Phenanthridine-6-amines for the treatment of cancers expressing ebv antigens

Abstract

This invention relates to 6-aminophenanthridine derivatives and their use as medicines, particularly for the treatment or prevention of EBV-related disorders.

Description

[0001] This invention relates to the treatment and prevention of EBV-related disorders, particularly those caused by latent EBV infection. Background Technology

[0002] Epstein-Barr virus (EBV), also known as human gamma herpesvirus 4, is a double-stranded DNA virus and one of nine human herpesvirus types in the herpes family. EBV is considered a successful infectious agent, as its prevalence is approximately 90% in all humans. It is generally well-tolerated. However, it has been associated with the development of several diseases, including autoimmune diseases such as multiple sclerosis, lymphoma, and epithelial cell carcinoma, particularly in immunocompromised subjects. The virus can remain latent for life after initial infection. Plasma EBV DNA, anti-EBV antibodies, and miRNA levels during the lysis / reactivation phase characterize EBV-related disease (Tan et al., Int J Cancer. 2020;146:2336-2347). The expression of multiple antigens has also been used to characterize EBV-related disease (Münz, Nat Rev Microbiol 2019, 17, 691–700). These antigens have been extensively studied in EBV-driven malignancies. EBNA-1 (Epstein–Barr nuclear antigen 1) is consistently expressed. This biomarker characterizes EBV-related diseases (Damania et al., Cell. 2022, 185, 3652-3670; see also Emmanuel Cancers (Basel). 2021, 30:4944.). Other biomarkers are expressed in different EBV-related diseases (Liu et al.: Cell Death and Disease (2015) 6, e1920; Chen et al., Genome Medicine (2021) 13:146). More than 200,000 new cancers caused by EBV are reported worldwide each year (Wong et al., J Cancer ResClin Oncol. 2022 Jan;148(1):31-46). EBV-related cancers include nasopharyngeal carcinoma (NPC), gastric cancer, post-transplant lymphoproliferative disorder (PTLD), HIV-associated lymphoma, Hodgkin lymphoma, Hodgkin's disease, and Burkitt lymphoma.

[0003] In fact, EBV plays a role in 30% to 50% of Hodgkin's disease cases in the United States (Haverkos et al., BloodAdv. 2023, 010330), while Burkitt lymphoma (which is the cause of more than half of all childhood cancers in Africa) is primarily associated with Epstein-Barr virus (Graham et al., Burkitt Lymphoma. 2023 Aug 7. In: StatPearls[Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan–. PMID:30844175). On the other hand, EBV-associated gastric cancer (EBVaGC), which accounts for about 10% of all gastric cancers, is often resistant to anti-tumor therapy (Sun et al., Gastric Oncol. 2020 Dec 14;10:583463). EBVaGC is the most common cancer among EBV-associated malignancies (Murphy et al., Gastroenterology 2009,137, 824–833).

[0004] Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication of long-term immunosuppressive therapy following organ transplantation or allogeneic hematopoietic cell transplantation. In most cases, Epstein-Barr virus (EBV) is present in large B-cell lymphomas. Most PTLD cases are serologically associated with Epstein-Barr virus (EBV) (Fujimoto et al., Cancers 2020 Feb 1;12(2):328). Finally, over 90% of HIV-associated lymphomas are associated with EBV (Zealiyas et al., Viruses. 2023 Aug 15;15(8):1743).

[0005] Recently, the role of EBV in multiple sclerosis (MS) has been established (Soldan et al., Nat RevMicrobiol. 2023 Jan;21:51-64). Soldan et al. summarized the latest findings on EBV involvement in the pathogenesis of MS. For example, the authors highlighted that, among other things, epidemiological studies strongly support the significant increased risk of developing MS from prior EBV infection. Soldan et al. also emphasized that autoantibodies in MS also cross-react with viral proteins, particularly EBNA1. Furthermore, EBV-positive B cells identified after death in MS lesions in the CNS demonstrate EBV+ cell infiltration in the CNS. Numerous pieces of evidence also suggest that EBV is involved in other autoimmune diseases, such as Sögren's syndrome, systemic lupus erythematosus, systemic scleroderma, and rheumatoid arthritis. EBNA1 expression has been used to characterize EBV-related autoimmune diseases (Sternbæk et al., Scand J ClinLab Invest. 2019;79:7-16; Trier et al., Antibodies 2019, 8:35). High plasma levels of antibodies against certain EBV antigens such as EBNA1 (or others such as LMP1, EBNA2, BALF5, EAD, BALF2, EA / R, VCA p18, or VCA p23) are often found in the context of EBV-related disease (Kieser et al., Curr Top Microbiol Immunol. 2015;391:119-49), (Giehler et al., Nat Commun. 2024;15:414).

[0006] A potential target for developing inhibitors of EBV's oncogenic or proliferative activity is the latent protein EBNA1, the only EBV protein consistently expressed across all latency types, and therefore consistently expressed in all EBV-related tumors. This multifunctional protein plays a role in the maintenance, replication, and segregation of the EBV genome, making it an attractive therapeutic target for treating EBV-related disorders, particularly cancer. Indeed, while its primary function is maintaining the viral genome, it is also involved in tumorigenesis. Several reports have shown that specific EBNA1 inhibition, including downregulation of EBNA1 expression via antisense oligodeoxynucleotides, leads to growth inhibition, thus validating EBNA1 as a therapeutic target in EBV-infected cells.

[0007] Based on the structure and biological behavior of EBNA1, drugs that act on EBNA1 are expected to have minimal off-target effects, thus such drugs appear to have high potential in treating and preventing any EBV-related disorders, especially in immunocompromised subjects.

[0008] To date, several potential EBNA1 inhibitors have been identified, including certain Hsp90 inhibitors, inhibitors that block EBNA1-DNA binding, and inhibitors based on truncated peptides from the EBNA1 dimer interface (Jiang, Theranostics, 2018, 8(19):5307-5319).

[0009] VK-1727 (an EBNA1-DNA binding inhibitor) was tested against specific EBV-positive cancers in various in vivo xenograft mouse models and showed inhibition of EBV-positive tumor proliferation (Soldan et al., Gastric Cancer (2021) 24:1076–88).

[0010] Recently, VK-1727 was shown to block the proliferation of spontaneous lymphoblastoid cell lines in patients with multiple sclerosis (MS), confirming that EBNA1 is also a target of interest in managing MS (Monaco et al., Neurology, Neuroimmunology, & Neuroinflammation, 2023, 10(5)). A derivative, VK-2019, is currently undergoing a phase 1 / 2 clinical trial for nasopharyngeal carcinoma (https: / / clinicaltrials.gov / ct2 / show / NCT03682055).

[0011] However, there is still a need for medications to treat or prevent EBV-related disorders. Summary of the Invention

[0012] This invention relates to compounds of formula (I):

[0013] (I)

[0014] in:

[0015] - Each of R1, R2, R3, R4, R7, R8, R9 and R 10 Independently represents H, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, -OCF3, -NO2, -CN, -OR 11 NHCOCHR 17 NHR 18 -NR 12 - R 13 -COOR 12 -CONR 12 R 13 NHCO(CH2) n NR 12 R13 -NHCOR 17 -SO2NR 12 R 13 -SO2R 12 -CH2SO2NR 12 R 13 OPOR 12 OR 13 (CH2)nNR 12 R 13 -(CH2) n COOR 12 -(CH2) n CONR 12 R 13 , -(CH2) q SO2NR 12 R 13 -S(O)NC(O)OR 14 ,

[0016] -(CH2) q Het1、NHCOR 17 -O(CH2) q B(OR 15 2、-(CH2) q B(OR 15 2. or

[0017] in:

[0018] Het1 is a 3- to 6-membered heterocycle, optionally and optionally fused with C3-C5 carbon rings.

[0019] R 11 It can be H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 dimethoxyalkyl, C1-C6 halohydroxyalkyl, or C1-C6 dihydroxyalkyl-(CH2). q Het2、-(CH2) q O(PO)(OR 15 2、-(CH2) n OHet2、-(CH2) n NR 12 R 13 -COCH(CH2SH)NHCOCH3, optional substituted C2-C 14 Alkoxyalkyl, -(CH2) n NR 15 COCH3、-(CH2) nCOOR 12 -(CH2) n CONR 12 R 13 -(CH2) q SO2NR 12 R 13 -COR 16 or –(CH2) n OCOR 16

[0020] Het2 is an optional substituted 3- to 6-membered heterocycle.

[0021] Each n is an independent integer from 1 to 6, preferably 1, 2, or 3.

[0022] Each 'o' is independently 1 or 2.

[0023] Each q is an independent integer from 0 to 6, preferably 0, 1, 2, or 3.

[0024] R 12 and R 13 It is independently H, C1-C6 alkyl or C 2-14 alkoxyalkyl, or

[0025] R 12 and R 13 Together with the N atoms they are attached to, they form optionally substituted 5- or 6-membered heterocycles.

[0026] R 14 It is a C1-C6 alkyl, C1-C6 alkoxyalkyl, or -(CH2) p Het3 or -(CH2) p Cyc1, where p is an integer from 0 to 6, preferably 1 to 3, Het3 is an optionally substituted saturated or unsaturated heterocycle, and Cyc1 is a C1-C6 cycloalkyl group.

[0027] R 15 It is H or C1-C6 alkyl, preferably C1-C3 alkyl.

[0028] R 16 C1-C6 alkyl, C1-C6 aminoalkyl, -CHR 17 NHCOR 17 or -OCHR 17 OCOR 17

[0029] Each R 17 Independently H or C1-C3 alkyl, and

[0030] R 18 It is H, or COCH3.

[0031] and

[0032] A is -NR5R6 or in

[0033] R5 is H.

[0034] R6 can be H, C1-C6 alkyl, or COO(CH2). n Het4, COR 21 or COOCHR 17 OCOR 17 ,in

[0035] oR 21 For OH, halogen, -O(CH2) n NR 22 R 23 Optional substitution of -O(CH2) n O(CH2) m CH3 or optionally substituted C2- 14 Alkoxyalkyl

[0036] oR 22 and R 23 Independently selected from H, C1-C6 alkyl groups or optionally substituted C2- 14 Alkoxyalkyl, and

[0037] oHet4 is an optionally substituted 3- to 6-membered heterocyclic ring.

[0038] R 20 H, C1-C8 alkyl, or optionally substituted C2-C 14 Alkoxyalkyl, and

[0039] R 19 The substituted 5 to 12 aryl or heteroaryl groups are optional.

[0040] Or its pharmaceutically acceptable salts and / or solvates,

[0041] It is used to treat or prevent EBV-related disorders.

[0042] In some embodiments, the compound of formula (I) is characterized by one or more of the following features:

[0043] -A is NR5R6, preferably -NH2 and / or

[0044] -R4 and R2 can be independently halogens, OH, C1-C6 alkoxy groups, or -O(CH2). n O(CH2) m CH3, and / or

[0045] - At least one of R7, R8, and R9 is not H, and / or

[0046] -R3 can be H, halogen, OH, C1-C6 alkoxy, or -O(CH2). n O(CH2) m CH3.

[0047] In some embodiments, the compound is of formula (Id).

[0048] (Id)

[0049] in

[0050] R3, R8, R9 and R 10 As defined in equation (I), and

[0051] Each R 24 Or R 25 Independently represents C1-C6 alkyl, C1-C6 hydroxyalkyl, or –(CH2). n O(CH2) m CH3, where n is an integer from 1 to 6, and m is an integer from 0 to 6.

[0052] Or its pharmaceutically acceptable salts and / or solvates.

[0053] In some implementations, R3 is H or OR 26 , where R 26 Indicates C1-C6 alkyl, C1-C6 hydroxyalkyl, or –(CH2). n O(CH2) m CH3, where n is an integer from 1 to 6 and m is an integer from 0 to 6.

[0054] In some implementations, the compound of formula (Id) is as follows:

[0055] -R3 is H

[0056] - Each R 25 and R 24 Independently, it is a C1-C6 alkyl group, preferably a C1-C3 alkyl group.

[0057] -R 10 It is H or a halogen, such as F, and

[0058] R8 and R9 are independently selected from OH, Cl, F, Br, OH, C1-C3 alkoxy groups, preferably OCH3, C1-C3 alkyl groups, CF3, OCF3, and O(CH2). n OH, Hetl, O(CH2) n NCOR 17 O(CH2)nNR 12 R 13 -NHCO(CH2) n R 12 R 13 O(CH2) q Het2, where

[0059] on is an integer from 1 to 6, preferably 1, 2 or 3.

[0060] oq is an integer from 1 to 6, preferably 0, 1, 2 or 3.

[0061] oHet1 is a 4-, 5-, or 6-membered heterocyclic ring, preferably pyrrolidinyl, optionally coated with halogen, -CONH2, or -COR. 17 -OH, C1-C3 alkoxy or C1-C3 alkyl substitution,

[0062] oHet2 is a 5- or 6-membered heterocycle, preferably piperidinyl, which may optionally be substituted with a halogen, -OH, C1-C3 alkoxy, or C1-C3 alkyl group.

[0063] oR 17 H or C1-C3 alkyl

[0064] oR 12 and R 13 It is independently H or C1-C3 alkyl, or forms a 5 or 6-membered heterocycle with the N atom to which it is attached, which is optionally substituted with a C1-C3 alkyl.

[0065] EBV-related disorders are preferably EBV-related autoimmune diseases, such as multiple sclerosis, active EBV infection, or EBV-positive cancer. Examples of EBV-positive cancer include EBV-positive nasopharyngeal carcinoma, NKT-cell lymphoma, gastric cancer, Hodgkin's lymphoma, post-transplant lymphoproliferative disorder (PTLD), Burkitt lymphoma, lymphoma in subjects with acquired immunodeficiency syndrome, diffuse large B-cell lymphoma, gastric cancer, parotid gland cancer, breast cancer, leiomyosarcoma, and any combination thereof.

[0066] In some implementations, the EBV-related disorder is selected from autoimmune EBV-related disorders, preferably multiple sclerosis, infectious mononucleosis, and chronic active EBV disease (CAEBV).

[0067] In some implementations, the compound is administered to subjects with weakened immune systems.

[0068] In a specific implementation, the compound is used to treat or prevent EBV-positive cancers selected from EBV-positive nasopharyngeal carcinoma, EBV-positive gastric cancer, and EBV-positive lymphoma, preferably PTLD.

[0069] In some implementations, the compound is used to prevent or treat EBV-positive cancers in immunocompromised subjects and / or transplant recipients.

[0070] This invention relates to compounds of formula (Id).

[0071] (Id)

[0072] in

[0073] R3, R8, R9 and R 10 As defined in claim 1, and

[0074] Each R 24 Or R 25 Independently represents C1-C6 alkyl, C1-C6 hydroxyalkyl, or –(CH2). n O(CH2) m CH3, where n is an integer from 1 to 6, m is an integer from 0 to 6, and the condition is that when R 24 and R 25 When it is CH3, R3, R 10 R8 and R9 are not all H.

[0075] Or its pharmaceutically acceptable salts and / or solvates.

[0076] The compounds of interest are as follows

[0077]

[0078]

[0079] Or its pharmaceutically acceptable salts or solvates.

[0080] These compounds are suitable for the treatment or prevention of EBV-related disorders, particularly EBV-positive cancers.

[0081] The present invention also relates to a prodrug of a compound of formula (Id), wherein the prodrug comprises an unstable moiety selected from:

[0082]

[0083] And amino acid residues, wherein the unstable portion is preferably linked to the amino group at position 6 of the aminophenanthrene backbone or to a group present at R8, R9 or R 10 The hydroxyl group in it.

[0084] This invention also relates to pharmaceutical compositions comprising compounds as defined herein and pharmaceutically acceptable excipients thereof. Such pharmaceutical compositions may be used to treat or prevent EBV-related disorders, preferably EBV-positive cancers.

[0085] The present invention also relates to a method for preparing a compound of formula (I) as described herein (where A is NH2), the method comprising the following steps:

[0086] -(a) Makes compound (II) (II) and compounds of formula (III) (III) Reaction to form a biphenyl compound of formula (IV),

[0087] (IV)

[0088] -(b) Under conditions that promote cyclization, the nitro functional group in compound (IV) is reduced to NH2, thereby obtaining the compound of formula (I) (where A is NH2), i.e.:

[0089] - (I)

[0090] Where R1-R 10 As defined in formula (I) of claim 1, X is a halogen, preferably Br, and each R 26 It is H, or C1-C6 alkyl, or R 26 The group together with B(O)2 forms a 5-membered heterocycle optionally substituted with one or more C1-C3 alkyl groups.

[0091] In some implementations, step (b) is carried out in the presence of Fe / NH4Cl.

[0092] In some embodiments, step (b) is carried out in the presence of B2(OH)4 and 4,4'-bipyridine, preferably in DMF and at room temperature.

[0093] This invention further relates to intermediate reagents selected from:

[0094] -2-(3,5-dimethoxy-2-nitro-phenyl)-4-[(1-methyl-4-piperidinyl)methoxy]benzonitrile

[0095] 2-(3,5-Dimethoxy-2-nitro-phenyl)-4-(trifluoromethyl)benzonitrile

[0096] -2-(3,5-dimethoxy-2-nitro-phenyl)-4,5-difluorobenzonitrile

[0097] -2-(3,5-dimethoxy-2-nitro-phenyl)-2,3-difluorobenzonitrile,

[0098] -2-(3,5-dimethoxy-2-nitro-phenyl)-4-fluorobenzonitrile,

[0099] -N-[3-cyano-4-(3,5-dimethoxy-2-nitro-phenyl)phenyl]-2-pyrrolidine-1-ylacetamide

[0100] -N-[2-(6-amino-2,4-dimethoxy-phenanthridine-9-yl)oxyethyl]acetamide

[0101] -2-(3,5-dimethoxy-2-nitro-phenyl)-4-[3-(dimethylamino)propoxy]-3-fluorobenzonitrile

[0102] -2-(3,5-dimethoxy-2-nitro-phenyl)-3-fluoro-4-[(1-methylazacyclobut-3-yl)methoxy]benzonitrile, and

[0103] -2-(3,5-dimethoxy-2-nitro-phenyl)-3-fluoro-4-[(1-methyl-4-piperidinyl)methoxy]benzonitrile.

[0104] The present invention further relates to the use of compounds as defined herein in the manufacture of medicaments for the treatment or prevention of EBV-related diseases (preferably EBV-positive cancers) in subjects.

[0105] The present invention further relates to a method for treating or preventing EBV-related diseases in a subject, the method comprising administering to the subject an effective amount of a compound as defined herein. Detailed Implementation

[0106] Given the high interest in EBNA1 as a therapeutic target for the treatment and prevention of EBV-related disorders, the inventors sought to identify inhibitors of this key protein. Unexpectedly, the inventors identified certain 6-aminophenanthridine derivatives, particularly those of formulas (I), (Ia)-(Id) as described herein, that specifically inhibited EBNA1 expression in Raji cells after reactivation with TPA.

[0107] The inventors further demonstrate that the compounds can inhibit the proliferation of various EBV-positive cancer cell lines, including EBV-positive lymphoma and EBV-positive carcinoma. Notably, the compounds of this invention are more effective than VK-2019 (an EBNA1-DNA binding inhibitor used as a positive control in in vitro assays), which is currently undergoing clinical trials for nasopharyngeal carcinoma. It is also noteworthy that the compounds of this invention are more effective in preventing the proliferation of EBV-positive cancer cell lines than in EBV-negative cell lines.

[0108] To the inventors’ knowledge, this bioactivity of 6-aminophenanthridine derivatives, particularly those of formulas (I), (Ia)-(Id) as described herein, has never been described or implied in the prior art.

[0109] To the inventors’ knowledge, certain 6-aminophenanthridine derivatives have been identified as potential prion inhibitors (e.g., Bach, 2003, Nature Biotechnology, 21, 9, 1075-1081) or adjuvants in vaccine compositions (WO201144734).

[0110] Therefore, the present invention relates to 6-aminophenanthridine derivatives of formula (I) or (Ia)-(Id) as described herein, or pharmaceutically acceptable salts, solvates and / or prodrugs thereof (hereinafter referred to as compounds of the present invention).

[0111] The present invention also relates to the use of the said compounds as medicines, particularly medicines for treating or preventing EBV-related disorders.

[0112] A further aspect of the invention is the use of the compound in the manufacture of medicines, particularly medicines for the treatment or prevention of EBV-related disorders.

[0113] This invention further relates to pharmaceutical compositions comprising a combination of the compound of the invention as an active ingredient and at least one pharmaceutically acceptable excipient. The invention also relates to the use of said compositions as pharmaceuticals, particularly for the treatment or prevention of EBV-related diseases. The compounds of the invention can be used as EBNA1 inhibitors, particularly as EBNA1 expression inhibitors.

[0114] The compounds of this invention can be used as antiproliferative agents against EBV-positive cells (especially EBV-positive B cells, EBV-positive epithelial cells and EBV-positive cancer cells, particularly EBV-positive lymphoma or EBV-positive carcinoma).

[0115] The present invention also relates to a method for treating or preventing EBV-related disorders in a subject, the method comprising administering an effective amount of the compound of the present invention or the pharmaceutical composition of the present invention to the subject.

[0116] As fully described below, the compounds of the present invention can be used to treat or prevent any type of EBV-related disorders, particularly EBV-positive cancers and EBV-induced autoimmune disorders, such as multiple sclerosis.

[0117] EBV-related diseases of interest include, but are not limited to, EBV-positive nasopharyngeal carcinoma (NPC), gastric cancer, post-transplant lymphoproliferative disorder (PTLD), lymphoma in subjects with HIV or AIDS, Hodgkin lymphoma, Hodgkin's disease, and Burkitt lymphoma.

[0118] Finally, the present invention relates to methods for preparing 6-aminophenanthridine derivatives as described herein, particularly 6-aminophenanthridine derivatives of formula (I) or (Ia)-(Id), and the corresponding intermediate reagents themselves.

[0119] General definition

[0120] As used herein, “treatment of a disease or disorder” or “treating a disease or disorder” includes curing, delaying, reducing or slowing the progression of a disease or disorder or one or more symptoms thereof, as well as reducing, slowing, reversing or eliminating one or more symptoms of a disease or disorder.

[0121] The term “treatment of disease / disorder” also encompasses the fact that “overall survival” and / or “progression-free survival” are improved in subjects.

[0122] Although not excluded, the wording “treat a disease or disorder” does not mean that the disease / disorder or its associated symptoms must be eliminated completely in the subject.

[0123] An improvement in progression-free survival (PFS) refers to an increase in the length of time a subject lives with the disease without its progression during and after treatment. Overall survival (OS) refers to the length of time a patient remains alive from the start of treatment. PFS and OS figures are typically determined as averages from appropriately sized clinical trials.

[0124] "Prevention of disease or disorder" includes preventing or delaying the onset of a disease or one or more symptoms associated with said disease. "Prevention of disease" also refers to any action aimed at improving a patient's health, such as the treatment, prevention, and delay and / or prevention of a patient from suffering from a disease or disorder. In some embodiments, the term also refers to minimizing the risk (or probability) of a patient developing said disease or symptoms compared to patients who have not yet been given the compounds of the present invention.

[0125] As used herein, "therapeutic effective amount" means the amount of the compound of the invention used in a subject to prevent, remove, alleviate, or reduce or delay one or more symptoms of a disease or disorder.

[0126] Epstein-Barr virus (EBV) is one of the most successful pathogens in humans, with over 90% of adults experiencing persistent infection. Primary infection mostly occurs in childhood and is asymptomatic, but in adolescents, primary infection can manifest as infectious mononucleosis (IM).

