1-6 alkyl and -C1-6 alkyl-(5- to 10-membered heterocyclyl) can be unsubstituted or substituted with R’, -OR’ or -NR’2;
- R’ is each independently selected from H, C1-6 alkyl, -C0-6 alkyl-(guanidinium), -C1-6 alkyl-(5- to 10-membered heterocyclyl), -C1-6 alkyl-(5- to 10-membered heterocyclyl substituted with -C0-6 alkyl-guanidinium) and C6-18 aryl;
- M is selected from -CH2-, -N- and -CR11-, wherein R11 is selected from H, C1-6 alkyl and -(C3 alkyl)-NH2;
- L is selected from H, guanidinium, -NR1R2R3, -C(O)NH2, and 5- to 10-membered heterocyclyl, wherein each R1 and R2 are independently selected from H, C1-6 alkyl, - C1-6 alkyl-OR’, and wherein the C1-6 alkyl and 5- to 10-membered heterocyclyl can be unsubstituted or substituted with C(O)-(CH2)1-3-R'2 and C1-6 alkyl;
- R3 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
- Y3 is selected from phenyl, optionally substituted with X;
- X is selected from halogen or C6-18 aryl; represents a single or a double bond;
Figure imgf000089_0003
or a salt or solvate thereof.
4. Compound for use according to any one of claims 1 to 3, wherein the compound of formula (I) is a compound of formulas (I') to (lvii)
Figure imgf000089_0001
wherein s, L, X, R, and R11 are as defined in any one of claims 1 to 3.
5. Compound for use according to any one of claims 1 to 4, wherein the compound of formula (I) is selected from:
Figure imgf000089_0002
Figure imgf000090_0001
Figure imgf000091_0001
or a salt or solvate thereof.
6. Compound for use according to claim 4, wherein the compound of formula (I) is: a compound of formula (Ii,) wherein s is selected from 1 , 2 or 3;
L is selected from -NH2, -NR1R2, and 5- to 10-membered heterocyclyl, wherein the 5- to 10-membered heterocyclyl can be unsubstituted or substituted with C1- 6 alkyl; R1 and R2 are each independently selected from H, C1-6 alkyl or -C1-6 alkyl-OH; and
X is H, phenyl or Cl; or a compound of formula (Iii), wherein s is 0 or 1 ; L is H;
R is selected from H, C1-6 alkyl, C1-6 alkyl-OH, C1-6 alkyl-NH2, and -C1-6 alkyl-(5- to 10-membered heterocyclyl) preferably selected from pyrrolidine, piperidine or piperazine; and X is H, phenyl or Cl; or - a compound of formula (lvii), wherein s is 1;
L is H;
R is H;
R11 is C1-6 alkyl; and X is H, phenyl or Cl.
7. Compound for use according to any one of claims 1 to 6, wherein the compound of formula (I) is selected from:
Figure imgf000092_0001
Figure imgf000093_0001
or a salt or solvate thereof.
8. Compound for use according to any one of claims 1 to 7, wherein the compound of formula (I) is selected from:
Figure imgf000093_0002
or a salt or solvate thereof.
9. Compound for use according to any one of claims 1 to 8 wherein the infection by viruses is selected from infections by RNA-viruses selected from the family Coronaviridae and Retroviridae, preferably Coronaviridae.
10. Compound for use according to any one of claims 1 to 9 wherein the infection by viruses is selected from infections by respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” and “Middle East respiratory syndrome-related coronavirus” .
11. Compound for use according to any one of claims 1 to 10 wherein the infection by viruses is selected from infections by respiratory syndrome-related coronaviruses selected from the group consisting of SARS-CoV-2, SARS-CoV and MERS-CoV.
12. Compound for use according to any one of claims 1 to 11 wherein the infection by viruses is SARS-CoV-2.
13. Compound for use according to claim 7 wherein the infection by viruses is selected from infections by respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” and “Middle East respiratory syndrome-related coronavirus” .
14. Compound for use according to claim 7 wherein the infection by viruses is selected from infections by respiratory syndrome-related coronaviruses selected from the group consisting of SARS-CoV-2, SARS-CoV and MERS-CoV.
15. Compound for use according to claim 7 wherein the infection by viruses is SARS-
CoV-2.
16. Compound for use according to any one of claims 1 to 15, which is for oral or inhalation administration.
17. A compound of formula (I”)
Figure imgf000094_0001
wherein,
- r is selected from 0 or 1 ;
- s is selected from 0, 1 , 2 or 3;
- R is absent or is selected from H, C1-6 alkyl and -C1-6 alkyl-(5- to 10-membered heterocyclyl), and wherein the C1-6 alkyl and -C1-6 alkyl-(5- to 10-membered heterocyclyl) can be unsubstituted or substituted with R’, -OR’ or -NR’2;
- R’ is each independently selected from H, C1-6 alkyl, -C0-6 alkyl-(guanidinium), -C1-6 alkyl-(5- to 10-membered heterocyclyl), -C1-6 alkyl-(5- to 10-membered heterocyclyl substituted with -C0-6 alkyl-guanidinium), and C6-18 aryl;
- M is selected from -CH2-, -N- and -CR11-, wherein R11 is selected from H, C1-6 alkyl and -(C3 alkyl)-NH2;
- L is selected from H, guanidinium, -NR1R2R3, -C(O)NH2, and 5- to 10-membered heterocyclyl, wherein each R1 and R2 are independently selected from H, C1-6 alkyl, - C1-6 alkyl-OR’, and wherein the C1-6 alkyl and 5- to 10-membered heterocyclyl can be unsubstituted or substituted with C(O)-(CH2)1-3-R'2 and C1-6 alkyl;
- R3 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
- Y3 is selected from phenyl, optionally substituted with X;
- X is selected from halogen or C6-18 aryl; represents a single or a double bond;
Figure imgf000095_0003
or a salt or solvate thereof, with the proviso that the compound of formula (I”) is not selected from the group consisting of
Figure imgf000095_0001
18. The compound of formula (I”) according to claim 17, wherein the compound of formula (I”) is a compound of formulas
Figure imgf000095_0002
wherein s, L, X, R and R11 are as defined in claim 17.
19. The compound of formula (I”) according to any one of claims 17 or 18, wherein R is absent or selected from H, methyl, C1-6 alkyl substituted with NR’2, -C1-6 alkyl- pyrrolidine), -C1-6 alkyl-(piperidine) and -C1-6 alkyl-(piperazine), wherein each R’ is independently selected from H and C6 aryl.
