WO2025113647A2 - Dérivés hétérocycliques et leur utilisation dans le traitement ou la prévention de troubles associés à ebv - Google Patents

Dérivés hétérocycliques et leur utilisation dans le traitement ou la prévention de troubles associés à ebv Download PDF

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WO2025113647A2
WO2025113647A2 PCT/CN2024/135702 CN2024135702W WO2025113647A2 WO 2025113647 A2 WO2025113647 A2 WO 2025113647A2 CN 2024135702 W CN2024135702 W CN 2024135702W WO 2025113647 A2 WO2025113647 A2 WO 2025113647A2
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alkyl
ebv
compound
dimethoxy
alkoxy
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WO2025113647A3 (fr
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Qian Zhong
Hervé Galons
Nassima Oumata
Musheng ZENG
Yongmin Zhang
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Scientiam Pharma
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Scientiam Pharma
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    • 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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention relates to the treatment and prevention of EBV-associated disorders, in particular, diseases due to latent EBV infections.
  • Epstein-Barr Virus also known as human gamma herpes virus 4
  • EBV Epstein-Barr Virus
  • human gamma herpes virus 4 is a double-stranded DNA virus that is one of the nine human herpesvirus types in the herpes family.
  • EBV is considered to be a successful infectious agent as the prevalence of EBV is about 90%of all humans. It is generally well tolerated. However, it has been associated with the development of several diseases, including auto-immune diseases such as multiple sclerosis, lymphomas, and epithelial cell cancers, in particular in immunocompromised subjects. After the primary infection, the virus can remain latent for life-long.
  • EBV DNA, anti-EBV antibodies, and miRNA levels characterize EBV-associated diseases (Tan et al Int J Cancer. 2020; 146: 2336-2347) .
  • the expression of several antigens is also used to characterize EBV-associated diseases (Münz, Nat Rev Microbiol 2019, 17, 691–700) .
  • these antigens have been extensively studied.
  • Epstein-Barr virus nuclear antigen 1 EBNA-1 is always expressed. This biomarker characterizes EBV-associated diseases.
  • Damania et al Cell. 2022, 185, 3652-3670 see also Emmanuel Cancers (Basel) . 2021, 30: 4 944.
  • EBV-associated cancers include nasopharyngeal carcinoma (NPC) , gastric carcinoma, posttransplant lymphoproliferative disorders (PTLD) , HIV-associated lymphoma, Hodgkin's lymphoma, Hodgkin's disease, and Burkitt's lymphoma.
  • NPC nasopharyngeal carcinoma
  • PTLD posttransplant lymphoproliferative disorders
  • EBV plays a role in 30 to 50%of cases of Hodgkin's disease in the U. S (Haverkos et al., Blood Adv. 2023, 010330) while Burkitt's lymphoma, which is responsible for over half of all childhood cancers in Africa, is mostly linked to the Epstein-Barr virus (Graham et al, Burkitt Lymphoma. 2023 Aug 7. In: StatPearls [Internet] . Treasure Island (FL) : StatPearls Publishing; 2023 Jan–. PMID: 30844175) .
  • EBV-associated gastric carcinoma (EBVaGC) which, represents approximately 10%of all gastric cancers, is generally resistant to antineoplastic therapies.
  • PTLD Posttransplant lymphoproliferative disorders
  • EBV Epstein-Barr virus
  • EBV auto-immune diseases
  • EBNA1 et al. Scand J Clin Lab Invest. 2019; 79: 7-16; Trier et al, Antibodies 2019, 8: 35
  • High plasma levels of antibodies to certain EBV antigens such as EBNA1 (or others e.g.
  • LMP1, EBNA2, BALF5, EAD, BALF2, EA/R, VCA p18, or VCA p23 are generally found in the context of EBV-associated diseases (Kieser et al, Curr Top Microbiol Immunol. 2015; 391: 119-49) , (Giehler et al. Nat Commun. 2024; 15: 414) .
  • EBNA1 latent protein EBNA1 which is the only EBV protein that is consistently expressed in all latency types, and therefore in all EBV-associated tumors.
  • This versatile protein functions in the maintenance, replication, and segregation of the EBV genome and can therefore serve as an attractive therapeutic target to treat EBV-associated disorders in particular cancers. Indeed, the main role of this protein is viral genome maintenance but it is also associated with oncogenesis.
  • drugs acting on EBNA1 are expected to have minimum off-target effects, whereby such drugs appear to have a high potential in the treatment and the prophylaxis of any EBV-associated disorders, in particular in immunocompromised subjects.
  • EBNA1 inhibitors As of today, several potential EBNA1 inhibitors have been identified, among them certain Hsp90 inhibitors, inhibitors blocking EBNA1-DNA binding, , and inhibitors based on truncated peptides from EBNA1 dimeric interface (Jiang, Theranostics, 2018, 8 (19) : 5307-5319) .
  • VK-1727 an EBNA1-DNA binding inhibitor, was tested in various in vivo xenograft mouse models for specific EBV-positive cancers and was shown to suppress EBV-positive tumor proliferation (Soldan et al., Gastric Cancer (2021) 24: 1076–88)
  • VK-1727 was shown to block the proliferation of spontaneous lymphoblastoid cell lines from patients with Multiple Sclerosis (MS) confirming that EBNA1 is a target of interest for the management of MS as well (Monaco et al., Neurology, Neuroimmunology, &Neuroinflammation, 2023, 10 (5) ) .
  • MS Multiple Sclerosis
  • a derivative, VK-2019 is presently undergoing phase 1/2 clinical trial against nasopharyngeal carcinoma ( https: //clinicaltrials. gov/ct2/show/NCT03682055 ) .
  • the Invention relates to a compound of formula (I) :
  • R 1 , R 2 , R 3, R 4 , R 7 , R 8 , R 9 and R 10 independently represents H, halogen, C 1 -C 8 alkyl, C 1 -C 8 halogenoalkyl, C 1 -C 8 hydroxyalkyl, -OCF 3 , -NO 2 , -CN, -OR 11 , NHCOCHR 17 NHR 18 , -NR 12 - R 13 , -COOR 12 , -CONR 12 R 13 , NHCO (CH 2 ) n NR 12 R 13 , -NHCOR 17 -SO 2 NR 12 R 13 , -SO 2 R 12 , -CH 2 SO 2 NR 12 R 13 , OPOR 12 OR 13 , (CH 2 ) nNR 12 R 13 , - (CH 2 ) n COOR 12 - (CH 2 ) n CONR 12 R 13 , - (CH 2 ) q SO 2 NR 12 R 13 ,
  • Het1 is a 3-to 6-membered heterocycle, optionally and optionally fused with a C 3 -C 5 carbocycle,
  • R 11 is H, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 dimethoxy alkyl, C 1 -C 6 halogeno hydroxyalkyl, C 1 -C 6 dihydroxyalkyl - (CH 2 ) q Het2, - (CH 2 ) q O (PO) (OR 15 ) 2 , - (CH 2 ) n OHet 2 , - (CH 2 ) n NR 12 R 13 , -COCH (CH 2 SH) NHCOCH 3 , C 2 -C 14 alkoxy alkyl optionally substituted, - (CH 2 ) n NR 15 COCH 3 , - (CH 2 ) n COOR 12 , - (CH 2 ) n CONR 12 R 13, - (CH 2 ) q SO 2 NR 12 R 13 , -COR 16 , or – (CH 2 ) n OCOR 16
  • Het2 is 3-to 6-membered heterocycle optionally substituted
  • n is independently an integer from 1 to 6, preferably 1, 2, or 3,
  • Each o is independently 1 or 2
  • Each q is independently an integer from 0 to 6, preferably 0, 1, 2 or 3,
  • R 12 and R 13 are independently H, C 1 -C 6 alkyl, or C 2-14 alkoxy alkyl, Or R 12 and R 13 form together, with the N atom to which they are bound, a 5-or 6-membered heterocycle optionally substituted,
  • R 14 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy alkyl, - (CH 2 ) p Het3 or - (CH 2 ) p Cyc1 with p an integer from 0 to 6, preferably from 1 to 3, Het3 being a saturated or unsaturated heterocycle optionally substituted and Cyc1 being a C 1 -C 6 cycloalkyl
  • R 15 is H or C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl,
  • R 16 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, -CHR 17 NHCOR 17 or -OCHR 17 OCOR 17
  • Each R 17 independently is H or a C 1 -C 3 alkyl
  • R 18 is H, or COCH 3 ,
  • A is either -NR 5 R 6 or wherein
  • ⁇ R 5 is H
  • R 6 is H, C 1 -C 6 alkyl, COO (CH 2 ) n Het4, COR 21 or COOCHR 17 OCOR 17 , wherein
  • R 21 is OH, halogen, -O (CH 2 ) n NR 22 R 23 , -O (CH 2 ) n O (CH 2 ) m CH 3 optionally substituted or C 2-14 alkoxy alkyl optionally substituted,
  • R 22 and R 23 are independently selected from H, C 1 -C 6 alkyl, or C 2-14 alkoxy alkyl optionally substituted, and
  • Het4 is a 3-to 6-membered heterocycle optionally substituted
  • R 20 is H, C 1 -C 8 alkyl, C 2 -C 14 alkoxy alkyl optionally substituted, and
  • ⁇ R 19 is either a 5-to 12-membered aryl or heteroaryl optionally substituted
  • the compound of formula (I) is characterized by one or several of the following features :
  • - A is NR 5 R 6 , preferably -NH 2 and/or
  • R 4 and R 2 are independently halogen, OH, C 1 -C 6 alkoxy, or -O (CH 2 ) n O (CH 2 ) m CH 3 , and/or
  • R 7 , R 8 and R 9 are not H, and/or
  • R 3 is H, halogen, OH, C 1 -C 6 alkoxy, or -O (CH 2 ) n O (CH 2 ) m CH 3 .
  • the compound is of formula (Id)
  • R 3 , R 8 , R 9 and R 10 are as defined in formula (I) .
  • Each R 24 or R 25 independently represent C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl or – (CH 2 ) n O (CH 2 ) m CH 3 with n is an integer from 1 to 6 and m is an integer from 0 to 6
  • R 3 is H or OR 26 wherein R 26 represents C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl or – (CH 2 ) n O (CH 2 ) m CH 3 with n is an integer from 1 to 6 and m is an integer from 0 to 6.
  • the compound of formula (Id) is such that:
  • each R 25 and R 24 is independently a C 1 -C 6 , preferably C 1 -C 3 alkyl,
  • R 10 is H, or a halogen such as F and
  • R 8 and R 9 are independently selected from OH, Cl, F, Br, OH, C 1 -C 3 alkoxy, preferably OCH 3 , C 1 -C 3 alkyl, CF 3 , OCF 3 , O (CH 2 ) n OH, Het1, O (CH 2 ) n NCOR 17 , O (CH2) nNR 12 R 13 , -NHCO (CH 2 ) n R 12 R 13 , O (CH 2 ) q Het2, wherein
  • ⁇ n is an integer from 1 to 6, preferably 1, 2 or 3
  • ⁇ q is an integer from 1 to 6, preferably 0, 1, 2 or 3
  • Het1 is a 4-, 5-or 6-membered heterocycle, preferably pyrrolidinyl, optionally substituted by an halogen, -CONH 2 , -COR 17 , -OH, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl,
  • Het2 a 5-or 6-membered heterocycle, preferably piperidinyl, optionally substituted by an halogen, -OH, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl.
  • ⁇ R 17 is H or a C 1 -C 3 alkyl
  • R 12 and R 13 are independently H or a C 1 -C 3 alkyl or form with the N atom to which they are bound a 5 or 6-membered heterocycle optionally substituted with a C 1 -C 3 alkyl.
  • the EBV-associated disorder is preferably an EBV-associated autoimmune diseases such as multiple sclerosis, an EBV active infection or an EBV-positive cancer.
  • EBV-positive cancers include EBV-positive nasopharyngeal carcinoma, NKT cell lymphoma, gastric carcinoma, Hodgkin's Lymphoma, post-transplant lymphoproliferative disease (PTLD) , Burkitt's lymphoma, lymphoma in subjects with acquired immune deficiency syndrome, Diffuse large B-cell lymphoma, gastric cancer, parotid carcinoma, breast carcinoma, leiomyosarcoma and any combination thereof.
  • PTLD post-transplant lymphoproliferative disease
  • the EBV-associated disorder is selected from autoimmune EBV-associated disorders, preferably multiple sclerosis, infectious mononucleosis and chronic active EBV disease (CAEBV) .
  • autoimmune EBV-associated disorders preferably multiple sclerosis, infectious mononucleosis and chronic active EBV disease (CAEBV) .
  • CAEBV chronic active EBV disease
  • the compound is administered to an immunocompromised subject.
  • the compound is used for treating or preventing an EBV-positive cancer selected from an EBV-positive nasopharyngeal carcinoma, an EBV-positive gastric carcinoma and an EBV-positive lymphoma, preferably PTLD.
