Polyelectrophilic metallated heterocycles derived from 2-(pyridin-2-yl)imidazo[1,2-a]pyridine and their use as chemotherapeutic agents

Abstract

The present invention relates to novel compounds based on polyelectrophilic metallated heterocycles derived from 2-(pyridin-2-yl)imidazo[1,2-a]pyridine, methods for obtaining them, as well as their use as chemotherapeutic agents, especially against tumors sensitive or resistant to other chemotherapeutic agents (e.g., cisplatin).

Description

[Technical Field]

[0001] FIELD OF THE INVENTION The present invention is comprised among the therapeutic treatments intended for various cancer types, with particular emphasis on tumors resistant to cisplatin or analogs in clinical use. In particular, the present invention provides a compound having a doubly electrophilic square planar metal center and at least one sp 3 The synthesized molecules incorporate at least three electrophilic centers, so that damage caused by nucleophilic substitution at bases located on two DNA strands (interstrand crosslinks), as well as damage caused by nucleophilic substitution at bases located on the same strand (intrastrand crosslinks), leads to severely distorted adducts where such damage is more prevalent and more difficult to repair. [Background technology]

[0002] background Cancer is one of the leading causes of death in developed countries. According to the World Health Organization (WHO), 10 million people died from malignant tumors in 2020. Similarly, approximately 20 million new cases of cancer were diagnosed in 2020; this number is expected to exceed 30 million by 2040 [Ferlay, J. et al., Global Cancer Observatory: Cancer Today, International Agency for Research on Cancer; 2020 (https: / / gco.iarc.fr / today, accessed September 10, 2021)]. Despite a 1.3% decrease in cancer mortality in recent years, tumors remain the leading cause of death in men and the second leading cause of death in women. This data clearly highlights the need to develop new, more effective therapeutic strategies in the fight against cancer.

[0003] The use of agents that damage cellular DNA (mainly radiation or genotoxic molecules) is one of the most widely used strategies in the fight against malignant tumors. This therapeutic strategy has been used with some success for several decades and continues to be important in the treatment of various cancer types. 3 Electrophilic molecules based on hybridized carbon atoms stand out among small molecules that can (at least in the first instance) form covalent adducts with DNA, thereby permanently deforming it [Larranaga, O. et al., ChemPhysChem., 2017, 18, 3390-3401] (Fig. 1A), or square-planar metal compounds incorporating platinum atoms in the oxidation state (+2) [De Cozar, A. et al., ChemPhysChem., 2016, 17, 3932-3947] (Fig. 1B). In both cases, the chemical process can result in either retention of configuration (square-planar metal electrophiles) or inversion (sp 3 Secondary nucleophilic substitution (S) involving carbon-centered electrophiles N 2) In both cases, the nucleophilic species is the DNA base guanine (G) and, to a lesser extent, adenine (A).

[0004] The first group includes nitrogen mustards [More, GS et al., Anticancer Agents Med. Chem., 2019, 19, 1080-1102], among which drugs such as chlorambucil, cyclophosphamide, ifosfamide, melphalan or bendamustine stand out.

[0005] The second group currently includes various drugs based on platinum complexes in the (+2) oxidation state, approved for clinical use in various countries [Dilruba, S. et al., Cancer Chemother. Pharmacol., 2016, 77, 1103-1124]. Cisplatin, carboplatin, and oxaliplatin are used clinically worldwide, while nedaplatin and miriplatin are used in Japan, hepatoplatin in South Korea, and lobaplatin (mixture of isomers) in China. Several prodrugs in which platinum has the (+4) oxidation state, which converts to the (+2) state in vivo, are also undergoing clinical trials [Mi, Q. et al., Int. J. Med. Phys. Clin. Eng. Rad. Oncol., 2018, 7, 231-247]. Highly successful Pt(+2) type drugs in chemotherapy [Kelland, Ll. et al., Nat. Rev. Cancer., 2007, 7, 573-584] have been selected from thousands of potential candidates [Kerpel-Fronius S., Cisplatin and its Analogues for Cancer Chemotherapy, Analogue-based Drug Discovery, Fischer J, Ganellin CR (eds.), Wiley-VCH: Weinhein., 2006, pp385-394]. Among all these compounds, cisplatin [Thomas, K. et al., Nature, 1965, 205, 698-699] (CisPt, cis-[Pt(NH3)2Cl2]) was the first metal compound of this type discovered and approved by the Food and Drug Administration (FDA) in 1978, and is an effective compound in solid tumors (e.g., ovarian, testicular, bladder, colorectal, and head and neck cancers) [Lebwohl, D. et al., Eur. J. Cancer., 1998, 34, 1522-1534]. However, CisPt has caused a series of problems, among which its nephrotoxicity, neuropathy, and ototoxicity, as well as its potential to cause nausea and vomiting, must be highlighted.Furthermore, many tumors are either inherently resistant to CisPt or may gradually develop this resistance after an initial favorable response [Galluzzi, L. et al., Oncogene, 2012, 31, 1869-1883]. Indeed, the other platinum derivatives mentioned above have been developed to at least partially alleviate these drawbacks. Publications on platinum derivatives containing aromatic monoazaheterocycles and polyazaheterocycles have also been published [Park, GY et al., Proc. Natl. Acad. Sci. USA, 2012, 109, 11987-11992; Tu, C. et al., Inorg. Chim. Acta., 2004, 357, 95-102; Fachetti, G. et al., Bioorg. Med. Chem. Lett., 2019, 29, 1257-1263].