20. The compound of formula (I”) according to any one of claims 17 to 19, wherein L is selected from H NH2 NMe2 NMe3 NEt2 NH(C16 alkyl OH) N(Me)(C16 alkyl
Figure imgf000096_0001
21. The compound of formula (I”) according to any one of claims 17 to 20, wherein the compound of formula (I”) is selected from,
Figure imgf000096_0002
Figure imgf000097_0001
Figure imgf000098_0001
22. The compound of formula (I”) according to claim 18, wherein the compound of formula (I”) is a compound of formula (Ii,) wherein s is 2;
L is selected from -NH2, -NR1R2, and 5- to 10-membered heterocyclyl, wherein the 5- to 10-membered heterocyclyl can be unsubstituted or substituted with C1- 6 alkyl;
R1 and R2 are each independently selected from H, C1-6 alkyl or -C1-6 alkyl-OH and
X is H, phenyl or Cl; or a compound of formula (Iii), wherein s is 0 or 1 ;
L is H;
R is selected from H, C1-6 alkyl-OH, C1-6 alkyl-NH2, and -C1-6 alkyl-(5- to 10- membered heterocyclyl) preferably selected from pyrrolidine, piperidine or piperazine; and X is H, phenyl or Cl; or a compound of formula (lvii), wherein s is 1;
L is H;
R is H;
R11 is C1-6 alkyl; and X is H or Cl.
23. Compound according to any one of claims 17 to 22, wherein the compound of formula (I”) is selected from:
Figure imgf000098_0002
Figure imgf000099_0001
or a salt or solvate thereof.
24. A compound of formula (II)
Figure imgf000099_0002
wherein
- q is selected from 1 , 2, 3 and 4;
- R4 is selected from H, =0, OR’, halogen, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6- 18)aryl(C1-6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R', -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; unsubstituted C6-18 aryl or C6-18 aryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl, (C6- 12)aryl(C2-6)alkynyl, -OR’, -OC(O)R', -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or - NO2; and unsubstituted 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, -OR’, - OC(O)R', -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR', -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1- 6)alkyl;
- R5 is selected from H, halogen, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1- 6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R', -R'2 , -C(O)R'2 , -C(O)R’, - C(O)OR’, -CN, or -NO2; unsubstituted C6-18 aryl or C6-18 aryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl, (C6-18)aryl(C1-6)alkyl, C6-12)aryl(C2-6)alkenyl, (C6- 12)aryl(C2-6)alkynyl, -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or - NO2; and unsubstituted 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, -OR’, - OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1- 6)alkyl;
- Z is selected from -NR6R7R8 and halogen;
- R6 and R7 are independently selected from H, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R', -R'2 , -C(O)R'2 , - C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl; or
- R6 and R7, together with the nitrogen atom to which they are attached can form a 5- to 7-membered heterocyclyl group; or
- R6, R7 and R8 together with the nitrogen atom to which they are attached can form a guanidinium group; or
- R8 is absent, H, C1-6 alkyl or C1-6 haloalkyl; represents a single or a double bond;
Figure imgf000100_0001
- G is selected from (C6-12)aryl and 5- to 10-membered heteroaryl, wherein the (C6- 12)aryl and 5- to 10-membered heteroaryl are optionally substituted with R9;
- R9 and R10 are independently selected from H, halogen, C1-6 alkyl, C1-6 haloalkyl, (C6- 12)aryl, (C6-12)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl, (C6-12)aryl(C2-6)alkynyl, -OR’, - OC(O)R', -R'2 , -C(O)R'2 , -C(O)R', -C(O)OR’, -CN, -NO2, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl, wherein the rings in the (C6-12)aryl, (C6-12)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl, (C6-12)aryl(C2-6)alkynyl, 5- to 10- membered heteroaryl or 5- to 10-membered heterocyclyl are optionally substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, -OR’, -OC(O)R’, -R'2 , - C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1-6)alkyl; or a salt or solvate thereof, with the proviso that the compound of formula (II) is not selected from the group consisting of clomiphene, tamoxifen, toremifene, droloxifene, afimoxifene, edoxifene and salts thereof, for use in the treatment or prevention of an infection by RNA-viruses, selected from the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
25. Compound for use according to claim 24, wherein
- q is selected from 1 , 2, 3 and 4;
- R4 is selected from H, =0, halogen, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6- 12)aryl(C1-6)alkyl and C1-6 alkyl substituted with -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , - C(O)R’, -C(O)OR’, -CN, or -NO2, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl;
- R5 is selected from unsubstituted C6-12 aryl or C6-12 aryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl(C1-6)alkyl, -OR’, -OC(O)R', -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; and unsubstituted 5- to 10-membered heteroaryl or 5- to 10- membered heteroaryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl(C1- 6)alkyl, -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6- 12)aryl(C1-6)alkyl;
- R6 and R7 are independently selected from H, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl(C1-6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R', -R'2 , -C(O)R'2 , - C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl; or
- R6 and R7, together with the nitrogen atom to which they are attached can form a 5- to 10-membered heterocyclyl group;
- R8 is absent or C1-6 alkyl; represents a single or a double bond.
Figure imgf000101_0001
26. Compound for use according to any one of claims 24 or 25, wherein
- q is selected from 1 , 2, 3 and 4;
- R4 is selected from H, halogen, =0, unsubstituted C1-6 alkyl and C1-6 alkyl substituted with -OR’, wherein R’ is selected from H, C1-6 alkyl and (C6-12)aryl(C1-6)alkyl;