[0127] EBV targets B cells and epithelial cells. The nature and mechanism by which EBV enters these cell types differ, requiring different glycoprotein complexes to bind to specific receptors on the target cells. EBV may also occasionally infect other cell types, such as T cells / natural killer cells.

[0128] Its most prominent feature is its ability to readily establish a lifelong infection (latency) primarily in B lymphocytes. In the latent state, EBV typically does not cause disease.

[0129] The EBV life cycle comprises three distinct phases: pre-latency, latency, and lysis. Each latency phase results in the production of a limited, diverse set of viral proteins (EBNA, LMP) and viral RNA (microRNA-BART, BHRF1-, and non-coding nuclear RNA-EBER). Notably, EBER is expressed in EBV-infected cells throughout all latency phases and is therefore a biomarker of interest. Periodically, the virus may be reactivated from the latency state through mechanisms not yet fully understood. During this lysis phase of infection, all EBV lysis genes (>80 genes) are expressed, efficient viral DNA replication occurs, and progeny viral particles are produced. In immune-active hosts, CD4+... + and CD8 + T cells, especially cytotoxic CD8 + T cells are effective in controlling this process.

[0130] In contrast, reactivation is clinically significant in immunocompromised patients (e.g., after stem cell or organ transplantation, in patients receiving autoimmune or cancer treatment, in cases of HIV / AIDS or immunodeficiency), leading to the development of lymphomas such as Burkitt lymphoma (BL) and Hodgkin lymphoma (HL), and is associated with EBV-related immune dysregulation.

[0131] Therefore, EBV has a recognized carcinogenic potential and is associated with ~1% of all human cancers. EBV can also cause a wide range of diseases, including lymphoproliferative disorders, inflammatory immune dysregulations, and epithelial carcinomas, particularly in immunocompromised subjects (e.g., lymphoma in HIV-infected individuals and post-transplant lymphoproliferative disorder (PTLD)). EBV has also been found to be associated with the pathogenesis of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, and systemic lupus erythematosus.

[0132] In the context of this invention, “EBV-related disease or disorder” (also referred to herein as “EBV-induced disease or disorder”) means any clinical pathology caused by or associated with Epstein Barr virus infection.

[0133] Therefore, EBV-related diseases or disorders can refer to any disease directly or indirectly caused or induced by EBV. In the context of this invention, EBV-related diseases are preferably diseases in which EBV has been identified as a pathogenic factor or causative agent, that is, diseases in which EBV has been identified as involved in the pathogenesis of the disease.

[0134] Examples of EBV-related diseases include, but are not limited to: active EBV infection, such as infectious mononucleosis or CAEBV, EBV-related cancers, or EBV-related autoimmune diseases.

[0135] EBV-related diseases also include conditions that are susceptible to immunosuppression or a weakened immune system, such as oral hairy leukoplakia, for example in subjects with AIDS or receiving immunosuppressive therapy.

[0136] EBV-related autoimmune diseases include, for example, multiple sclerosis, rheumatoid arthritis, Sjorgen syndrome, and systemic lupus erythematosus.

[0137] In some implementations, EBV-related disorders are lymphoproliferative disorders. Epstein-Barr virus-associated lymphoproliferative disorders (also known as EBV-related lymphoproliferative disorders or EBV+LPD) are a group of disorders in which one or more types of lymphocytes (i.e., B cells, T cells, NK cells, and histiocyte-dendritic cells) are infected with Epstein-Barr virus (EBV). This leads to excessive division of the infected cells and is associated with the development of a variety of non-cancerous, precancerous, and cancerous lymphoproliferative disorders (LPDs). These LPDs include well-known disorders that occur during initial EBV infection, infectious mononucleosis, CAEBV, and EBV+ lymphomas such as post-transplant lymphoproliferative disorder (PTLD).

[0138] As used herein, the terms “cancer” or “malignancy” refer to a disease or condition characterized by abnormal or aberrant cell proliferation, differentiation, and / or migration, usually accompanied by aberrant or aberrant molecular phenotypes, including one or more genetic mutations or other genetic changes associated with tumor formation, tumor marker expression, loss of expression or activity of tumor suppressor factors, and / or aberrant or aberrant cell surface marker expression. Cancer can include, but is not limited to, any aggressive or potentially aggressive cancer, tumor, or other malignancy, such as those listed in the NCI Cancer Index, which includes all major cancer forms, such as sarcoma, carcinomas, lymphomas, leukemias, and germ cell tumors.

[0139] "EBV-associated cancer" refers to cancers associated with Epstein-Barr virus (EBV). In the context of this invention, cancers of interest are EBV-positive, meaning that the cancer cells contain the viral genome and / or express viral miRNAs, viral non-coding nuclear RNAs, and / or viral proteins derived from EBV. Notably, different types of EBV-associated cancers express different combinations of EBV latent gene products. EBV-associated (or EBV+) cancers can be identified by detecting the viral genome, viral miRNAs, viral non-coding nuclear RNAs, and / or latent proteins (e.g., EBNA or LMPs (e.g., LMP1) or SSTR2) in cancer cells or tumors.

[0140] For a review of EBV-related tumors, please refer to Shannon-Lowe and Rickinson, Frontiers in Oncology, 2019, vol.9, https: / / doi.org / 10.3389 / fonc.2019.00713, the contents of which are incorporated herein by reference.

[0141] For example, EBV-positive cancer cells can express one or more EBV antigens.

[0142] In some implementations, EBV-positive cancer cells express EBNA1.

[0143] Using techniques known in the art, EBV-positive cells (which may be neoplastic or non-neoplastic) can be detected and measured in subjects by detecting and / or quantifying viral genomes, and / or viral miRNAs, and / or viral non-coding nuclear RNAs and / or viral proteins derived from EBV.

[0144] It should also be noted that high serum viral DNA load and / or high serum anti-EBV antibody (e.g., anti-EBNA1 antibody) titers can also be used as biomarkers for the diagnosis or monitoring of EBV-related disorders, particularly EBV-related cancers.

[0145] EBV-related cancers include, but are not limited to, EBV-positive nasopharyngeal carcinoma, NKT-cell lymphoma, Hodgkin's lymphoma, post-transplant lymphoproliferative disorder (PTLD), Burkitt lymphoma, lymphoma in subjects with acquired immunodeficiency syndrome, diffuse large B-cell lymphoma, gastric cancer (EBVaGC), parotid gland cancer, breast cancer, leiomyosarcoma, and any combination thereof.

[0146] Most of the time, EBV-related cancers are carcinomas or lymphomas.

[0147] As used herein, the term “pharmaceutically acceptable” means, to a reasonable extent of medical judgment, a composition, compound, salt, or solvation that is suitable for contact with the tissues of a subject or can be administered to a subject without excessive toxicity or other complications, and that is commensurate with a reasonable benefit / risk ratio.

[0148] As used herein, "alkyl" refers to a saturated hydrocarbon group, which may be straight-chain, branched, or cyclic. For example, C1-C6 alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, pentyl, cyclopentyl, hexyl, and cyclohexyl. C1-C4 alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, cyclobutyl, and cyclopropyl. C1-C3 alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, and cyclopropyl.

[0149] In a preferred embodiment, the term "alkyl" refers to a straight-chain or branched hydrocarbon chain. For example, C1-C3 alkyl preferably refers to methyl, ethyl, propyl, and isopropyl.

[0150] As used herein, “cycloalkyl” refers to a saturated cyclic hydrocarbon group. For example, “C3-C6 cycloalkyl” includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0151] "Halogen" refers to a halogen atom, such as Cl, Br, I, or F. Preferred halogens are Br, Cl, and F, with F being more preferred.

[0152] "Alkoxy" refers to a group of the formula RO-, where R represents an alkyl group. Examples of alkoxy (or C1-C6 alkoxy) include, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy, and hexoxy.

[0153] "Carboxyalkyl" refers to a group of the formula -A-COOH, where A represents an alkylene group (e.g., C1-C6 alkylene).

[0154] "Alkyl group" refers to a –C(O)-R group, where R is an alkyl group (e.g., C1-C6 alkyl).

[0155] "Hydroxyalkyl" refers to an alkylene group (e.g., C1-C6 alkylene) substituted with one or more -OH groups (e.g., 1, 2, or 3 OH groups). Hydroxyalkyl groups can be straight-chain or branched, for example: .

[0156] "Aminoalkyl" refers to a group of the formula -A-NH2, where A represents an alkylene group (e.g., C1-C6 alkylene).

[0157] "Halogenated alkyl" refers to an alkyl (e.g., C1-C6 alkyl) group in which one or more H atoms are replaced by halogens (i.e., one or more H atoms are replaced by halogens). Examples of halogenated alkyl groups are -CF3 or -CH2-CHF2.

[0158] "alkylene group" refers to a divalent alkyl (e.g., C1-C6 alkyl) group, which can be straight-chain or branched.

[0159] "Alkoxyalkyl" refers to an alkylene group containing an alkoxy group. Such groups typically contain 2-14 carbon atoms. An example of an alkoxyalkyl group is, for instance, the formula -(CH2). n O(CH2) m A group consisting of CH3, where n is an integer from 1 to 6 and m is an integer from 0 to 6, or (CH2). n OCH3, where n is an integer from 1 to 6, such as 1, 2 or 3.

[0160] As used herein, the term "heterocyclic" refers to a saturated or unsaturated aliphatic or aromatic cyclic hydrocarbon group in which at least one ring carbon atom has been replaced by a heteroatom, preferably selected from nitrogen, oxygen, or sulfur atoms. Advantageously, the heterocycle comprises 3 to 10 ring atoms, preferably 3, 4, 5, or 6 ring atoms, wherein at least one ring atom is a heteroatom, such as a nitrogen, oxygen, or sulfur atom. The term "heterocyclic" encompasses both heteroaryl groups and aliphatic heterocyclic groups. For example, examples of heterocycles include cycloheteroalkyl groups, i.e., cycloalkyl groups in which one or more carbon atoms have been replaced by heteroatoms. The term "heterocycle" includes, for example, azirropropyl, azirroheptyl, diazirroheptyl, dioxopentyl, benzo[1,3]dioxopentenyl, azirrobutyl, oxacyclobutyl, pyrazolinyl, pyranyl, thiomorpholinyl, pyrazolinyl, piperidinyl, piperazinyl, 1,4-dioxacyclohexyl, imidazolinyl, pyridinyl, pyrrololinyl, pyrrolylyl, piperidinyl, imidazolinyl, morpholinyl, 1,4-dithiaalkyl, pyrrolylyl, pyrimidinyl, oxadiazolyl, etc. The terms "heterocyclic" and "heterocyclic" refer to groups of compounds including oxozolinyl, oxazolinyl, isoxazolinyl, isoxazolinyl, thiooxoheterocyclic butyl, thiopyranyl, thiomorpholinyl, thiazolinyl, thiazolinyl, isothiazolinyl, isothiazolinyl, dihydropyranyl, dihydrofuranyl, dihydrothiopyranyl, pyrroleyl, thiophenyl, quinolinyl, furanyl, isoquinolinyl, dihydrothiophene, dihydropiperidinyl, tetrahydropiperidinyl, tetrahydrothiopyranyl, tetrahydropyranyl, tetrahydrofuranyl, and tetrahydrothiophene. In some embodiments, "heterocyclic" is a "heterocyclic alkyl group" containing 3 to 6 carbon atoms and one or two heteroatoms as ring atoms. Preferred heterocyclic alkyl groups include piperidinyl, pyrroleyl, piperazineyl, thiomorpholinyl, and morpholinyl. More preferably, the heterocyclic alkyl group is selected from N-piperidinyl, N-pyrrolidinyl, N-piperazinyl, N-thiomorpholinyl and N-morpholinyl.

[0161] The term "aryl" refers to a monocyclic and bicyclic ring system 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. In some embodiments of the invention, "aryl" refers to an aromatic ring system. Exemplary aryl groups are phenyl, biphenyl, naphthyl, anthracene, etc., which optionally contain one or more substituents. As used herein, the term "aryl" also includes groups in the scope of which the aromatic ring is fused with one or more non-aromatic rings, such as indanyl, phthalimide, naphthimidyl, phenanthridine, or tetrahydronaphthyl. The term "heteroaryl" refers to a group having 5 to 10 ring atoms (preferably 5, 6, or 9 ring atoms); having 6, 10, or 14 π electrons shared in the cyclic array; and having 1 to 5 heteroatoms in addition to carbon atoms. Heteroaryl groups include, but are not limited to, thiophene, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridinyl, pyridinyl, indoleazinyl, purine, naphthidyl, and pteridinyl. The term "heteroaryl" also includes groups in which the heteroaryl ring is fused with one or more aryl, alicyclic, or heterocyclic rings, wherein the linking group or linking point is located on the heteroaryl ring. Non-limiting examples include indolyl, isoindolyl, benzothiophenyl, benzofuranyl, dibenzofuranyl, indazoleyl, benzimidazolyl, benzothiazolyl, quinolinyl, isoquinolinyl, cenolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinazinyl, carbazoleyl, acridineyl, phenazinyl, phenothiazinyl, phenotoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. The heteroaryl group is optionally monocyclic or bicyclic.

[0162] As used in this article, the term "unsaturated" refers to a portion having one or more unsaturated units, that is, one or more double or triple bonds.

[0163] As used in this article, the term "saturated" refers to the portion that does not have a degree of unsaturation.

[0164] The term "substituted" means that one or more hydrogen atoms on a specified atom or group are replaced by non-hydrogen substituents, provided that the substitution does not exceed the normal valence of the specified atom under existing conditions. Throughout this application, the term "optionally substituted" may be replaced by the terms "substituted or unsubstituted".

[0165] Examples of substituents include, but are not limited to, CF3, OCF3, C1-C6 alkyl, C1-C6 hydroxyalkyl, C2-C6 alkoxyalkyl, C1-C6 haloalkyl, halogen, NH2, C1-C6 alkylamine, di-(C1-C6 alkyl)amine, etc.

[0166] As used herein, the terms “one or more” or “at least one” mean one or more, such as 1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, and more particularly 1, 2 or 3.

[0167] - Compounds according to the present invention

[0168] This invention relates to aminophenanthridine derivatives, particularly medicaments used to treat or prevent EBV-related disorders.

[0169] In a first aspect, the aminophenanthridine derivative of the present invention is a compound of formula (I):

[0170] (I)

[0171] in:

[0172] - Each of R1, R2, R3, R4, R7, R8, R9 and R 10 Independently represents H, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, -OCF3, -NO2, -CN, -OR 11 NHCOCHR 17 NHR 18 -NHCO(CH2) n NR 12 R 13 -NHCOR 17 -NR 12 - R 13 -COOR 12 -CONR 12 R 13 -SO2NR 12 R 13 -SO2R 12 -CH2SO2NR 12 R 13 OPOR 12 OR 13 (CH2)nNR 12 R 13 -(CH2) n COOR 12 -(CH2) n CONR 12 R 13 -(CH2) q SO2NR 12 R 13 -S(O)NC(O)OR 14 -(CH2) q Het1、NHCOR 17-O(CH2) q B(OR 15 2、-(CH2) q B(OR 15 2. or

[0173] in:

[0174] Het1 is a 3- to 6-membered heterocycle, which is optionally substituted (e.g., preferably selected from halogens, -CONHR). 15 -COR 17 -OH, C1-C3 alkoxy groups, COOR 15 (or one or more substituents of C1-C3 alkyl groups), and optionally fused with C3-C5 carbocyclic rings,

[0175] R 11 It can be H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 dimethoxyalkyl, C1-C6 halohydroxyalkyl, or C1-C6 dihydroxyalkyl-(CH2). q Het2、-(CH2) n OHet2、-(CH2) n NR 12 R 13 , -COCH(CH2SH)NHCOCH3, -(CH2) q O(PO)(OR 15 2. Optional substitution of C2-C 14 Alkoxyalkyl (e.g., substituted with one or more substituents preferably selected from halogens, -CF3, OH, OCF3, C1-C3 alkyl and C1-C3 alkoxy), -(CH2). n NR 15 COCH3、-(CH2) n COOR 12 -(CH2) n CONR 12 R 13 -(CH2) q SO2NR 12 R 13 -COR 16 or –(CH2) n OCOR 16 ,

[0176] Het2 is a 3- to 6-membered heterocycle, which is optionally substituted (e.g., by one or more preferably selected from halogen, OH, -CF3, OCF3, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, -C(=O)R) 17 and (CH2) q (Substituents of NHCOCH3)

[0177] Each n is an independent integer from 1 to 6, preferably 1, 2, or 3.

[0178] Each 'o' is independently 1 or 2.

[0179] Each q is an independent integer from 0 to 6, preferably 0, 1, 2, or 3.

[0180] R 12 and R 13 Independently H, C1-C6 alkyl or C2- 14 Alkoxyalkyl groups (optionally substituted with one or more substituents preferably selected from halogens, -CF3, OCF3, C1-C3 alkyl groups, and C1-C3 alkoxy groups), or

[0181] R 12 and R 13 Together with the N atoms to which they are attached, they form 5- or 6-membered heterocycles, which are optionally substituted (e.g., substituted by one or more substituents preferably selected from halogens, -CF3, OCF3, C1-C3 alkyl, C1-C3 hydroxyalkyl, C2-C4 alkoxyalkyl, and C1-C3 alkoxy).

[0182] R 14 It is a C1-C6 alkyl, C1-C6 alkoxyalkyl, or -(CH2) p Het3 or -(CH2) p Cyc1, where p is an integer from 0 to 6, preferably 1 to 3, Het3 is a saturated or unsaturated heterocycle optionally substituted with one or more substituents (e.g., halogen, C1-C3 alkyl, and C1-C3 alkoxy), and Cyc1 is a C1-C6 cycloalkyl group.

[0183] R 15 It is H or C1-C6 alkyl, preferably C1-C3 alkyl.

[0184] R 16 C1-C6 alkyl, C1-C6 aminoalkyl, -CHR17 NHCOR 17 or -OCHR 17 OCOR 17

[0185] Each R 17 Independently H or C1-C3 alkyl, and

[0186] R 18 It is H or COCH3.

[0187] and

[0188] A is -NR5R6, or ,in

[0189] R5 is H.

[0190] R6 can be H, C1-C6 alkyl, or COO(CH2). n Het4, COR 21 or COOCHR 17 OCOR 17 ,in

[0191] oR 21 For OH, halogen, -O(CH2) n NR 22 R 23 Optional substitution of -O(CH2) n O(CH2) m CH3 or optionally substituted C2- 14 Alkoxyalkyl groups (e.g., substituted with one or more substituents preferably selected from halogens, -CF3, OCF3, OH, C1-C3 alkyl groups, and C1-C3 alkoxy groups),

[0192] oR 22 and R 23 Independently selected from H, C1-C6 alkyl groups or optionally substituted C2- 14 Alkoxyalkyl groups (e.g., substituted with one or more substituents preferably selected from halogens, -CF3, OCF3, OH, C1-C3 alkyl groups, and C1-C3 alkoxy groups), and

[0193] oHet4 is an optionally substituted 3- to 6-membered heterocycle (e.g., selected from C1-C3 alkyl groups, -COOR groups). 17 CONHR 17 C1-C3 alkoxy groups and -(CH2) n OR 17 (one or more substituents are substituted),

[0194] R 20 H, C1-C8 alkyl, or optionally substituted C2-C 14 Alkoxyalkyl (e.g., substituted with one or more substituents preferably selected from halogens, CF3, C1-C3 methyl and C1-C3 alkoxy), and

[0195] R 19 It is a 5- to 12-membered aryl or heteroaryl group (e.g., phenyl or pyridyl), which is optionally substituted with one or more substituents (e.g., preferably selected from halogens, CF3, C1-C3 alkyl, C1-C3 hydroxyalkyl, and C1-C3 alkoxy groups).

[0196] Or its pharmaceutically acceptable salts and / or solvates,

[0197] In some embodiments, the compound of formula (I) is as follows:

[0198] - Each of R1, R2, R3, R4, R7, R8, R9 and R 10 Independently represents H, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, -OCF3, -NO2, -CN, -OR 11 NHCOCHR 17 NHR 18 -NR 12 - R 13 -COOR 12 -CONR 12 R 13 -SO2NR 12 R 13 -SO2R 12 -CH2SO2NR 12 R 13 OPOR 12 OR 13 (CH2)nNR 12 R 13 -(CH2) n COOR 12 -(CH2) n CONR 12 R 13 , -(CH2) q SO2NR 12 R 13 -S(O)NC(O)OR 14 ,

[0199] -(CH2) qHet1、NHCOR 17 -O(CH2) q B(OR 15 2、-(CH2) q B(OR 15 2. or

[0200] in:

[0201] Het1 is an optionally substituted 3- to 6-membered heterocycle (e.g., preferably substituted with one or more members selected from halogens, -CONHR). 15 -OH, C1-C3 alkoxy groups, COOR 15 (or C1-C3 alkyl substituents), and optionally fused with C3-C5 carbocyclic rings,

[0202] R 11 It can be H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 dimethoxyalkyl, C1-C6 halohydroxyalkyl, or C1-C6 dihydroxyalkyl-(CH2). q Het2、-(CH2) q O(PO)(OR 15 2. Optional substitution of C2-C 14 Alkoxyalkyl (e.g., substituted with one or more substituents preferably selected from halogens, -CF3, OH, OCF3, C1-C3 alkyl and C1-C3 alkoxy), -(CH2) n NR 15 COCH3、-(CH2) n COOR 12 -(CH2) n CONR 12 R 13 -(CH2) q SO2NR 12 R 13 -COR 16 or –(CH2) n OCOR 16

[0203] Het2 is an optionally substituted 3- to 6-membered heterocycle (e.g., preferably selected from halogens, OH, -CF3, OCF3, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, and (CH2). q (Substituents in NHCOCH3).

[0204] In some embodiments, one or more halogen atoms present in the compound structure of formula (I) are selected from F, Cl and Br, with F being preferred.

[0205] In some implementation schemes, R1-R 10 At least one group in the compound contains a heterocyclic moiety. Possible heterocycles present in the compound of formula (I) (e.g., Het1, Het2, Het3, and / or Het4) preferably contain one or two cyclic heteroatoms, preferably O or N. Possible heterocycles can be substituted or unsubstituted, saturated or unsaturated. Heterocycles are typically 3- to 6-membered saturated heterocycles, such as piperidinyl, aziridine, pyrrolidinyl, piperazine, morpholinyl, oxadienoyl, tetrahydropyranyl, and tetrahydrofuranyl, preferably aziridine, oxadienoyl, piperidinyl, pyrrolidinyl, piperazine, and morpholinyl.

[0206] Het1 is preferably a pyrrolidinyl group, which is optionally surrounded by one or more elements selected from halogens, -CONHR 15 -OH, C1-C3 alkoxy groups, COOR 15 Or substituted with C1-C3 alkyl groups, and optionally fused with C3-C5 carbocyclic rings, preferably fused with C3 carbocyclic rings. R 15 Preferably, it is an H or C1-C3 alkyl group.

[0207] Het2 is preferably selected from nitrogen-heterocyclic butyl, oxocyclic butyl, pyrrolyl, piperidinyl, morpholinyl, piperazine, oxocyclic butyl, tetrahydropyranyl, and tetrahydrofuranyl, wherein the heterocycle is optionally substituted, for example, by one or more substituents selected from: halogen, OH, -CF3, OCF3, C1-C6 preferably C1-C3 alkyl, C1-C6 preferably C1-C3 aminoalkyl, C1-C6 preferably C1-C3 hydroxyalkyl, C1-C6 preferably C1-C3 alkoxy, -C(=O)CH3, and (CH2). q NHCOCH3 (where q is an integer from 0 to 6).