  • the compound is for preventing or treating an EBV-positive cancer in an immunocompromised subject and/or in a transplanted subject.
  • the Invention relates to a compound of formula (Id)
  • R 3 , R 8 , R 9 and R 10 are as defined in Claim 1, and
  • Each R 24 or R 25 independently represent C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl or – (CH 2 ) n O (CH 2 ) m CH 3 with n is an integer from 1 to 6 and m is an integer from 0 to 6, with proviso that R 3 , R 10 , R 8 , and R 9 are not all H, when R 24 and R 25 are CH 3 .
  • Such compounds are suitable for use in the treatement or the prevention of an EBV-associated disease, in particular an EBV-positive cancer.
  • the Invention also relates to a prodrug of a compound of formula (Id) , wherein the prodrug comprises a labile moiety selected from:
  • said labile moiety being preferably linked to the amino group at position 6 of the aminophenanthridine backbone or to a hydroxyl group present in R 8 , R 9 or R 10 .
  • the Invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound as defined herein and a pharmaceutically acceptable excipient thereof.
  • Such a pharmaceutical composition can be used in the treatment or the prevention of an EBV-associated disease, preferably an EBV-positive cancer.
  • the invention also relates to a method for preparing a compound of formula (I) as described herein wherein A is NH 2 , which comprises the steps of :
  • R 1 -R 10 are as defined in formula (I) in Claim 1, X is halogen, preferably Br and each R 26 is H, or C 1 -C 6 alkyl , or R 26 groups form together with B (O) 2 a 5-membered heterocycle optionally substituted with one or several C 1 -C 3 alkyl.
  • step (b) is performed in the presence of Fe/NH 4 Cl.
  • step (b) is performed in the presence of B 2 (OH) 4 and 4, 4’ bipyridine, preferably in DMF and at room temperature.
  • the Invention further relates to an intermediate reagent selected from the group consisting of :
  • the Invention further relates to the use of a compound as defined herein in the manufacture of a medicament for treating or preventing an EBV-associated disease, preferably an EBV-positive cancer in a subject.
  • the Invention further relates to a method for treating or preventing an EBV-associated disease in a subject comprising administering an effective amount of a compound as defined herein to the subject.
  • the compounds were able to inhibit the proliferation of several EBV-positive cancer cell lines, including EBV-positive lymphoma and EBV-positive carcinoma.
  • EBV-positive lymphoma EBV-positive lymphoma
  • EBV-positive carcinoma EBV-positive carcinoma
  • the compounds of the Invention were more effective than VK-2019, an EBNA1-DNA binding inhibitor used as a positive control in the in vitro assy, which is currently under clinical clinical trial against nasopharyngeal carcinoma.
  • the compounds of the Invention were more effective in preventing proliferation in EBV-positive cancer cell lines than in EBV-negative cell lines.
  • 6-aminophenanthridine derivatives have been identified as possible prion inhibitors (e.g. Bach, 2003, Nature Biotechnology, 21, 9, 1075_1081) or as adjuvant in vaccine compositions (WO201144734) .
  • the Invention relates to 6-aminophenanthridine derivatives as described herein, of formula (I) or (Ia) - (Id) or pharmaceutically acceptable salts, solvates and/or prodrugs thereof per se (hereafter the compounds of the invention) .
  • the Invention is also concerned with said compounds for use as drugs, in particular in the treatment or the prevention of EBV-associated disorders.
  • a further aspect of the invention is the use of said compounds in the manufacture of a drug, in particular for the treatment or the prevention of an EBV-associated disorder.
  • the Invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention as an active ingredient in combination with at least one pharmaceutically acceptable excipient.
  • the Invention also relates to said composition for use as a medicine, in particular for treating or preventing an EBV-related disease.
  • the compounds of the Invention may be used as EBNA1 inhibitors, in particular as EBNA1-expression inhibitors.
  • the compounds of the Invention may be used as anti-proliferative agent against EBV-positive cells, in particular EBV-positive B cells, EBV-positive epithelial cells and EBV-positive cancer cells, in particular EBV-positive lymphomas or EBV-positive carcinomas .
  • the Invention also relates to a method for treating or preventing an EBV-associated disorder in a subject comprising administering said subject with an effectively amount of a compound of the invention or a pharmaceutical composition of the invention.
  • the compounds of the invention can be used to treat or prevent any kind of EBV-associated disorders, in particular EBV-positive cancers and EBV-induced autoimmune disorders such as multiple sclerosis.
  • EBV-associated diseases of interest encompass, without being limited to, EBV-positive nasopharyngeal carcinoma (NPC) , gastric carcinoma, posttransplant lymphoproliferative disorders (PTLD) , lymphoma in subjets with HIV or AIDS, Hodgkin's lymphoma, Hodgkin's disease, and Burkitt's lymphoma.
  • NPC EBV-positive nasopharyngeal carcinoma
  • PTLD posttransplant lymphoproliferative disorders
  • lymphoma in subjets with HIV or AIDS AIDS
  • Hodgkin's lymphoma Hodgkin's disease
  • Burkitt's lymphoma Burkitt's lymphoma.
  • the Invention refers to a method for preparing 6-aminophenanthridine derivatives as described herein, in particular of formula (I) or (Ia) - (Id) , and the corresponding intermediate reagents per se.
  • the treatment of a disease or a disorder includes curing, delaying, alleviating or slowing the progression of the disease or the disorder or that of one or more of its symptoms as well as the attenuation, the slowing, the reverse or the elimination of one or more of the symptoms of the disease or the disorder.
  • treatment of a disease/disorder also encompasses the fact of improving “the overall survival” and/or “the progression free survival” in a subject.
  • the wording “treating or treatment of a disease or disorder” does not mean that the disease/disorder or a symptom associated therewith be necessary and completely eliminated in the subject.
  • progression-free survival refers to increasing the length of time during and after the treatment of the disease that the subject lives with the disease without getting worse.
  • all survival refers to the length of time from the start of the treatment for the disease that the patient is still alive.
  • the progression of free survival and the “overall survival” figures are typically determined as mean values determined from an appropriate-sized clinical trial.
  • prevention of a disease or a disorder includes preventing or delaying the onset of the disease or one or more symptoms associated with said disease.
  • the “prevention of a disease” also refers to any act intended to ameliorate the health status of patients such as therapy, prophylaxis and retardation of the disease or the disorder and/or to prevent the patient from being afflicted by the disease or the disorder. In some embodiments, this term also refers to minimizing the risk (or the probability) for a patient to develop said disease or symptom, as compared to a patient who has not been administered the compound of the invention.
  • a therapeutically effective amount is meant an amount of the compound of the invention which prevents, removes, slows down the disease or disorder or reduces or delays one or several symptoms of said disease in the subject.
  • Epstein-Barr virus is one of the most successful pathogens in humans with more than 90%of the adult population persistently infected. Primary infection mostly occurs in childhood and is asymptomatic but can also manifest as infectious mononucleosis (IM) when primary infection occurs in the adolescent.
  • IM infectious mononucleosis
  • the target cells of EBV include B cells and epithelial cells.
  • the nature and mechanism of EBV entry into these cell types are different, requiring different glycoprotein complexes to bind to specific receptors on the target cells.
  • EBV may also occasionally infect other cell types such as T/natural killer cells
  • EBV The lifecycle of EBV encompasses three different phases, pre-latent phase, latent phase and lytic phase.
  • Each latency program leads to the production of a limited, distinct set of viral proteins (EBNAs, LMPs) and viral RNAs (microRNAs –BART, BHRF1-and non-coding nuclear RNAs -EBER) .
  • EBNAs viral proteins
  • microRNAs –BART viral RNAs
  • BHRF1-and non-coding nuclear RNAs -EBER viral proteins
  • EBER is expressed by EBV-infected cells in all latency stages and is thus abiomarker of interest.
  • the virus may become reactivated from the latent state through mechanisms that are unclear.
  • this lytic phase of infection all lytic genes of EBV (>80 genes) are expressed, potent viral DNA replication takes place and progeny virus particles are produced.
  • CD4 + and CD8 + T cells especially cytotoxic CD8 + T cells, are effective at controlling this process.
  • reactivation is clinically significant in immunocompromised patients (e.g. after stem cell or organ transplantation, in patients treated for autoimmunity or cancer, in the setting of HIV/AIDS or immunodeficiencies) leading to the development of lymphomas such as Burkitt's lymphoma (BL) and Hodgkin's lymphoma (HL) and being associated with EBV associated immune dysregulation.
  • lymphomas such as Burkitt's lymphoma (BL) and Hodgkin's lymphoma (HL) and being associated with EBV associated immune dysregulation.
  • EBV has a well-established oncogenic potential and is associated with ⁇ 1%of all human cancers.
  • EBV can cause also a broad range of diseases ranging from lymphoproliferative diseases, inflammatory immune dysregulations, epithelial cancers, in particular in immunodeficient subjects (e.g. lymphomas in HIV-infected individuals and post-transplant lymphoproliferative disorder (PTLD) .
  • PTLD post-transplant lymphoproliferative disorder
  • EBV has also been found to be implicated in the pathogenesis of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis and systemic lupus erythematosus.
  • EBV-associated disease or disorder also called herein “EBV-induced disease or disorder” refers to any clinical pathology resulting from or linked to an infection by an Epstein Barr virus.
  • EBV-associated disease or disorder can mean any disease caused or induced, directly or indirectly, by EBV.
  • an EBV-associated disease is preferably a disease in which EBV has been identified as a pathogenic actor or factor, namely in which EBV has been identified as being involved in the pathogenesis of the disease.
  • EBV-associated diseases include without being limited to, active EBV infections such as infectious mononucleosis or CAEBV, EBV-associated cancers or an EBV-associated autoimmune diseases.
  • EBV-associated diseases also encompass conditions predisposed by immunosuppression or a weak immune system such as oral hairy leukoplakia, e.g. in subjects with AIDS or under immunosuppressive treatment.
  • EBV-associated autoimmune diseases include, for example, multiple sclerosis, rheumatoid arthritis Sjorgen's syndrome, and systemic lupus erythematosus.
  • the EBV-associated disorder is a lymphoproliferative disease.
  • Epstein–Barr virus–associated lymphoproliferative diseases are a group of disorders in which one or more types of lymphoid cells i.e. B cells, T cells, NK cells, and histiocytic-dendritic cells, are infected with the Epstein–Barr virus (EBV) .
  • EBV Epstein–Barr virus
  • LPDs include the well-known disorder occurring during the initial infection with the EBV, infectious mononucleosis, CAEBV and also EBV+ lymphoma such as post-transplant lymphoproliferative disease (PTLD) .
  • PTLD post-transplant lymphoproliferative disease
  • cancer refers to diseases or conditions characterized by aberrant or abnormal cell proliferation, differentiation and/or migration often accompanied by an aberrant or abnormal molecular phenotype that includes one or more genetic mutations or other genetic changes associated with oncogenesis, expression of tumor markers, loss of tumor suppressor expression or activity and/or aberrant or abnormal cell surface marker expression.
  • Cancers may include any aggressive or potentially aggressive cancers, tumors or other malignancies such as listed in the NCI Cancer Index, including all major cancer forms such as sarcomas, carcinomas, lymphomas, leukemias and blastomas, although without limitation thereto.
  • EBV-associated cancer refers to a cancer that has been linked to the Epstein-Barr virus (EBV) .
  • the cancer of interest is positive to EBV, which means that the cancer cells contain viral genome, and/or express viral miRNA, viral non-coding nuclear RNAs and/or viral proteins from EBV.
  • EBV-associated cancers of different types express different combinations of EBV latent gene products.
  • EBV-associated (or EBV+) cancers can be identified by the detection of viral genome, viral miRNA, viral non-coding nuclear RNAs and/or proteins expressed in latency phase (e.g. EBNAs or LMPs (e.g. LMP1) or SSTR2) in the cancer cells or tumors.
  • EBV-positive cancer cells can express one or several EBV antigens.
  • the EBV-positive cancer cells express EBNA1.
  • EBV positive cells (which can be tumoral or not) can be detected and measured in a subject using techniques known in the art through the detection and/or quantification of viral genome, and/or viral miRNA, and/or viral non-coding nuclear RNAs and/or viral proteins from EBV.
  • high serum viral DNA loads and/or high serum anti-EBV antibody (e.g. anti EBNA1 antibody) titer can be also used as biomarkers in the diagnosis or monitoring of EBV-associated disorders, in particular in EBV-associated cancers.
  • EBV-associated cancers encompass, without being limited to, EBV-positive nasopharyngeal carcinoma, NKT cell lymphoma, Hodgkin's Lymphoma, post-transplant lymphoproliferative disease (PTLD) , Burkitt's lymphoma, lymphoma in subjects with acquired immune deficiency syndrome, Diffuse large B-cell lymphoma, gastric cancer (EBVaGC) , parotid carcinoma, breast carcinoma, leiomyosarcoma and any combination thereof.