- R5 is selected from unsubstituted C6-12 aryl or C6-12 aryl substituted with halogen, or with -OR’, wherein R’ is selected from H, C1-6 alkyl and (C6-12)aryl(C1-6)alkyl;
- R6 and R7 are independently selected from H, unsubstituted C1-6 alkyl or C1-6 alkyl substituted with -OR’, wherein R’ is selected from H, C1-6 alkyl and (C6-12)aryl(C1- 6)alkyl; and represents a single or a double bond.
Figure imgf000102_0002
27. Compound for use according to any one of claims 24 to 26, wherein the compound of formula (II) is selected from:
Figure imgf000102_0001
Figure imgf000103_0001
or a salt or solvate thereof.
28. Compound for use according to any one of claims 24 to 27, wherein the compound of formula (II) is selected from:
Figure imgf000104_0001
29. Compound for use according to any one of claims 24 to 28, wherein the compound of formula (II) is:
Figure imgf000104_0002
or a salt or solvate thereof.
30. Compound for use according to any one of claims 24 to 29 wherein the infection by viruses is selected from infections by respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” and “Middle East respiratory syndrome-related coronavirus” .
31. Compound for use according to any one of claims 24 to 30 wherein the infection by viruses is selected from infections by respiratory syndrome-related coronaviruses selected from the group consisting of SARS-CoV-2, SARS-CoV and MERS-CoV.
32. Compound for use according to any one of claims 24 to 31 wherein the infection by viruses is SARS-CoV-2.
33. Compound for use according to claim 28 wherein the infection by viruses is selected from infections by respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” and “Middle East respiratory syndrome-related coronavirus” .
34. Compound for use according to claim 28 wherein the infection by viruses is selected from infections by respiratory syndrome-related coronaviruses selected from the group consisting of SARS-CoV-2, SARS-CoV and MERS-CoV.
35. Compound for use according to claim 28 wherein the infection by viruses is SARS-CoV-2.
36. Composition comprising: a) a compound of formula (II),
Figure imgf000105_0001
wherein
- q is selected from 1, 2, 3 and 4;
- R4 is selected from H, =0, OR’, halogen, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R’, - R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; unsubstituted C6-18 aryl or C6-18 aryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl, (C6- 18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl, (C6-12)aryl(C2-6)alkynyl, -OR’, - OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; and unsubstituted 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl, or 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1- 6)alkyl, -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1-6)alkyl;
- R5 is selected from H, halogen, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6- 18)aryl(C1-6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; unsubstituted C6-18 aryl or C6-18 aryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl, (C6-18)aryl(C1- 6)alkyl, C6-12)aryl(C2-6)alkenyl, (C6-12)aryl(C2-6)alkynyl, -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; and unsubstituted 5- to 10- membered heterocyclyl or 5- to 10-membered heteroaryl or 5- to 10- membered heterocyclyl or 5- to 10-membered heteroaryl substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, -OR’, -OC(O)R’, - R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl and (C6- 18)aryl(C1-6)alkyl;
- Z is selected from -NR6R7R8 and halogen;
- R6 and R7 are independently selected from H, unsubstituted C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, C1-6 alkyl substituted with -OR’, -OC(O)R’, - R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6- 18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl; or
- R6 and R7, together with the nitrogen atom to which they are attached can form a 5- to 7-membered heterocyclyl group; or
- R6, R7 and R8 together with the nitrogen atom to which they are attached can form a guanidinium group; or
- R8 is absent, H, C1-6 alkyl or C1-6 haloalkyl;
- ^ represents a single or a double bond;
- G is selected from (C6-12)aryl and 5- to 10-membered heteroaryl, wherein the (C6-12)aryl and 5- to 10-membered heteroaryl are optionally substituted with R9;
- R9 and R10 are independently selected from H, halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-12)aryl, (C6-12)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl, (C6- 12)aryl(C2-6)alkynyl, -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, - CN, -NO2, 5- to 10-membered heteroaryl and 5- to 10-membered heterocyclyl, wherein the rings in the (C6-12)aryl, (C6-12)aryl(C1-6)alkyl, (C6- 12)aryl(C2-6)alkenyl, (C6-12)aryl(C2-6)alkynyl, 5- to 10-membered heteroaryl or 5- to 10-membered heterocyclyl are optionally substituted with halogen, C1-6 alkyl, C1-6 haloalkyl, (C6-18)aryl(C1-6)alkyl, -OR’, -OC(O)R’, -R'2 , -C(O)R'2 , -C(O)R’, -C(O)OR’, -CN, or -NO2; wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1-6)alkyl; or a salt or solvate thereof; and b) a compound selected from the group consisting of nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, ribavirin, favipiravir, chloroquine, hydroxychloroquine, lopinavir, ritonavir, umifenovir and recombinant type I interferon, preferably nirmatrelvir, molnupiravir, clofazimine, indomethacine, invermectin, disulfiram, boceprevir, paritaprevir, telaprevir, simeprevir, remdesivir, lopinavir and ritonavir.
37. Composition according to claim 36, for use in the treatment or prevention of an infection by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
38. Composition for use according to claim 37 wherein the infection by viruses is selected from infections by respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” and “Middle East respiratory syndrome-related coronavirus” .