[0006] However, most tumors develop adaptive mechanisms to repair such DNA damage (e.g., non-homologous and / or homologous recombination, base excision repair, and activation of alkyltransferases, topoisomerases, endonucleases, or exonucleases, among others), thereby conferring resistance to various Pt-derived molecules [Lebwohl, D. et al., Eur. J. Cancer., 1998, 34, 1522-1534; Galluzzi, L. et al., Oncogene, 2012, 31, 1869-1883]. Moreover, these chemotherapeutic agents are likely to bind off-target to sulfur-rich molecules and / or proteins (e.g., glutathione (GSH) in its reduced form) or to amino acids (e.g., cysteine, methionine, or metallothioneins), which inhibit their action on DNA [Moore, JK et al., Mol. Cell. Biol., 1996, 16, 2164-2173; Davis, JA et al., Transl. Cancer Res., 2013, 2, 130-143; Pegg, EA et al., Chem. Res. Toxicol., 2011, 24, 618-639; Bjoras, M. et al., Cold Spring Harb. Perspect. Biol., 2013, 5 a0125B3; Lindahl, T. et al., Science, 1999, 286, 1897-1905; Karanam, K. et al., Mol. Cell., 2012, 47, 320-329].

[0007] CisPt and related drugs act by a similar mechanism of action, causing cancer cell death by irreversible damage to nuclear DNA [Thomas, K. et al., Nature, 1965, 205, 698-699]. This process involves (i) cellular uptake by passive diffusion and active transport (e.g., via the copper transporter CTR1 or via organic cation transporters OCT1-3); (ii) intracellular activation by reaction with water molecules in the presence of low concentrations (10-20 mM) of chloride ions, e.g., cis-[Pt(NH3)2Cl(OH2)] +and cis-Pt(NH3)2(OH2)2] 2+etc.; electrophilic compounds that bind to DNA); and finally (iii) consisting of several steps or chemical reactions, including the nuclear incorporation of the DNA nitrogenous bases G and A and their interaction with the N7 nitrogen atom, preferably an interaction that forms a bond between two guanine residues [Thomson, AJ et al., Prog. Nucleic Acid Res. Mol. Biol., 1979, 22, 71-133; Lippard, SJ, Science, 1982, 218, 1075-1082]. Thus, in vitro assays [Fichtinger-Schepman, AMJ et al., Biochemistry, 1985, 24, 707-713] have shown that CisPt gives rise to 47-50% of single-strand adducts containing two adjacent G units of the cis-[Pt(NH3)2{d(GpG)}] (or cis-GG) type, along with 23-28% of intrastrand adducts incorporating two consecutive A and G units of the cis-[Pt(NH3)2{d(ApG)}] (or cis-AG) type, as well as 8-10% of intrastrand adducts formed by two Pt-G bonds separated by another X base in the form of cis-[Pt(NH3)2{d(GpXpG)}] (or cis-GXG); finally, approximately 2-3% of Cis-Pt DNA adducts consist of a bond to only one G base. In vitro studies carried out with CisPt analogues [Eastman, A., Biochemistry, 1986, 25, 3912-3915] showed similar results. Moreover, studies carried out with ex vivo samples from cancer patients [Fichtinger-Schepman, A. M. et al., Cancer Res., 1987, 47, 3000-3004] yielded similar results, with the proportions of cis-GG, cis-AG and cis-GXG being 65%, 22% and 13%, respectively.These results indicate that lesions involving two DNA strands (interstrand crosslinks) are much more difficult for cancer cells to repair [Deans, AJ et al., Nat. Rev. Cancer, 2011, 11, 467-480; McHugh, PJ et al., Lancet Oncol., 2001, 2, 483-490], and therefore account for a very low proportion of CisPt-DNA adducts (less than 5%) [Lippard, SJ, Science, 1982, 218, 1075-1082] (Figure 2A). In the case of nitrogen mustard and natural drugs (e.g., mitomycin C), this proportion is 5-10% [Gargiulo, D., Nucleic Acids Symp. Ser., 1995, 169-170].