  • EBV-positive nasopharyngeal carcinoma encompass, without being limited to, EBV-positive nasopharyngeal carcinoma, NKT cell lymphoma, Hodgkin's Lymphoma, post-transplant lymphoproliferative disease (PTLD) , Burkitt's lymphoma, lymphoma in subjects with acquired immune deficiency syndrome, Diffuse large B-cell lymphoma, gastric cancer (EBVaGC
  • an EBV-associated cancer is either a carcinoma or a lymphoma.
  • compositions, compounds, salts or solvates and the like that are, within the scope of sound medical judgment, suitable for contact with the tissues of the subject, or which can be administered to the subject, without excessive toxicity or other complications commensurate with a reasonable benefit/risk ratio.
  • an “Alkyl” refers to a saturated hydrocarbon radical which can be a straight or branched chain or a cyclic hydrocarbon group.
  • a C 1 -C 6 alkyl encompasses, without being limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl.
  • a C 1 -C 4 alkyl encompasses for instance methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, and cyclopropyl.
  • a C 1 -C 3 alkyl encompasses for instance methyl, ethyl, propyl, isopropyl, and cyclopropyl.
  • alkyl refers to straight or branched hydrocarbon chains.
  • a C 1 -C 3 alkyl preferably refers to methyl, ethyl, propyl, and isopropyl.
  • a “cycloalkyl” refers to a saturated cyclic hydrocarbon group.
  • a “C 3 -C 6 cycloalkyl” encompasses, without being limited to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Halogen denotes a halogen atom such as Cl, Br, I, or F. Preferred halogens are Br, Cl and F, more preferably F.
  • alkoxy refers to a radical of formula R-O-wherein R represents an alkyl group.
  • alkoxy or C 1 -C 6 alkoxy
  • examples of alkoxy include for instance, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, hexyloxy.
  • a “carboxyalkyl” refers to a radical of formula -A-COOH wherein A represents an alkylene (e.g. C 1 -C 6 alkylene) group.
  • alkanoyl refers to a radical –C (O) -R wherein R is an alkyl (e.g. C 1 -C 6 alkyle) .
  • R is an alkyl (e.g. C 1 -C 6 alkyle) .
  • a “hydroxyalkyl” refers to a alkylene (e.g. C 1 -C 6 alkylene) group substituted with one or several -OH (e.g. 1, 2 or 3 OH) .
  • the hydroxyalkyl can be linear or branched e.g.
  • aminoalkyl refers to a radical of formula -A-NH 2 wherein A represents an alkylene (e.g. C 1 -C 6 alkylene) group.
  • halogenoalkyl refers to a alkyl (e.g. C 1 -C 6 alkyl) group substituted with one or several halogen atoms (i.e. in which one or several H is/are replaced by a halogen, ) .
  • alkyl e.g. C 1 -C 6 alkyl
  • halogenoalkyl examples are -CF 3 or -CH 2 -CHF 2 .
  • alkylene group refers to a bivalent alkyl (e.g. C 1 -C 6 alkyl) group which can be linear or branched
  • alkoxy alkyl refers to an alkylene bearing an alkoxy group. Such group generally comprises from 2 to 14 Carbon atoms.
  • alkoxy alkyl are for instance radical of formula –- (CH 2 ) n O (CH 2 ) m CH 3 wherein n is an integer from 1 to 6 and m is an integer from 0 to 6 or (CH 2 ) n OCH 3 with n is an integer from 1 to 6, e.g. 1, 2 or 3.
  • heterocycle refers to a saturated or unsaturated, aliphatic or aromatic cyclic hydrocarbon group in which at least one ring carbon atom has been replaced with a heteroatom, preferably selected from nitrogen, oxygen, or sulphur atom.
  • the heterocycle comprises from 3 to 10 ring atoms, preferably 3, 4, 5 or 6 ring atoms, wherein at least one of the ring atoms is a heteroatom such as nitrogen, oxygen or sulphur atom.
  • heterocycle encompasses heteroaryl groups as well as aliphatic heterocyclic groups.
  • heterocycles encompass cycloheteroalkyl groups, namely a cycloalkyl wherein one or several carbon atoms have been replaced by a heteroatom.
  • heterocycle includes for instance aziridinyl, azepanyl, diazepanyl, dioxolanyl, benzo [1, 3] dioxolyl, azetidinyl, oxetanyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolidinyl, piperidyl, piperazinyl, 1, 4-dioxanyl, imidazolinyl, pyridyl, pyrrolinyl, pyrrolidinyl, piperidinyl, imidazolidinyl, morpholinyl, 1, 4-dithianyl, pyrrolidinyl, pyrimidinyl, oxozolinyl, oxazolidiny
  • the “heterocycle” is a “heterocycloalkyl group” comprising 3 to 6 carbon atoms and one or two heteroatoms as ring atoms.
  • Preferred heterocycloalkyl groups include piperidinyl, pyrrolidinyl, piperazinyl, thiomorpholinyl and morpholinyl. More preferably, the heterocycloalkyl group is selected from N-piperidinyl, N-pyrrolidinyl, N-piperazinyl, N-thiomorpholinyl and N-morpholinyl.
  • aryl refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members.
  • aryl refers to an aromatic ring system.
  • Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracyl and the like, which optionally includes one or more substituents.
  • aryl is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.
  • heteroaryl refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 ⁇ electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms.
  • Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl.
  • heteroaryl also include groups in which a hetero aromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring.
  • Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido [2, 3-b] -l, 4-oxazin-3
  • unsaturated means that a moiety has one or more units of unsaturation, i.e. one or more double or triple bonds.
  • saturated means that a moiety has no unsaturation.
  • substituted means that one or more hydrogen atoms on the designated atom or group are replaced by a non-hydrogen substituent, provided that the designated atom's normal valency under the existing circumstances is not exceeded.
  • optionally substituted can be replaced with terms “substituted or unsubstituted” throughout this application.
  • substituents encompass, without being limited to, CF 3 , OCF 3 , C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 2 -C 6 alkoxy alkyl, C 1 -C 6 haloalkyl, halogen, NH 2 , C 1 -C 6 alkylamine, di- (C 1 -C 6 alkyl) amine and the like.
  • one or more or “at least one” means 1 or more than 1, e.g. 1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more particularly 1 , 2 or 3.
  • the invention relates to aminophenanthridine derivatives, in particular for use as a drug in the treatment or the prevention of an EBV-associated disorder.
  • the aminophenanthridine derivative of the Invention is a compound of formula (I) :
  • R 1 , R 2 , R 3, R 4 , R 7 , R 8 , R 9 and R 10 independently represents H, halogen, C 1 -C 8 alkyl, C 1 -C 8 halogenoalkyl, C 1 -C 8 hydroxyalkyl, -OCF 3 , -NO 2 , -CN, -OR 11 , NHCOCHR 17 NHR 18 , -NHCO (CH 2 ) n NR 12 R 13 , -NHCOR 17 -NR 12 - R 13 , -COOR 12 , -CONR 12 R 13 , -SO 2 NR 12 R 13 , -SO 2 R 12 , -CH 2 SO 2 NR 12 R 13 , OPOR 12 OR 13 , (CH 2 ) nNR 12 R 13 , - (CH 2 ) n COOR 12 , - (CH 2 ) n CONR 12 R 13 , - (CH 2 ) n CONR 12 R 13 ,
  • Het1 is a 3-to 6-membered heterocycle, optionally substituted (e.g. preferably by one or several substituents selected from halogen, -CONHR 15 , -COR 17, -OH, C 1 -C 3 alkoxy, COOR 15 or C 1 -C 3 alkyl) , and optionally fused with a C 3 -C 5 carbocycle,
  • R 11 is H, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 dimethoxy alkyl, C 1 -C 6 halogeno hydroxyalkyl, C 1 -C 6 dihydroxyalkyl - (CH 2 ) q Het2, - (CH 2 ) n OHet 2 ,
  • n is independently an integer from 1 to 6, preferably 1, 2, or 3,
  • Each o is independently 1 or 2
  • Each q is independently an integer from 0 to 6, preferably 0, 1, 2 or 3,
  • R 12 and R 13 are independently H, C 1 -C 6 alkyl, or C 2-14 alkoxy alkyl (optionally substituted by one or several substituents preferably selected from halogen, -CF 3 , OCF 3 , C 1 -C 3 alkyl and C 1 -C 3 alkoxy) , Or
  • R 12 and R 13 form, together with the N atom to which they are bound, a 5-or 6-membered heterocycle optionally substituted (e.g. by one or several substituents preferably selected from halogen, -CF 3 , OCF 3 , C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 2 -C 4 alkoxy alkyl and C 1 -C 3 alkoxy) .
  • substituents preferably selected from halogen, -CF 3 , OCF 3 , C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 2 -C 4 alkoxy alkyl and C 1 -C 3 alkoxy
  • R 14 is C 1 -C 6 alkyl, C 1 -C 6 alkoxy alkyl, - (CH 2 ) p Het3 or - (CH 2 ) p Cyc1 with p an integer from 0 to 6, preferably from 1 to 3, Het3 being a saturated or unsaturated heterocycle optionally substituted by one or several substituents such as halogens, C 1 -C 3 alkyl and C 1 -C 3 alkoxy. and Cyc1 being a C 1 -C 6 cycloalkyl
  • R 15 is H or C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl,
  • R 16 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, -CHR 17 NHCOR 17 or -OCHR 17 OCOR 17
  • Each R 17 independently is H or a C 1 -C 3 alkyl
  • R 18 is H, or COCH 3 ,
  • A is either -NR 5 R 6 or wherein
  • ⁇ R 5 is H
  • R 6 is H, C 1 -C 6 alkyl, COO (CH 2 ) n Het4, COR 21 or COOCHR 17 OCOR 17 , wherein
  • R 21 is OH, halogen, -O (CH 2 ) n NR 22 R 23 , -O (CH 2 ) n O (CH 2 ) m CH 3 optionally substituted or C 2-14 alkoxy alkyl optionally substituted (e.g. by one or several substituents preferably selected from halogen, -CF 3 , OCF 3 , OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy) ,
  • R 22 and R 23 are independently selected from H, C 1 -C 6 alkyl, or C 2-14 alkoxyalkyl optionally substituted (e.g. by one or several substituents preferably selected from halogen, -CF 3 , OCF 3 , OH, C 1 -C 3 alkyl and C 1 -C 3 alkoxy) , and
  • Het4 is a 3-to 6-membered heterocycle optionally substituted (e.g. by one or several substituents selected from C 1 -C 3 alkyl, -COOR 17 , CONHR 17 , C 1 -C 3 alkoxy, and - (CH 2 ) n OR 17 )
  • R 20 is H, C 1 -C 8 alkyl, C 2 -C 14 alkoxy alkyl optionally substituted (e.g. by one or several substituents preferably selected from halogens, CF 3 , C 1 -C 3 methyl and C 1 -C 3 alkoxy) , and
  • ⁇ R 19 is either a 5-to 12-membered aryl or heteroaryl (e.g phenyl, or pyridinyl) optionally substituted by one or several substituents (e.g. preferably selected from halogens, CF 3 , C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl and C 1 -C 3 alkoxy)
  • substituents e.g. preferably selected from halogens, CF 3 , C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl and C 1 -C 3 alkoxy
  • the compound of formula (I) is such that :
  • R 1 , R 2 , R 3, R 4 , R 7 , R 8 , R 9 and R 10 independently represents H, halogen, C 1 -C 8 alkyl, C 1 -C 8 halogenoalkyl, C 1 -C 8 hydroxyalkyl, -OCF 3 , -NO 2 , -CN, -OR 11 , NHCOCHR 17 NHR 18 , -NR 12 - R 13 , -COOR 12 , -CONR 12 R 13 , -SO 2 NR 12 R 13 , -SO 2 R 12 , -CH 2 SO 2 NR 12 R 13 , OPOR 12 OR 13 , (CH 2 ) nNR 12 R 13 , - (CH 2 ) n COOR 12 , - (CH 2 ) n CONR 12 R 13 , - (CH 2 ) q SO 2 NR 12 R 13 , -S (O) NC (O) OR 14 ,
  • Het1 is a 3-to 6-membered heterocycle, optionally substituted (e.g. preferably by one or several substituents selected from halogen, -CONHR 15 , -OH, C 1 -C 3 alkoxy, COOR 15 or C 1 -C 3 alkyl) , and optionally fused with a C 3 -C 5 carbocycle,
  • R 11 is H, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 dimethoxy alkyl, C 1 -C 6 halogeno hydroxyalkyl, C 1 -C 6 dihydroxyalkyl - (CH 2 ) q Het2, - (CH 2 ) q O (PO) (OR 15 ) 2 , C 2 -C 14 alkoxy alkyl optionally substituted (e.g.