39. Composition for use according to claim 37 wherein the infection by viruses is selected from infections by respiratory syndrome-related coronaviruses selected from the group consisting of SARS-CoV-2, SARS-CoV and MERS-CoV.
40. Composition for use according to claim 37 wherein the infection by viruses is
SARS-CoV-2.
41. Composition for use according to any one of claims 37 to 40, wherein the compound of formula (II) is clomiphene, or salts thereof, preferably clomiphene citrate.
42. Composition for use according to any one of claims 37 to 41 , wherein the compound of formula (II) is cis-clomiphene.
43. Composition for use according to any one of claims 37 to 41 , wherein the compound of formula (II) is trans-clomiphene.
44. Compound of formula
Figure imgf000108_0001
or a salt or solvate thereof.
45. A compound of formula (III) wherein
Figure imgf000108_0002
- A is selected from -CH-, -N-, and -C(OH)- when is a double bond, or is selected
Figure imgf000108_0003
from -NH-, -C(O)-, -CH2- and -CH(OH)- when
Figure imgf000108_0004
is a single bond;
- B is selected from -CH- and -N- when
Figure imgf000108_0005
is a double bond, and is selected from - CH2-, -N- and -NH- when is a single bond;
Figure imgf000108_0008
- Y is selected from -NH- and -CH2- when s a single bond, or is selected from -N-
Figure imgf000108_0006
and -CH- when double bond;
Figure imgf000108_0007
provided that when B is -NH-, then Y is -N- or -CH-, when B is -N-, then Y is -N-, -NH- or -CH-, and when B is -CH-, then Y = -N- or -CH-;
- C is selected from -NR1-, C1-6 alkyl, C3-7 cycloalkyl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein R1 is selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl and (C6-18)aryl(C1-6)alkyl;
- D is selected from guanidinium, -NR2R3R4, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl, wherein R2 and R3 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl and wherein the C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R', R'2 , C(O)R'2 , C(O)R’, C(O)OR’, CN, NO2, -(CH2)1-6-OR’, -(CH2)1-6- OC(O)R’, -(CH2)1-6- R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, - (CH2)1-6-CN, -(CH2)1-6- NO2, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl;
- E is selected from C6-12 aryl and 5- to 10-membered heteroaryl;
- R4 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
- Rs is selected from halogen, OR’, OC(O)R', R'2 , C(O)R'2 , C(O)R', C(O)OR’, CN, NO2, -(CH2)1-6-OR’, -(CH2)1-6-OC(O)R’, -(CH2)1-6-R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6- C(O)R’, -(CH2)1-6-C(O)OR', -(CH2)1-6-CN, -(CH2)1-6-NO2, C1-6 alkyl, C3-7 cycloalkyl, C1- 6 haloalkyl, C6-ib aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl or (C6-12)aryl(C2-6)alkynyl, -NR6R7R8, 5- to 10-membered heterocyclyl and 5- to 10- membered heteroaryl, wherein R6 and R7 are independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6- 12)aryl(C2-6)alkynyl and wherein the C6-18 aryl, 5- to 10-membered heterocyclyl and 5- to 10-membered heteroaryl can be unsubstituted or substituted with halogen, OR’, OC(O)R', R'2 , C(O)R'2 , C(O)R’, C(O)OR', CN, NO2, -(CH2)1-6-OR’, -(CH2)1-6- OC(O)R’, -(CH2)1-6- R'2 , -(CH2)1-6-C(O)R'2 , -(CH2)1-6-C(O)R’, -(CH2)1-6-C(O)OR’, - (CH2)1-6-CN, -(CH2)1-6- NO2, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl or (C6-12)aryl(C2-6)alkynyl, wherein each R’ is independently selected from H, C1-6 alkyl, C1-6 haloalkyl, C3-7 cycloalkyl, C6-18 aryl, C6-C12 haloaryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and (C6-12)aryl(C2-6)alkynyl;
- R8 is absent, H or C1-6 alkyl optionally substituted with at least one fluoride;
- m is selected from 0 and 1 ;
- n is selected from 0, 1 , 2, 3, 4, 5 and 6, wherein when n is 3-6 the resulting alkyl chain can contain at least one double bond;
- x is 0 or 1;
- z is 0, 1, 2, 3 or 4;
- each R is independently selected from H, C1-6 alkyl, -(CH2)1-6-0-C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-18 aryl, (C6-18)aryl(C1-6)alkyl, (C6-12)aryl(C2-6)alkenyl and
(C6-12)aryl(C2-6)alkynyl;
Figure imgf000110_0004
represents a single or a double bond; or a salt, solvate, tautomer or stereoisomer thereof, for use in the treatment or prevention of an infection by RNA-viruses, preferably of the family Coronaviridae, Orthomyxoviridae, Filoviridae, Flaviviridae, Retroviridae and Togaviridae.
46. Compound for use according to claim 45, wherein the compound of formula (III) is a compound of formula (IN’) or (III”)
Figure imgf000110_0001
wherein C, D, E, R, R5, m, n, x and z are as defined in claim 45.
47. Compound for use according to any one of claims 45 or 46, wherein the group is a group of the following formula:
Figure imgf000110_0002
wherein
Figure imgf000110_0003
- o is selected from 0 and 1 ;
- p is selected from 0, 1 , 2, 3, 4 and 5;
- R is independently selected from H, C1-6 alkyl, C3-7 cycloalkyl, C1-6 haloalkyl, C6-12 aryl and (C6-12)aryl(C1-6)alkyl; preferably R is selected from H and C1-6 alkyl.
48. Compound for use according to any one of claims 45 to 47, wherein the
Figure imgf000111_0001
Figure imgf000112_0001
or a salt, solvate or stereoisomer thereof.
49. Compound for use according to any one of claims 45 to 48 wherein the infection by viruses is selected from infections by respiratory syndrome-related coronaviruses selected from the species “Severe respiratory syndrome-related coronavirus” and “Middle East respiratory syndrome-related coronavirus” .
50. Compound for use according to claim 49, wherein the respiratory syndrome- related coronavirus is selected from the group consisting of SARS-CoV-2, SARS-CoV and MERS-CoV, preferably SARS-CoV-2.
51. Compound for use according to claim 49, wherein the respiratory syndrome- related coronavirus is SARS-CoV-2.
PCT/EP2022/053938 2021-02-17 2022-02-17 Small-molecule agents with antiviral activity against rna viruses WO2022175384A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP21382127 2021-02-17
EP21382127.5 2021-02-17