[0008] A limited number of hybrid chemotherapeutic agents combine the features of nitrogen mustards and CisPt analogues [Chen, Y. et al., Front. Pharmacol., 2018, 9, 1453; Qin, X., Eur. J. Med. Chem., 2017, 137, 167-175]. One example is a hybrid of chlorambucil with a platinum complex in which the metal center is in the oxidation state (+4). This hybrid has shown interesting properties due to its enhanced in vitro activity relative to its two components, especially against CisPt-resistant cell lines [Qin, X., Eur. J. Med. Chem., 2017, 137, 167-175].

[0009] Similarly, in recent years, there has been increasing interest in metallodrugs that incorporate various metal centers in addition to Pt(II, IV); for example, Ti (titanocenyl dichloride, budotitanium), Cu (cassiopeins, elesclomol), Ru (NAMI-A, KP1339 / IT139), As (arsenic trioxide), Ga (KP46, Ga(III) nitrate, Ga(III) trichloride), and and Au (auranofin, gold sodium thiomalate), all of which are in various stages of clinical trials [Pena, Q. et al., Chem. Soc. Rev., 2022, 51, 2544-2582; Anthony, EJ et al., Chem. Sci., 2020, 11, 12888-12917; Mjos, KD; Orvig, C., Chem. Rev., 2014, 114, 4540-4563]. It should also be noted that these compounds with metal centers are not without problems, such as low solubility (budotitanium), low activity (NAMI-A), cardiotoxicity (cassiopain), hepatotoxicity and nephrotoxicity (titanocenyl dichloride), and poor biodistribution (Ga(III) trichloride).

[0010] Based on the foregoing, natural molecules or S-type compounds incorporating an electrophilic square planar metal center coordinated to a fused aromatic nitrogen-containing heterocycle and at least one benzyl-based electrophilic species are provided. N It should be noted that the behavior of type 2 polyelectrophilic salts as chemotherapeutic agents is unknown. Summary of the Invention [Means for solving the problem]

[0011] Brief description of the invention The present authors have proposed a method for preparing a metal complex consisting of a doubly electrophilic square planar metal center and at least one sp 3 We have developed a series of compounds whose structures are based on aromatic heterocycles that incorporate electrophilic species based on hybridized carbon centers.

[0012] The criteria to be followed when designing the compounds of the present invention are as follows: a) The presence of a metal electrophile (e.g., Pt(II)) and a chloromethyl group, along with more than two electrophilic positions S N The feasibility of these secondary nucleophilic substitution processes is shown in Figure 3, which includes a computational study of the transition state geometries, as well as activation energies; b) contain intercalating heterocycles that can interact with DNA bases by pi-stacking; c) contain a basic nitrogenous center susceptible to in vivo transport via organic cation transporters (OCTs); d) (i) in vivo tracking of the intracellular distribution of various chemotherapeutic agents; (ii) containing fluorophores that allow the diagnosis of the permeability of the analyzed (tumor or healthy) cells to these agents, matching one of the areas of emergent medical technologies identified by the European Union [European Innovation Council, Identification of emergent technologies and breakthrough innovations, EIC Working Paper 1 / 2022, DOI: 10.2826 / 06288].

[0013] Based on the experimental data provided herein, it has been observed that the compounds of the present invention significantly reduce cell viability in all of the tumor lines tested (e.g., extrahepatic and intrahepatic cholangiocarcinoma lines, ovarian cancer lines, and breast cancer lines) compared to cisplatin without affecting the viability of normal cells, thereby making these compounds potent as well as selective with respect to tumor cells.