  • substituents preferably selected from halogen, -CF 3 , OH, OCF 3 , C 1 -C 3 alkyl and C 1 -C 3 alkoxy) , - (CH 2 ) n NR 15 COCH 3 , - (CH 2 ) n COOR 12 , - (CH 2 ) n CONR 12 R 13, - (CH 2 ) q SO 2 NR 12 R 13 , -COR 16 , or – (CH 2 ) n OCOR 16
  • Het2 is 3-to 6-membered heterocycle optionally substituted (e.g. by one or several substituents preferably selected from halogen, OH, -CF 3 , OCF 3 , C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkoxy, and (CH 2 ) q NHCOCH 3 ) .
  • the one or several halogen atoms present in the structure of the compound of formula (I) are selected from F, Cl and Br, preferably F.
  • At least one group among R 1 -R 10 includes a heterocycle moiety.
  • the possible heterocycle (s) present in the compound of formula (I) e.g. Het1, Het2, Het3 and/or Het4 preferably comprise (s) one or two ring heteroatoms, preferably O or N.
  • the possible heterocycles can be substituted or unsubstituted, saturated or unsaturated.
  • the heterocycle (s) is/are typically 3-to 6-membered saturated heterocycles such as piperidinyl, azetidinyl, pyrrolidinyl, piperazinyl, morpholinyl, oxetanyl, tetrahydropyranyl, and tetrahydrofuranyl, preferably azetidinyl; oxetanyl, piperidinyl, pyrrolidinyl, piperazinyl, and morpholinyl.
  • Het1 is preferably a pyrrolidinyl optionally substituted with one or several substituents selected from halogen, -CONHR 15 , -OH, C 1 -C 3 alkoxy, COOR 15 or C 1 -C 3 alkyl, and optionally fused with a C 3 -C 5 carbocycle, preferably a C 3 carbocycle.
  • R 15 is preferably H or C 1 -C 3 alkyl.
  • Het2 is preferably selected from azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxetanyl, tetrahydropyranyl, and tetrahydrofuranyl, said heterocycle being optionally substituted e.g.
  • Het3 is preferably selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl, said heterocycle being optionally substituted by one or several substituents such as halogens, C 1 -C 3 alkyl and C 1 -C 3 alkoxy.
  • Het4 is preferably selected from piperazinyl and piperidinyl; said heterocycle being optionally substituted by one or several substituents such asC 1 -C 3 alkyl, -COOR 17 , CONHR 17 , C 1 -C 3 alkoxy, and - (CH 2 ) n OR 17 with R 17 is H or a C 1 -C 3 alkyl.
  • the compound of formula (I) comprises at least one -NR 12 R 13 wherein R 12 and R 13 form together with the N atom a 5-or 6-membered heterocycle which can be substituted or unsubstituted.
  • Preferred heterocycles encompass piperidinyl, pyrrolidinyl, piperazinyl, and morpholinyl, said heterocycles being optionally substituted, e.g. by at least one substituent selected from halogens, OH, CF 3 , C 1 -C 6 alkoxy, C 1 -C 6 alkyl, C 2 -C 4 alkoxy alkyl, -CONH 2 , and C 1 -C 6 hydroxyalkyl.
  • the compound of formula (I) can comprise at least one -NR 12 R 13 selected from:
  • At least one -NR 12 R 13 present in the molecule of formula (I) is such that R 12 and R 13 are C 1 -C 3 alkyl, in particular both R 12 and R 13 are -CH 3 .
  • each R 1 , R 2 , R 3, R 4 , R 7 , R 8 , R 9 and R 10 independently represents H, halogen such as F, Br or Cl, C 1 -C 6 alkoxy, C 1 -C 8 alkyl, C 1 -C 8 halogenoalkyl such as -CF 3 , -OCF 3 , -NO 2 , -CN, OH,
  • R 7 , R 8 , R 9 and R 10 are independently selected from H, halogens, OH, C 1 -C 3 alkoxy and moieties from (1” ’ ) to (19” ’ ) as shown above.
  • the compound of formula (I) is such that A is -NR 5 R 6. In a particular embodiment, both R 5 and R 6 are H.
  • R 5 is H and R 6 is selected from the group consisting of:
  • ⁇ -COR 21 with R 21 is -O (CH 2 ) n O (CH 2 ) m CH 3 with n is an integer from 1 to 6 and m is an integer from 0 to 5,
  • ⁇ -O (CH 2 ) n NR 22 R 23 with R 22 and R 23 are independently selected from H, methyl and -O (CH 2 ) n O (CH 2 ) m CH 3 with n is an integer from 1 to 6 and m is an integer from 0 to 5, and
  • the compound of formula (I) is such that:
  • - A is -NR 5 R 6 with R 5 and R 6 are as defined in Formula (I) , preferably both are H,
  • R 3 , R 1 and R 7 are H
  • R 4 and R 2 are C 1 -C 6 alkoxy, e.g. methoxy or ethoxy, or O (CH 2 ) n O (CH 2 ) m CH 3 with n is an integer from 1 to 6 and m is and an integer from 0 to 6 such as CH 3 O (CH 2 ) 3 O-, preferably both R 4 and R 2 are C 1 -C 6 alkoxy,
  • R 8 , R 9 and R 10 are independently selected from H, OH, C 1 -C 6 alkoxy, halogen preferably F, C 1 -C 8 halogenoalkyl such as -CF 3 , -OCF 3 , -OR 11 , -NR 12 R 13 and NHCO (CH 2 ) n NR 12 R 13 wherein n, R 11 , R 12 and R 13 are as defined in formula (I) .
  • R 8 , R 9 and R 10 are independently selected from H, halogen preferably F,
  • R 8 , R 9 and R 10 are independently selected from H, F, Cl, Br, CF 3 , OCF 3 , OH, C 1 -C 3 alkoxy such as OMe, C 1 -C 3 alkyl such as -CH 3 , and moieties (25” ’ ) , (1” ) , (53” ) , (44” ) , (39” ) , (40” ) , (26” ’ ) , (55” ) , (56” ) , (43” ) , (17” ) , (20” ) , (23” ) , (13” ’ ) , (58” ) , (28” ’ ) , (59” ) , (61” ) (60” ) , (8” ) , (27” ) , (28” ) , (62” ) , (29” ’ ) , (30” ’ ) and (
  • R 8 , R 9 and R 10 are independently selected from H, F, Cl, CF 3 , OCF 3 , OH, C 1 -C 3 alkoxy such as OMe, and moieties (25” ’ ) , (1” ) , (53” ) , (44” ) , (39” ) , (40” ) , (26” ’ ) , (55” ) , (56” ) , (8” ) , (27” ) , (28” ) , (62” ) , (29” ’ ) , (30” ’ ) , (33” ’ ) and (43” ) as shown above.
  • the compound of formula (I) is such that:
  • - A is -NR 5 R 6 with R 5 and R 6 are as defined in Formula (I) , preferably both are H,
  • R 3 , R 1 and R 7 are H
  • R 4 and R 2 are C 1 -C 6 alkoxy, e.g. methoxy or ethoxy, or O (CH 2 ) n O (CH 2 ) m CH 3 with n is an integer from 1 to 6 and m is and an integer from 0 to 6 such as CH 3 O (CH 2 ) 3 O-
  • Each R 8 , R 9 and R 10 is independently selected from H, F, Cl, CF 3 , OCF 3 , OH, C 1 -C 3 alkoxy such as OMe, and moieties (25” ’ ) , (1” ) , (53” ) , (44” ) , (39” ) , (40” ) , (26” ’ ) , (55” ) , (56” ) , (8” ) , (27” ) , (28” ) , (62” ) , (29” ’ ) , (30” ’ ) , (33” ’ ) and (43” ) .
  • R 10 is H or a halogen, e.g. F.
  • R 10 and R 8 are independently H or a halogen e.g. F, and at least one among R 10 and R 8 is H.
  • R 9 is not H or a halogen.
  • the Invention relates to a compound of formula (Ia) :
  • R 2 , R 3, R 4 , R 6 , R 8 , R 9 and R 10 are as defined in formula (I)
  • the compound of formula (Ia) is such that
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, halogens, CF 3 , (CH 2 ) n O (CH 2 ) m CH 3 with n is an integer from 1 to 6 and m is and an integer from 0 to 6,
  • R 8 , R 9 and R 10 are independently selected from the group consisting of H, halogen, C 1 -C 8 alkyl, C 1 -C 8 halogenoalkyl such as CF 3 , -OCF 3 , -NO 2 , -CN, -OR 11 , NHCOCHR 17 NHR 18 , NHCO (CH 2 ) n NR 12 R 13 , -NR 12 - R 13 , -NHCOR 17, -COOR 12 , -CONR 12 R 13 , -SO 2 NR 12 R 13 , -SO 2 R 12 , -CH 2 SO 2 NR 12 R 13 , OPOR 12 OR 13 , (CH 2 ) nNR 12 R 13 , - (CH 2 ) n COOR 12 - (CH 2 ) n CONR 12 R 13 - (CH 2 ) n CONR 12 R 13 - (CH 2 ) q SO 2 NR 12 R 13 , -S (O) NC
  • Het1 is a 4-, 5-or 6-membered heterocycle, optionally substituted (e.g. preferably by one or several substituents selected from halogen, -CONHR 15 , -OH, -COR 17 , C 1 -C 3 alkoxy, COOR 15 or C 1 -C 3 alkyl) , and optionally fused with a C 3 -C 5 carbocycle,
  • R 11 is H, C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl, C 1 -C 6 halogeno hydroxylalkyl, C 1 -C 6 dihydroxyalkyl - (CH 2 ) q Het2, - (CH 2 ) q OPO (OR 15 ) 2 , - (CH 2 ) n OHet2, - (CH 2 ) n NR 12 R 13 , -COCH (CH 2 SH) NHCOCH 3 , C 2-14 alkoxy alkyl optionally substituted (e.g.
  • substituents preferably selected from halogen, -CF 3 , OH, OCF 3 , C 1 -C 3 alkyl and C 1 -C 3 alkoxy) , - (CH 2 ) n NR 15 COCH 3 , - (CH 2 ) n COOR 12 , - (CH 2 ) n CONR 12 R 13, - (CH 2 ) q SO 2 NR 12 R 13 , -COR 16 , or – (CH 2 ) n OCOR 16
  • Het2 is 3-to 6-membered heterocycle optionally substituted (e.g. by one or several substituents preferably selected from halogen, OH, -CF 3 , OCF 3 , C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkoxy, -COCH 3 and (CH 2 ) q NHCOCH 3 .
  • ⁇ n is an integer from 1 to 6, preferably 1, 2, or 3,
  • ⁇ o 1 or 2
  • ⁇ q is an integer from 0 to 6, preferably 0, 1, 2 or 3,
  • R 12 and R 13 are independently H, C 1 -C 6 alkyl, or C 2-14 alkoxyalkyl optionally substituted by one or several substituents (e.g. preferably selected from halogen, -CF 3 , OCF 3 , C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 2 -C 4 alkoxy alkyl and C 1 -C 3 alkoxy) , OR R 12 and R 13 form together with the N atom to which they are bound a 5-or 6-membered heterocycle optionally substituted (e.g.
  • substituents preferably selected from halogen, -CF 3 , OCF 3 , C 1 -C 3 alkyl, C 1 -C 3 hydroxyalkyl, C 2 -C 4 alkoxy alkyl and C 1 -C 3 alkoxy) .
  • R 14 is C 1 -C 6 alkyl, C 1 -C 6 alkoxyalkyl, - (CH 2 ) p Het3 or - (CH 2 ) p Cyc1 with p an integer from 0 to 6, preferably from 1 to 3, Het3 being a saturated or unsaturated 4-, 5-or 6-membered heterocycle optionally substituted by one or several substituents such as halogens, C 1 -C 3 alkyl and C 1 -C 3 alkoxy. and Cyc1 being a C 1 -C 6 cycloalkyl
  • R 15 is H or C 1 -C 6 alkyl, preferably C 1 -C 3 alkyl,
  • R 16 is C 1 -C 6 alkyl, C 1 -C 6 aminoalkyl, -CHR 17 NHCOR 17 or -OCHR 17 OCOR 17
  • Each R 17 independently is H or a C 1 -C 3 alkyl
  • R 18 is H, or COCH 3 ,
  • R 6 is H, COO (CH 2 ) n Het4, or COOCHR 17 OCOR 17 , wherein Het4 is a 4-, 5-or 6-membered heterocycle optionally substituted (e.g. by one or several substituents selected from C 1 -C 3 alkyl, -COOR 17 , CONHR 17 , C 1 -C 3 alkoxy, and - (CH 2 ) n OR 17 ) .