Publications (1)

Publication Number Publication Date
WO2022175384A1 true WO2022175384A1 (en) 2022-08-25

Family

ID=74732854

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2022/053938 WO2022175384A1 (en) 2021-02-17 2022-02-17 Small-molecule agents with antiviral activity against rna viruses

Country Status (1)

Country Link
WO (1) WO2022175384A1 (en)

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0106462A2 (en) * 1982-09-04 1984-04-25 Pfizer Limited Dihydropyridines
EP0229623A2 (en) * 1986-01-09 1987-07-22 Hoechst Aktiengesellschaft Diaryl-substituted alkylamines, procedure for their preparation, their application and medicaments containing them
WO1999024421A1 (en) * 1997-11-07 1999-05-20 Schering Corporation Imidazoylalkyl substituted with a five, six or seven membered heterocyclic ring containing one nitrogen atom
WO2000032574A1 (en) * 1998-11-27 2000-06-08 Sanofi-Synthelabo Novel 2-pyridone derivatives, preparation method and therapeutic use
WO2003011856A1 (en) * 2001-07-27 2003-02-13 Sanofi-Synthelabo Aminoalkylimidazole derivatives preparation and therapeutic use thereof
US20050096384A1 (en) * 2003-09-18 2005-05-05 Barry Forman Compounds and methods for treating breast cancer and other diseases
JP2005120014A (en) * 2003-10-16 2005-05-12 Toray Fine Chemicals Co Ltd Method for producing arylmethylpiperazine derivative
WO2011073328A1 (en) * 2009-12-16 2011-06-23 Novo Nordisk A/S Glp-1 receptor agonist compounds with a modified n-terminus
JP2013032299A (en) 2011-08-01 2013-02-14 Pola Chemical Industries Inc External preparation for skin
US20140005196A1 (en) 2012-06-28 2014-01-02 California State University Fullerton Method of inhibiting apolipoprotein-e expression comprising administering a triarylmethyl amine compound
WO2015157223A1 (en) 2014-04-07 2015-10-15 University Of Maryland, Baltimore Methods of treating coronavirus infection
EP3009123A1 (en) * 2008-12-22 2016-04-20 Pola Chemical Industries Inc. Melanin production inhibitor

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0106462A2 (en) * 1982-09-04 1984-04-25 Pfizer Limited Dihydropyridines
EP0229623A2 (en) * 1986-01-09 1987-07-22 Hoechst Aktiengesellschaft Diaryl-substituted alkylamines, procedure for their preparation, their application and medicaments containing them
WO1999024421A1 (en) * 1997-11-07 1999-05-20 Schering Corporation Imidazoylalkyl substituted with a five, six or seven membered heterocyclic ring containing one nitrogen atom
WO2000032574A1 (en) * 1998-11-27 2000-06-08 Sanofi-Synthelabo Novel 2-pyridone derivatives, preparation method and therapeutic use
WO2003011856A1 (en) * 2001-07-27 2003-02-13 Sanofi-Synthelabo Aminoalkylimidazole derivatives preparation and therapeutic use thereof
US20050096384A1 (en) * 2003-09-18 2005-05-05 Barry Forman Compounds and methods for treating breast cancer and other diseases
JP2005120014A (en) * 2003-10-16 2005-05-12 Toray Fine Chemicals Co Ltd Method for producing arylmethylpiperazine derivative
EP3009123A1 (en) * 2008-12-22 2016-04-20 Pola Chemical Industries Inc. Melanin production inhibitor
WO2011073328A1 (en) * 2009-12-16 2011-06-23 Novo Nordisk A/S Glp-1 receptor agonist compounds with a modified n-terminus
JP2013032299A (en) 2011-08-01 2013-02-14 Pola Chemical Industries Inc External preparation for skin
US20140005196A1 (en) 2012-06-28 2014-01-02 California State University Fullerton Method of inhibiting apolipoprotein-e expression comprising administering a triarylmethyl amine compound
WO2015157223A1 (en) 2014-04-07 2015-10-15 University Of Maryland, Baltimore Methods of treating coronavirus infection

Non-Patent Citations (26)