[0208] Het3 is preferably selected from pyrrolidinyl, piperidinyl, morpholinyl, and piperazineyl, wherein the heterocycle is optionally substituted with one or more substituents (e.g., halogen, C1-C3 alkyl, and C1-C3 alkoxy).

[0209] Het4 is preferably selected from piperazinyl and piperidinyl; the heterocycle is optionally substituented by one or more substituents (e.g., C1-C3 alkyl, -COOR). 17 CONHR 17 C1-C3 alkoxy groups and -(CH2) n OR 17 , where R 17 (Substituted with H or C1-C3 alkyl).

[0210] In some other embodiments, the compound of formula (I) contains at least one -NR 12 R 13 , where R 12 and R 13 Together with the N atom, a 5- or 6-membered heterocycle is formed, which may be substituted or unsubstituted. Preferred heterocycles include piperidinyl, pyrrolidinyl, piperazineyl, and morpholinyl, which are optionally substituted, for example, by at least one substituent selected from halogen, OH, CF3, C1-C6 alkoxy, C1-C6 alkyl, C2-C4 alkoxyalkyl, -CONH2, and C1-C6 hydroxyalkyl. For example, a compound of formula (I) may contain at least one -NR selected from the following 12 R 13 :

[0211]

[0212] and

[0213] Alternatively, in some embodiments, at least one -NR is present in the molecule of formula (I). 12 R 13 It's like this: R 12 and R 13 It is a C1-C3 alkyl group, especially R 12 and R 13 Both are -CH3.

[0214] In a specific embodiment, the compound of formula (I) is such that each of R1, R2, R3, R4, R7, R8, R9 and R 10 Independently represents H, halogens (e.g., F, Br, or Cl), C1-C6 alkoxy groups, C1-C8 alkyl groups, C1-C8 haloalkyl groups, such as -CF3, -OCF3, -NO2, -CN, OH,

[0215] In the specific implementation plan, R7, R8, R9 and R 10 Independently selected from H, halogens, OH, C1-C3 alkoxy groups and the portions (1''') to (19''') shown above.

[0216] In a preferred embodiment, the compound of formula (I) is such that A is -NR5R6. In a specific embodiment, both R5 and R6 are H.

[0217] In another embodiment, R5 is H, and R6 is selected from:

[0218] -COR 21 , where R 21 -O(CH2) n O(CH2) m CH3, where n is an integer from 1 to 6, and m is an integer from 0 to 5.

[0219] -O(CH2) n NR 22 R 23 , where R 22 and R 23 Independently selected from H, methyl, and -O(CH2) n O(CH2) m CH3, where n is an integer from 1 to 6, m is an integer from 0 to 5, and...

[0220]

[0221] In a specific implementation scheme, the compound of formula (I) is as follows:

[0222] -A is -NR5R6, where R5 and R6 are defined as in equation (I), and preferably both are H.

[0223] -R3, R1, and R7 are H.

[0224] -R4 and R2 are C1-C6 alkoxy groups, such as methoxy or ethoxy, or O(CH2). n O(CH2) m CH3, where n is an integer from 1 to 6 and m is an integer from 0 to 6, for example CH3O(CH2)3O-, preferably R4 and R2 are both C1-C6 alkoxy groups.

[0225] - Each R8, R9 and R 10 As defined in equation (I).

[0226] In some implementations, R8, R9, and R 10 Independently selected from H, OH, C 1 -C 6 Alkoxy, halogen, preferably F, C1-C8 haloalkyl, such as -CF3, -OCF3, -OR 11 -NR 12 R 13 and NHCO(CH2) n NR 12 R 13, where n and R 11 R 12 and R 13 As defined in equation (I).

[0227] In some implementations, R8, R9, and R 10 Independently selected from H and halogens, preferably F and -OR. 11 and -NR 12 R 13 , where n and R 11 R 12 and R 13 As defined in equation (I).

[0228] In some implementations, R8, R9, and R 10 Independently selected from H, F, Cl, Br, CF3, OCF3, OH, C1-C3 alkoxy (e.g. OMe), C1-C3 alkyl (e.g. -CH3) and the moiety shown above (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 (33”').

[0229] In some implementations, R8, R9, and R 10 Independently selected from H, F, Cl, CF3, OCF3, OH, C1-C3 alkoxy (e.g., OMe) and the fractions shown above (25”'), (1”), (53”), (44”), (39”), (40”), (26”'), (55”), (56”), (8”), (27”), (28”), (62”), (29”'), (30”'), (33”') and (43”).

[0230] In a specific implementation scheme, the compound of formula (I) is as follows:

[0231] -A is -NR5R6, where R5 and R6 are as defined in equation (I), preferably both are H.

[0232] -R3, R1, and R7 are H

[0233] -R4 and R2 are C1-C6 alkoxy groups, such as methoxy or ethoxy, or O(CH2). n O(CH2) m CH3, where n is an integer from 1 to 6 and m is an integer from 0 to 6, for example CH3O(CH2)3O-

[0234] - Each R8, R9 and R 10 Independently selected from H, F, Cl, CF3, OCF3, OH, C1-C3 alkoxy (e.g., OMe) and some of (25”'), (1”), (53”), (44”), (39”), (40”), (26”'), (55”), (56”), (8”), (27”), (28”), (62”), (29”'), (30”'), (33”') and (43”).

[0235] In some implementation schemes, R 10 It is H or a halogen, such as F.

[0236] In some implementation schemes, R 10 R8 is independently H or a halogen (e.g., F), and R 10 At least one of R8 is H.

[0237] In some implementations, R9 is not H or halogen.

[0238] In a specific aspect, the present invention relates to compounds of formula (Ia):

[0239] (Ia)

[0240] Among them, R2, R3, R4, R6, R8, R9 and R 10 As defined in equation (I)

[0241] Or its pharmaceutically acceptable salts and / or solvates

[0242] In some implementations, the compound of formula (Ia) is as follows:

[0243] -R2, R3, and R4 are independently selected from H, C1-C6 alkyl, C1-C6 alkoxy, halogen, CF3, and (CH2). n O(CH2) m CH3, where n is an integer from 1 to 6, and m is an integer from 0 to 6.

[0244] -R8, R9 and R 10 Independently selected from H, halogens, C1-C8 alkyl groups, C1-C8 haloalkyl groups, such as CF3, -OCF3, -NO2, -CN, -OR 11 NHCOCHR 17 NHR 18 NHCO(CH2) n NR 12 R 13 ,-NR 12 -R 13 -NHCOR 17 -COOR 12 -CONR 12 R 13 -SO2NR 12 R 13 -SO2R 12 -CH2SO2NR 12 R 13 OPOR 12 OR 13 (CH2)nNR 12 R 13 -(CH2) n COOR 12 -(CH2) n CONR 12 R 13 -(CH2) q SO2NR 12 R 13 -S(O)NC(O)OR 14 Het1, -(CH2) q B(OR 15 2、-O(CH2) q B(OR 15 2. NHCOR 17

[0245] in:

[0246] Het1 is an optionally substituted 4-, 5-, or 6-membered heterocycle (e.g., preferably substituted with one or more halogenated compounds, -CONHR). 15 -OH, -COR 17 C1-C3 alkoxy groups, COOR 15 (or C1-C3 alkyl substituents), and optionally fused with C3-C5 carbocyclic rings,

[0247] R 11 It can be H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 halohydroxyalkyl, or C1-C6 dihydroxyalkyl-(CH2). q Het2、-(CH2) q OPO(OR 15 2、-(CH2) n OHet2,

[0248] -(CH2) n NR 12 R 13-COCH(CH2SH)NHCOCH3, optional substituted C2- 14 Alkoxyalkyl (e.g., substituted with one or more substituents preferably selected from halogens, -CF3, OH, OCF3, C1-C3 alkyl and C1-C3 alkoxy), -(CH2). n NR 15 COCH3、-(CH2) n COOR 12 -(CH2) n CONR 12 R 13 -(CH2) q SO2NR 12 R 13 -COR 16 or –(CH2) n OCOR 16

[0249] Het2 is an optionally substituted 3- to 6-membered heterocycle (e.g., substituted by one or more elements preferably selected from halogens, OH, -CF3, OCF3, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, -COCH3, and (CH2). q Substituents in NHCOCH3

[0250] n is an integer from 1 to 6, preferably 1, 2 or 3.

[0251] o is 1 or 2.

[0252] q is an integer from 0 to 6, preferably 0, 1, 2, or 3.

[0253] R 12 and R 13 C is independently H, C1-C6 alkyl, or optionally substituted with one or more substituents (e.g., preferably selected from halogens, -CF3, OCF3, C1-C3 alkyl, C1-C3 hydroxyalkyl, C2-C4 alkoxyalkyl, and C1-C3 alkoxy). 2-14 alkoxyalkyl, or R 12 and R 13 Together with the N atoms to which they are attached, they form optionally substituted 5- or 6-membered heterocycles (e.g., substituted by one or more substituents preferably selected from halogens, -CF3, OCF3, C1-C3 alkyl, C1-C3 hydroxyalkyl, C2-C4 alkoxyalkyl, and C1-C3 alkoxy).

[0254] R 14 It is a C1-C6 alkyl, C1-C6 alkoxyalkyl, or -(CH2) p Het3 or -(CH2) p Cyc1, where p is an integer from 0 to 6, preferably 1 to 3, Het3 is a saturated or unsaturated 4, 5, or 6-membered heterocycle optionally substituted with one or more substituents (e.g., halogen, C1-C3 alkyl, and C1-C3 alkoxy), and Cyc1 is a C1-C6 cycloalkyl group.

[0255] R 15 It is H or C1-C6 alkyl, preferably C1-C3 alkyl.

[0256] R 16 C1-C6 alkyl, C1-C6 aminoalkyl, -CHR 17 NHCOR 17 or -OCHR 17 OCOR 17

[0257] Each R 17 Independently H or C1-C3 alkyl, and

[0258] R 18 It is H or COCH3.

[0259] and

[0260] -R6 represents H, COO(CH2). n Het4, or COOCHR 17 OCOR 17 Het4 is an optionally substituted 4-, 5-, or 6-membered heterocycle (e.g., substituted by one or more C1-C3 alkyl groups, -COOR). 17 CONHR 17 C1-C3 alkoxy groups and -(CH2) n OR 17 (Substituents).

[0261] In some embodiments, the compound of formula (Ia) may be further characterized by one, more, or all of the following characteristics:

[0262] -R6 is H, and / or

[0263] -R2, R3, and R4 are independently selected from H, C1-C6 alkoxy groups, and O(CH2). n O(CH2) m CH3, where n is an integer from 1 to 6, m is an integer from 0 to 6, and / or

[0264] -R8, R9 and R 10 Independently selected from H, halogens (preferably F, Br or Cl), CF3, NH2, C1-C6 alkoxy, C1-C6 hydroxyalkyl, -OR 11 Het1, NHCOR 17 NHCO(CH2) n NR 12 R 13 O(CH2) q B(OR 15 2. SO2NR 12 R 13 ,in

[0265] q is an integer from 0 to 6, preferably 0, 1, 2, or 3.

[0266] R 11 It is H, C1-C6 hydroxyalkyl, -(CH2) n NHCOR17、-(CH2) n OCOCHR 15 NH2, ( CH2) n OHet2、-(CH2) q Het2 or -(CH2) n NR 12 R 13 ,

[0267] Het2 is an optionally substituted 3- to 6-membered heterocycle (e.g., substituted by one or more elements preferably selected from halogens, OH, -CF3, OCF3, C1-C3 alkyl, C1-C3 aminoalkyl, C1-C3 hydroxyalkyl, C1-C3 alkoxy, -COCH3, and (CH2). q Substituents of NHCOCH3

[0268] n is an integer from 1 to 6, preferably 1, 2, 3 or 4.

[0269] Het1 is an optionally substituted 4-, 5-, or 6-membered heterocycle, preferably a 5- or 6-membered heterocycle (e.g., preferably substituted with one or more elements selected from halogens, -CONHR). 15 -OH, C1-C3 alkoxy groups, -COCH3, -COOR 15 (or C1-C3 alkyl substituents), and optionally fused with C3-C5 carbocyclic rings,

[0270] R 12 and R13 It can be independently an H or C1-C3 alkyl group, or together with the -N atom to which it is attached, form a 5- or 6-membered heterocycle optionally substituted with a C1-C3 alkyl group.

[0271] R 17 and R 15 It is independently H or C1-C3 alkyl.

[0272] In some embodiments, the compound of formula (Ia) may be further characterized by one, more, or all of the following characteristics:

[0273] -R6 is H, and / or

[0274] -R2, R3, and R4 are independently selected from H, C1-C6 alkoxy groups, and O(CH2). n O(CH2) m CH3, where n is an integer from 1 to 6, m is an integer from 0 to 6, and / or

[0275] -R8, R9 and R 10 Independently selected from H, halogens (preferably F, Br or Cl), CF3, NH2, C1-C6 alkoxy, C1-C6 hydroxyalkyl, -OR 11 Het1 O(CH2) q Het1、NHCOR 17 O(CH2) q B(OR 15 2. SO2NR 12 R 13 ,in

[0276] q is 0, 1, 2 or 3.

[0277] R 11 It can be H, C1-C6 hydroxyalkyl, or -(CH2). n NHCOR17、-(CH2) n OCOCHR 15 NH2, where n is 1, 2, 3, or 4.

[0278] Het1 is an optionally substituted 5- or 6-membered heterocycle (e.g., preferably substituted with one or more elements selected from halogens, -CONHR). 15 -OH, C1-C3 alkoxy groups, -COOR 15 (or C1-C3 alkyl substituents), and optionally fused with C3-C5 carbocyclic rings,

[0279] R 12R 13 R 17 and R 15 It is independently H or C1-C3 alkyl.

[0280] In some further embodiments, at least one of the groups R2, R3, and R4 is a C1-C6 alkoxy group, preferably a C1-C3 alkoxy group. Preferably, at least two of the groups R2, R3, and R4 are C1-C6 alkoxy groups, preferably C1-C3 alkoxy groups.

[0281] In a specific embodiment, the compound for treating or preventing EBV-related disorders has the formula (Ia) or (I) as described above, wherein R2 and R4 are C1-C3 alkoxy groups, preferably methoxy groups. Preferably, R3 is H.

[0282] In another embodiment, the compound for treating or preventing EBV-related disorders has formula (Ia) or (I) as described above, wherein R8, R9, and R 10 Independently selected from H, Br, F, Cl, H, CF3, C1-C3 alkoxy groups, and O(CH2). n OH, O(CH2) n OCH3, O(CH2) n NHCOCH3, O(CH2) n OCOCR 15 NH2, OCOCR 15 NH2, CH2B(OH)2, NH2, -NHCOCH3, Het1, O(CH2) q Het2、-O(CH2)nOHet2 ,-O(CH2) n NR 12 R 13 , -OCOCH(CH2SH)NHCOCH3, NHCO(CH2) n NR 12 R 13 ,in

[0283] n is an integer from 1 to 6, preferably 1, 2 or 3.

[0284] q is an integer from 0 to 6, preferably 0, 1, 2, or 3.

[0285] Het1 is an optionally substituted 4-, 5-, or 6-membered heterocycle, preferably pyrroloalkyl (e.g., preferably substituted with one or more halogens, -CONHR). 15 -OH, C1-C3 alkoxy groups, COOR 15 (or C1-C3 alkyl substituents),

[0286] Het2 is an optionally substituted 5- or 6-membered heterocycle, preferably piperidinyl (e.g., preferably substituted with one or more elements selected from halogens, -CONHR). 15 -OH, C1-C3 alkoxy groups, COOR 15 (or C1-C3 alkyl substituents),

[0287] R 12 and R 13 It is independently an H or C1-C3 alkyl group, or together with the -N atom to which it is attached, it forms a 5- or 6-membered heterocycle optionally substituted with a C1-C3 alkyl group.

[0288] R 15 It is H or C1-C3 alkyl.

[0289] In some implementations, the compound of formula (Ia) is as follows:

[0290] -R6 is H.

[0291] -R2, R3, and R4 are independently selected from H, C1-C6 alkoxy groups, and O(CH2). n O(CH2) m CH3, where n is an integer from 1 to 6, and m is an integer from 0 to 6.

[0292] -R8, R9 and R 10 Independently selected from H, F, Cl, Br, CF3, OCF3, OH, C1-C3 alkoxy (e.g. OMe), C1-C3 alkyl (e.g. -CH3) and the moieties (25'''), (1''), (53"), (44"), (39"), (40"), (26")'), (55"), (56"), (8"), (27"), (28"), (62"), (29")'), (30")'), (33")') and (43") as shown above.

[0293] In some implementations, the compound of formula (Ia) is as follows:

[0294] -R6 is H.

[0295] -R2 and R4 are independently C1-C6 alkoxy groups, preferably methoxy groups.

[0296] -R3 is H, and

[0297] -R8, R9 and R 10Independently selected from H, F, Cl, CF3, OCF3, OH, C1-C3 alkoxy groups (e.g., OMe) and the portions (25”'), (1”), (53”), (44”), (39”), (40”), (26”'), (55”), (56”), (8”), (27”), (28”), (62”), (29”'), (30”'), (33”'), and (43”) as shown above. Preferably, R8, R9, and R 10 One of the groups is H.

[0298] In some implementations, the compound of formula (Ia) is as follows:

[0299] -R6 is H.

[0300] -R2 and R4 are independently C1-C6 alkoxy groups, preferably methoxy groups.

[0301] -R3 is H, and

[0302] -R8 and R9 are independently selected from H, F, Cl, CF3, OCF3, OH, C1-C3 alkoxy groups (e.g., OMe) and the moieties (25”'), (1”), (53”), (44”), (39”), (40”), (26”'), (55”), (56”), (8”), (27”), (28”), (62”), (29”'), (30”'), (33”'), and (43”) as shown above.

[0303] -R 10 It is H or halogen, preferably F.

[0304] In some implementations, the compound of formula (Ia) is as follows:

[0305] -R6 is H.

[0306] -R2 and R4 are independently C1-C6 alkoxy groups, preferably methoxy groups.

[0307] -R3 is H, and

[0308] R8 and R9 are independently selected from H, F, Cl, CF3, OCF3, OH, C1-C3 alkoxy groups (e.g., OMe) and the 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 in R8 and R9 is H or F, provided that R8 and R9 are not both H.

[0309] -R10 It is H or halogen, preferably F.

[0310] In some implementations, the compound of formula (Ia) is such that R2 and R4 are not both H.

[0311] In some specific implementations, R2 and R4 are different from H.

[0312] In a further embodiment, the compound of the present invention has formula (Ia), wherein:

[0313] -R6 is H.

[0314] - At least one of R2 and R4 (preferably both) is not H, and

[0315] - At least one of R8 and R9 is not H.

[0316] In a further aspect, the present invention relates to compounds of formula (Ib).

[0317] (Ib)

[0318] Among them, R2, R3, R4, R8, R9 and R 10 As defined in equation (I) or (Ia) above,

[0319] Or its pharmaceutically acceptable salts and / or solvates.

[0320] In a specific implementation scheme, the compound of formula (Ib) is as follows:

[0321] -R2, R3, and R4 are independently selected from H, C1-C6 alkoxy groups, and O(CH2). n OH, where n is 2 or 3. Preferably, (a) R3 is H, and (b) R2 and R4 are C1-C3 alkoxy, preferably methoxy, and / or

[0322] -R8, R9 and R 10 Independently selected from H, Br, F, Cl, H, CF3, C1-C3 alkoxy groups, and O(CH2). n OH, O(CH2) n OCH3, O(CH2) n NHCOCH3, O(CH2) n OCOCR 15 NH2, OCOCR 15 NH2, CH2B(OH)2, NH2, NH2COCH3, Het1, O(CH2) q Het2, where

[0323] on is 1, 2, or 3.

[0324] oq can be 0, 1, 2, or 3.

[0325] oHet1 is an optionally substituted 4-, 5-, or 6-membered heterocycle, preferably pyrroloalkyl (e.g., preferably substituted with one or more halogens, -CONHR). 15 -OH, C1-C3 alkoxy groups, COOR 15 (or C1-C3 alkyl substituents),

[0326] oHet2 is an optionally substituted 5- or 6-membered heterocycle, preferably piperidinyl (e.g., preferably substituted with one or more elements selected from halogens, -CONHR). 15 -OH, C1-C3 alkoxy groups, COOR 15 (or C1-C3 alkyl substituents),

[0327] oR 15 It is H or C1-C3 alkyl.

[0328] The conditions are R8, R9, and R 10 At least one of them is H.

[0329] In some implementations, R8, R9, and R 10 At least two of them are H.

[0330] In some implementations, the compound of formula (Ib) is as follows:

[0331] -R2, R3, and R4 are independently selected from H, C1-C6 alkoxy groups, and O(CH2). n O(CH2) m CH3, where n is an integer from 1 to 6, and m is an integer from 0 to 6.

[0332] -R8, R9 and R 10 Independently selected from H, F, Cl, CF3, OCF3, OH, C1-C3 alkoxy (e.g., OMe) and the fractions shown above (25”'), (1”), (53”), (44”), (39”), (40”), (26”'), (55”), (56”), (8”), (27”), (28”), (62”), (29”'), (30”'), (33”') and (43”).

[0333] In some implementations, the compound of formula (Ib) is as follows:

[0334] -R2 and R4 are independently C1-C6 alkoxy groups, preferably methoxy groups.

[0335] -R3 is H, and

[0336] -R8, R9 and R10 Independently selected from H, F, Cl, CF3, OCF3, OH, C1-C3 alkoxy (e.g., OMe) and the fractions shown above (25”'), (1”), (53”), (44”), (39”), (40”), (26”'), (55”), (56”), (8”), (27”), (28”), (62”), (29”'), (30”'), (33”') and (43”).

[0337] In some implementations, the compound of formula (Ib) is as follows:

[0338] -R2 and R4 are independently C1-C6 alkoxy groups, preferably methoxy groups.

[0339] -R3 is H, and

[0340] -R8 and R9 are independently selected from H, F, Cl, CF3, OCF3, OH, C1-C3 alkoxy groups (e.g., OMe) and the moieties (25”'), (1”), (53”), (44”), (39”), (40”), (26”'), (55”), (56), (8”), (27”), (28”), (62”), (29”'), (30”'), (33”') and (43”),

[0341] -R 10 It is H or halogen, preferably F.

[0342] In some implementations, the compound of formula (Ib) is as follows:

[0343] -R6 is H.

[0344] -R2 and R4 are independently C1-C6 alkoxy groups, preferably methoxy groups.

[0345] -R3 is H, and

[0346] -R8 and R9 are independently selected from H, F, Cl, CF3, OCF3, OH, C1-C3 alkoxy groups (e.g., OMe) and the moieties (25”'), (1”), (53”), (44”), (39”), (40”), (26”'), (55”), (56”), (8”), (27”), (28”), (62”), (29”'), (30”'), (33”'), and (43”) as shown above.

[0347] As shown above, at least one group in R8 and R9 is H or F, provided that R8 and R9 are not both H.

[0348] -R 10 It is H or halogen, preferably F.

[0349] In some implementations, the compound of formula (Ib) is such that R2 and R4 are not both H.

[0350] In some specific implementations, R2 and R4 are different from H.

[0351] In a further embodiment, the compound of the present invention has formula (Ib), wherein:

[0352] - At least one of R2 and R4 (preferably both) is not H, and

[0353] - At least one of R8 and R9 is not H.

[0354] In another aspect, the present invention relates to compounds of formula (Ic).

[0355] (Ic)

[0356] Among them, R2, R3, R4, R8, R9 and R 10 As defined by equations (I), (Ia), or (Ib) above.

[0357] Or its pharmaceutically acceptable salts and / or solvates.