  • the compound of formula (Ia) may be further characterized by one, several or all of the following features:
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H, C 1 -C 6 alkoxy, and O (CH 2 ) n O (CH 2 ) m CH 3 with n is an integer from 1 to 6 and m is and an integer from 0 to 6, and/or
  • R 8 , R 9 and R 10 are independently selected from the group consisting of H, halogen, preferably F, Br or Cl, CF 3 , NH 2 , C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, -OR 11 , Het1, NHCOR 17 , NHCO (CH 2 ) n NR 12 R 13 , O (CH 2 ) q B (OR 15 ) 2 , SO 2 NR 12 R 13 wherein
  • ⁇ q is an integer from 0 to 6, preferably 0, 1, 2 or 3,
  • R 11 is H, C 1 -C 6 hydroxyalkyl, - (CH 2 ) n NHCOR17, - (CH 2 ) n OCOCHR 15 NH 2, ( CH 2 ) n OHet2, - (CH 2 ) q Het2 or - (CH 2 ) n NR 12 R 13 ,
  • Het2 is 3-to 6-membered heterocycle optionally substituted (e.g. by one or several substituents preferably selected from halogen, OH, -CF 3 , OCF 3 , C 1 -C 3 alkyl, C 1 -C 3 aminoalkyl, C 1 -C 3 hydroxyalkyl, C 1 -C 3 alkoxy, -COCH 3 and (CH 2 ) q NHCOCH 3 .
  • ⁇ n is an integer from 1 to 6, preferably 1, 2, 3 or 4
  • Het1 is a 4-, 5-or 6-, preferably 5-or 6-membered heterocycle, optionally substituted (e.g. preferably by one or several substituents selected from halogen, -CONHR 15 , -OH, C 1 -C 3 alkoxy, -COCH 3 , -COOR 15 or C 1 -C 3 alkyl) , and optionally fused with a C 3 -C 5 carbocycle,
  • R 12 , and R 13 are independently H or C 1 -C 3 alkyl or form together with the -N atom to which they are bound, a 5-or 6-membered heterocycle optionally substituted by a C 1 -C 3 alkyl.
  • R 17 and R 15 are independently H or C 1 -C 3 alkyl
  • the compound of formula (Ia) may be further characterized by one, several or all of the following features:
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H, C 1 -C 6 alkoxy, and O (CH 2 ) n O (CH 2 ) m CH 3 with n is an integer from 1 to 6 and m is and an integer from 0 to 6, and/or
  • R 8 , R 9 and R 10 are independently selected from the group consisting of H, halogen, preferably F, Br or Cl, CF 3 , NH 2 , C 1 -C 6 alkoxy, C 1 -C 6 hydroxyalkyl, -OR 11 , Het1 O (CH 2 ) q Het1, NHCOR 17 , O (CH 2 ) q B (OR 15 ) 2 , SO 2 NR 12 R 13 wherein
  • ⁇ q 0, 1, 2 or 3
  • R 11 is H, C 1 -C 6 hydroxyalkyl, - (CH 2 ) n NHCOR17, - (CH 2 ) n OCOCHR 15 NH 2 n is 1, 2, 3 or 4
  • Het1 is a 5-or 6-membered heterocycle, optionally substituted (e.g. preferably by one or several substituents selected from halogen, -CONHR 15 , -OH, C 1 -C 3 alkoxy, -COOR 15 or C 1 -C 3 alkyl) , and optionally fused with a C 3 -C 5 carbocycle,
  • R 12 , R 13 , R 17 and R 15 are independently H or C 1 -C 3 alkyl.
  • At least one group among R 2 , R 3 and R 4 is a C 1 -C 6 , preferably a C 1 -C 3 alkoxy.
  • at least two groups among R 2 , R 3 and R 4 are C 1 -C 6 , preferably a C 1 -C 3 alkoxy.
  • the compound for use in the treatment or the prevention of an EBV-associated disorder is of formula (Ia) or (I) as described above wherein R 2 and R 4 are C 1 -C 3 alkoxy, preferably methoxy.
  • R 3 is H.
  • the compound for use in the treatment or the prevention of an EBV-associated disorder is of formula (Ia) or (I) as described above wherein R 8 , R 9 and R 10 are independently selected from H, Br, F, Cl, H, CF 3 , C 1 -C 3 alkoxy, O (CH 2 ) n OH, O (CH 2 ) n OCH 3 , O (CH 2 ) n NHCOCH 3 , O (CH 2 ) n OCOCR 15 NH 2 , OCOCR 15 NH 2 , CH 2 B (OH) 2 , NH 2 , -NHCOCH 3 , Het1, O (CH 2 ) q Het2, -O (CH 2 ) nOHet2 , -O (CH 2 ) n NR 12 R 13 , -OCOCH (CH 2 SH) NHCOCH 3 , NHCO (CH 2 ) n NR 12 R 13 , wherein
  • ⁇ n is an integer from 1 to 6, preferably 1, 2 or 3
  • ⁇ q is an integer from 0 to 6, preferably 0, 1, 2 or 3
  • Het1 is a 4-, 5-or 6-membered heterocycle, preferably pyrrolidinyl, optionally substituted (e.g. preferably by one or several substituents selected from halogen, -CONHR 15 , -OH, C 1 -C 3 alkoxy, COOR 15 or C 1 -C 3 alkyl) ,
  • Het2 is a 5-or 6-membered heterocycle, preferably piperidinyl, optionally substituted (e.g. preferably by one or several substituents selected from halogen, -CONHR 15 , -OH, C 1 -C 3 alkoxy, COOR 15 or C 1 -C 3 alkyl) ,
  • R 12 , and R 13 are independently H or C 1 -C 3 alkyl or form together with the -N atom to which they are bound, a 5-or 6-membered heterocycle optionally substituted by a C 1 -C 3 alkyl.
  • R 15 is H or C 1 -C 3 alkyl
  • the compound of formula (Ia) is such that
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H, C 1 -C 6 alkoxy, and O (CH 2 ) n O (CH 2 ) m CH 3 with n is an integer from 1 to 6 and m is and an integer from 0 to 6,
  • R 8 , R 9 and R 10 are independently selected from H, F, Cl, Br, CF 3 , OCF 3 , OH, C 1 -C 3 alkoxy such as OMe, C 1 -C 3 alkyl such as -CH 3 , and moieties (25” ’ ) , (1” ) , (53” ) , (44” ) , (39” ) , (40” ) , (26” ’ ) , (55” ) , (56” ) , (8” ) , (27” ) , (28” ) , (62” ) , (29” ’ ) , (30” ’ ) , (33” ’ ) and (43” ) as shown above.
  • the compound of formula (Ia) is such that
  • R 2 , R 4 are independently a C 1 -C 6 alkoxy, preferably a methoxy,
  • R 8 , R 9 and R 10 are independently selected from H, F, Cl, CF 3 , OCF 3 , OH, C 1 -C 3 alkoxy such as OMe, and moieties (25” ’ ) , (1” ) , (53” ) , (44” ) , (39” ) , (40” ) , (26” ’ ) , (55” ) , (56” ) , (8” ) , (27” ) , (28” ) , (62” ) , (29” ’ ) , (30” ’ ) , (33” ’ ) and (43” ) as shown above.
  • one group among R 8 , R 9 and R 10 is H.
  • the compound of formula (Ia) is such that
  • R 2 , R 4 are independently a C 1 -C 6 alkoxy, preferably a methoxy,
  • R 8 , and R 9 are independently selected from H, F, Cl, CF 3 , OCF 3 , OH, C 1 -C 3 alkoxy such as OMe, and moieties (25” ’ ) , (1” ) , (53” ) , (44” ) , (39” ) , (40” ) , (26” ’ ) , (55” ) , (56” ) , (8” ) , (27” ) , (28” ) , (62” ) , (29” ’ ) , (30” ’ ) , (33” ’ ) and (43” ) as shown above.
  • R 10 is H or a halogen, preferably F.
  • the compound of formula (Ia) is such that
  • R 2 , R 4 are independently a C 1 -C 6 alkoxy, preferably a methoxy,
  • R 8 , and R 9 are independently selected from H, F, Cl, CF 3 , OCF 3 , OH, C 1 -C 3 alkoxy such as OMe, and moieties (25” ’ ) , (1” ) , (53” ) , (44” ) , (39” ) , (40” ) , (26” ’ ) , (55” ) , (56” ) , (8” ) , (27” ) , (28” ) , (62” ) , (29” ’ ) , (30” ’ ) , (33” ’ ) and (43” ) as shown above, wherein at least one group amond R 8 and R 9 is H or F with proviso that both R 8 and R 9 are not H.
  • R 10 is H or a halogen, preferably F.
  • the compound of formula (Ia) is such that R 2 and R 4 are not both H.
  • R 2 and R 4 are both different from H.
  • the compound of the Invention is of formula (Ia) wherein :
  • R 8 and R 9 At least one among R 8 and R 9 are not H.
  • the invention relates to a compound of formula (Ib)
  • R 2 , R 3, R 4 R 8 , R 9 and R 10 are as defined in formula (I) or (Ia) above
  • the compound of formula (Ib) is such that:
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H, C 1 -C 6 alkoxy and O (CH 2 ) n OH with n is 2 or 3.
  • R 3 is H
  • R 2 , and R 4 are C 1 -C 3 alkoxy, preferably methoxy, and/or
  • R 8 , R 9 and R 10 are independently selected from H, Br, F, Cl, H, CF 3 , C 1 -C 3 alkoxy, O (CH 2 ) n OH, O (CH 2 ) n OCH 3 , O (CH 2 ) n NHCOCH 3 , O (CH 2 ) n OCOCR 15 NH 2 , OCOCR 15 NH 2 , CH 2 B (OH) 2 , NH 2 , NH 2 COCH 3 , Het1, O (CH 2 ) q Het2 wherein
  • ⁇ n 1, 2 or 3
  • ⁇ q 0, 1, 2 or 3
  • Het1 is a 4-, 5-or 6-membered heterocycle, preferably pyrrolidinyl, optionally substituted (e.g. preferably by one or several substituents selected from halogen, -CONHR 15 , -OH, C 1 -C 3 alkoxy, COOR 15 or C 1 -C 3 alkyl) ,
  • Het2 a 5-or 6-membered heterocycle, preferably piperidinyl, optionally substituted (e.g. preferably by one or several substituents selected from halogen, -CONHR 15 , -OH, C 1 -C 3 alkoxy, COOR 15 or C 1 -C 3 alkyl) ,
  • R 15 is H or C 1 -C 3 alkyl
  • At least two among R 8 , R 9 and R 10 are H.
  • the compound of formula (Ib) is such that
  • R 2 , R 3 and R 4 are independently selected from the group consisting of H, C 1 -C 6 alkoxy, and O (CH 2 ) n O (CH 2 ) m CH 3 with n is an integer from 1 to 6 and m is and an integer from 0 to 6,
  • R 8 , R 9 and R 10 are independently selected from H, F, Cl, CF 3 , OCF 3 , OH, C 1 -C 3 alkoxy such as OMe, and moieties (25” ’ ) , (1” ) , (53” ) , (44” ) , (39” ) , (40” ) , (26” ’ ) , (55” ) , (56” ) , (8” ) , (27” ) , (28” ) , (62” ) , (29” ’ ) , (30” ’ ) , (33” ’ ) and (43” ) as shown above.
  • the compound of formula (Ib) is such that
  • R 2 , and R 4 are independently a C 1 -C 6 alkoxy, preferably a methoxy,
  • R 8 , R 9 and R 10 are independently selected from H, F, Cl, CF 3 , OCF 3 , OH, C 1 -C 3 alkoxy such as OMe, and moieties (25” ’ ) , (1” ) , (53” ) , (44” ) , (39” ) , (40” ) , (26” ’ ) , (55” ) , (56” ) , (8” ) , (27” ) , (28” ) , (62” ) , (29” ’ ) , (30” ’ ) , (33” ’ ) and (43” ) as shown above.
  • the compound of formula (Ib) is such that
  • R 2 , and R 4 are independently a C 1 -C 6 alkoxy, preferably a methoxy,
  • R 8 , and R 9 are independently selected from H, F, Cl, CF 3 , OCF 3 , OH, C 1 -C 3 alkoxy such as OMe, and moieties (25” ’ ) , (1” ) , (53” ) , (44” ) , (39” ) , (40” ) , (26” ’ ) , (55” ) , (56) , (8” ) , (27” ) , (28” ) , (62” ) , (29” ’ ) , (30” ’ ) , (33” ’ ) and (43” ) as shown above.
  • R 10 is H or a halogen, preferably F.
  • the compound of formula (Ib) is such that
  • R 2 , and R 4 are independently a C 1 -C 6 alkoxy, preferably a methoxy,
  • R 8 , and R 9 are independently selected from H, F, Cl, CF 3 , OCF 3 , OH, C 1 -C 3 alkoxy such as OMe, and moieties (25” ’ ) , (1” ) , (53” ) , (44” ) , (39” ) , (40” ) , (26” ’ ) , (55” ) , (56” ) , (8” ) , (27” ) , (28” ) , (62” ) , (29” ’ ) , (30” ’ ) , (33” ’ ) and (43” ) as shown above
  • R 8 and R 9 are H or F with proviso that both R 8 and R 9 are not H.
  • R 10 is H or a halogen, preferably F.
  • the compound of formula (Ib) is such that R 2 and R 4 are not both H.
  • R 2 and R 4 are both different from H.