* Cited by examiner, † Cited by third party
Title
BINISTI C ET AL: "Structure-activity relationships in platelet-activating factor (PAF). 11-From PAF-antagonism to phospholipase A"2 inhibition: syntheses and structure-activity relationships in 1-arylsulfamido-2-alkylpiperazines", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, ELSEVIER, AMSTERDAM, NL, vol. 36, no. 10, 1 October 2001 (2001-10-01), pages 809 - 828, XP004372890, ISSN: 0223-5234, DOI: 10.1016/S0223-5234(01)01274-0 *
CALDERONE ALBA ET AL.: "Selective Estrogen Receptor Modulators in COVID-19: A Possible Therapeutic Option?", FRONTIERS IN PHARMACOLOGY, vol. 11, 15 July 2020 (2020-07-15), XP055828840, DOI: 10.3389/fphar.2020.01085
CALDERONE ALBA ET AL: "Selective Estrogen Receptor Modulators in COVID-19: A Possible Therapeutic Option?", vol. 11, 15 July 2020 (2020-07-15), XP055828840, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7381128/pdf/fphar-11-01085.pdf> DOI: 10.3389/fphar.2020.01085 *
CAPUZZI STEPHEN J ET AL.: "Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors", JOURNAL OF MEDICINAL CHEMISTRY, vol. 61, no. 8, 26 April 2018 (2018-04-26), pages 3582 - 3594, XP055828973, DOI: 10.1021/acs.jmedchem.8b00035
CAPUZZI STEPHEN J. ET AL: "Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors", vol. 61, no. 8, 26 April 2018 (2018-04-26), pages 3582 - 3594, XP055828973, ISSN: 0022-2623, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.8b00035> DOI: 10.1021/acs.jmedchem.8b00035 *
DATABASE REGISTRY [online] CAS; 19 March 2012 (2012-03-19), ANONYMOUS: "Ethanone, 2-amino-1-[4-[[1-(triphenylmethyl)-1H-imidazol-4-yl]methyl]-1-piperidinyl]-", XP055917143, retrieved from STN Database accession no. 1361198-04-0 *
GAO KAIFU ET AL.: "Repositioning of 8565 Existing Drugs for COVID-19", JOURNAL OF PHYSICAL CHEMISTRY LETTERS, vol. 11, no. 13, 2 July 2020 (2020-07-02), pages 5373 - 5382, XP055853857, DOI: 10.1021/acs.jpclett.0c01579
GAO KAIFU ET AL: "Repositioning of 8565 Existing Drugs for COVID-19", vol. 11, no. 13, 2 July 2020 (2020-07-02), US, pages 5373 - 5382, XP055853857, ISSN: 1948-7185, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acs.jpclett.0c01579> DOI: 10.1021/acs.jpclett.0c01579 *
IYER J R ET AL: "O-CHLOROTHRITYL DERIVATIVES AS POTENTIAL ANTIFUNGAL AGENTS", INDIAN DRUGS, INDIAN DRUG MANUFACTURERS' ASSOCIATION, IN, vol. 22, no. 7, 1 January 1985 (1985-01-01), pages 370 - 372, XP002913119, ISSN: 0019-462X *
JEON SANGEUN ET AL.: "Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 64, no. 7, 4 May 2020 (2020-05-04), pages e00819 - 20, XP055825491, DOI: 10.1128/AAC.00819-20
JEON SANGEUN ET AL: "Identification of Antiviral Drug Candidates against SARS-CoV-2 from FDA-Approved Drugs", ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, vol. 64, no. 7, 4 May 2020 (2020-05-04), US, pages e00819 - 20, XP055825491, ISSN: 0066-4804, DOI: 10.1128/AAC.00819-20 *
KARUNAKARAN KALYANI B. ET AL: "Potentially repurposable drugs for COVID-19 identified from SARS-CoV-2 Host Protein Interactome", PREPRINT (VERSION 1), 28 May 2020 (2020-05-28), XP055853838, Retrieved from the Internet <URL:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336709/pdf/nihpp-rs30363v1.pdf> [retrieved on 20211021], DOI: 10.21203/rs.3.rs-30363/v1 *
KARUNAKARAN KALYANI B. ET AL: "SUPPLEMENTARY MATERIAL: Potentially repurposable drugs for COVID-19 identified from SARS-CoV-2 Host Protein Interactome", PREPRINT (VERSION 1), 28 May 2020 (2020-05-28), XP055853841, Retrieved from the Internet <URL:https://doi.org/10.21203/rs.3.rs-30363/v1> [retrieved on 20211021], DOI: 10.21203/rs.3.rs-30363/v1 *