[0358] In a specific implementation scheme, the compound of formula (Ic) is as follows:

[0359] -R2 and R4 are independently selected from H, C1-C6 alkoxy groups, and O(CH2). n OH, where n is 2 or 3. Preferably, R2 and R4 are C1-C3 alkoxy groups, such as OCH3, and

[0360] -R8 and R9 are independently selected from H, Cl, F, Br, OH, C1-C3 alkoxy, preferably OCH3, C1-C3 alkyl, CF3, and O(CH2). n OH, Hetl, O(CH2) q Het2, where

[0361] on is 1, 2, or 3.

[0362] oq can be 0, 1, 2, or 3.

[0363] oHet1 is a 5- or 6-membered heterocycle optionally substituted with halogen, -CONH2, -OH, C1-C3 alkoxy, or C1-C3 alkyl, preferably pyrrolidinyl.

[0364] oHet2 is a 5- or 6-membered heterocycle optionally substituted with a halogen, -OH, C1-C3 alkoxy and / or C1-C3 alkyl, preferably piperidinyl.

[0365] In some implementations, the compound of formula (Ic) is such that R2 and R4 are not both H.

[0366] In some specific implementations, R2 and R4 are different from H.

[0367] In a further embodiment, the compound of the present invention has formula (Ic), wherein:

[0368] - At least one of R2 and R4 (preferably both) is not H, and

[0369] - At least one of R8 and R9 is not H.

[0370] In a further aspect, the present invention relates to compounds of formula (Id).

[0371] (Id)

[0372] in

[0373] R3 and R 10 As defined by any of the above formulas (I), (Ia), or (Ib),

[0374] R8 and R9 are defined as in any of the above equations (I), (Ia), (Ib) or (Ic), and

[0375] Each R 24 Or R 25 Independently represents C1-C6 alkyl, C1-C6 hydroxyalkyl, or –(CH2). n O(CH2) m CH3, where n is an integer from 1 to 6, and m is an integer from 0 to 6.

[0376] Or its pharmaceutically acceptable salts and / or solvates.

[0377] In some implementations, R3 is H or OR 26 , where R 26 Indicates C1-C6 alkyl, C1-C6 hydroxyalkyl, or –(CH2). n O(CH2) m CH3, where n is an integer from 1 to 6 and m is an integer from 0 to 6.

[0378] In the preferred embodiment, (a) R3 is H, and (b) each R 25 and R 24 It is independently a C1-C6 alkyl group, preferably a C1-C3 alkyl group.

[0379] In a more specific implementation, the compound of formula (Id) is as follows:

[0380] -R3 is H

[0381] - Each R 25 and R 24 Independently, it is a C1-C6 alkyl group, preferably a C1-C3 alkyl group.

[0382] -R 10 It is H or a halogen, such as F.

[0383] In a more specific implementation, the compound of formula (Id) is as follows:

[0384] -R3 is H

[0385] - Each R 25 and R 24 Independently, it is a C1-C6 alkyl group, preferably a C1-C3 alkyl group.

[0386] -R 10 It is H or F.

[0387] In some embodiments, the compound of formula (Id) is such that R8 and R9 are independently selected from OH, Cl, F, Br, OH, C1-C3 alkoxy, preferably OCH3, C1-C3 alkyl, CF3, OCF3, O(CH2). n OH, Hetl, O(CH2) n NCOR 17 O(CH2)nNR 12 R 13 -NHCO(CH2) n R 12 R 13 O(CH2) q Het2, where

[0388] on is an integer from 1 to 6, preferably 1, 2 or 3.

[0389] oq is an integer from 1 to 6, preferably 0, 1, 2 or 3.

[0390] oHet1 is optional halogenated, -CONH2, -COR 17 A 4-, 5-, or 6-membered heterocycle substituted with -OH, C1-C3 alkoxy, or C1-C3 alkyl, preferably pyrrolidinyl.

[0391] oHet2 is a 5- or 6-membered heterocycle optionally substituted with a halogen, -OH, C1-C3 alkoxy, or C1-C3 alkyl group, preferably piperidinyl.

[0392] oR 17It is H or C1-C3 alkyl.

[0393] oR 12 and R 13 It is independently H or C1-C3 alkyl, or forms an optionally substituted 5- or 6-membered heterocycle with the N atom to which it is attached (e.g., substituted with a C1-C3 alkyl).

[0394] Preferably, R3 is H, and each R 25 and R 24 Independently, it is a C1-C6 alkyl group, preferably a C1-C3 alkyl group, and R 10 It can be H or F.

[0395] In a more specific implementation, the compound of formula (Id) is as follows:

[0396] -R3 is H

[0397] - Each R 25 and R 24 Independently, it is a C1-C6 alkyl group, preferably a C1-C3 alkyl group.

[0398] -R 10 It is H

[0399] Compounds of formula (Id) can be further characterized as follows: R8 and R9 are independently selected from OH, Cl, F, Br, OH, C1-C3 alkoxy groups, preferably OCH3, C1-C3 alkyl groups, CF3, and O(CH2). n OH, Hetl, O(CH2) q Het2, where

[0400] on is 1, 2, or 3

[0401] oq is 0, 1, 2, or 3

[0402] oHet1 is a 5- or 6-membered heterocycle optionally substituted with halogen, -CONH2, -OH, C1-C3 alkoxy, or C1-C3 alkyl, preferably pyrrolidinyl.

[0403] oHet2 is a 5- or 6-membered heterocycle optionally substituted with a halogen, -OH, C1-C3 alkoxy or C1-C3 alkyl, preferably piperidinyl.

[0404] In some additional or alternative embodiments, the compound of the present invention is of formula (Id) or a pharmaceutical salt or solvate thereof, provided that R 24 and R 25 When it is CH3, R3, R 10 R8 and R9 are not all H.

[0405] More generally, the compounds of the present invention are not the compounds n°2 shown in Table 1 below. Or its medicinal salts or solvates.

[0406] For example, the compounds of the present invention may be selected from the compounds exemplified in the exemplary portions shown in the table below, and their pharmaceutical salts and / or solvates:

[0407]

[0408]

[0409]

[0410] Table 1: Examples of compounds according to the present invention

[0411] In some embodiments, the present invention relates to compounds of formula (I) selected from compounds n°3, 4, 5, 6, 7, 8, 9, 10, 11, and 12, and their pharmaceutical salts or solvates.

[0412] In some embodiments, the present invention relates to compounds 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, 27bis, and their pharmaceutical salts or solvates.

[0413] In some embodiments, the present invention relates to compounds 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 their pharmaceutical salts or solvates.

[0414] As further explanation, the compounds of the present invention may be selected from the following compounds and their pharmaceutical salts and / or solvates:

[0415]

[0416]

[0417]

[0418] Table 2: Further examples of compounds according to the present invention

[0419] Certain compounds of the present invention, particularly those of formulas (Ib), (Ic), and (Id) and those shown in Tables 1 and 2 above, contain amino and / or hydroxyl groups thereon, to which unstable portions may be coupled, for example, via amide bonds, urethane bonds, or ester bonds, to provide prodrugs.

[0420] Therefore, in a further aspect, the present invention also relates to prodrugs of compounds of any of formulas (I), (Ia), (Ib), (Ic), and (Id), preferably prodrugs of the compounds of any of formulas (Ib)-(Id) themselves, and further relates to their use in the treatment or prevention of EBV-related disorders. The unstable moiety coupled to a hydroxyl or amino functional group is selected for cleavage in vivo, thereby releasing the active moiety (i.e., the compound of formula (I) or (Ia)-(Id)). The unstable moiety may also be selected to increase the solubility of the compound and / or improve its pharmacokinetic characteristics. Typically, the unstable functional group is coupled to the main chain of the compound via a carbamate, ester, or amide bond.

[0421] In some embodiments, the prodrug of the present invention is characterized in that the unstable moiety is coupled to an amino group at the 6-position of the phenanthridine skeleton present in the compounds of the present invention (particularly of formula (Ib), (Ic), or (Id), or as shown in Tables 1 or 2 above). For example, the unstable moiety is selected from...

[0422]

[0423] Amino acid residues; this list is non-exhaustive.

[0424] In some other embodiments, the prodrug of the present invention is characterized in that the unstable moiety is coupled to a hydroxyl group at position 7, 8, 9, or 10 of the phenanthridine skeleton of the compounds of the present invention (particularly formula (Ib), (Ic), or (Id), or as shown in Tables 1 or 2 above). For example, the unstable moiety is selected from:

[0425]

[0426] amino acid residues, phosphate esters,

[0427] This list is not exhaustive.

[0428] In some embodiments, the prodrug is selected from prodrugs of compounds n°3, 4, 5, 6, 7, 8, 9, 10, 11, and 12.

[0429] In some embodiments, 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 their pharmaceutical salts or solvates.

[0430] In some embodiments, 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 their pharmaceutical salts or solvates.

[0431] Certain compounds of the present invention (including the prodrugs of the present invention) may contain one or more chiral centers. Therefore, the present invention also includes the separation of all diastereomers and all enantiomers, such as (R) or (S) of the compounds of the present invention (i.e., compounds of formula (I) or (Ia)-(Ic) as described above and any prodrugs thereof), and any mixtures thereof in any proportion, such as racemic mixtures of enantiomers. The separation of a single stereoisomer of a compound of the present invention, such as a single enantiomer or a single diastereomer, can be achieved by any suitable method described in the art, such as recrystallization or chromatography, especially chiral chromatography.

[0432] The present invention also covers isotopic forms of the compounds of the present invention (including the prodrugs of the present invention), particularly isotopic forms in which one or more hydrogen atoms are substituted, for example, with deuterium.

[0433] This invention also covers all possible polymorphic or pseudopolymorphic forms of the compounds of this invention (including the prodrugs of this invention). The compounds of this invention can be in an amorphous state or a crystalline state.

[0434] The compounds of this invention (including the prodrugs of this invention) can exist as hydrates or as solvates, meaning that the compounds of this invention can contain solvent molecules, particularly water or alcohol molecules such as isopropanol or ethanol, as structural elements of their crystal lattice. Therefore, this invention includes all hydrates or solvates of the compounds of this invention. In a preferred embodiment, the compounds of this invention are in anhydrous form or as hydrates.

[0435] The compounds of this invention can exist in free form, for example as a free base, a free acid, an amphoteric ion, or as a salt. Depending on the functional groups present in the compound, acid addition salts or base addition salts can be prepared.

[0436] Generally, the compounds of the present invention can be any salt, organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, or a salt used, for example, to isolate or purify the compounds of the present invention.

[0437] In some embodiments, the compounds of the present invention are in the form of acid addition salts.

[0438] Acid addition salts can be formed by reacting with inorganic acids or "mineral acids" such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, aminosulfonic acid, bisulfuric acid, phosphoric acid, or nitric acid, or by reacting with organic acids such as formic acid, acetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, and adipic acid. This list is not exhaustive.

[0439] In some other embodiments, the compounds of the present invention are in the form of base addition salts.

[0440] Bases that can be used to obtain such salts include, for example, 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-methylglucosamine, and this list is not exhaustive.

[0441] The salt form of the compounds of the present invention can be prepared by methods well known to those skilled in the art, for example by contacting the free state of the compounds of the present invention with a suitable base or acid.

[0442] The compounds of the present invention can be prepared by any method described in the prior art for the synthesis of phenanthrene derivatives. For example, those skilled in the art can use the methods described in Gug et al., Tetrahedron, 2004, 4705-4708 or Gug et al., Tetrahedron Letters, 2005, 3725-3727 by conventional work. In particular, those skilled in the art can carry out and / or employ Suzuki-Miyaura coupling in the presence of suitable catalytic conditions as illustrated in the Examples section herein.

[0443] In developing valuable drug synthesis routes, it is often sought to avoid final coupling with palladium.

[0444] The inventors have conceived a novel method for preparing 6-aminophenanthrene diphenyl derivatives. This method is based on the reaction of (a) a nitroarylboronic acid derivative with a 2-bromonitrile derivative to form the corresponding biphenyl derivative. Then, under mild conditions, the reduction of the nitro group present in (b) the biphenyl derivative initiates cyclization, thereby forming the 6-aminophenanthrene diphenyl derivative. Notably, the reduction of the nitro group and the final cyclization can be carried out without a palladium catalyst, for example by using Fe / NH4Cl or by using B2(OH)2: under such conditions, the final 6-aminophenanthrene diphenyl compound is palladium-free. The method of the present invention also has the advantage of providing high yields.

[0445] In a specific aspect, the present invention relates to a method for preparing a compound of formula (I) as described above, wherein A is NH2, comprising the following steps:

[0446] -(a) Makes compound (II)

[0447] (II) and compounds of formula (III) (III) The reaction forms a biphenyl compound of formula (IV).

[0448] (IV)

[0449] -(b) Under conditions that promote cyclization, the nitro functional group in compound (IV) is reduced to NH2 to obtain the compound of formula (I), where A is NH2, i.e.:

[0450] - (I)

[0451] Where R1-R 10 As defined in equation (I) above, X is a halogen, preferably Br, and each R 26 It is H, or C1-C6 alkyl, or R 26 The group together with B(O)2 forms a 5-membered heterocycle optionally substituted with one or more C1-C3 alkyl groups.

[0452] In some embodiments, the compound of formula (II) is

[0453] (IIa)

[0454] Step (a) is preferably carried out in the presence of a Pd catalyst (especially Pd(PPh3)4) and a suitable base (e.g., Na2CO3, K2CO3, K3PO4, etc.).

[0455] Step (b) can be performed under any conditions known in the art to reduce the nitro group to aniline under mild conditions without reducing the nitrile group.

[0456] Step (b) is preferably carried out in the absence of a Pd catalyst, for example, by using Fe (typically Fe powder) and ammonium chloride (NH4Cl) in a suitable solvent (e.g., MeOH). Step (b) can also be carried out in the presence of 4,4'-bipyridine, for example in a solvent (e.g., DMF), promoted by B2(OH)4. Notably, when carried out in the presence of B2(OH)4, step (b) can be carried out at room temperature (e.g., at about 20-25°C).

[0457] In some embodiments, the present invention relates to intermediate reagents for preparing compounds of formula (I), said compounds being of formula (IV):

[0458] (IV), where R1, R2, R3, R4, R7, R8, R9 and R 10 As defined by any of equations (I), (Ia), (Ib), and (Ic).

[0459] In some embodiments, the present invention relates to intermediate reagents for preparing compounds of formula (I), said compounds being of formula (IV):

[0460] (IV), where R1, R2, R3, R4, R7, R8, R9 and R 10 As defined by any of equations (I), (Ia), (Ib), and (Ic),

[0461] Or (IVd)

[0462] (IVd)

[0463] Among them, R3, R8, R9 and R 10 As defined by either (I) or (Id), and

[0464] R 25 and R 24 As defined in formula (Id)

[0465] For example, intermediate reagents can be selected from:

[0466] -2-(3,5-dimethoxy-2-nitro-phenyl)-4-[(1-methyl-4-piperidinyl)methoxy]benzonitrile

[0467] 2-(3,5-Dimethoxy-2-nitro-phenyl)-4-(trifluoromethyl)benzonitrile

[0468] -2-(3,5-dimethoxy-2-nitro-phenyl)-4,5-difluorobenzonitrile

[0469] -2-(3,5-dimethoxy-2-nitro-phenyl)-2,3-difluorobenzonitrile and

[0470] -2-(3,5-dimethoxy-2-nitro-phenyl)-4-fluorobenzonitrile,

[0471] -N-[3-cyano-4-(3,5-dimethoxy-2-nitro-phenyl)phenyl]-2-pyrrolidine-1-ylacetamide

[0472] -N-[2-(6-amino-2,4-dimethoxy-phenanthridine-9-yl)oxyethyl]acetamide

[0473] -2-(3,5-dimethoxy-2-nitro-phenyl)-4-[3-(dimethylamino)propoxy]-3-fluorobenzonitrile

[0474] -2-(3,5-dimethoxy-2-nitro-phenyl)-3-fluoro-4-[(1-methylazacyclobut-3-yl)methoxy]benzonitrile, and

[0475] -2-(3,5-dimethoxy-2-nitro-phenyl)-3-fluoro-4-[(1-methyl-4-piperidinyl)methoxy]benzonitrile.

[0476] - Therapeutic uses of the compounds of this invention

[0477] As described above, the present invention also relates to compounds of the present invention (e.g., compounds of formula (I), (Ia)-(Id), compounds shown in Table 1 or Table 2, and their prodrugs), which are used as pharmaceuticals, particularly as EBNA1 inhibitors.

[0478] In a specific aspect, this invention relates to compounds of the invention (e.g., compounds of formula (I), (Ia)-(Id), compounds shown in Table 1 or Table 2, and their prodrugs) for the treatment or prevention of EBV-related diseases in subjects. EBV-related diseases are as defined above in the "General Definitions" section. In specific embodiments, EBV-related diseases include EBV-related cancers, non-cancerous EBV-related lymphoproliferative disorders (LPDs) (e.g., CAEBV, infectious mononucleosis, and other non-malignant EBV+LPDs), and EBV-related autoimmune disorders. EBV-related diseases of interest include, but are not limited to, EBV-positive (+) cancers, such as EBV(+)-nasopharyngeal carcinoma (NPC), gastric cancer, post-transplant lymphoproliferative disorder (PTLD), HIV-associated lymphoma, Hodgkin lymphoma, Hodgkin's disease, Burkitt lymphoma, and multiple sclerosis. EBV-related diseases also include primary EBV infections, such as infectious mononucleosis and chronic active EBV disease (CAEBV).

[0479] In the specific implementation plan, EBV-related diseases are non-cancerous EBV + lymphoproliferative disorder, EBV + lymphoma, EBV + nasopharyngeal carcinoma, or EBV + gastric cancer.

[0480] In some implementations, EBV-related diseases are characterized by the presence of B cells and / or cancer cells (e.g., lymphoma or epithelial carcinoma) expressing EBV antigens (preferably EBNA1).

[0481] As used herein, the term "subject" includes humans and animals, preferably mammals. Preferably, the mammal is a human and can be of any age (e.g., infant, child, adult, or elderly) or any sex (female or male).

[0482] Subjects have EBV-related disorders or are at risk of developing EBV-related disorders, for example, due to their immune status.

[0483] In some implementations, the subjects are immunocompromised, such as having primary (e.g., hereditary) immunodeficiency or secondary immunodeficiency due to immunosuppressive therapy (e.g., in the case of organ transplantation), chemotherapy, or glucocorticoids, concomitant infections, especially viral infections (e.g., HIV, SARS-CoV-2), or metabolic or hormonal disorders (e.g., hypothyroidism, anemia, and hyperglycemia).

[0484] In the specific implementation plan, the subject is infected with EBV, for example, the subject has a latent EBV infection and / or the subject experiences an active / acute EBV infection, such as infectious mononucleosis or CAEBV, and / or the subject experiences reactivation of latent EBV infection.

[0485] In some implementation schemes, the subjects were latently infected with EBV.

[0486] The EBV infection status in a subject can be determined by methods well-known in the art, such as by testing for antibodies, such as viral capsid antigen (VCA)-IgM and IgG, anti-early antigen (EA) IgG, and EBV nuclear antigen (EBNA, e.g., EBNA1) antibodies. In some embodiments, the subject has a long-term EBV infection, such as for at least 6 months, 12 months, 2 years, 3 years, or longer.

[0487] In some implementations, the EBV-related disease to be treated or prevented in the subjects is due to latent EBV infection or due to reactivation of latent EBV infection.

[0488] Serology can be used to test for EBV infection and even to assess acute and distant / latent infection in healthy individuals.

[0489] High serum titers can also serve as tumor markers for some EBV-related cancers. For example, EBV viral load testing via quantitative DNA amplification of blood samples has been shown to be useful for the early diagnosis and monitoring of patients with PTLD (Houen and Hartwig Trier, Front Immunol. 2020; 11: 587380).

[0490] In some other implementations, the subject is in the acute phase of EBV infection. In specific implementations, the subject is in the acute phase of EBV infection and is symptomatic. For example, the subject may have CAEBV or infectious mononucleosis.

[0491] In some implementation schemes, the subjects are characterized by one or more of the following characteristics:

[0492] - The subject has a hereditary or iatrogenic immunodeficiency and / or

[0493] -The subject is receiving immunosuppressive therapy and / or

[0494] -The subject has received transplantation and / or

[0495] - The subject had infectious mononucleosis or CAEBV and / or

[0496] - Subjects experienced reactivation of EBV infection, preferably in the form of symptoms.

[0497] In the specific implementation plan, the subjects are receiving or have already undergone immunosuppressive therapy.

[0498] In another implementation, the subject will undergo or has already undergone a transplant, such as a solid organ transplant (SOT) or an allogeneic hematopoietic cell transplant (HSCT). In some implementations, the patient is receiving an allogeneic transplant.

[0499] In a specific embodiment, the compounds of the present invention are used to treat or prevent EBV+ cancer in immunocompromised subjects (preferably subjects under immunosuppressive therapy).

[0500] Immunosuppressive drugs include, but are not limited to, anti-T lymphocyte serum or antibodies, cyclosporine, calcineurin inhibitors (such as tacrolimus, sirolimus, everolimus), antimetabolites (such as mycophenolate mofetil), or certain corticosteroids (such as prednisone).

[0501] In specific embodiments, the compounds of the present invention are used to treat or prevent EBV+ cancer in transplant subjects, preferably in transplant subjects undergoing immunosuppressive therapy.

[0502] For example, EBV+ cancer is EBV+PTLD, EBV+nasopharyngeal carcinoma, or EBV+gastric cancer, with EBV+PTLD being preferred.

[0503] The compounds of this invention can be administered topically, parenterally, or enterally. In fact, the compounds of this invention can be administered via any conventional route, including but not limited to oral, buccal, sublingual, rectal, intravenous, intramuscular, subcutaneous, intradermal, mucosal, transmucosal, intracerebral, intrathecal, intraperitoneal, intraocular, intratumoral, or intranasal routes. The route of administration may vary depending on the impairment to be treated or prevented, or the characteristics of the subject.

[0504] The compounds of the present invention are typically administered via a suitable medium; generally, they are administered as pharmaceutical compositions. Examples of pharmaceutical compositions comprising the compounds of the present invention are further provided below.

[0505] The dosage regimen of the compounds of the present invention can be determined and adjusted by those skilled in the art based on the specific characteristics of the subject, namely his / her age, sex, race, weight, health and physical condition, medical history, EBV-related disorder to be treated and its stage, comorbidities, co-treatments and other relevant characteristics.

[0506] The compounds of this invention are typically administered to subjects at an effective therapeutic dose.

[0507] As used herein, "therapeutic effective amount or dose" means the amount of a therapeutic agent used in a subject to prevent, eliminate, alleviate, or reduce or delay the onset of one or more symptoms or disorders caused by said disease.

[0508] Typically, the amount of compound to be administered to a patient can range from about 0.001 mg / kg to 500 mg / kg body weight.

[0509] The compounds of the present invention can generally be administered long-term, at least once a week or once daily. For example, the compounds of the present invention can be administered daily for several consecutive days or months until the desired therapeutic effect is achieved. For example, the compounds of the present invention can be administered daily for at least three months, such as at least six months or at least twelve months. The compounds of the present invention can be administered once, twice or three times daily, preferably once or twice daily.

[0510] Depending on the condition to be treated, the compound may also be administered as an acute treatment, for example, in one or two doses.

[0511] In some embodiments, the compounds of the present invention may be used in combination with a second therapeutic agent. The second therapeutic agent is typically selected to treat or prevent EBV-related disorders.

[0512] For example, the second treatment agent can be an antiviral drug, radiotherapy, immunotherapy agent, or anticancer agent.