  • the compound of the Invention is of formula (Ib) wherein :
  • R 8 and R 9 At least one among R 8 and R 9 are not H.
  • the invention relates to a compound of formula (Ic)
  • R 2 , R 3, R 4 R 8 , R 9 and R 10 are as defined in formula (I) , (Ia) or (Ib) above or a pharmaceutically acceptable salt and/or solvate thereof
  • the compound of formula (Ic) is such that:
  • R 2 - R 2 , and R 4 are independently selected from the group consisting of H, C 1 -C 6 alkoxy and O (CH 2 ) n OH with n is 2 or 3.
  • R 2 and R 4 are C 1 -C 3 alkoxy such as OCH 3 and
  • R 8 and R 9 are independently selected from H, Cl, F, Br, OH, C 1 -C 3 alkoxy, preferably OCH 3 , C 1 -C 3 alkyl, CF 3 , O (CH 2 ) n OH, Het1, O (CH 2 ) q Het2 wherein
  • ⁇ n 1, 2 or 3
  • ⁇ q 0, 1, 2 or 3
  • Het1 is a 5-or 6-membered heterocycle, preferably pyrrolidinyl, optionally substituted by an halogen, -CONH 2 , -OH, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl,
  • Het2 a 5-or 6-membered heterocycle, preferably piperidinyl, optionally substituted by an halogen, -OH, C 1 -C 3 alkoxy, and/or C 1 -C 3 alkyl.
  • the compound of formula (Ic) is such that R 2 and R 4 are not both H. In some particular embodiments R 2 and R 4 are both different from H.
  • the compound of the Invention is of formula (Ic) wherein :
  • R 8 and R 9 At least one among R 8 and R 9 are not H.
  • the invention relates to a compound of formula (Id)
  • R 3 , and R 10 are as defined in any one of formula (I) , (Ia) or (Ib) hereabove
  • R 8 , and R 9 are as defined in any one of formula (I) , (Ia) , (Ib) or (Ic) hereabove, and
  • Each R 24 or R 25 independently represent C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl or – (CH 2 ) n O (CH 2 ) m CH 3 with n is an integer from 1 to 6 and m is an integer from 0 to 6
  • R 3 is H or OR 26 wherein R 26 represents C 1 -C 6 alkyl, C 1 -C 6 hydroxyalkyl or – (CH 2 ) n O (CH 2 ) m CH 3 with n is an integer from 1 to 6 and m is an integer from 0 to 6
  • R 3 is H and (b) each R 25 and R 24 is independently a C 1 -C 6 , preferably C 1 -C 3 alkyl.
  • the compound of formula (Id) is such that:
  • each R 25 and R 24 is independently a C 1 -C 6 , preferably C 1 -C 3 alkyl,
  • R 10 is H or a halogen such as F.
  • the compound of formula (Id) is such that:
  • each R 25 and R 24 is independently a C 1 -C 6 , preferably C 1 -C 3 alkyl,
  • - R 10 is H or F.
  • the compound of formula (Id) is such that R 8 and R 9 are independently selected from OH, Cl, F, Br, OH, C 1 -C 3 alkoxy, preferably OCH 3 , C 1 -C 3 alkyl, CF 3 , OCF 3 , O (CH 2 ) n OH, Het1, O (CH 2 ) n NCOR 17 , O (CH2) nNR 12 R 13 , -NHCO (CH 2 ) n R 12 R 13 , O (CH 2 ) q Het2, wherein
  • ⁇ n is an integer from 1 to 6, preferably 1, 2 or 3
  • ⁇ q is an integer from 1 to 6, preferably 0, 1, 2 or 3
  • Het1 is a 4-, 5-or 6-membered heterocycle, preferably pyrrolidinyl, optionally substituted by an halogen, -CONH 2 , -COR 17 , -OH, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl,
  • Het2 a 5-or 6-membered heterocycle, preferably piperidinyl, optionally substituted by an halogen, -OH, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl.
  • ⁇ R 17 is H or a C 1 -C 3 alkyl
  • R 12 and R 13 are independently H or a C 1 -C 3 alkyl or form with the N atom to which they are bound a 5 or 6-membered heterocycle optionally substituted (e.g. with a C 1 -C 3 alkyl)
  • R 3 is H
  • each R 25 and R 24 is independently C 1 -C 6 , preferably C 1 -C 3 alkyl
  • R 10 is H or F.
  • the compound of formula (Id) is such that:
  • each R 25 and R 24 is independently a C 1 -C 6 , preferably C 1 -C 3 alkyl,
  • R 8 and R 9 are independently selected from OH, Cl, F, Br, OH, C 1 -C 3 alkoxy, preferably OCH 3 , C 1 -C 3 alkyl, CF 3 , O (CH 2 ) n OH, Het1, O (CH 2 ) q Het2 wherein
  • ⁇ n 1, 2 or 3
  • ⁇ q 0, 1, 2 or 3
  • Het1 is a 5-or 6-membered heterocycle, preferably pyrrolidinyl, optionally substituted by an halogen, -CONH 2 , -OH, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl,
  • Het2 a 5-or 6-membered heterocycle, preferably piperidinyl, optionally substituted by an halogen, -OH, C 1 -C 3 alkoxy, or C 1 -C 3 alkyl) .
  • the compound of the invention is of formula (Id) or a pharmaceutically salt or solvate thereof with proviso that R 3 , R 10 , R 8 , and R 9 are not all H, when R 24 and R 25 are CH 3 .
  • the compound of the invention is not the compound n°2 as shown below in table 1 or a pharmaceutically salt or solvate thereof.
  • the compounds of the Invention may be selected from the compounds exemplified in the exemplary section as shown in the below table as well as pharmaceutically salts and/or solvates thereof :
  • the invention relates to a compound of formula (I) selected from compounds n°3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, and pharmaceutically salts or solvates thereof.
  • the invention relates to a compound of formula (I) selected from compounds n°3, 4, 5, 6, 7, 7bis, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18bis, 19, 20, 21, 22, 23, 24, 25, 25bis, 26, 26, 27, 27 bis and pharmaceutically salts or solvates thereof.
  • the invention relates to a compound of formula (I) selected from compounds n°3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 21 and pharmaceutically salts or solvates thereof.
  • the compounds of the Invention may be selected from the following compounds as well as pharmaceutically salts and/or solvates thereof :
  • Certain compounds of the Invention in particular those of formula (Ib) , (Ic) , (Id) and those shown above in Table 1 and 2, comprises an amino group and/or a hydroxy group on which a labile moiety can be coupled, e.g. through amide, carbamate or ester bond so as to provide a prodrug.
  • the Invention also relates to a prodrug of a compound of any one or formula (I) , (Ia) , (Ib) , (Ic) , and (Id) , preferably of any one of formulae (Ib) - (Id) per se but also for its use in the treatment or the prevention of an EBV-associated disorder.
  • the labile moiety coupled to the hydroxy function or the amino function is selected so as to be cleaved in vivo, whereby the active moiety (namely the compound of formula (I) or (Ia) - (Id) ) is released.
  • the labile moiety can be also selected so as to increase the solubility of the compound and/or improve its pharmacokinetics profile.
  • the labile function is coupled through a carbamate, ester, or amide bond to the compound backbone.
  • the prodrug of the invention is characterized in that the labile moiety is coupled to the amino group present at position 6 of the phenanthridine backbone of a compound of the Invention (in particular of formula (Ib) , (Ic) or Id) or as shown in table 1 or 2 hereabove) .
  • the labile moiety is selected from
  • the prodrug of the invention is characterized in that the labile moiety is coupled to a hydroxy group present at position 7, 8, 9 or 10 of the phenanthridine backbone of a compound of the Invention (in particular of formula (Ib) , (Ic) or Id) or as shown in table 1 or 2 hereabove) .
  • the labile moiety is selected from:
  • the prodrug is selected from prodrugs of compounds n°3, 4, 5, 6, 7, 8, 9, 10, 11, and 12.
  • the prodrug is selected from prodrugs of compounds n°3, 4, 5, 6, 7, 7bis, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 18bis, 19, 20, 21, 22, 23, 24, 25, 25bis, 26, 26, 27, 27bis and pharmaceutically salts or solvates thereof.
  • the prodrug is selected from prodrugs of compounds n°3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 21 and pharmaceutically salts or solvates thereof.
  • Certain compounds of the invention can comprise one or several chiral centers.
  • the present invention also includes all the diastereo-isomers and all enantiomers, e.g. (R) or (S) of the compounds of the invention (namely the compounds of formula (I) or (Ia) - (Ic) as described above as well as any prodrug thereof) in isolated forms as well as any mixtures thereof in any ratio, e.g. in racemic mixtures for enantiomers.
  • Isolation of a single stereoisomer of a compound of the invention, e.g. a single enantiomer or a single diastereoisomer, of said compound can be achieved by any suitable method described in the state in the art, such as recrystallization or chromatography, especially chiral chromatography.
  • the present invention also encompasses isotopic forms of the compounds of the invention (including the prodrugs of the invention) in particular those in which one or more hydrogen atom (s) are replaced, for example, by deuterium.
  • the present invention also encompasses all possible polymorphic or pseudo-polymorphic forms of the compounds (including the prodrugs of the invention) of the invention.
  • the compounds of the invention may be in amorphous state or in crystalline state.
  • the compounds of the present invention can exist as a hydrate or as a solvate, which means that the compounds of the present invention can contain solvent molecules, in particular molecules of water or alcohol such as isopropanol or ethanol, as structural element of its crystal lattice.
  • the present invention includes all hydrates or solvates of the compounds of the invention.
  • the compound of the Invention is in anhydrous form or is an hydrate.
  • the compounds of the present invention may exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or in the form of a salt.
  • acid-addition salt or base-addition salt can be prepared.
  • the compound of the invention may be in any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, or which is used, for example, for isolating or purifying the compounds of the present invention.
  • the compound of the invention is in the form of an acid-addition salt.
  • Acid-addition salt can be formed by reaction with an inorganic acid, or "mineral acid” , such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, citric, tartaric, stearic, lactic, oxalic, malonic, succinic, malic, adipic, this list being not exhaustive.
  • the compound of the invention is in the form of a base-addition salt.
  • Bases that can be used to obtain such salts are for instance alkali metal hydroxides, including potassium hydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metal hydroxides, such as barium hydroxide and calcium hydroxide; and organic bases, such as piperidine, diethanolamine and N-methylglucamine, this list being not exhaustive.
  • Said salt forms of the compounds of the invention can be prepared by methods well known by the skilled artisan, e.g. by contacting the compounds of the invention in free state with an appropriate base or acid.
  • the compounds of the Invention can be prepared by any methods described in the prior art for the synthesis of phenanthridine derivatives.
  • the skilled artisan can adapt, by routine work, the methods described in Gug et al. Tetrahedron, 2004, 4705-4708 or in Gug et al., Tetrahedron Letters, 2005, 3725-3727.
  • the skilled artisan may implement and/or adapt Suzuki-Miyaura coupling in the presence of appropriate a catalytic conditions as exemplified herein in the example section.
  • the Inventors conceived a new method for preparing 6-aminophenanthridine derivative.
  • This method is based on the reaction of (a) a nitroaryl boronic acid derivative with a 2-bromonitrile derivative so as to form the corresponding biphenyl derivative. Then, the reduction (b) of the nitro group present in the biphenyl derivative in mild conditions triggers the cyclisation whereby the 6-aminophenanthridine derivative is formed.
  • the reduction of the nitro group and the final cyclisation may be performed without palladium catalyzer, e.g by using Fe/NH 4 Cl or by using B 2 (OH) 2 , : in such conditions, the final 6-aminophenanthridine compound is palladium-free.
  • the method of the invention also has the advantage to provide high yields.
  • the present invention relates to a method for preparing a compound of formula (I) as described above wherein A is NH 2 , which comprises the steps of :
  • R 1 -R 10 are as defined in formula (I) hereabove, X is halogen, preferably Br and each R 26 is H, or C 1 -C 6 alkyl , or R 26 groups form together with B (O) 2 a 5-membered heterocycle optionally substituted with one or several C 1 -C 3 alkyl.
  • the compound of formula (II) is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the step (a) is preferably performed in the presence of a Pd catalyst, in particular Pd (PPh 3 ) 4 and an appropriate base such as Na 2 CO 3 , K 2 CO 3 , K 3 PO 4 and the like.
  • a Pd catalyst in particular Pd (PPh 3 ) 4 and an appropriate base such as Na 2 CO 3 , K 2 CO 3 , K 3 PO 4 and the like.
  • Step (b) can be performed in the presence of any condition known in the art to reduce, under mild conditions, nitro into aniline without reducing the nitrile group.
  • Step (b) is preferably performed in the absence of a Pd-catalyzer, e.g. by using Fe (typically Fe powder) and ammonium chloride (NH 4 Cl) in an appropriate solvent, e.g. MeOH.