MARTIN WILLIAM R. ET AL.: "Repurposing of FDA-Approved Toremifene to Treat COVID-19 by Blocking the Spike Glycoprotein and NSP14 of SARS-CoV-2", JOURNAL OF PROTEOME RESEARCH, vol. 19, 10 September 2020 (2020-09-10), pages 4670 - 4677, XP055828827, DOI: 10.1021/acs.jproteome.0c00397
MARTIN WILLIAM R. ET AL: "Repurposing of FDA-Approved Toremifene to Treat COVID-19 by Blocking the Spike Glycoprotein and NSP14 of SARS-CoV-2", vol. 19, no. 11, 10 September 2020 (2020-09-10), pages 4670 - 4677, XP055828827, ISSN: 1535-3893, Retrieved from the Internet <URL:https://pubs.acs.org/doi/pdf/10.1021/acs.jproteome.0c00397> DOI: 10.1021/acs.jproteome.0c00397 *
PICARD SYLVIE ET AL: "Parallel Supported Synthesis of Polyamine-Imidazole Conjugates", ORGANIC LETTERS, vol. 6, no. 25, 9 November 2004 (2004-11-09), US, pages 4711 - 4714, XP055916955, ISSN: 1523-7060, DOI: 10.1021/ol0480630 *
PRASANTA GHORAI ET AL: "Acylguanidines as Bioisosteres of Guanidines: N G -Acylated Imidazolylpropylguanidines, a New Class of Histamine H 2 Receptor Agonists", JOURNAL OF MEDICINAL CHEMISTRY, vol. 51, no. 22, 27 November 2008 (2008-11-27), pages 7193 - 7204, XP055086371, ISSN: 0022-2623, DOI: 10.1021/jm800841w *
R. JEFFREY BAUMANN ET AL.: "Clomiphene Analogs with Activity In Vitro and In Vivo against Human Breast Cancer Cells", BIOCHEMICAL PHARMACOLOGY, vol. 55, 1 March 1998 (1998-03-01), pages 841 - 851, XP055039842, DOI: 10.1016/S0006-2952(97)00574-1
R.JEFFREY BAUMANN ET AL: "Clomiphene Analogs with Activity In Vitro and In Vivo against Human Breast Cancer Cells", BIOCHEMICAL PHARMACOLOGY, vol. 55, no. 6, 1 March 1998 (1998-03-01), pages 841 - 851, XP055039842, ISSN: 0006-2952, DOI: 10.1016/S0006-2952(97)00574-1 *
SAMANT LALIT R ET AL: "Comparative Docking analysis of rational drugs against COVID- 19 Main Protease", CHEMRXIV., 1 January 2020 (2020-01-01), XP055853936, Retrieved from the Internet <URL:https://chemrxiv.org/engage/chemrxiv/article-details/60c749fd702a9b828b18b20c> [retrieved on 20211022], DOI: 10.26434/chemrxiv.12136002.v1 *
TORRIANI GIULIA ET AL.: "Identification of Clotrimazole Derivatives as Specific Inhibitors of Arenavirus Fusion", JOURNAL OF VIROLOGY, vol. 93, 1 March 2019 (2019-03-01), XP055853837, DOI: 10.1128/JVI.01744-18
TORRIANI GIULIA ET AL: "Identification of Clotrimazole Derivatives as Specific Inhibitors of Arenavirus Fusion", JOURNAL OF VIROLOGY, vol. 93, no. 6, 1 March 2019 (2019-03-01), US, XP055853837, ISSN: 0022-538X, DOI: 10.1128/JVI.01744-18 *
XIONG HUA-LONG ET AL.: "Several FDA-Approved Drugs Effectively Inhibit SARS- CoV-2 Infection in vitro", FRONTIERS IN PHARMACOLOGY, vol. 11, 5 February 2021 (2021-02-05)
XIONG HUA-LONG ET AL: "Several FDA-Approved Drugs Effectively Inhibit SARS-CoV-2 Infection in vitro", FRONTIERS IN PHARMACOLOGY, vol. 11, 5 February 2021 (2021-02-05), XP055828756, DOI: 10.3389/fphar.2020.609592 *
ZHAO YUGUANG ET AL.: "Toremifene interacts with and destabilizes the Ebola virus glycoprotein", NATURE, MACMILLAN JOURNALS LTD., vol. 535, 29 June 2016 (2016-06-29), pages 169 - 172, XP037508948, DOI: 10.1038/nature18615
ZHAO YUGUANG ET AL: "Toremifene interacts with and destabilizes the Ebola virus glycoprotein", NATURE, MACMILLAN JOURNALS LTD., ETC, LONDON, vol. 535, no. 7610, 29 June 2016 (2016-06-29), pages 169 - 172, XP037508948, ISSN: 0028-0836, [retrieved on 20160629], DOI: 10.1038/NATURE18615 *