[0513] Second therapeutic agents used in combination with the compounds of the present invention include, but are not limited to: anti-CD20 antibodies (e.g., rituximab), bispecific anti-CD19 / CD3 antibodies (e.g., bonatetumab), immune checkpoint modulators, such as anti-PD-1, anti-PD-L1, or anti-CTLA-4 antibodies (e.g., pembrolizumab and nivolumab), chemotherapeutic agents (e.g., alkylating agents, platinum coordination complexes, antimetabolites, taxanes, topoisomerase inhibitors, vinca alkaloids, and intercalating agents), CHOP chemotherapy (doxorubicin, cyclophosphamide, vincristine, prednisone), BET bromide domain inhibitors, olaparib and other PARP inhibitors, HDAC inhibitors, antiproliferative agents (e.g., mycophenolate mofetil, mycophenolate sodium, azathioprine, cyclophosphamide), and antiviral agents, such as ganciclovir; valganciclovir and acyclovir.

[0514] The pharmaceutical composition of the present invention

[0515] The compounds of this invention are typically administered in the form of pharmaceutical compositions.

[0516] Therefore, in another aspect, the present invention relates to pharmaceutical compositions comprising (i) a compound according to the invention and (ii) one or more pharmaceutically acceptable excipients.

[0517] For example, the pharmaceutical composition of the present invention may include:

[0518] - 0.01% to 90% by weight of the compounds of the present invention, and

[0519] - 10% to 99.99% by weight of excipients,

[0520] Percentages are expressed as a percentage relative to the total weight of the composition.

[0521] The dosage unit of the pharmaceutical composition typically contains about 0.1 mg to about 3000 mg of the compound according to the invention.

[0522] Such pharmaceutical compositions are preferably used for the treatment or prevention of EBV-related disorders as described above.

[0523] The pharmaceutical compositions of the present invention can 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).

[0524] Pharmaceutically acceptable excipients that can be used are specifically described in the Handbook of Pharmaceuticals Excipients, American Pharmaceutical Association (Pharmaceutical Press; 6th revised edition, 2009). Generally, the pharmaceutical compositions of the present invention can be obtained by mixing the compounds of the present invention with at least one pharmaceutically acceptable excipient.

[0525] According to the present invention, a pharmaceutically acceptable excipient is any ingredient commonly used in the formulation of a pharmaceutical composition that is inactive and non-toxic, and whose purpose may be to impart a specific consistency or other specific physical or taste characteristics to the final product while avoiding any chemical interaction with the therapeutically active compound. Examples of suitable excipients include, but are not limited to: solvents (e.g., water or water / ethanol mixtures), fillers, carriers, diluents, binders, anti-caking agents, plasticizers, disintegrants, lubricants, fragrances, buffers, stabilizers, colorants, dyes, antioxidants, anti-adhesion agents, softeners, preservatives, surfactants, waxes, emulsifiers, wetting agents, and flow aids. Examples of diluents include, but are not limited to, microcrystalline cellulose, starch, modified starch, calcium hydrogen phosphate dihydrate, calcium sulfate trihydrate, calcium sulfate dihydrate, calcium carbonate, monosaccharides or disaccharides (e.g., lactose, dextrose, sucrose, mannitol, galactose, and sorbitol), xylitol, and combinations thereof. Examples of adhesives include, but are not limited to, starches (e.g., potato starch, wheat starch, corn starch); gums (e.g., gum arabic, gum arabic, and gelatin); hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose; polyvinylpyrrolidone, copovidone, polyethylene glycol, and combinations thereof. Examples of lubricants include, but are not limited to, fatty acids and their derivatives, such as calcium stearate, glyceryl monostearate, glyceryl palmitate stearate, magnesium stearate, zinc stearate, or stearic acid, or polyalkylene glycols, such as PEG. Gliders may be selected from colloidal silica, silica, talc, etc. Examples of disintegrants include, but are not limited to, crospovidone, crospovidone carboxymethyl cellulose salts (e.g., crospovidone carboxymethyl cellulose sodium), starches and their derivatives. Examples of surfactants include, but are not limited to, dimethyl silicone oil, triethanolamine, polysorbates and their derivatives, such as Tween® 20 or Tween® 40, poloxamer, fatty alcohols (e.g., lauryl alcohol), cetyl alcohol, and alkyl sulfates (e.g., sodium dodecyl sulfate (SDS)). Examples of emulsifiers include, for example, fatty acid esters of ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils, polyethylene glycol, and sorbitol, or mixtures thereof.

[0526] It goes without saying that the excipients (one or more) to be combined with the compounds of the present invention may vary depending on (i) the pharmacokinetic characteristics sought for the active ingredient, (ii) the dosage form and (iii) the route of administration.

[0527] The pharmaceutical composition can be of any type. For example, the pharmaceutical composition can be a solid oral dosage form, a liquid oral dosage form, a suspension (e.g. for intravenous administration), a dosage form for topical application (e.g., cream, ointment, gel, etc.), a skin patch, a mucosal patch or tablet, an aerosol for intranasal administration, etc.

[0528] This pharmaceutical composition can provide immediate, controlled, or prolonged release of the compounds of the present invention.

[0529] Oral solid dosage forms include, but are not limited to, tablets, capsules, pills, powders, and granules. Optionally, the oral solid form can be prepared with coating and shell, such as enteric coating. Examples of coating compositions that can be used are polymers and waxes. The compound can also be used in microencapsulated form, if suitable, in conjunction with one or more of the excipients described above.

[0530] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs. Liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, solubilizers, and emulsifiers, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butanediol, dimethylformamide, oils, fatty acid esters of polyethylene glycol and sorbitol, or mixtures thereof. If desired, the composition may also include other excipients, such as wetting agents, emulsifiers and suspending agents, sweeteners, and / or flavoring agents. Suspensions may contain suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitol esters, microcrystalline cellulose, bentonite, agar, etc.

[0531] Ointments, pastes, creams, and gels may contain excipients such as oils, waxes, paraffin waxes, starches, tragacanth gums, cellulose derivatives, polyethylene glycols, silicones, bentonite, silicic acid, talc, and zinc oxide, or mixtures thereof.

[0532] The pharmaceutical composition may also be in the form of an aerosol or sprayable composition, which can be delivered intranasally using an inhaler system or a nebulizer.

[0533] In some embodiments, the pharmaceutical composition of the present invention is an injectable composition, such as a composition for injection.

[0534] The pharmaceutical compositions of the present invention may be in the form of ready-to-use liquid compositions, concentrated liquid compositions diluted before administration, or powders such as lyophilized powders dissolved or suspended in a suitable medium before administration to a subject.

[0535] Further aspects and advantages of the invention are disclosed in the following experimental section, which should be regarded as illustrative rather than limiting the scope of this application.

[0536] Example

[0537] Example A: Chemical Synthesis

[0538] General synthetic route

[0539] Method A (Option 1)

[0540] First, the nitro derivative A1 is reduced to bromoaniline A2, which then reacts with 2-cyanoboroate. Alternatively, 2-bromoaniline A2, as previously known, can react with borate A3 to give A4. In some cases, bromoaniline A2 has been found to be unstable.

[0541]

[0542] Scheme 1. Reagents and conditions. a: Fe, NH4Cl, MeOH, H2O; b: Pd[P(C6H5)3]4, Na2CO3, dioxane, H2O

[0543] Method B (Option 2)

[0544] In the second procedure, the same 6-aminophenanthrene is formed by converting the two reactive groups.

[0545]

[0546] Scheme 2. Reagents and conditions: Pd[P(C6H5)3]4, Na2CO3, dioxane, H2O.

[0547] Method C (Scheme 3 - Invention)

[0548] First, nitroarylboronic ester C2 is prepared from 2-bromonitrobenzene C1. In the second step, Suzuki coupling with 2-bromonitrile C3 provides a substituted biphenyl C4. In the final step, reduction of the nitro group directly provides a tricyclic compound C6. The putative intermediate C5 is not isolated. By method C, coupling (b) is not the final step, thus limiting residual Pd contamination of C6. Furthermore, less Pd is used under conditions b' than in b. The reductive cyclization (c') of tetrahydroxydiboron [B2(OH)4] is more efficient than c, proceeds rapidly at room temperature, and is easier to post-process.

[0549]

[0550] Scheme 3. Reagents and conditions: a: bis(pinacol)diboron, Pd(DPPF), KOAc, dioxane. b: Pd[P(C6H5)3]4, Na2CO3, dioxane, H2O. b': Pd(OAc)2, Xphos, K2CO3, EtOH, toluene, H2O. c: Iron powder, NH4Cl, MeOH, H2O. c': B2(OH)4, 4,4'-bipyridine, DMF.

[0551] Example 1: Preparation of 6-Aminophenanthridine 1

[0552] The compound was prepared by method B.

[0553]

[0554] Scheme 4. Preparation of 6-aminophenanthrene.

[0555] The reaction was carried out under an argon atmosphere. Under nitrogen, a solution of 2 M Na₂CO₃ (15 mL) was added to 2-bromobenzonitrile 1b (5 g, 27.46 mmol) in 150 mL of dioxane. After stirring at 75 °C for 5 min, Pd[P(C₆H₅)₃]₄ (1.54 g, 0.14 mmol) was added, followed by pinacol ester 2-aminophenylboronic acid (6.01 g, 27.46 mmol). The reaction was stirred at 90 °C for 8 h. The mixture was then cooled to 20 °C and filtered through diatomaceous earth. The solution was concentrated to half its initial volume under vacuum and extracted with CH₂Cl₂ (30 mL) and water (30 mL). The combined organic layers were washed with 20 mL of brine, dried over Na₂SO₄, and evaporated. The solid crystallized after concentration. It was ground with Et2O (2 x 10 mL) and filtered through a Buchner funnel to give 1, yield 52%.

[0556] 1H-NMR (DMSO-d6, 400 MHz): δ 8.66 (d, J = 8.0 Hz, 1H), 8.46 (d, J =7.8 Hz, 1H), 8.34 (d, J = 8.9 Hz, 1H), 7.84 (td, J = 7.1, 3.5 Hz, 1H), 7.67(ddd, J = 8.1, 7.1, 1.1 Hz, 1H), 7.58 – 7.46 (m, 2H), 7.28 (ddd, J = 8.2,6.4, 1.9 Hz, 1H), 7.03 (s, 2H).

[0557] Example 2 Preparation of 2,4-dimethoxyphenanthridine-6-amine 2

[0558] The synthesis of compound 2 was previously reported, but that required a mixture of liquid ammonia and a strong base. This product was synthesized using methods A and C.

[0559]

[0560] Scheme 5. Preparation of 2,4-dimethoxyphenanthrene-6-amine by method C.

[0561] Step 1 Preparation 1-Bromo-3,5-dimethoxy-2-nitro-benzene 2b

[0562] 3,5-Dimethoxybromobenzene 2a (10 g, 50 mmol) was dissolved in 100 mL of acetic anhydride and cooled to -5 °C. Concentrated nitric acid (65%, 6 mL) was slowly introduced into a pressure-equilibrated dropping funnel. The acid was added slowly. After the addition was complete, the cooling bath was removed, and the solution was stirred at 0 °C for one hour, followed by stirring at 20 °C for 20 minutes. The reaction mixture was cooled again and poured into 100 mL of ice water with vigorous stirring. The yellow solid was filtered and washed twice with 10 mL of H₂O and 10 mL of cyclohexane. After drying under vacuum at 60 °C for 24 hours, 2b was given in 70% yield.

[0563] 1 ¹H-NMR (DMSO-d₆, 400 MHz): δ 6.97 (d, J = 2.3 Hz, ¹H), 6.87 (d, J = 2.3 Hz, ¹H), 3.90 (s, ³H), 3.87 (s, ³H). The solid was contaminated with 10–20% 1-bromo-3,5-dimethoxy-4-nitro-bromobenzene. 1 H-NMR (DMSO-d6, 400 MHz): 7.15(s, 2H); 3.85(s, 6H).

[0564] In the improved procedure, the crystalline material is filtered before being poured into water. The solid is washed with 5 mL of acetic anhydride, then rinsed twice with 10 mL of water. The crystals are then dried under vacuum. The contaminant second isomer is then reduced to less than 5%.

[0565] The second preparation involves 2-(3,5-dimethoxy-2-nitro-phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane. Cyclopentane 2c

[0566] The reaction was carried out under an argon atmosphere. KOAc (4.49 g, 0.7 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (Pd(DPPFCl2)) (0.558 g, 0.76 mmol) were added under stirring to a solution of 1-bromo-3,5-dimethoxy-2-nitro-benzene 2b (4.00 g, 15 mmol) and bis(pinacolyl)diborone (5.810 g, 22 mmol) in 75 mL of dioxane. The temperature was raised to 85 °C and stirred for 12 hours. The filter cake was washed with a small amount of ethyl acetate, and the filtrate mixture was concentrated under vacuum to half its initial volume and extracted with ethyl acetate (30 mL) and water (30 mL). The combined organic layers were washed with brine, dried over Na2SO4, and evaporated. The solid was crystallized by crystallization in ethyl acetate after concentration to give 2c in 80% yield. 1 H-NMR (DMSO-d6, 400 MHz): δ 6.87 (d, J= 2.5 Hz, 1 H), 6.61 (d, J= 2.5 Hz, 1 H), 3.91 (3 H, s), 3.89 (3 H, s), 1.28 (12 H, s).

[0567] The second step involves preparing 2-(3,5-dimethoxy-2-nitro-phenyl)benzonitrile 2d

[0568] Boronate ester 2c reacted with 2-bromobenzonitrile 1b to give 2d. The reaction was carried out under an argon atmosphere. Under nitrogen, a solution of 2M Na₂CO₃ (30 mL) was added to 2-bromobenzonitrile 1b (1.5 g, 8.2 mmol) in 60 mL of dioxane. After stirring at 75 °C for 5 min, Pd[P(C₆H₅)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-dioxaboranecyclopentane 2c. The reaction was stirred at 90 °C for 8 h. The reaction mixture was then cooled at 20 °C and filtered through diatomaceous earth. The solution was concentrated to half its initial volume under vacuum and extracted with ethyl acetate (30 mL) and water (30 mL). The combined organic layers were washed with 20 mL of brine, dried over Na₂SO₄, and evaporated. The solid crystallized after concentration. It was ground with Et₂O (2 x 10 mL) and filtered through a Buchner funnel to give 2d. Yield: 36%. 1 H-NMR (DMSO-d6, 400 MHz): δ 7.95(d, J = 7.9 Hz,1H), 7.85 (d, J = 7.9 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.35 (t, J = 7.5 Hz,1H), 6.93 (d, J= 2.4Hz, 1H), 6.68 (d, J= 2.4Hz, 1H), 3.96 (s, 3H), 3.90(s, 3H).

[0569] The third step involves the reduction of 2d to prepare 2,4-dimethoxyphenanthridine-6-amine.

[0570] 2.5 g of iron powder 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. The reaction was monitored by TLC for 4 hours, and the cooled reaction mixture was filtered through diatomaceous earth. The precipitate was washed twice with 20 mL of methanol-CH2Cl2 (80-20). The solution was concentrated to half its initial volume under vacuum and extracted with ethyl acetate (2 × 30 mL) and water (30 mL). The combined organic layers were washed with 20 mL of brine, dried over Na2SO4, and evaporated. The residue was recrystallized by AcOEt (2 x 10 mL) and filtered through a Buchner funnel to give 2, in 81% yield. 1H-NMR (DMSO-d6, 400 MHz): δ 8.64 (d, J = 8.1 Hz, 1H), 8.30 (d, J = 8.1Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.65 (t, J = 7.6 Hz, 1H), 7.49 (s, 1H), 6.79 (s, 2H), 6.71 (s, 1H), 3.91 (s, 3H), 3.88 (s, 3H).

[0571] Should 1 The H-NMR spectrum is the same as that obtained by method A.

[0572] Example 3: Preparation of 6-amino-2,4-dimethoxy-phenanthrene-9-ol 3

[0573] The compound was obtained by method C.

[0574]

[0575] Scheme 6. Preparation of 6-amino-2,4-dimethoxy-phenanthrene-9-ol.

[0576] The first step is to prepare 2-bromo-4-hydroxybenzonitrile 3b

[0577] A mixture of 2-bromo-4-methoxybenzonitrile 3a (2.12 g, 10 mmol) in a 1 M boron tribromide heptane solution (50 mL, 50 mmol) was refluxed for 48 hours. The mixture was then cooled to -20 °C and H₂O (50 mL) was added. After stirring at -20 °C for 1 hour, the mixture was extracted with CH₂Cl₂ (3 x 30 mL). The solution was washed with H₂O (2 x 10 mL). After drying on Na₂SO₄, the solvent was evaporated. The residue was crystallized by grinding with Et₂O (2 x 5 mL). The yield was 68%. 1 H-NMR (DMSO-d6, 400 MHz): δ 11.17 (s, 1H), 7.80 (d, J = 8.6 Hz, 1H), 7.24 (d, J =2.3 Hz, 1H), 6.98 (dd, J = 8.6, 2.3 Hz, 1H).

[0578] The second step involves preparing 2-(3,5-dimethoxy-2-nitro-phenyl)-4-hydroxybenzonitrile 3c.

[0579] The reaction of 3b with 2c was carried out under the same conditions as the synthesis of 2d, yielding 3c in 76% yield. 1H-NMR (CDCl3, 400 MHz): δ 11.25 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H), 6.93 (dd, J = 8.5, 2.5Hz, 1H), 6.82 (d, J = 2.5 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 6.51 (t, J = 3.2Hz, 1H), 3.95 (s, 3H), 3.88 (s, 3H).

[0580] The third step is the reduction and cyclization of 3c to 3.

[0581] Cyclization was carried out using iron powder and ammonium chloride, in the same manner as in the synthesis of compound 2. Compound 3 was isolated in 67% yield. 1 H-NMR (DMSO-d6, 400 MHz): δ 11.26 (d, J = 10.0 Hz, 1H), 8.90 (s, 2H), 8.51 (d,J = 8.3 Hz, 1H), 7.99 (s, 1H), 7.42 (s, 1H), 7.33 (d, J = 2.3Hz, 1H), 6.99(d, J = 2.3Hz, 1H), 4.05 (s, 3H), 3.94 (s, 3H).

[0582] Example 4: Preparation of 9-chloro-2,4-dimethoxy-phenanthridine-6-amine 4

[0583] Product 4a was prepared by reducing nitro derivative 2b with Fe / NH4Cl, as previously described in the reduction of 2d to 2. In the second step, 4a was reacted with commercially available 4-chloro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzonitrile 4b under the same coupling conditions as in Preparation Example 1.

[0584]

[0585] Scheme 7. Preparation of 9-chloro-2,4-dimethoxy-phenanthridine-6-amine.

[0586] Step 1: Restore 2b to 4a

[0587] The reduction reaction was carried out using Fe / NH4Cl in methanol / H2O. The solution was concentrated under vacuum. The amine was purified on a short silica gel column using cyclohexane-AcOEt 8:2 as eluent to give 4a (Rf=0.85), compared with 2b (Rf=0.4). The yield of 4a was 58%, and it was found to be unstable at 20 °C and must be stored at -20 °C. 1H-NMR (DMSO-d6, 400 MHz): δ 6.60 (d, J= 2.3Hz, 1 H), 6.54 (d, J= 2.3Hz, 1 H), 4.3 (brs, 2H), 3.58 (s, 3H), 3.36 (s, 3H).

[0588] Step 2: Suzuki Connection

[0589] Compound 4 was isolated in 62% yield. 1 H-NMR (400 MHz, DMSO-d6): δ 8.48 (dd, J = 11.4,2.5 Hz, 1H), 8.39 (dd, J = 9.1, 5.9 Hz, 1H), 7.53 (td, J = 8.8, 2.5 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 6.83 (s, 2H), 6.73 (d, J = 2.4 Hz, 1H), 3.91 (s,3H), 3.87 (s, 3H).

[0590] Example 5: Preparation of Compound 7; Preparation of 9-fluoro-2,4-dimethoxy-phenanthrene-6-amine 5

[0591] Method B

[0592]

[0593] Scheme 8. Preparation of 9-fluoro-2,4-dimethoxy-phenanthrene-6-amine 7

[0594] Commercially available 4-fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborhexacyclopentan-2-yl)benzonitrile 5a was used. Suzuki coupling was performed using the same procedure as in synthesis 4. Compound 5 was isolated in 35% yield. 1 H-NMR (400 MHz, DMSO) d6 ): δ 8.68 (d, J = 8.9 Hz, 1H), 8.52 (d, J = 2.1 Hz, 1H), 8.51 (d, J =8.2 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 6.62 (brs, 2H), 6.78 (d, J = 2.4 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H).

[0595] Example 6: Preparation of 2,4,9-trimethoxyphenanthridine-6-amine 6.

[0596] Compound 6 was obtained by method C.

[0597]

[0598] Scheme 9. Preparation of 2,4,9-trimethoxyphenanthridine-6-amine 6.

[0599] The first step is to prepare 2-(3,5-dimethoxy-2-nitro-phenyl)-4-methoxy-benzonitrile 6a

[0600] The reaction was carried out using the previously prepared 2d method. The yield was 42%. 1 H-NMR (DMSO-d6, 400 MHz): δ7.90 (d, J = 8.7 Hz, 1H), 7.19 (dd, J = 8.7, 2.6 Hz, 1H), 6.97 (m, 2H), 6.69(d, J = 2.4 Hz, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.85 (s, 3H).

[0601] The second step involves the preparation of 2,4,9-trimethoxyphenanthridine-6-amine.

[0602] The condition used to obtain 2 from 2d converts 6a to 6, yield / 69%. 1 H-NMR(DMSO-d6, 400 MHz): δ8.24 (d, J = 9.0 Hz, 1H), 7.94 (s, 1H), 7.44 (s, 1H), 7.26 (d, J = 8.9 Hz,1H), 6.71 (s, 1H), 6.68 (s, 2H), 4.01 (s, 3H), 3.92 (s, 3H), 3.87 (s, 3H).

[0603] Example 7 Preparation of (2R)-1-(6-amino-2,4-dimethoxy-phenanthrene-9-yl)pyrrolidine-2-carboxamide 7

[0604] Product 7 was prepared according to method C.

[0605]

[0606] Scheme 10. Preparation of (2R)-1-(3-bromo-4-cyano-phenyl)pyrrolidine-2-carboxamide 7

[0607] The first step is to prepare (R)-1-(3-bromo-4-cyano-phenyl)pyrrolidine-2-carboxamide 7b

[0608] D-prolylamide (1.55 g, 13.4 mmol) and diisopropylethylamine (DIEA, 4.75 mL, 26.8 mmol) were dissolved in DMSO (20 mL). 2-Bromo-4-fluorobenzonitrile 7a (2.55 g, 13.7 mmol) was added to this solution, and the mixture was heated at 100 °C with stirring for 2 h. After cooling, the mixture was diluted with 100 mL of H₂O and extracted with AcOEt (3 × 20 mL). The organic layer was washed with brine (2 × 20 mL) and H₂O. After drying with Na₂SO₄, the solution was concentrated under vacuum to give 7b, which was crystallized and ground with Et₂O (2 × 5 mL) and filtered. The yield was 86%. 1 H-NMR (DMSO-d6, 400 MHz): 7.55 (d, J = 8.8 Hz, 1H), 672 (s, 1H), 6.83 (d, J = 8.0 H, 1H), 6.59 (s, 2H), 4.18 (d, J = 10.6 Hz, 1H), 3.72 – 3.55 (m, 1H), 3.46 – 3.38 (m, 1H), 2.27 (d,J = 3.1 Hz, 1H), 2.03 (dd,J = 9.8, 7.9 Hz, 3H).