  • Step b) may be also promoted by B 2 (OH) 4 in the presence of 4, 4’ -bipyridine, e.g. ina solvent such as DMF.
  • step (b) when performed in the presence of B 2 (OH) 4 can be performed at room temperature (e.g. at about 20-25 °C) .
  • the Invention relates to an
  • R 1 , R 2 , R 3 , R 4 , R 7 , , R 8 , R 9 and R 10 being as defined in any one of formula (I) , (Ia) , (Ib) and (Ic)
  • the Invention relates to an intermediate reagent for the preparation of a compound of formula (I) , said compound being of formula (IV) :
  • R 1 , R 2 , R 3 , R 4 , R 7 , , R 8 , R 9 and R 10 being as defined in any one of formula (I) , (Ia) , (Ib) and (Ic) ,
  • R 3 , R 8 , R 9 and R 10 being as defined in any one of formula (I) or (Id) and
  • the intermediate reagent may be selected from :
  • the Invention also relates to the compounds of the Invention (e.g. of formula (I) , (Ia) - (Id) , shown in tables 1 or 2 as well as prodrug thereof) , for use as drugs, in particular as EBNA1 inhibitors.
  • compounds of the Invention e.g. of formula (I) , (Ia) - (Id) , shown in tables 1 or 2 as well as prodrug thereof
  • drugs in particular as EBNA1 inhibitors.
  • the Invention relates to the compounds of the Invention (e.g. of formula (I) , (Ia) - (Id) , shown in tables 1 or 2 as well as prodrug thereof) for use in the treatment or the prevention of an EBV-associated disease in a subject.
  • the EBV-associated disease is as defined in the section dedicated to “general definitions” hereabove.
  • EBV-associated diseases include EBV-associated cancers, non-cancerous EBV-associated lymphoproliferative disorders (LPD) (e.g. CAEBV, infectious mononucleosis and other non-malignant EBV+ LPDs) and EBV-associated autoimmune disorders.
  • LPD non-cancerous EBV-associated lymphoproliferative disorders
  • EBV-associated diseases of interest encompass, without being limited to, EBV-positive (+) cancers for instance EBV (+) -nasopharyngeal carcinoma (NPC) , gastric carcinoma, posttransplant lymphoproliferative disorders (PTLD) , HIV-associated lymphoma, Hodgkin's lymphoma, Hodgkin's disease, Burkitt's lymphoma and multiple sclerosis.
  • EBV-associated disease also encompasses primary infection with EBV such as infectious mononucleosis and chronic active EBV disease (CAEBV) .
  • EBV-positive (+) cancers for instance EBV (+) -nasopharyngeal carcinoma (NPC) , gastric carcinoma, posttransplant lymphoproliferative disorders (PTLD) , HIV-associated lymphoma, Hodgkin's lymphoma, Hodgkin's disease, Burkitt's lymphoma and multiple sclerosis.
  • EBV-associated disease also encompasses primary infection
  • the EBV-associated disease is a non-cancerous EBV+lymphoproliferative disorder, an EBV+ lymphoma, an EBV+ nasopharyngeal carcinoma or an EBV+ gastric carcinoma.
  • EBV-associated disease is characterized by the presence of B cells and/or cancer cells (e.g. lymphoma or carcinoma) expressing an EBV antigen, preferably EBNA1.
  • B cells and/or cancer cells e.g. lymphoma or carcinoma
  • EBV antigen preferably EBNA1.
  • the term “subject” encompasses human beings and animals, preferably mammals.
  • the mammal is human and can be of any age (e.g. infant, child, adult or elder people) or any gender (female or male) .
  • the subject suffers from EBV-associated disorder or is at risk of developing a EBV-associated disorder, e.g. because of its immune status.
  • the subject is immunocompromised, e.g. suffers from primary (e.g. inherited) immunodeficiency or from a secondary immunodeficiency due to immunosuppressive treatment (e.g. in the context of organ transplant) , chemotherapy, or glucocorticoids, concomitant infections, in particular viral ones (e.g. HIV, SARS-COV2) , or metabolic or hormonal disorders such as hypothyroidism, anemia, and hyperglycemia.
  • immunosuppressive treatment e.g. in the context of organ transplant
  • chemotherapy e.g. in the context of organ transplant
  • glucocorticoids e.g. in the context of organ transplant
  • concomitant infections e.g. HIV, SARS-COV2
  • metabolic or hormonal disorders such as hypothyroidism, anemia, and hyperglycemia.
  • the subject is infected with EBV e.g. the subject is latently infected with EBV and/or the subject experiments active/acute EBV infection such as infectious mononucleosis or CAEBV and/or the subject experiments a reactivation of a latent infection with EBV.
  • active/acute EBV infection such as infectious mononucleosis or CAEBV
  • the subject is latently infected with EBV.
  • the EBV infection status in the subject can be determined by methods well known in the state in the art, e.g. by testing antibodies such as Viral capsid antigen (VCA) -IgM and IgG, anti-early antigen (EA) IgG and EBV nuclear antigen (EBNA e.g. EBNA1) antibodies.
  • VCA Viral capsid antigen
  • EA anti-early antigen
  • EBNA EBV nuclear antigen
  • the subject has a long-term EBV infection, e.g. of at least 6 months, 12 months, 2 years, 3 years or longer.
  • the EBV-associated disease to treat or prevent in the subject is due to a latent infection with EBV or to the reactivation of a latent EBV infection.
  • Serology can be used to test for EBV infection and even for evaluating acute versus remote/latent infection in healthy individuals.
  • a high serological titer can also serve as a tumor marker for some EBV-associated cancers.
  • EBV viral load testing by quantitative DNA amplification of blood samples has proven useful for early diagnosis and monitoring patients with PTLD (Houen and Hartwig Trier, Front Immunol. 2020; 11: 587380) .
  • the subject is in the acute phase of EBV infection.
  • the subject is in the acute phase of EBV infection and is symptomatic.
  • the subject can suffer from CAEBV or infectious mononucleosis.
  • the subject is characterized by one or several of the following features:
  • the subject has inherited or iatrogenic immunodeficiency and/or
  • the subject is receiving immunosuppressive treatment and/or
  • the subject suffers from infectious mononucleosis or CAEBV and/or
  • the subject is under, or has been subjected, to an immunosuppressive treatment.
  • the subject is to be subjected to, or has been subjected to, transplantation, e.g. solid organ transplantation (SOT) or allogeneic hematopoietic cell (HSCT) transplantation.
  • transplantation e.g. solid organ transplantation (SOT) or allogeneic hematopoietic cell (HSCT) transplantation.
  • SOT solid organ transplantation
  • HSCT allogeneic hematopoietic cell
  • the patient is receiving an allogeneic transplant.
  • the compound of the Invention is for use in the treatment or in the prevention of an EBV+ cancer in an immunocompromised subject, preferably in a subject under immunosuppressive treatment.
  • Immunosuppressive drugs encompass, without being limited to, anti-T lymphocytes serum or antibodies, cyclosporine, calcineurin inhibitors such as tacrolimus, sirolimus, everolimus, anti-metabolites such as mycophenolate mofetil, or certain corticoids such as prednisone.
  • the compound of the Invention is for use in the treatment or in the prevention of an EBV+ cancer in a transplanted subject, preferably in a transplanted subject under immunosuppressive treatment.
  • the EBV+ cancer is EBV+ PTLD, EBV+ nasopharyngeal carcinoma or EBV+gastric carcinoma, preferably EBV+ PTLD
  • the administration route of the compound of the invention may be topical, parenteral, or enteral.
  • the compounds of the invention may be administered by any conventional route including, but not limited to, oral, buccal, sublingual, rectal, intravenous, intramuscular, subcutaneous, intradermal, mucosal, transmucosal, intra-cerebral, intra-thecal, intra-peritoneal, intra-ocular, intra-tumoral or intranasal route.
  • the route of administration may vary depending on the disorder to treat or prevent or the feature of the subject.
  • the compound of the invention is typically administered by means of an appropriate vehicle; Typically, it is administered as a pharmaceutical composition.
  • an appropriate vehicle Typically, it is administered as a pharmaceutical composition.
  • Examples of pharmaceutical compositions comprising a compound of the invention is provided further below.
  • the dose regimen of the compounds of the invention may be determined and adapted by the one skilled in the art in view of the specific features of the subject, namely his/her age, gender, ethnic group, weight, health and physical condition, medical history, the EBV-associated disorder to treat and its stage, co-morbidities, co-therapy and other relevant features.
  • the compounds of the invention are typically administered at an effective therapeutic dose to the subject.
  • atherapeutically effective amount or dose refers to an amount of a therapeutic agent which prevents, removes, slows down a disease of interest or alleviates or reduces or delays the onset of one or several symptoms or disorders caused by said disease in the subject.
  • the amount of the compound to be administrated to a patient may range from about 0.001 mg/kg to 500 mg/kg of body weight.
  • the compounds of the invention may be typically administered chronically, at least once a week or daily.
  • the compound of the invention can be administered every day during several consecutive days, or months until the achievement of the desired therapeutic effect.
  • the compounds of the invention can be daily administered during at least three months, e.g. at least 6 months or at least 12 months.
  • the compound of the invention may be administered once, twice or three times a day, preferably once or twice a day.
  • the compound may be also administered as an acute treatment, e.g. in one or two doses.
  • the compound of the Invention can be used in combination with a second therapeutic agent.
  • the second therapeutic agent is typically selected with respect to the EBV-associated disorder to treat or to prevent.
  • the second therapeutic agent can be antiviral drugs, radiotherapy, immunotherapeutic agents, anticancer agents.
  • Second therapeutic agents to be used in combination with the compound of the invention encompass, without being limited to, anti-CD20 antibodies such as rituximab, bispecific anti-CD19/CD3 antibodies such as blinatumomab, immune checkpoint modulators such as anti-PD-1, anti-PD-L1 or anti-CTLA-4 antibody (e.g.
  • pembrolizumab and nivolumab chemotherapeutic agents such as alkylating agents, platinum coordination complex, antimetabolites, taxane, topoisomerase inhibitors, vinca alkaloids and intercalating agents, CHOP chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone) , BET Bromodomain Inhibitors, olaparib, and other PARP inhibitors, HDAC inhibitors, antiproliferative agents (e.g. Mycophenolate Mofetil, Mycophenolate Sodium, Azathioprine, cyclophosphamide) , antiviral agents, such as ganciclovir; valganciclovir, and aciclovir.
  • chemotherapeutic agents such as alkylating agents, platinum coordination complex, antimetabolites, taxane, topoisomerase inhibitors, vinca alkaloids and intercalating agents
  • CHOP chemotherapy doxorubicin, cyclophospham
  • the compound of the Invention is typically administered in the form of a pharmaceutical composition.
  • the Invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising (i) a compound according to the invention in combination with (ii) one or several pharmaceutically acceptable excipients.
  • composition of the invention may comprise:
  • a dosage unit of said pharmaceutical composition generally comprises from about 0.1 mg to about 3000 mg of a compound according to the invention.
  • Such a pharmaceutical composition is preferably to be used in the treatment or the prevention of a EBV-associated disorder as described above.
  • composition of the invention may be formulated according to standard methods such as those described in Remington: The Science and Practice of Pharmacy (Lippincott Williams &Wilkins; Twenty first Edition, 2005) .
  • compositions of the invention may be obtained by admixing the compound of the invention with at least one pharmaceutically acceptable excipient.
  • pharmaceutically acceptable excipient any ingredient commonly used in the formulation of a pharmaceutical composition, which is inactive and non-toxic, the purpose of which may be to impart a particular consistency, or other particular physical or taste characteristics to the finished product, while avoiding any chemical interaction with the therapeutically active compound.
  • excipients include, but are not limited to, solvents such as water or water/ethanol mixtures, fillers, carriers, diluents, binders, anti-caking agents, plasticizers, disintegrants, lubricants, flavors, buffering agents, stabilizers, colorants, dyes, anti-oxidants, anti-adherents, softeners, preservatives, surfactants, wax, emulsifiers, wetting agents, and glidants.
  • solvents such as water or water/ethanol mixtures
  • fillers such as water or water/ethanol mixtures
  • carriers such as water or water/ethanol mixtures
  • diluents such as water or water/ethanol mixtures
  • binders such as water or water/ethanol mixtures
  • anti-caking agents plasticizers, disintegrants, lubricants, flavors, buffering agents, stabilizers, colorants, dyes, anti-oxidants, anti-adherents, softeners, preservatives, surfactants, wax,
  • diluents include, without being limited to, microcrystalline cellulose, starch, modified starch, dibasic calcium phosphate dihydrate, calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, mono-or disaccharides such as lactose, dextrose, sucrose, mannitol, galactose and sorbitol, xylitol and combinations thereof.
  • binders include, without being limited to, starches, e.g., potato starch, wheat starch, corn starch; gums, such as gum tragacanth, acacia gum and gelatin; hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose; polyvinyl pyrrolidone, copovidone, polyethylene glycol and combinations thereof.