Similar Documents

Publication Publication Date Title
JP6598974B2 (en) Novel tricyclic 4-pyridone-3-carboxylic acid derivatives for the treatment and prevention of hepatitis B virus infection
CA2948080A1 (en) Novel dihydroquinolizinones for the treatment and prophylaxis of hepatitis b virus infection
FI88504B (en) PROTECTION OF THERAPEUTIC FRAME THERAPEUTIC 4-BENZYL-1- (2H) -Phthalazine derivative
JP6903658B2 (en) Heterocyclic indole for use in influenza virus infection
IL237048A (en) Fused bicyclic sulfamoyl derivatives and the use thereof as medicaments for the treatment of hepatitis b
US8048889B2 (en) 3,4-disubstituted coumarin and quinolone compounds
US8329703B2 (en) Pyrazole compounds
CN116751164A (en) Protease inhibitors, their preparation and use
WO2023065606A1 (en) New deuterated cyano compound, and preparation method therefor and composition and use thereof
CN112062800B (en) Phosphoramidate derivatives of nucleoside compounds and uses thereof
CN112521386B (en) Polycyclic pyridone compounds having antiviral action, pharmaceutical combinations and uses thereof
EP2028938A1 (en) 3,4-disubstituted coumarin and quinolone compounds
JP5404607B2 (en) Aniline derivative having anti-RNA virus action
WO2023036945A1 (en) Phenoxy-acetyl-thioureido-benzenesulfonamide derivatives, and their uses
Miyano et al. New antiarrhythmic agents. N-aryl-8-pyrrolizidinealkanamides
CN115135646B (en) Substituted polycyclic compounds, pharmaceutical compositions and uses thereof
WO2022175384A1 (en) Small-molecule agents with antiviral activity against rna viruses
Wu et al. Synthesis of Pyrazine‐1, 3‐thiazine Hybrid Analogues as Antiviral Agent Against HIV‐1, Influenza A (H1N1), Enterovirus 71 (EV 71), and Coxsackievirus B3 (CVB 3)
KR20210134621A (en) Internal cyclic sulfamidine amide-aryl amide compounds and their use for the treatment of hepatitis B
WO2017121188A1 (en) Hepatitis c virus inhibitor, pharmaceutical composition and application thereof
CN112724156B (en) Polycyclic pyridone derivative, pharmaceutical composition and application thereof
CN115160301B (en) Mountain nuciferine derivative, and preparation method and application thereof
KR20180036522A (en) Stilbene derivatives and preparation method thereof
KR101935794B1 (en) Inhibitor of function of cyclophilin and use of the same
EP3939664A1 (en) Compounds for use in the treatment of viral infections by virus of the family coronaviridae

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22706594

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22706594

Country of ref document: EP

Kind code of ref document: A1