[0609] The second step is to prepare (2R)-1-[4-cyano-3-(6,8-dimethoxy-2-nitro-3-quinolinyl)phenyl]pyrrole. Alkyl-2-carboxamide 7c

[0610] The Suzuki cross-coupling reaction was carried out under the same reaction conditions as for obtaining 2d from 2c. 7c was separated in 68% yield. 1 H NMR (400 MHz, DMSO-d6): δ 7.17 (m, 1H), 7.00 (s, 1H), 6.64 (s, 2H), 6.41 (m, 1H), 4.22 – 4.06 (m, 1H), 4.01 (s, 3H), 3.95 (s, 3H), 3.60 (s, 1H), 3.39 – 3.26 (m, 1H), 2.31 (t, J = 17.7 Hz, 1H), 2.02 (dd, J = 18.6, 13.4 Hz, 3H).

[0611] Step 3: Preparation of (2R)-1-(6-amino-2,4-dimethoxy-phenanthridine-9-yl)pyrrolidine-2-methyl Amide 7.

[0612] The cyclization from 7c to 7 was carried out using a mixture of Fe powder and NH4Cl in MeOH / H2O, as described in preparation 2 from 2d. Yield: 78%. 1H-NMR (DMSO-d6, 400 MHz): δ 8.12 (d, J = 9.0 Hz, 1H), 7.66 (s,1H), 7.27 (dd, J = 10.5, 1.7 Hz, 2H), 7.20 (s, 1H), 6.88 (d, J = 9.1 Hz, 1H),6.76 – 6.60 (m, 3H), 4.25 (d, J = 7.0 Hz, 1H), 3.89 (s, 3H), 3.88 (s, 3H),3.76 (t, J = 7.1 Hz, 1H), 3.56 – 3.41 (m, 1H), 2.38 – 2.23 (m, 1H), 2.08(ddd, J = 33.5, 15.7, 12.1 Hz, 3H).

[0613] 13 C NMR (DMSO-d6, 101 MHz): δ 175.54, 154.71, 153.56, 148.49, 148.29,134.70, 126.41, 121.50, 114.46, 102.46, 100.15, 95.80, 55.92, 48.88, 31.40.

[0614] Example 8: 2-(6-amino-2,4-dimethoxy-phenanthrene-9-yl)oxyethanol

[0615] Product 8 was obtained through method C.

[0616]

[0617] Scheme 11. Preparation of 2-(6-amino-2,4-dimethoxy-phenanthrene-9-yl)oxyethanol 8.

[0618] The first step involves the synthesis of 2-bromo-4-(2-tetrahydropyran-2-yloxyethoxy)benzonitrile 8b

[0619] NaH (60% suspension in paraffin oil, 0.2 g, 5.5 mmol) was introduced into a two-necked round-bottom flask containing a magnetic rotating rod. A pressure equalization dropping funnel was immediately placed on one neck, and a diaphragm was placed on the other neck to generate an argon atmosphere via a needle. The flask was then placed in a cooling bath at -5°C, and THF (10 mL) was added dropwise. Stirring was only initiated when the NaH was completely covered by THF. 2-Tetrahydropyran-2-yloxyethanol 8a (0.90 g, 6 mmol) was added to the suspension, and the cooling bath was removed. After stirring at 0–5°C for 20 minutes, a solution of 2-bromo-4-fluorobenzonitrile 7a (1 g, 5 mmol) was slowly added below 5°C. The cooling bath was removed after complete addition. The mixture was stirred at 20°C for 2 hours. After cooling to -10°C, a 10% 2M NH4Cl solution (20 mL) was slowly added. The mixture was concentrated under vacuum to remove most of the THF. The product was extracted with AcOEt (3 × 10 mL). The AcOEt solution was washed with brine and H2O (2 x 10 mL). After drying on Na2SO4, the organic layer was evaporated, crystallized, ground with Et2O, and filtered through a Buchner funnel to give 2-bromo-4-(2-tetrahydropyran-2-yloxyethoxy)benzonitrile 8b in 65% yield.

[0620] 1 H-NMR (DMSO-d6, 400 MHz): δ 7.85 (d, J = 8.7 Hz, 1H), 7.49 (s, 1H), 7.15 (d, J = 10.9 Hz, 1H), 4.65 (s, 1H), 4.28 (s, 2H), 3.92 (m, 1H), 3.73 (m,2H), 3.44 (d, J = 11.4 Hz, 1H), 1.65 (dd, J = 14.4, 8.1 Hz, 2H), 1.46 (d, J =6.0 Hz, 3H).

[0621] The second step is to prepare 2-(3,5-dimethoxy-2-nitro-phenyl)-4-(2-tetrahydropyran-2-yloxyethoxy) Benzonitrile 8c

[0622] Compound 8c was prepared by Suzuki coupling as described in the preparation of 2d.

[0623] 1H-NMR (DMSO-d6, 400 MHz): δ 7.88 (d, J = 8.7 Hz, 1H), 7.20 (d, J =8.7 Hz, 1H), 6.98 (d, J = 10.5 Hz, 2H), 6.68 (s, 1H), 4.64 (s, 1H), 4.24 (s, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 3.75 (s, 2H), 3.42 (s, 1H), 1.66 (m, 2H), 1.46 (d, J = 8.6 Hz, 2H), 1.08 (m, 4H).

[0624] The third step involves the preparation of 2,4-dimethoxy-9-(2-tetrahydropyran-2-yloxyethoxy)phenanthridine-6-amine (8d).

[0625] Cyclization was carried out using Fe / NH4Cl in a CH3OH / H2O mixture as detailed previously. The yield was 35%. 1 H-NMR (DMSO-d6, 400 MHz): δ 8.22 (d, J = 9.0 Hz, 1H), 7.98 (s, 1H), 7.45 (s,1H), .28 (d, J = 8.9 Hz, 1H), 6.70 (s, 1H), 6.64 (s, 2H), 4.71 (s, 1H), 4.43(s, 2H), 4.03 (d, J = 11.8 Hz, 1H), 3.92 (s, 3H), 3.86 (s, 3H), 3.84 (d, J =3.7 Hz, 2H), 3.46 (m, 2H), 1.68 (m, 2H), 1.46 (m, 4H).

[0626] The fourth step involves deprotecting the protecting group to obtain 2-(6-amino-2,4-dimethoxy-phenanthridine-9-yl)oxyethanol 8.

[0627] PTSA (p-toluenesulfonic 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 was stirred at 20 °C for 6 hours. The solution was concentrated under vacuum. The remaining solid was extracted with 1 M Na₂CO₃ (2 mL) and AcOEt (50 mL). The organic layer was washed with H₂O (20 mL). After drying with Na₂SO₄, AcOEt was evaporated to give 8d in 95% yield.

[0628] 1H-NMR (DMSO-d6, 400 MHz): δ 8.28 (d, J = 8.9 Hz, 1H), 8.00 (s, 1H), 7.48 (s, 1H), 7.32 (d, J = 8.6 Hz, 1H), 6.75 (s, 1H), 6.69 (s, 2H), 5.02 (t,J = 8.2 Hz, 1H), 4.33 (s, 2H), 3.95 (d, J = 14.0 Hz, 3H), 3.88 (d, J = 4.6Hz, 3H), 3.88 (d, J = 4.6 Hz, 2H). 13 C-NMR (DMSO-d6 , 101 MHz): δ 160.56,154.88, 153.59, 135.73, 126.91, 121.22, 117.18, 113.84, 105.87, 100.63,95.75, 70.48, 60.12, 55.74.

[0629] Example 9: Preparation of 2,4-dimethoxy-9-[(1-methyl-4-piperidinyl)methoxy]phenanthridine-6-amine 9

[0630] Compound 9 was prepared by method C.

[0631]

[0632] Scheme 12. Preparation of 2,4-dimethoxy-9-[(1-methyl-4-piperidinyl)methoxy]phenanthridine-6-amine 9.

[0633] The first step involves the synthesis of 2-bromo-4-[(1-methyl-4-piperidinyl)methoxy]benzonitrile 9b

[0634] First, 2-bromo-4-fluorobenzonitrile is reacted with (1-methyl-4-piperidinyl)methanol 9a.

[0635] 9b was obtained in 94% yield under the same conditions as the synthesis of 8b. 1 H NMR (400 MHz, DMSO-d6) δ7.84 (d, J = 7 Hz, 1H), 7.46 (d, J = 2.4 Hz, 1H), 7.13 (dd, J = 8.7, 2.4 Hz,1H), 3.96 (d, J = 6.0 Hz, 2H), 2.77 (d, J = 11.3 Hz, 2H), 2.15 (s, 3H), 1.84 (t, J = 11.8 Hz, 2H), 1.71 (d, J = 11.6 Hz, 3H), 1.29 (m, 2H).

[0636] The second step involves the preparation of 2-(3,5-dimethoxy-2-nitro-phenyl)-4-[(1-methyl-4-piperidinyl)methoxy]benzene. Formonitrile 9c

[0637] Based on the 2d synthesis, it was obtained with a yield of 65%. 1 H-NMR (DMSO-d6, 400 MHz): δ 7.87 (d, J =8.7 Hz, 1H), 7.17 (dd, J = 8.7, 2.5 Hz, 1H), 6.96 (t, J = 2.3 Hz, 2H), 6.68(d, J = 2.4 Hz, 1H), 3.96 (s, 3H), 3.93 (d, J = 5.9 Hz, 2H), 3.90 (s, 3H), 2.77 (d, J = 11.2 Hz, 2H), 2.15 (s, 3H), 1.85 (t, J = 10.7 Hz, 2H), 1.70 (d,J = 10.3 Hz, 3H), 1.28 (m, 2H).

[0638] The third step is to prepare 2,4-dimethoxy-9-[(1-methyl-4-piperidinyl)methoxy]phenanthridine-6-amine 9.

[0639] Reductive cyclization was performed as described in 2d synthesis 2. Compound 9 was obtained in 55% yield. 1 H NMR (400 MHz, DMSO-d6): δ 8.23 ​​(d, J = 9.0 Hz, 1H), 7.93 (d, J = 2.2 Hz, 1H), 7.43 (d, J =2.3 Hz, 1H), 7.26 (dd, J = 9.0, 2.2 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 6.67(s, 2H), 4.10 (d, J = 5.8 Hz, 2H), 3.92 (s, 3H), 3.87 (s, 3H), 2.87 (d, J =11.1 Hz, 2H), 2.22 (s, 3H), 1.98 (t, J = 11.0 Hz, 2H), 1.91 (s, 1H), 1.83 (d,J = 11.7 Hz, 2H), 1.41 (m, 2H).

[0640] Example 13 Preparation of 2,4-dimethoxy-9-(trifluoromethyl)phenanthridine-6-amine 10

[0641] Compound 10 was prepared by method C.

[0642]

[0643] Scheme 13. Preparation of 2,4-dimethoxy-9-(trifluoromethyl)phenanthridine-6-amine 10.

[0644] The first step was to prepare 2-(3,5-dimethoxy-2-nitro-phenyl)-4-(trifluoromethyl)benzonitrile 10b.

[0645] The Suzuki coupling conditions described in preparation 2d were used. The yield was 41%.

[0646] 1 H-NMR (DMSO-d6, 400 MHz): δ 9.08 (s, 1H), 8.58 (d, J = 8.6 Hz, 1H), 8.02 (d, J = 8.6 Hz, 1H), 7.67 (d, J = 2.5 Hz, 1H), 7.05 (s, 2H), 6.83 (d, J= 2.4 Hz, 1H), 4.00 (s, 3H), 3.94 (s, 3H).

[0647] The second step is to prepare 2,4-dimethoxy-9-(trifluoromethyl)phenanthridine-6-amine 10.

[0648] Cycloning was performed as described in 2d synthesis 2. The yield was 66%.

[0649] 1 H-NMR (DMSO-d6, 400 MHz): δ 9.03 (s, 1H), 8.53 (d, J = 8.6 Hz, 1H), 7.96 (dd, J = 8.6, 1.3 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 7.00 (s, 2H), 6.77 (d, J = 2.4 Hz, 1H), 3.95 (s, 3H), 3.89 (s, 3H).

[0650] Example 11: Preparation of 8,9-difluoro-2,4-dimethoxy-phenanthrene-6-amine 11

[0651] Compound 11 was prepared by method C.

[0652]

[0653] Scheme 14. Preparation of 8,9-difluoro-2,4-dimethoxy-phenanthrene-6-amine 11

[0654] The first step was to prepare 2-(3,5-dimethoxy-2-nitro-phenyl)-4,5-difluorobenzonitrile 11b

[0655] Compound 11b was prepared under the Suzuki conditions used to obtain 2d. The yield was 42%.

[0656] 1H-NMR (DMSO-d6, 400 MHz): δ 8.39 (m, 1H), 7.82 (dd, J = 10.7, 7.7 Hz,1H), 7.06 (d, J = 2.5 Hz, 1H), 6.81 (t, J = 3.3 Hz, 1H), 4.02 (s, 3H), 3.96(s, 3H).

[0657] The second step involves the preparation of 8,9-difluoro-2,4-dimethoxy-phenanthridine-6-amine.

[0658] The reductive cyclization of 11b yields 11, as described in the synthesis of 2 from 2d. Yield: 45%.

[0659] 1H-NMR (DMSO-d6, 400 MHz): δ 8.51(dd, J = 10.4, 7.8 Hz, 1H), 8.42 (m,1H), 7.45 (d, J = 2.5 Hz, 1H), 6.85 (s, 2H), 6.78 (d, J = 2.5 Hz, 1H), 3.91(s, 3H), 3.87(s, 3H).

[0660] Example 12 Preparation of 4-methoxy-2-(2-methoxyethoxy)phenanthridine-6-amine 12

[0661] Compound 12 was prepared according to method A.

[0662]

[0663] Scheme 15. Preparation of 4-methoxy-2-(2-methoxyethoxy)phenanthridine-6-amine 12

[0664] The first step is to prepare 3-bromo-5-methoxyphenol 12a.

[0665] Sodium tert-butoxide (9.44 g, 97.9 mmol) was added in portions to a mixture of 2-(diethylamino)ethanethiol hydrochloride (8 g, 46.9 mmol) in DMF (60 mL) in an ice bath, while maintaining the temperature below 25 °C. After 5 minutes, the reaction was warmed to room temperature and stirred for another 5 minutes. Compound 2a, 1-bromo-3,5-dimethoxy-benzene (8.5 g, 39.16 mmol), was added, and the mixture was refluxed. The reaction was monitored by TLC. The reaction was completed over 4 hours, and the mixture was cooled in an ice bath. The solution was adjusted to pH 1 at 5 °C by the slow addition of 1 M HCl (40 mL). The mixture was extracted with ethyl acetate and concentrated under reduced pressure. The solid was crystallized from the solid after grinding with cyclohexane to give 12a in 85% yield, which was a yellow solid.

[0666] The second step involves alkylation with 1-bromo-2-methoxyethane to obtain 1-bromo-3-methoxy-5-(2-methoxyethoxy)benzene.12b。

[0667] A solution of 3-bromo-5-methoxyphenol 12a (5 g, 24.62 mmol) in DMSO (60 mL) was added to K₂CO₃ (13.61 g, 98.50 mmol) and 1-bromo-2-methoxyethane (4.68 g, 49.25 mmol) at 20 °C with stirring. After stirring for 12 hours, the mixture was poured into cold H₂O (150 mL) and extracted with AcOEt (3 x 20). After drying with Na₂SO₄ and evaporating under vacuum, 12b was obtained in 98% yield. 1 H-NMR (DMSO-d6, 400 MHz): δ 6.73 (s, 2 H), 6.52 (s, 1H), 4.09 (d, J=2.5Hz, 2H), 3.75 (s, 3 H), 3.63 (s, 2 H), 3.31 (s, 3H).

[0668] The third step, nitration of 12b, produces 12c.

[0669] As shown in the preparation of 2b, nitric acid (65%) in acetic anhydride is used.

[0670] A mixture of two isomers was formed. It was crystallized at 12°C and separated by filtration. The yield was 33%. 1 H-NMR (DMSO-d6, 400 MHz): δ 6.73 (s, 2H), 6.52 (s, 1H), 4.09 (d, J=2.5Hz, 2H), 3.75 (s, 3H), 3.63 (s, 2H), 3.31 (s, 3H).

[0671] The fourth step involves reducing 12c to obtain 2-amino-3-bromo-5-(2-methoxyethoxy)phenol 12d.

[0672] Using Fe and NH4Cl in MeOH and H2O, the process described in section 2 for the reduction of 2d to 12d yielded 28% of the original. 1 H-NMR (DMSO-d6, 400 MHz): δ 6.61 (d, J = 7.5 Hz, 1H), 6.55 (s, 1H), 4.29(s, 2H), 4.10 (dd, J = 6.2, 3.0 Hz, 2H), 3.68 (d, J = 6.1 Hz, 2H), 3.67 (s,3H), 3.34 (s, 3H).

[0673] Step 5 yields 4-methoxy-2-(2-methoxyethoxy)phenanthridine-6-amine.

[0674] Under the conditions used to prepare 1, 12d was condensed with 1b to obtain 12, with a yield of 16%. 1 H-NMR (DMSO-d6, 400MHz): δ 8.64 (d, J = 8.3 Hz, 1H), 8.31 (d, J = 8.3 Hz, 1H), 7.80 (t, J = 7.6Hz, 1H), 7.65 (d, J = 15.1 Hz, 1H), 7.51 (s, 1H), 6.75 (d, J = 10.1 Hz, 3H), 4.24 (d, J = 9.3 Hz, 2H), 3.90 (s, 3H), 3.74 (d, J = 3.3 Hz, 2H), 3.36 (s, 3H).

[0675] Example 13. Preparation of 2,4-dimethoxy-9-(trifluoromethoxy)phenanthridine-6-amine

[0676] Compound 13 was prepared by method C.

[0677]

[0678] Scheme 16. Preparation of 4-methoxy-2-(2-methoxyethoxy)phenanthridine-6-amine 13.

[0679] The first step is to condense 2c with the commercially available 13a to obtain 13b.

[0680] In a round-bottom flask equipped with two inlet tubes with stopcocks, add 13a (2.66 g, 10 mmol), 2c (3.71 g, 12 mmol), K2CO3 (2.07 g, 15 mmol), Pd(OAc)2 (0.07 g, 0.3 mmol), and XPhos (2-dicyclohexylphosphine-2′) to the flask. , 4′,6′-triisopropylbiphenyl (0.30 g, 0.6 mmol) was introduced sequentially as a solid. The flask was evacuated and purged with argon. This process (vacuum followed by argon purging) was repeated twice. Then, a mixture of 14 mL toluene, 6 mL EtOH, and 2 mL H₂O was introduced. The flask was evacuated and purged with argon. Immediately afterwards, the flask was immersed in an oil bath at 80 °C. Stirring was initiated and maintained at the same temperature for 2 hours. After cooling to 20 °C, the mixture was filtered through diatomaceous earth to remove Pd. Water was added, and the mixture was extracted with AcOEt (3 x 20 mL). After concentrating the organic layer, compound 13b crystallized. The yield was 86%.

[0681] Experiments have shown that different ratios of EtOH to toluene (e.g., toluene 3:EtOH 7:H2O 1) have no significant effect on the reaction results. The yield is 78%.

[0682] 1 H-NMR (DMSO-d6, 400 MHz): δ 8.17 (d, J = 8.6 Hz, 1H), 7.69 (ddd, J =8.6, 2.4, 1.0 Hz, 1H), 7.54 (d, J = 1.0 Hz, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.81 (d, J = 2.4 Hz, 1H), 3.97 (s, 3H), 3.91 (s, 3H).

[0683] The second step involves cyclizing 13b into 2,4-dimethoxy-9-(trifluoromethoxy)phenanthridine-6-amine.

[0684] Transform 13b into 13 using the condition of obtaining 2 from 2d. The yield is 45%.

[0685] 1 H-NMR (DMSO-d6, 400 MHz): δ 8.79 (s, 1H), 8.72 (d, J = 9.6 Hz, 1H), 8.45 (brs, 2H), 7.83 (d, J = 8.6 Hz, 1H), 7.62 (d, J = 2.4 Hz, 1H), 6.92 (d,J = 2.4 Hz, 1H), 3.98 (s, 3H), 3.95 (s, 3H).

[0686] Example 14: Preparation of 6-amino-2,4-dimethoxy-phenanthrene-8-ol

[0687] Compound 14 was obtained by method C.

[0688]

[0689] Step 1 2-(3,5-dimethoxy-2-nitro-phenyl)-5-hydroxy-benzonitrile 14b

[0690] Use the coupling procedure described in preparation 13b.

[0691] The yield was 72%. 1 H NMR (400 MHz, DMSO) δ 10.47 (s, 1H), 7.23 (m, 2H), 7.12(m, 1H), 6.93 (d, J = 2.4 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 3.94 (s, 3H), 3.89 (s, 3H).

[0692] Step 2: 6-Amino-2,4-dimethoxy-phenanthridine-8-ol 14

[0693] The reduction and cyclization were performed as described in section 2 for conversion from 2d to 2. The yield was 38%.

[0694] 1 H NMR (300 MHz, DMSO) δ 10.33 (s, 1H), 8.55 (d, J = 9.0 Hz, 1H), 7.71 (s, 3H), 7.46 (d, J = 9.7 Hz, 2H), 6.76 (d, J = 2.0 Hz, 1H), 3.94 (s,3H), 3.91 (s,3H).

[0695] Examples 15, 16, 17 and 18: 2-(6-amino-8-fluoro-2,4-dimethoxy-phenanthrin-9-yl)oxyethanol 9-[3-(dimethylamino)propoxy]-8-fluoro-2,4-dimethoxy-phenanthidine-6-amine 16, 8-fluoro-2,4-dimethoxy-9- [[(3R)-1-methylpyrrolidin-3-yl]methoxy]phenanthridine-6-amine 17 and 8-fluoro-2,4-dimethoxy-9-[(1-methyl-4-] Preparation of piperidinyl)methoxy]phenanthridine-6-amine 18.

[0696]

[0697] Scheme 17 Preparation of compounds 15, 16, 17 and 18

[0698] The first step is to prepare nitrile 15a, 16a, 17a, and 18a.

[0699] Nitriles 15a, 16a, 17a and 18a were obtained under the same conditions as 8b.

[0700] 2-Bromo-5-fluoro-4-(2-tetrahydropyran-2-yloxyethoxy)benzonitrile 15a .

[0701] Yield: 34%. 1 H-NMR (DMSO-d6, 400 MHz): 7.99 (d, J = 11.1 Hz, 1H), 7.74 (d,J = 7.7 Hz, 1H), 4.66 (d, J = 3.8 Hz, 1H), 4.47 – 4.31 (m, 2H), 3.99 – 3.84(m, 1H), 3.74 (ddd, J = 12.0, 5.4, 3.8 Hz, 2H), 3.44 (dd, J = 10.9, 5.4 Hz, 1H), 1.81 – 1.54 (m, 2H), 1.57 – 1.29 (m, 4H).

[0702] 2-Bromo-4-[3-(dimethylamino)propoxy]-5-fluorobenzonitrile 16a

[0703] The yield was 67%. 1 H-NMR (DMSO-d6, 400 MHz): δ 7.96 (d, J = 11.1 Hz, 1H), 7.68 (d, J = 7.7 Hz, 1H), 4.22 (t, J = 6.3 Hz, 2H), 2.34 (t, J = 6.3 Hz, 2H), 2.14(s, 6H), 1.87 (p, J = 6.3 Hz 2H).