  • lubricants include, without being limited to, fatty acids and derivatives thereof such as calcium stearate, glyceryl monostearate, glyceryle palmitostearate magnesium stearate, zinc stearate, or stearic acid, or polyalkyleneglycols such as PEG.
  • the glidant may be selected among colloidal silica, dioxide silicon, talc and the like.
  • disintegrants encompass, without being limited to, crospovidone, croscarmellose salts such as sodium croscarmellose, starches and derivatives thereof.
  • surfactants encompass, without being limited to, simethicone, triethanolamine, polysorbates and derivatives thereof such as 20 or poloxamers, fatty alcohol such as laurylic alcohol, cetylic alcohol and alkylsulfate such as sodium dodecylsulfate (SDS) .
  • emulsifiers encompass for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propyleneglycol, 1, 3-butyleneglycol, dimethylformamide, oils, polyethyleneglycol and fatty acid esters of sorbitan or mixtures of these substances.
  • excipient (s) to be combined with the compound of the invention may vary upon (i) the pharmacokinetic profile sought for said active ingredient, (ii) the dosage form and (iii) the route of administration.
  • the pharmaceutical composition may be of any type.
  • the pharmaceutical composition may be a solid oral dosage form, a liquid oral dosage form, a suspension, for instance for intravenous route, a dosage form for topical application such as cream, ointment, gel and the like, a skin patch, a muco-adhesive patch or tablet, an aerosol for intranasal administration and the like.
  • the pharmaceutical composition may provide an immediate-release, a controlled-release or a prolonged-release of the compound of the invention.
  • Oral solid dosage forms encompass, without being limited to, tablets, capsules, pills, powders and granules.
  • said oral solid forms may be prepared with coatings and shells, such as enteric coatings.
  • coating compositions which can be used are polymeric substances and waxes.
  • the compound can also be used in microencapsulated form, if appropriate, with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butyleneglycol, dimethylformamide, oils, polyethylene glycol and fatty acid esters of sorbitan or mixtures of these substances, and the like.
  • inert diluents commonly used in the art, such as water or other solvents, solubilizing agents and emulsifiers, as for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
  • composition can also include other excipients such as wetting agents, emulsifying and suspending agents, sweetening, and/or flavoring agents.
  • Suspensions may contain suspending agents, such as, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, bentonite, agar-agar, and the like.
  • the ointments, pastes, creams and gels may contain excipients such as oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • the pharmaceutical composition may be also in the form of aerosol or a sprayable composition which may be delivered intranasally by using an inhaler system or a nebulizer.
  • the pharmaceutical composition of the invention is an injectable composition e.g. a composition for injection.
  • the pharmaceutical composition of the invention may be in the form of a liquid composition ready to be administered, in the form of a concentrated liquid composition to be diluted before administration, or in the form of a powder e.g. a freeze-dried powder which is to be dissolved or suspended in an appropriate vehicle just before being administered to the subject.
  • the nitroderivative A1 was first reduced into the bromoaniline A2 which was reacted with the 2-cyanoboronic esters.
  • 2-bromoanlines A2 can be reacted with boronic ester A3 to afford A4.
  • bromoanilines A2 were found unstable.
  • Nitroarylboronic esters C2 were first prepared from 2-bromonitrobenzenes C1.
  • the Suzuki coupling reaction with the 2-bromonitrile C3 provided the substituted biphenyls C4.
  • reduction of the nitro group directly provided the tricyclic compound C6.
  • the putative intermediate C5 was not isolated.
  • the coupling (b) is not the last step thus limiting the residual contamination by Pd of C6. Further, less Pd is used under b’ conditions than in b.
  • the reduction cyclization by tetrahydroxydiboron [B 2 (OH) 4 ] (c’) was more efficient than c, proceeded rapidly at room temperature and, work-up was easier.
  • This compound was prepared by method B.
  • the reaction was conducted under an argon atmosphere.
  • a solution of 2 M Na 2 CO 3 (15 mL) was added under nitrogen to a 2-bromobenzonitrile 1b (5 g, 27.46 mmol) in 150 mL dioxane.
  • Pd [P (C 6 H 5 ) 3 ] 4 (1.54 g, 0.14 mmol) was added followed by (6.01 g, 27.46 mmol) of 2-aminophenylboronic acid pinacol ester 1a.
  • the reaction was stirred 8 h at 90 °C. Then cooled at 20°C, the reaction mixture was filtered on celite.
  • the crystallized material was filtrated before being poured into water.
  • the solid was rinsed with 5 mL acetic anhydride. And then twice with 10 mL water.
  • the crystal were dried in vacuum. The contaminant second isomer was then less than 5%.
  • the boronic ester 2c was reacted with 2-bromobenzonitrile 1b to afford 2d.
  • the reaction was conducted under an argon atmosphere.
  • a solution of 2 M Na 2 CO 3 (30 mL) was added under nitrogen to a 2-bromobenzonitrile 1b (1.5 g, 8.2 mmol) in 60 mL of dioxane.
  • Pd [P (C 6 H 5 ) 3 ] 4 (0.476 g, 0.41 mmol) was added followed by (2.19 g, 10 mmol) of 2- (3, 5-dimethoxy-2-nitro-phenyl) -4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolane 2c.
  • the reaction was stirred 8 h at 90 °C. Then cooled at 20°C, the reaction mixture was filtered on celite. The solution was concentrated in a vacuum to half of its initial volume and extracted with ethyl acetate (30 mL) and water (30 mL) . The combined organic layers were washed with brine 20 mL, dried over Na 2 SO 4, and evaporated. The solid crystallized upon concentration. It was triturated with Et 2 O (2x10 mL) and filtered on Buchner to afford 2d. Yield 36 %.
  • Fe powder 2.5 g and 2.5 g of ammonium chloride were added to a solution of 2d (2.6 g, 10 mmol) in 64 mL of methanol, and 10 mL of water.
  • the mixture was heated to reflux at 80° C.
  • TLC monitored the reaction for 4 hours and the cooled reaction mixture was filtered on celite.
  • the precipitate was washed twice with 20 mL methanol-CH 2 Cl 2 (80-20)
  • the solution was concentrated under vacuum to half of its initial volume and extracted with ethyl acetate (2x30 mL) and water (30 mL) .
  • the combined organic layers were washed with brine 20 mL, dried over Na 2 SO 4 , and evaporated.
  • This compound was obtained by method C.
  • Product 4a was prepared by reduction of the nitro derivative 2b using Fe/NH 4 Cl as described before in the reduction of 2d into 2.
  • 4a was reacted with the commercially available 4-chloro-2- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) benzonitrile 4b by the same coupling conditions as for the preparation of example 1.
  • Example 6 preparation of preparation of 2, 4, 9-trimethoxyphenanthridin-6-amine 6.
  • Compound 8c was prepared by Suzuki coupling as described in the preparation of 2d.
  • PTSA paratoluenesulfonic acid (0.17 g, 1 mmol) was added to a solution of 8d (0.1 g, 0.25 mmol) in MeOH (50 mL) . The solution is stirred at 20 °C for 6 h. The solution is concentrated in vacuum. The remaining solid is extracted with 1 M Na 2 CO 3 (2 mL) and AcOEt (50 mL) . The organic layer is washed with H 2 O (20 mL) . After drying over Na 2 SO 4 and, evaporation of AcOEt, 8 was obtained in 95%yield.
  • Compound 9 was prepared by method C.
  • Compound 10 was prepared by method C.
  • Compound 11 was prepared by method C.
  • Compound 12 was prepared according to method A.
  • Nitric acid (65%) in acetic anhydride was used as indicated in the preparation of 2b.
  • Compound 13 was prepared by method C.
  • Compound 14 was obtained by method C.
  • Examples 15, 16, 17 and 18 Preparation of 2- (6-amino-8-fluoro-2, 4-dimethoxy- phenanthridin-9-yl) oxyethanol 15, 9- [3- (dimethylamino) propoxy] -8-fluoro-2, 4-dimethoxy- phenanthridin-6-amine 16, 8-fluoro-2, 4-dimethoxy-9- [ [ (3R) -1-methylpyrrolidin-3- yl] methoxy] phenanthridin-6-amine 17 and 8-fluoro-2, 4-dimethoxy-9- [ (1-methyl-4- piperidyl) methoxy] phenanthridin-6-amine 18.
  • 1st step is the preparation of nitriles 15a, 16a, 17a 18a.
  • Nitriles 15a, 16a, 17a, and 18a were obtained in the same conditions as 8b.
  • Bromacetyl bromide (0.95 mL, 10 mmol) was added slowly and under stirring to a cold -5 °Csolution of 5-amino-2-bromo-benzonitrile, (1.97 g, 10 mmol) , and DIEA (2.1 mL, 12 mmol) in 15 mL CH 3 CN. After complete addition, the mixture was extracted with H 2 O and AcOEt. Derivative 19b crystallized upon the concentration of the organic phase. Yield 89%.
  • Compound 20 was prepared by method C.
  • the derivative 21b was prepared according to the process used to obtain 13b. Yield 68%.
  • Tetrahydroxydiborane (B 2 OH 4 ) (0.091 g, 1 mmol) and, 21b were added to a solution 4, 4’ -bipyridine (0.008 g, 0.005 mmol) in 1 mL DMF.
  • the mixture was stirred 0.5 h at 20 °C and 2 mL of a 2M Na 2 CO 3 solution was added. Stirring was pursued for 1 h and the mixture was extracted with AcOEt (3x20 mL) and water 10 mL. The organic layer was washed with 10 mL brine and 10 mL H 2 O. After drying, 21 crystallized upon evaporation of the AcOEt solution. Yield 78%.
  • Nitriles were obtained according to the process used for 8b by reaction of alcohols with 2-bromo-3, 4-difluoro-benzonitrile using NaH in THF.
  • This compound was obtained by method C.
  • Compound 25a was prepared by reacting 2-bromo-4-fluorobenzonitrile, 7a with commercially available [ (2S) -1-methylpyrrolidin-2-yl] methanol.
  • Step 2 Preparation of 2- (3, 5-dimethoxy-2-nitro-phenyl) -6- [ [ (2S) -1-methylpyrrolidin-2- yl] methoxy] benzonitrile.
  • Step 3 Preparation of 2, 4-dimethoxy-9- [ [ (2S) -1-methylpyrrolidin-2- yl] methoxy] phenanthridin-6-amine 25
  • Example 26 Preparation of 2, 4-dimethoxy-9- (oxetan-3-yloxy) phenanthridin-6-amine 26.
  • Example 1 Determination of the expression of EBNA1 following activation of EBV by TPA.
  • protein lysates were prepared from cells and separated on SDS-Page followed by transfer on a nitrocellulose membrane (GE healthcare) .
  • Primary antibodies against actin and EBNA1 Anti-EBNA-1 Antibody, clone 1EB12 were used followed by the secondary antibody.
  • the signals were detected with the ECL Western Blot detection reagent (GE healthcare) .
  • Inhibition of EBNA1 is expressed by the micromolar concentration of the tested Compound which inhibits the expression of EBNA1 by 50%in the treated cells as compared to untreated cells (controls with DMSO or HCPD solutions) .
  • Active compounds with IC 50 ⁇ 5 ⁇ M are indicated A.
  • Compounds with 20 ⁇ M > IC 50 >5 ⁇ M are indicated B.
  • Compounds IC 50 > 20 ⁇ M are indicated C.
  • Table 3 Inhibition of EBNA1 expression in Raji cells (IC 50 ) .
  • Example 2 Evaluation of sensitivity to compounds of EBV positive and EBV negative cell lines
  • Cells were cultured in RPMI 1640 Gibco medium with 10%FBS (Fetal bovine serum) and incubated at 37°C. Prepared compounds were dissolved in DMSO. The compounds under study and Cisplatin were diluted to different concentrations using a medium and all the cells (approximately 4.10 5 cell. mL -1 ) were incubated for 48 h. Then, the medium was aspirated and the cells were incubated with medium-diluted cell counting kit-8 for 2 h at 37 °C. The cellular viability of each compound and cisplatin on the cells was determined by measuring the absorbance of the converted dye at 450 nm using a microplate reader.
  • FBS Fetal bovine serum
  • VK-2019-ester is the methyl ester.
  • VK-2019-acid is the result of the saponification of VK-2019 ester, namely:
  • IC 50 Activity of the tested compounds against EBV-positive gastric cancer cells YCCEL1 compared to inhibition of lung cancer cell line A549.
  • IC 50 Concentration of the tested compounds that inhibit cell proliferation by 50%as compared to untreated cells (control cells treated with DMSO) .

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Abstract

L'invention concerne des dérivés de 6-aminophénanthridine et leur utilisation en tant que médicaments, en particulier dans le traitement ou la prévention de troubles associés à EBV.
PCT/CN2024/135702 2023-11-30 2024-11-29 Dérivés hétérocycliques et leur utilisation dans le traitement ou la prévention de troubles associés à ebv Pending WO2025113647A2 (fr)

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