[0704] 2-Bromo-5-fluoro-4-[(1-methyl-4-piperidinyl)methoxy]benzonitrile 17a

[0705] The yield was 73%. 1 H-NMR (DMSO-d6, 400 MHz): δ 7.98 (d, J = 11.1 Hz, 1H), 7.69 (d, J = 7.7 Hz, 1H), 4.05 (d, J = 6.2 Hz, 2H), 2.77 (d, J = 11.4 Hz, 2H), 2.15 (s, 3H), 1.85 (dd, J = 11.6, 9.7 Hz, 2H), 1.70 (d, J = 10.9 Hz, 3H), 1.29 (m, 2H).

[0706] 2-Bromo-5-fluoro-4-[[(3R)-1-methylpyrrolidone-3-yl]methoxy]benzonitrile 18.

[0707] The yield was 78%. 1 H-NMR (400 MHz, DMSO) δ 7.98 (d, J = 11.1 Hz, 1H), 7.71 (d,J = 7.7 Hz, 1H), 4.08 (dd, J = 7.1, 3.6 Hz, 2H), 2.56 (m, 2H), 2.37 (m, 2H), 2.24 (s, 3H), 1.95 (m, 1H), 1.50 (tdd, J = 7.8, 4.6, 3.0 Hz, 1H), 1.40 (s, 1H).

[0708] The second step involves the preparation of 2-(3,5-dimethoxy-2-nitro-phenyl)benzonitrile.

[0709] The coupling procedure used to prepare 13b was used to obtain compounds 15b, 16b, 17b, and 18b.

[0710] 2-(3,5-Dimethoxy-2-nitro-phenyl)-5-fluoro-4-(2-tetrahydropyran-2-yloxyethoxy)benzonitrile 15b

[0711] The yield was 76%. 1H-NMR (DMSO-d6, 400 MHz): δ 8.00 (d, J = 11.1 Hz, 1H), 7.33(d, J = 8.1 Hz, 1H), 6.98 (d, J = 2.5 Hz, 1H), 6.71 (d, J = 2.5 Hz, 1H), 4.65(d, J = 3.3 Hz, 1H), 4.31 (s, 2H), 3.95 (d, J = 9.0 Hz, 3H), 3.94 (d, J = 2.8Hz, 2H), 3.90 (s, 3H), 3.81 – 3.64 (m, 2H), 3.43 (d, J = 11.5 Hz, 1H), 1.76 –1.55 (m, 2H), 1.56 – 1.29 (m, 4H).

[0712] 2-(3,5-Dimethoxy-2-nitro-phenyl)-4-[3-(dimethylamino)propoxy]-5-fluorobenzonitrile 16b

[0713] The yield was 67%. 1 H NMR (300 MHz, DMSO) δ 7.99 (d, J = 11.1 Hz, 1H), 7.28 (d,J = 8.0 Hz, 1H), 6.98 (d, J = 2.3 Hz, 1H), 6.72 (d, J = 2.3 Hz, 1H), 4.16 (t,J = 6.4 Hz, 2H), 3.97 (s, 3H), 3.91 (s, 3H), 2.35 (t, J = 6.4 Hz, 2H), 2.15(s, 6H), 1.88 (p, 2H).

[0714] 2-(3,5-Dimethoxy-2-nitro-phenyl)-5-fluoro-4-[(1-methyl-4-piperidinyl)methoxy]benzonitrile 17b

[0715] The yield was 85%. 1H-NMR (DMSO-d6, 400 MHz): δ 7.98 (d, J = 11.1 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 3.99(d, J = 6.1 Hz, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 2.76 (d, J = 11.4 Hz, 2H), 2.15 (s, 3H), 1.84 (t, J = 10.8 Hz, 2H), 1.68 (d, J = 10.8 Hz, 3H), 1.29 (m,2H).

[0716] 2-(3,5-Dimethoxy-2-nitro-phenyl)-5-fluoro-4-[[(3R)-1-methylpyrrolidine-3-yl]methoxy] Benzonitrile 18b

[0717] Yield: 55%. 1 H-NMR (DMSO-d6, 400 MHz): δ 7.98 (d, J = 11.1 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.98 (d, J = 2.4 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 3.99(d, J = 6.1 Hz, 2H), 3.96 (s, 3H), 3.90 (s, 3H), 2.56 (m, 2H), 2.37 (m, 2H), 2.24 (s, 3H), 1.95 (m, 1H), 1.50 (tdd, J = 7.8, 4.6, 3.0 Hz, 1H), 1.40 (s,1H).

[0718] The third step involves cyclizing the biaryl derivative into a 6-aminophenanthridine derivative.

[0719] Use the reduction conditions to convert 2d to 2.

[0720] 8-Fluoro-2,4-Dimethoxy-9-(2-Tetrahydropyran-2-yloxyethoxy)phenanthridine-6-amine 15c.

[0721] Yield: 33%. 1H-NMR (DMSO-d6, 400 MHz): δ 8.55 (d, J = 9.0 Hz, 1H), 7.71(s, 2H), 7.46 (d, J = 9.7 Hz, 2H), 6.76 (d, J = 2.0 Hz, 1H), 4.65 (d, J =3.3 Hz, 1H), 4.31 (s, 2H), 3.94 (s, 3H), 3.91 (s, 3H), 3.81 – 3.64 (m, 2H),3.43 (d, J = 11.5 Hz, 1H), 1.76 – 1.55 (m, 2H), 1.56 – 1.29 (m, 4H).

[0722] 9-[3-(dimethylamino)propoxy]-8-fluoro-2,4-dimethoxy-phenanthridine-6-amine 16.

[0723] The yield was 44%. 1 H NMR (300 MHz, DMSO) δ 8.13 (dd, J = 15.8, 11.0 Hz, 2H),7.46 (s, 1H), 6.72 (s, 1H), 6.65 (s, 2H), 4.39 (t, J = 5.7 Hz, 2H), 3.93 (s,3H), 3.87 (s, 3H), 2.44 (t, J = 5.7 Hz, 2H), 2.18 (s, 6H), 2.06 – 1.92 (m,2H).

[0724] 8-Fluoro-2,4-Dimethoxy-9-[[(3R)-1-methylpyrrolidone-3-yl]methoxy]phenanthrene-6-amine 17

[0725] 1 H-NMR (DMSO-d6, 400 MHz): δ 1 H NMR (400 MHz, DMSO) δ 8.15 (d, J =12.7 Hz, 1H), 8.14 – 8.05 (m, 1H), 7.48 (d, J = 2.5 Hz, 1H), 6.72 (d, J = 2.4Hz, 1H), 6.65 (s, 2H), 4.25 (d, J = 7.1 Hz, 2H), 3.93 (s, 3H), 3.87 (s, 3H),2.75 – 2.55 (m, 2H), 2.28 (s, 3H), 2.01 (dt, J = 13.0, 7.0 Hz, 2H), 1.63 (dt,J = 13.0, 7.2 Hz, 1H), 1.40 (s, 2H).

[0726] 8-Fluoro-2,4-Dimethoxy-9-[(1-Methyl-4-piperidinyl)methoxy]phenanthridine-6-amine 18

[0727] 1 H-NMR (DMSO-d6, 400 MHz): 8.16 (d, J = 9.1 Hz, 1H), 7.68 (s, 1H), 7.62 (t, J = 8.5 Hz, 1H), 6.88 (s, 2H), 6.79 (s, 1H), 4.08 (m, 2H), 3.96 (s, 3H), 3.91 (s, 3H), 2.84 (m, 2H), 2.21 (s, 3H), 1.97 (m, 2H), 1.75 (m, 3H), 1.33 (m 2H).

[0728] The fourth step converts 15c to 2-(6-amino-8-fluoro-2,4-dimethoxy-phenanthidine-9-yl)oxyethanol 15.

[0729] Under the same conditions as 8, the tetrahydropyranosyl protecting group was removed to obtain 15. The yield was 79%. 1 H-NMR(DMSO-d6, 400 MHz): δ 8.16 (d, J = 12.8 Hz, 1H), 8.13 (m, 1H), 7.47 (d, J =2.5 Hz, 1H), 6.71 (d, J = 2.4 Hz, 1H), 6.66 (s, 2H), 5.03 (t, J = 5.4 Hz,1H), 4.39 (m, 2H), 3.93 (s, 3H), 3.86 (s,, 3H), 3.85 (m, 2H).

[0730] Example 19. N-(6-amino-2,4-dimethoxy-phenanthrene-8-yl)-2-pyrrolidine-1-yl-acetamide 19

[0731]

[0732] Scheme 18: Preparation of N-(6-amino-2,4-dimethoxy-phenanthrene-8-yl)-2-pyrrolidine-1-yl-acetamide 19. Compound 19 was obtained by method C.

[0733] The first step was to prepare 2-bromo-N-(4-bromo-3-cyano-phenyl)acetamide 19b

[0734] Bromoacetyl bromide (0.95 mL, 10 mmol) was slowly added under stirring to a solution of 5-amino-2-bromobenzonitrile (1.97 g, 10 mmol) and DIEA (2.1 mL, 12 mmol) cooled at -5 °C in 15 mL of CH3CN. After the addition was complete, the mixture was extracted with H2O and AcOEt. Derivative 19b was crystallized after concentration in the organic phase. The yield was 89%.1 H NMR (400MHz, DMSO) δ 10.86 (s, 1H); 7.84(d, J= 2 Hz, 1H); 7.76(d, J= 5 Hz, 1H); 7.73(dd, J= 5 Hz, J= 2 Hz 1H); 4.09(s, 2H).

[0735] Step 2: N-(4-bromo-3-cyano-phenyl)-2-pyrrolidine-1-yl-acetamide 19c

[0736] Pyrrolidine (1.6 mL, 20 mmol) was added to a solution of brominated derivative 19b (1.6 g, 5 mmol) in 10 mL of CH3CN. After stirring at 20 °C for 15 min, the mixture was extracted with H2O / AcOEt. After evaporation of the organic phase, compound 19c crystallized (yield 55%).

[0737] 1 H NMR (300 MHz, DMSO) δ 10.31 (s, 1H), 8.27 (s, 1H), 7.85 (m, 2H), 3.31 (s, 2H), 2.59 (brs, 4H), 1.76 (brs, 4H).

[0738] The third step involves preparing N-[3-cyano-4-(3,5-dimethoxy-2-nitro-phenyl)phenyl]-2-pyrrolidine-1-yl- Acetamide 19d

[0739] A coupling procedure to convert 13a to 13b was used. The yield was 69%. 1 H NMR (400 MHz, DMSO) δ 10.20(s, 1H), 8.25 (d, J = 2.0 Hz, 1H), 7.96 (dd, J = 8.5, 2.1 Hz, 1H), 7.38 (d, J= 8.6 Hz, 1H), 6.96 (d, J = 2.3 Hz, 1H), 6.70 (d, J = 2.3 Hz, 1H), 3.96 (s,3H), 3.89 (s, 3H), 3.32 (s, 2H), 2.61 (s, 4H), 1.77 (s, 4H).

[0740] The fourth step is the preparation of N-(6-amino-2,4-dimethoxy-phenanthrene-8-yl)-2-pyrrolidine-1-yl-acetamide 19.

[0741] The reduction was performed as described in the 2d to 2 transformation. The yield was 24%.

[0742] 1H NMR (400 MHz, DMSO) δ 9.90 (s, 0H), 8.60 (d, J = 9.2 Hz, 1H), 8.30 (d, J = 1.9 Hz, 1H), 8.15 (d, J = 8.9 Hz, 1H), 7.45 (d, J = 2.4 Hz, 1H), 6.68(d, J = 2.4 Hz, 1H), 6.56 (s, 2H), 3.90 (s, 3H), 3.80 (m, 3H), 3.33 (s, 2H), 2.67 (s, 4H), 1.80 (s, 4H).

[0743] 13 C NMR (400 MHz, DMSO) δ 168.40, 154.39, 153.85, 152.29, 136.82,128.74, 123.44, 122.71, 120.54, 118.78, 113.70, 99.16, 94.27, 54.85, 53.28, 23.00.

[0744] Example 20: Preparation of 1-[4-[(6-amino-2,4-dimethoxy-phenanthrene-9-yl)oxymethyl]-1-piperidinyl]ketene

[0745]

[0746] Scheme 19 Preparation of 1-[4-[(6-amino-2,4-dimethoxy-phenanthrene-9-yl)oxymethyl]-1-piperidinyl]ketene

[0747] Compound 20 was prepared by method C.

[0748] The first step was to prepare 4-[(1-acetyl-4-piperidinyl)methoxy]-2-bromobenzonitrile 20a.

[0749] Compound 20a was prepared by reacting commercially available 1-[4-(hydroxymethyl)-1-piperidinyl]acetone with 7a in a yield of 49%. 1 H NMR (400 MHz, DMSO) δ 7.85 (d, J = 8.7 Hz, 1H), 7.47 (s, 1H), 7.14 (d,J = 8.7 Hz, 1H), 3.99 (d, J = 6.4 Hz, 2H), 3.83 (d, J = 13.4 Hz, 1H), 3.04(m, 1H), 1.99(s, 3H), 1.95(m 2H); 1.76(m, 4H), 1.17(m, 2H).

[0750] The second step involves preparing 4-[(1-acetyl-4-piperidinyl)methoxy]-2-(3,5-dimethoxy-2-nitro-phenyl) Benzonitrile 20b.

[0751] The coupling procedure exemplified in the preparation of 13b using Pd(OAc)2 and Xphos provides 20b in 76% yield. NMR(400 MHz, DMSO) δ 7.88 (d, J = 8.7 Hz, 1H), 7.18 (m, 1H), 6.97 (d, J = 2.7Hz, 2H), 6.68 (d, J = 2.3 Hz, 1H), 4.39 (d, J = 12.5 Hz, 1H), 3.96 (s, 3H), 3.94 (d, J = 4.7 Hz, 2H), 3.90 (s, 3H), 3.03 (t, J = 12.1 Hz, 1H), 1.99 (s, 3H), 1.72 (dd, J = 44.5, 30.7 Hz, 2H), 1.18 (m, 4H).

[0752] The third step involves preparing 1-[4-[(6-amino-2,4-dimethoxy-phenanthridine-9-yl)oxymethyl]-1-piperidinyl]ethyl Enone 20.

[0753] Reduction cyclization was performed as illustrated in 2d reduction to 2. The yield was 21%.

[0754] 1 H NMR (400 MHz, DMSO) δ 8.22 (d, J = 9.1 Hz, 1H), 7.93 (d, J = 2.4Hz, 1H), 7.43 (d, J = 2.5 Hz, 1H), 7.27 (dd, J = 9.0, 2.4 Hz, 1H), 6.70 (d, J= 2.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 2H), 4.44 (d, J = 13.1 Hz, 1H), 4.13 (d,J = 6.2 Hz, 2H), 3.96 (s, 3H), 3.86 (s, 3H), 3.09 (t, J = 12.0 Hz, 1H), 2.75– 2.56 (m, 1H), 2.01 (d, J = 9.5 Hz, 3H), 1.93 – 1.71 (m, 2H), 1.32 (dd, J =29.8, 17.4 Hz, 4H).

[0755] Example 21. Preparation of N-[2-(6-amino-2,4-dimethoxy-phenanthrene-9-yl)oxyethyl]acetamide 21

[0756]

[0757] Scheme 20. N-[2-(6-amino-2,4-dimethoxy-phenanthrene-9-yl)oxyethyl]acetamide 21 The synthesis of.

[0758] The first step is to prepare N-[2-(3-bromo-4-cyano-phenoxy)ethyl]acetamide 21a

[0759] Compound 21a was prepared by reacting 2-bromo-4-fluorobenzonitrile 7a with commercially available N-(2-hydroxyethyl)acetamide. The yield was 56%. 1 H NMR (400 MHz, DMSO) δ 8.10 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.48 (s, 1H), 7.14 (d, J = 8.9 Hz, 1H), 4.11 (d, J = 5.2 Hz, 2H), 3.41 (d, J= 5.7 Hz, 2H), 1.82 (s, 3H).

[0760] The second step involves the preparation of N-[2-[2-cyano-3-(3,5-dimethoxy-2-nitro-phenyl)phenoxy]ethyl]acetamide. 21b

[0761] Derivative 21b was prepared according to the method used to obtain 13b. The yield was 68%.

[0762] 1 H NMR (400 MHz, DMSO) δ 8.13 (s, 1H), 7.95 – 7.85 (m, 1H), 7.54 (ddd, J = 4.2, 2.5, 1.1 Hz, 1H), 6.97 (d, J = 2.6 Hz, 1H), 6.68 (d, J = 2.4Hz, 1H), 4.10 (d, J = 16.3 Hz, 2H), 3.96 (s, 3H), 3.90(s, 3H), 3.48 – 3.35(m, 2H), 1.82 (s, 3H).

[0763] Step 3: N-[2-(6-amino-2,4-dimethoxy-phenanthrin-9-yl)oxyethyl]acetamide 21

[0764] Tetrahydroxydiborane (B₂OH₄) (0.091 g, 1 mmol) and 21b were added to a solution of 4,4'-bipyridine (0.008 g, 0.005 mmol) in 1 mL DMF. The mixture was stirred at 20 °C for 0.5 h, and 2 mL of 2M Na₂CO₃ solution was added. After stirring for 1 h, the mixture was extracted with AcOEt (3 x 20 mL) and 10 mL of water. The organic layer was washed with 10 mL of brine and 10 mL of H₂O. After drying, 21b was crystallized while evaporating the AcOEt solution. The yield was 78%. 1 H NMR (400 MHz, DMSO) δ 8.22(d, J = 8.0 Hz, 1H), 8.00 (brt, 1H), 7.48 (d, J = 2.5 Hz, 1H), 7.25 (dd, J =8.0, 2.4 Hz, 1H), 6.69 (d, J = 2.5 Hz, 1H), 6.65 (brs, 2H), 4.27 (t, 2H), 3.93 (s, 3H), 3.86 (s, 3H), 3.51 (brq, 2H), 1.86 (s, 3H).

[0765] Examples 22, 23, and 24: Preparation of 9-[3-(dimethylamino)propoxy]-10-fluoro-2,4-dimethoxy-phenanthidine-6-amine 22, 10-fluoro-2,4-dimethoxy-9-[(1-methyl-4-piperidinyl)methoxy]phenanthidine-6-amine 23, and 10-fluoro-2,4-dimethoxy-9-[(1-methylazacyclobut-3-yl)methoxy]phenanthidine-6-amine 24

[0766]

[0767] Preparation of compounds 22, 23 and 24 in scheme 21.

[0768] Compounds 22, 23 and 24 were prepared according to method C.

[0769] The first step is to prepare nitrile 22a, 23a and 24a.

[0770] According to the method used in 8b, nitriles are obtained by reacting an alcohol with 2-bromo-3,4-difluorobenzonitrile using NaH in THF.

[0771] 2-Bromo-4-[3-(dimethylamino)propoxy]-3-fluorobenzonitrile 22a

[0772] Yield: 55%. 1H NMR (400 MHz, DMSO) δ 7.64 (dd, J = 11.6, 9.0 Hz, 1H), 7.56 (dd, J = 9.0, 4.2 Hz, 1H), 4.34 (td, J = 6.2, 2.0 Hz, 2H), 2.39 (t, J =7.0 Hz, 2H), 2.11 (d, J = 8.3 Hz, 7H), 1.85 (m, 2H).

[0773] 2- Bromo-3-fluoro-4-[(1-methyl-4-piperidinyl)methoxy]benzonitrile 23a.

[0774] Yield: 65%. 1 H NMR (400 MHz, DMSO) δ 7.78 (m, 1H), 7.39 (t, J = 8.4 Hz,1H), 4.05 (d, J = 6.1 Hz, 2H), 2.77 (d, J = 11.3 Hz, 2H), 2.15 (s, 3H), 1.85(t, J = 11.0 Hz, 2H), 1.70 (d, J = 12.2 Hz, 3H), 1.30 (m, 2H).

[0775] 2-Bromo-3-fluoro-4-[(1-methylazacyclobut-3-yl)methoxy]benzonitrile 24a.

[0776] Yield: 55%. 1 H NMR (400 MHz, DMSO) δ 7.99 (d, J = 11.1 Hz, 1H), 7.72 (d,J = 7.7 Hz, 1H), 4.31 (d, J = 6.9 Hz, 2H), 3.27 (t, J = 7.2 Hz, 2H), 2.95 (t,J = 6.2 Hz, 2H), 2.77 (m, 1H), 2.20 (s, 3H).

[0777] The second step involves the coupling of 2-bromonitrile with borate ester 2c.

[0778] The conditions used to prepare 13b are applied.

[0779] 2-(3,5-Dimethoxy-2-nitro-phenyl)-4-[3-(dimethylamino)propoxy]-3-fluorobenzonitrile 22b

[0780] The yield was 68%. 1H NMR (400 MHz, DMSO) δ 7.71 (dd, J = 11.8, 8.6 Hz, 1H), 7.13 (dd, J = 8.6, 4.3 Hz, 1H), 6.98 (s, 1H), 6.74 (d, J = 2.4 Hz, 1H), 4.37(s, 2H), 3.97 (s, 3H), 3.91 (s, 3H), 2.43 (t, J = 6.9 Hz, 2H), 2.15 (s, 6H), 1.88 (m, 2H).

[0781] 2-(3,5-Dimethoxy-2-nitro-phenyl)-3-fluoro-4-[(1-methyl-4-piperidinyl)methoxy]benzonitrile 23b。

[0782] δ 7.79 (d, J = 8.4 Hz, 1H), 7.41 (dd, J = 14 Hz, 10.5 Hz, 1H), 7.00(s, 1H), 6.76 (d, J = 2.0 Hz, 1H), 4.05 (dd, J = 15.1, 8.5 Hz, 2H), 3.97 (s,3H), 3.90 (s, 3H), 2.84 (d, J = 9.3 Hz, 2H), 2.21 (s, 3H), 1.97 (s, 2H), 1.75(s, 3H), 1.33 (d, J = 11.6 Hz, 2H).

[0783] 2-(3,5-Dimethoxy-2-nitro-phenyl)-3-fluoro-4-[(1-methylazacyclobut-3-yl)methoxy]benzyl Nitrile 24b

[0784] δ 7.99 (d, J = 11.0 Hz, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.98 (d, J =2.2 Hz, 1H), 6.71 (d, J = 2.3 Hz, 1H), 4.26 (s, 2H), 3.97 (s, 3H), 3.91 (s,3H), 3.27 (d, J = 7.1 Hz, 2H), 2.95 (s, 2H), 2.76 (m, 1H), 2.20 (s, 3H).

[0785] The third step involves the reductive cyclization of biaryl 22b, 23b, and 24b.

[0786] The reduction cyclization exemplified in the preparation of 21 was used.

[0787] 9-[3-(dimethylamino)propoxy]-10-fluoro-2,4-dimethoxy-phenanthidine-6-amine 22.

[0788] The yield was 78%.1 1H NMR (400 MHz, DMSO) δ 8.46 (m, 1H), 7.74 (dd, J = 10.9, 9.3 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 7.09 (brs, 2H), 6.70 (d, J = 2.0 Hz, 1H), 4.25 (t, J = 6.2 Hz, 2H), 3.89 (s, 3H), 3.87 (s, 3H), 2.42 (t, J = 6.7 Hz, 2H), 2.15 (s, 6H), 1.99 (s, 2H).

[0789] 10-Fluoro-2,4-Dimethoxy-9-[(1-Methyl-4-piperidinyl)methoxy]phenanthridine-6-amine 23

[0790] The yield was 81%. 1 1H NMR (400 MHz, DMSO) δ 8.43 (m, 1H), 7.68 (dd, J = 10.3, 9.3 Hz, 1H), 7.42 (d, J = 2.0 Hz, 1H), 6.88 (brs, 2H), 6.79 (d, J = 2.0 Hz, 1H), 4.15 (d, J = 5.8 Hz, 2H), 3.88 (s, 3H), 3.87 (d, J = 10.0 Hz, 3H), 3.15 (s, 2H), 2.21 (s, 3H), 1.97 (s, 2H), 1.75 (s, 3H), 1.33 (m, 2H).

[0791] 10-Fluoro-2,4-Dimethoxy-9-[(1-Methylazacyclobut-3-yl)methoxy]phenanthrene-6-amine 24.

[0792] The yield was 85% 1 1H NMR (400 MHz, DMSO) δ 8.41 (m, 1H), 7.72 (dd, J = 10.8, 9.3 Hz, 1H), 7.42 (d, J = 2 Hz, 1H), 7.09 (s, 2H), 6.70 (s, 1H), 4.31 (d, J = 6.9 Hz, 2H), 3.98 (s, 3H), 3.91 (s, 3H), 3.27 (t, J = 7.2 Hz, 2H), 2.95 (t, J = 6.2 Hz, 2H), 2.77 (m, 1H), 2.20 (s, 3H).

[0793] Example 25. Preparation of 2,4-dimethoxy-9-[[(2S)-1-methylpyrrolidine-2-yl]methoxy]phenanthrene-6-amine 25.

[0794] The compound was obtained by method C.

[0795]

[0796] Scheme 22: Preparation of 2,4-dimethoxy-9-[[(2S)-1-methylpyrrolidone-2-yl]methoxy]phenanthrene-6-amine 25

[0797] Step 1: Synthesis of 2-bromo-4-[[(2S)-1-methylpyrrolidone-2-yl]methoxy]benzonitrile

[0798] Compound 25a was prepared by reacting 2-bromo-4-fluorobenzonitrile 7a with commercially available [(2S)-1-methylpyrrolidone-2-yl]methanol.

[0799] Yield: 65%. 1 H NMR (400 MHz, DMSO) δ 7.84 (d, J = 8.7 Hz, 1H), 7.46 (d, J= 2.4 Hz, 1H), 7.13 (dd, J = 8.7, 2.5 Hz, 1H), 4.08 (dd, J = 9.8, 5.3 Hz, 1H), 3.96 (dd, J = 9.8, 5.8 Hz, 1H), 2.94 (dt, J = 6.3, 4.2 Hz, 1H), 2.57 (m,1H), 2.32 (m, 3H), 2.22 (m, 1H), 1.94 (m, 1H), 1.66 (m, 2H), 1.62 (m, 1H).

[0800] Step 2: 2-(3,5-dimethoxy-2-nitro-phenyl)-6-[[(2S)-1-methylpyrrolidine-2-yl]methoxy Preparation of benzonitrile.

[0801] Using Pd(OAc)2 and Xphos, the coupling procedure exemplified in the preparation of 13b yielded 25b. The yield was 68%. 1HNMR (400 MHz, DMSO) δ 7.87 (d, J = 8.7 Hz, 1H), 7.18 (dd, J = 8.7, 2.4 Hz,1H), 6.97 (m, 2H), 6.68 (d, J = 2.3 Hz, 1H), 4.08 (m, 1H), 3.96 (s, 3H), 3.89(s, 3H), 2.95 (m, 1H), 2.57 (m, 1H), 2.35 (s, 3H), 2.19 (q, J = 8.7 Hz, 1H), 1.94 (m, 1H), 1.63 (m, 3H), 1.59 (m, 1H).

[0802] Step 3: Preparation of 2,4-dimethoxy-9-[[(2S)-1-methylpyrrolidone-2-yl]methoxy]phenanthrene-6-amine 25 Preparation

[0803] As described in the synthesis of Example 21, reductive cyclization was performed using tetrahydroxydiborane and 4,4'-bipyridine.

[0804] The yield was 89%. 1 H NMR (400 MHz, DMSO) δ 7.65 (d, J = 8.7 Hz, 1H), 7.01 (dd,J = 8.7, 2.4 Hz, 1H), 6.86 (m, 1H), 6.68 (d, J = 2.3 Hz, 2H), 4.01 (m, 1H),3.94 (s, 3H), 3.90 (s, 3H), 2.95 (m, 1H), 2.57 (m, 1H), 2.35 (d, J = 5.3 Hz,3H), 2.19 (q, J = 8.7 Hz, 1H), 1.94 (m, 1H), 1.63 (m, 3H), 1.59 (m, 1H).

[0805] Example 26: Preparation of 2,4-dimethoxy-9-(oxetanebut-3-yloxy)phenanthridine-6-amine 26

[0806]

[0807] Scheme 23: Preparation of 2,4-dimethoxy-9-(oxacyclobut-3-yloxy)phenanthridine-6-amine 26.

[0808] The first step was to prepare 2-bromo-4-(oxetanebut-3-yloxy)benzonitrile 26a.

[0809] Oxalide-3-ol reacted with 2-bromo-4-fluorobenzonitrile 7a to give compound 26a. The yield was 49%. 1H NMR(400 MHz, DMSO) δ 7.88 (d, J = 8.7 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.02(dd, J = 8.7, 2.5 Hz, 1H), 5.44 (m, 1H), 4.95 (ddd, J = 7.1, 6.0, 0.8 Hz, 2H), 4.54 (ddd, J = 7.5, 4.7, 0.7 Hz, 2H).

[0810] The second step involves the preparation of 2-(3,5-dimethoxy-2-nitro-phenyl)-6-(oxetane-3-yloxy)benzonitrile 26b.

[0811] The coupling procedure used to prepare 13b was used to obtain 26b in 78% yield. 1 H NMR (400 MHz, DMSO) δ 7.88(d, J = 8.7 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 7.02 (dd, J = 8.7, 2.5 Hz,1H), 6.97 (m, 2H), 6.68 (d, J = 2.3 Hz, 1H), 5.43 (m, 1H), 4.92 (m, 2H), 4.50 (m, 2H), 3.96 (s, 3H), 3.90 (s, 3H).

[0812] Preparation of 2,4-dimethoxy-9-(oxacyclobut-3-yloxy)phenanthridine-6-amine 26.

[0813] The reduction and cyclization as described in Example 21 yielded 26, with a yield of 59%. 1 H NMR (400 MHz, DMSO) δ7.79 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 2.5 Hz, 1H), 7.01 (dd, J = 8.7, 2.5Hz, 1H), 6.94 (m, 2H), 6.65 (d, J = 2.3 Hz, 1H), 5.40 (m, 1H), 4.90 (m, 2H), 4.50 (m, 2H), 3.92 (s, 3H), 3.86 (s, 3H).

[0814] Example 27 Preparation of (2R)-2-[(6-amino-2,4-dimethoxy-phenanthrene-9-yl)amino]but-1-ol 27.

[0815]

[0816] Preparation of Scheme 24 (2R)-2-[(6-amino-2,4-dimethoxy-phenanthridine-9-yl)amino]but-1-ol 27.

[0817] The first step is to prepare (2(S)-2-[(6-amino-2,4-dimethoxy-phenanthrene-9-yl)amino]but-1-ol

[0818] Compound 27a was prepared in 69% yield using commercially available R-aminobutanol, following the method used to obtain compound 7b from 7a. 1 H NMR (400 MHz, DMSO) δ 7.46 (d, J = 8.7 Hz, 1H), 6.94 (d, J = 2.1 Hz, 1H), 6.75 (d, J = 7.9 Hz, 1H), 6.67 (dd, J = 8.8, 2.2 Hz, 1H), 4.74 (t, J =5.4 Hz, 1H), 3.36 (dt, J = 13.0, 4.7 Hz, 3H), 1.64 (m, 1H), 1.39 (m, 1H), 0.88 (t, J = 7.4 Hz, 3H).

[0819] The second step involves the preparation of 2-(3,5-dimethoxy-2-nitro-phenyl)-4-[[(1S)-1-(hydroxymethyl)propyl]amino]benzonitrile 27b

[0820] Based on the catalysts used in the synthesis of 13b, Pd(OAc)2 and Xphos were used to obtain compound 27b in 76% yield. 1 H NMR (400 MHz, DMSO) δ 8.02 (d, J = 8.7 Hz, 1H), 7.34 (s, 1H)6.94 (m, 2H), 6.75 (d, J = 7.9 Hz, 1H), 6.67 (m, J = , 1H), 4.74 (t, J = 5.4Hz, 1H), 3.96 (s, 3H), 3.90 (s, 3H), 3.38 (m, 2H), 1.62 (m, 1H), 1.40 (m,1H), 0.87 (t, J = 7.4 Hz, 3H).

[0821] The third step involves the preparation of (2R)-2-[(6-amino-2,4-dimethoxy-phenanthridine-9-yl)amino]but-1-ol 27

[0822] Using the reductive cyclization exemplified in the preparation of 21, 27 was obtained in 69% yield.

[0823] 1 H NMR (400 MHz, DMSO) δ 7.74 (d, J = 8.7 Hz, 1H), 7.34 (s, 1H) 6.90(m, 2H), 6.75 (d, J = 7.9 Hz, 1H), 6.68 (m, J = , 3H), 4.70 (t, J = 5.4 Hz,1H), 3.92 (s, 3H), 3.89 (s, 3H), 3.32 (m, 2H), 1.60 (m, 1H), 1.39 (m, 1H),0.85 (t, J = 7.4 Hz, 3H).

[0824] Example B: Biological assay

[0825] Example 1: Determination of EBNA1 expression after TPA activation of EBV.

[0826] 1. method

[0827] Raji cells (a non-producer cell line of Burkitt lymphoma carrying EBV) were used to evaluate the activity of the prepared compounds.

[0828] Cells were cultured in RPMI 1640 Gibco medium and incubated at 37 °C. EBV reactivation was induced using TPA (12-O-tetradecanoylphorbol-13-acetate). The compounds were dissolved in aqueous DMSO or HPCD (2-hydroxypropyl-β-cyclodextrin).

[0829] Raji cells (approximately 10) 5 cells.mL -1 ) and TPA 25 ng / mL -1 Incubate with the preparative compound at 1 µM to 20 µM for 48 hours. DMSO or HPCD solution was used as a control. After 48 hours of incubation, protein lysates were prepared from cells, separated on SDS-Page, and then transferred to nitrocellulose membranes (GE Healthcare). Primary antibodies against actin and EBNA1 (anti-EBNA-1 antibody, clone 1EB12) were used, followed by secondary antibodies. Signals were detected using ECL Western blot assay kits (GE Healthcare).

[0830] 2. active

[0831] The activities are shown in Table 1. EBNA1 inhibition is expressed as a micromolar concentration of the test compound, which inhibited EBNA1 expression by 50% in treated cells compared to untreated cells (controls using DMSO or HCPD solution). IC50 50 Active compounds < 5 µM are designated as A. 20 µM > IC 50 Compounds with a molecular weight >5 µM are designated as B. IC 50 Compounds with a molecular weight greater than 20 µM are represented as C.

[0832]

[0833] Table 3: Inhibition of EBNA1 expression in Raji cells (IC50) 50 ).

[0834] Example 2: Evaluation of the sensitivity of EBV-positive and EBV-negative cell lines to the compound;

[0835] 1. Method

[0836] Cells were cultured in RPMI 1640 Gibco medium with 10% FBS (fetal bovine serum) and incubated at 37°C. The prepared compounds were dissolved in DMSO. The compounds and cisplatin were diluted to different concentrations using the medium, and all cells (approximately 4.10 g / cm³) were cultured. 5 cells.mL -1 Cells were incubated for 48 hours. Then, the culture medium was aspirated, and the cells were incubated with a Cell Counting Kit-8 diluted with the medium at 37°C for 2 hours. Cell viability for each compound and cisplatin was determined by measuring the absorbance of the conversion dye at 450 nm using a microplate reader.

[0837] VK-2019-ester is a methyl ester. VK-2019-acid is the result of the saponification of VK-2019 ester, that is:

[0838] 2. Cells

[0839] Experiments were performed on EBV-positive and EBV-negative cells. The following cell lines were selected to assess their sensitivity to the prepared compounds.

[0840]

[0841] 3. result

[0842] The activity of the compound against EBV-positive gastric cancer cells YCCEL1 was tested compared with its inhibition of the lung cancer cell line A549. IC 50Units are in µM. IC 50 This refers to the concentration of the test compound that inhibited cell proliferation by 50% compared to untreated cells (control cells treated with DMSO).

[0843]

[0844] Table 4: Antiproliferative effect (IC50) 50 )

[0845] Comparison of the compound's activity against EBV-carrying cells and its activity against EBV-negative cells. IC50 50 The concentration of the test compound that inhibited cell proliferation by 50% compared to untreated cells (control cells treated with DMSO).

[0846]

[0847] Table 5: Antiproliferative effect (IC50) 50 )

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, used for the treatment or prevention of EBV-related disorders: (I) in: - Each of R1, R2, R3, R4, R7, R8, R9 and R 10 Independently represents H, halogen, C1-C8 alkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, -OCF3, -NO2, -CN, -OR 11 NHCOCHR 17 NHR 18 -NR 12 - R 13 -COOR 12 -CONR 12 R 13 NHCO(CH2) n NR 12 R 13 -NHCOR 17 -SO2NR 12 R 13 -SO2R 12 -CH2SO2NR 12 R 13 OPOR 12 OR 13 (CH2)nNR 12 R 13 -(CH2) n COOR 12 -(CH2) n CONR 12 R 13 -(CH2) q SO2NR 12 R 13 -S(O)NC(O)OR 14 , -(CH2) q Het1, NHCOR 17 、-O(CH2) q B(OR 15 )2、-(CH2) q B(OR 15 )2、 or , in: Het1 is a 3- to 6-membered heterocycle that is optionally fused with C3-C5 carbon rings. R 11 It can be H, C1-C6 alkyl, C1-C6 hydroxyalkyl, C1-C6 dimethoxyalkyl, C1-C6 halohydroxyalkyl, or C1-C6 dihydroxyalkyl-(CH2). q Het2、-(CH2) q O(PO)(OR 15 2、-(CH2) n OHet2、-(CH2) n NR 12 R 13 -COCH(CH2SH)NHCOCH3, optional substituted C2-C 14 Alkoxyalkyl, -(CH2) n NR 15 COCH3、-(CH2) n COOR 12 -(CH2) n CONR 12 R 13 -(CH2) q SO2NR 12 R 13 -COR 16 or –(CH2) n OCOR 16 Het2 is an optional substituted 3- to 6-membered heterocycle. Each n is an independent integer from 1 to 6, preferably 1, 2, or 3. Each 'o' is independently 1 or 2. Each q is an independent integer from 0 to 6, preferably 0, 1, 2, or 3. R 12 and R 13 Independently H, C1-C6 alkyl or C 2-14 alkoxyalkyl, or R 12 and R 13 Together with the N atoms they are attached to, they form optionally substituted 5- or 6-membered heterocycles. R 14 It is a C1-C6 alkyl, C1-C6 alkoxyalkyl, or -(CH2) p Het3 or -(CH2) p Cyc1, where p is an integer from 0 to 6, preferably 1 to 3, Het3 is an optionally substituted saturated or unsaturated heterocycle, and Cyc1 is a C1-C6 cycloalkyl group. R 15 It is H or C1-C6 alkyl, preferably C1-C3 alkyl. R 16 C1-C6 alkyl, C1-C6 aminoalkyl, -CHR 17 NHCOR 17 or -OCHR 17 OCOR 17 Each R 17 Independently H or C1-C3 alkyl, and R 18 It is H, or COCH3. and A is -NR5R6 or ,in R5 is H. R6 can be H, C1-C6 alkyl, or COO(CH2). n Het4, COR 21 or COOCHR 17 OCOR 17 ,in oR 21 For OH, halogen, -O(CH2) n NR 22 R 23 Optional substitution of -O(CH2) n O(CH2) m CH3 or optionally substituted C2- 14 Alkoxyalkyl oR 22 and R 23 Independently selected from H, C1-C6 alkyl groups or optionally substituted C2- 14 Alkoxyalkyl, and oHet4 is an optionally substituted 3- to 6-membered heterocyclic ring. R 20 H, C1-C8 alkyl, or optionally substituted C2-C 14 Alkoxyalkyl, and R 19 It is an optional substituted 5 to 12 aryl or heteroaryl group.

2. The compound for use according to claim 1, characterized by one or more of the following features: - A is NR5R6, preferably -NH2 and / or - R4 and R2 can be independently halogens, OH, C1-C6 alkoxy groups, or -O(CH2). n O(CH2) m CH3, and / or - At least one of R7, R8, and R9 is not H, and / or - R3 can be H, halogen, OH, C1-C6 alkoxy, or -O(CH2). n O(CH2) m CH3.

3. The compound for use according to claim 1, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the compound is of formula (Id). (Id) in R3, R8, R9 and R 10 As defined in claim 1, and Each R 24 Or R 25 Independently represents C1-C6 alkyl, C1-C6 hydroxyalkyl, or –(CH2). n O(CH2) m CH3, where n is an integer from 1 to 6 and m is an integer from 0 to 6.

4. The compound for use according to claim 3, wherein R3 is H or OR. 26 , where R 26 Indicates C1-C6 alkyl, C1-C6 hydroxyalkyl, or –(CH2). n O(CH2) m CH3, where n is an integer from 1 to 6 and m is an integer from 0 to 6.

5. The compound for use according to claim 3 or 4, wherein: -R3 is H - Each R 25 and R 24 Independently, it is a C1-C6 alkyl group, preferably a C1-C3 alkyl group. -R 10 It is H or a halogen, such as F, and R8 and R9 are independently selected from OH, Cl, F, Br, OH, C1-C3 alkoxy groups, preferably OCH3, C1-C3 alkyl groups, CF3, OCF3, and O(CH2). n OH, Hetl, O(CH2) n NCOR 17 O(CH2)nNR 12 R 13 -NHCO(CH2) n R 12 R 13 O(CH2) q Het2, where on is an integer from 1 to 6, preferably 1, 2 or 3. oq is an integer from 1 to 6, preferably 0, 1, 2 or 3. oHet1 is a 4-, 5-, or 6-membered heterocyclic ring, preferably pyrrolidinyl, optionally coated with halogen, -CONH2, or -COR. 17 -OH, C1-C3 alkoxy or C1-C3 alkyl substitution, oHet2 is a 5- or 6-membered heterocycle, preferably piperidinyl, which may optionally be substituted with a halogen, -OH, C1-C3 alkoxy, or C1-C3 alkyl group. oR 17 H or C1-C3 alkyl oR 12 and R 13 It is independently H or C1-C3 alkyl, or forms a 5- or 6-membered heterocycle optionally substituted with a C1-C3 alkyl atom with the N atom to which it is attached.

6. The compound for use according to any one of claims 1 to 5, wherein the EBV-related barrier is EBV-positive cancer.

7. The compound for use according to claim 6, wherein the EBV-positive cancer is selected from EBV-positive nasopharyngeal carcinoma, NKT-cell lymphoma, gastric cancer, Hodgkin lymphoma, post-transplant lymphoproliferative disorder (PTLD), Burkitt lymphoma, lymphoma in subjects with acquired immunodeficiency syndrome, diffuse large B-cell lymphoma, gastric cancer, parotid gland cancer, breast cancer, leiomyosarcoma, and any combination thereof.

8. The compound for use according to any one of claims 1 to 5, wherein the EBV-related disorder is selected from EBV-related autoimmune disorders, preferably multiple sclerosis, infectious mononucleosis, and chronic active EBV disease (CAEBV).

9. The compound for use according to any one of claims 1 to 8, wherein the compound is administered to an immunocompromised subject.

10. The compound for use according to any one of claims 1 to 8, wherein the compound is used to treat or prevent EBV-positive cancer, the EBV-positive cancer being selected from EBV-positive nasopharyngeal carcinoma, EBV-positive gastric cancer and EBV-positive lymphoma, preferably PTLD.

11. The compound of claim 10 for use, wherein the compound is used to prevent or treat EBV-positive cancer in immunocompromised subjects and / or transplant subjects.

12. A compound of formula (Id) or a pharmaceutically acceptable salt and / or solvate thereof. (Id) in R3, R8, R9 and R 10 As defined in claim 1, and Each R 24 Or R 25 Independently represents C1-C6 alkyl, C1-C6 hydroxyalkyl, or –(CH2). n O(CH2) m CH3, where n is an integer from 1 to 6, m is an integer from 0 to 6, and the condition is that when R 24 and R 25 When it is CH3, R3, R 10 R8 and R9 are not all H.

13. The compound of claim 12 or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from: 。 14. A prodrug of the compound as defined in claim 10 or 11, wherein the prodrug comprises an unstable portion selected from: And amino acid residues, wherein the unstable moiety is preferably associated with the amino group at the 6-position of the aminophenanthrene skeleton or with R8, R9 or R 10 The hydroxyl groups present in it are linked.

15. A pharmaceutical composition comprising a compound as defined in any one of claims 12 to 13 or a prodrug as described in claim 14 and a pharmaceutically acceptable excipient thereof.

16. The pharmaceutical composition of claim 15, for the treatment or prevention of EBV-related diseases, preferably EBV-positive cancers.

17. A method for preparing the compound of formula (I) according to claim 1 or 2, wherein A is NH2, the method comprising the following steps: -(a) Makes compound (II) (II) and compounds of formula (III) (III) Reaction to form a biphenyl compound of formula (IV), (IV) -(b) Under conditions that promote cyclization, the nitro functional group in compound (IV) is reduced to NH2 to obtain the compound of formula (I), where A is NH2, i.e.: - (I) Where R1-R 10 As defined in formula (I) of claim 1, X is a halogen, preferably Br, and each R 26 It is H or C1-C6 alkyl, or R 26 The group together with B(O)2 forms a 5-membered heterocycle optionally substituted with one or more C1-C3 alkyl groups.

18. The method of claim 17, wherein step (b) is carried out in the presence of Fe / NH4Cl.

19. The method of claim 17, wherein step (b) is carried out in the presence of B2(OH)4 and 4,4'-bipyridine, preferably in DMF and at room temperature.

20. Intermediate reagents, selected from: -2-(3,5-dimethoxy-2-nitro-phenyl)-4-[(1-methyl-4-piperidinyl)methoxy]benzonitrile 2-(3,5-Dimethoxy-2-nitro-phenyl)-4-(trifluoromethyl)benzonitrile -2-(3,5-dimethoxy-2-nitro-phenyl)-4,5-difluorobenzonitrile -2-(3,5-dimethoxy-2-nitro-phenyl)-2,3-difluorobenzonitrile and -2-(3,5-dimethoxy-2-nitro-phenyl)-4-fluorobenzonitrile, -N-[3-cyano-4-(3,5-dimethoxy-2-nitro-phenyl)phenyl]-2-pyrrolidine-1-ylacetamide -N-[2-(6-amino-2,4-dimethoxy-phenanthridine-9-yl)oxyethyl]acetamide -2-(3,5-dimethoxy-2-nitro-phenyl)-4-[3-(dimethylamino)propoxy]-3-fluorobenzonitrile -2-(3,5-dimethoxy-2-nitro-phenyl)-3-fluoro-4-[(1-methylazacyclobut-3-yl)methoxy]benzonitrile, and -2-(3,5-dimethoxy-2-nitro-phenyl)-3-fluoro-4-[(1-methyl-4-piperidinyl)methoxy]benzonitrile.

21. Use of the compound as defined in any one of claims 1 to 5 or 12 to 14 in the manufacture of a medicament for treating or preventing EBV-related diseases, preferably EBV-positive cancers, in a subject.

22. A method of treating or preventing EBV-related diseases in a subject, comprising administering to the subject an effective amount of a compound as defined in any one of claims 1 to 5 or 12 to 14.

Images