[0014] Furthermore, these compounds have been shown to increase the rate of cell death in addition to causing greater DNA damage in these tumor lines compared to data obtained with cisplatin.

[0015] Moreover, a reduction in the volume and weight of tumors treated with the compounds of the present invention has been observed in in vivo assays compared to tumors treated with cisplatin.

[0016] Therefore, a first aspect of the present invention is a compound represented by the following formula (1): [ka] or a salt, solvate or stereoisomer thereof, In formula (1), M is a metal center selected from Pt(II), Cu(II) and Au(III), provided that when M is Au(III), formula (I) is Cl - , PF6 - , and R8C(O)O - (wherein R8 is a C1-C6 alkyl group); X1 and X2 are both chloride or together are ( - O-C(O)-C(O)-O - ), ( - OC(O)-C(R9)(R 10 )-C(O)O - ) and ( - OC(O)-CH(R 11 )O - ), in which an oxygen atom (O - ) is attached to the metal center, and R and R 10 are independently a C1-C6 alkyl group, or together with the carbon to which they are attached form a C4-C6 cycloalkyl group; R 11 is a C1-C6 alkyl group; Z1 is hydrogen or can form a single covalent bond together with Z2; Z2 is hydrogen, halogen, or can be joined to Z1 to form a single covalent bond, or can be attached to R5 to form an aryl group optionally substituted with at least one C1-C6 alkyl group, halogen, or OH; Y is N or CR 12 where R 12is H or a C1-C6 alkyl group optionally substituted at the end of the chain with a halogen, hydroxyl, or leaving functional group; R1-R4 are independently selected from H; C1-C6 alkyl groups optionally substituted at the chain ends with halogen, hydroxyl, or a leaving functional group; R5-R7 can all be H, or can be joined together in an R5-R6 pair, or R6-R7 can form a C6 aryl group optionally substituted with at least one C1-C6 alkyl group, halogen, or hydroxyl.

[0017] A second aspect of the present invention is a method for preparing a compound of formula (1) as defined above, comprising the step of: [ka] (wherein Y, Z1, Z2, and R1 to R7 have the meanings defined above). The compound was synthesized by adding gold trichloride (AuCl3), copper dichloride (CuCl2), and the compound of the following formula (3): [ka] (wherein X1 and X2 have the meanings defined above, and DMSO represents the dimethyl sulfoxide ligand). with a metal salt selected from the group consisting of platinum salts of

[0018] A further aspect of the present invention is a compound of formula (2): [ka] i.e., a precursor of the compound of formula (1), or a salt, solvate or stereoisomer thereof, In equation (2), Z1 is hydrogen or can form a single covalent bond together with Z2; Z2 is hydrogen, halogen, or can be joined to Z1 to form a single covalent bond, or can be attached to R5 to form an aryl group optionally substituted with at least one C1-C6 alkyl group, halogen, or OH; Y is N or CR 12 where R 12 is H or a C1-C6 alkyl group optionally substituted at the end of the chain with a halogen, hydroxyl, or leaving functional group; R1-R4 are independently selected from H and C1-C6 alkyl groups optionally substituted at the chain ends with halogen, hydroxyl, C(O)OMe groups, or leaving functional groups; R5-R7 can all be H, or taken together in an R5-R6 pair, or R6-R7 can form a C6 aryl group optionally substituted with at least one C1-C6 alkyl group, halogen, or hydroxyl; However, Z1=Z2=R 1 =R 2 =R 3 =R 4 =R5=R6=R 7 =H and Y=CR 12 Compounds where =CH are not included.

[0019] Another aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (1) as defined above, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient or vehicle thereof.

[0020] A further aspect of the present invention relates to a compound of general formula (1) as defined above, or a pharmaceutically acceptable salt, or stereoisomer, or solvate, or prodrug thereof, for use as a medicinal product, or a pharmaceutical composition as defined above.

[0021] A final aspect of the present invention relates to a compound of formula (1) as defined above, or a pharmaceutically acceptable salt, or stereoisomer, or solvate, or prodrug thereof, or a pharmaceutical composition as defined above, for use in the treatment of cancerous conditions, hematological and liver malignancies, proliferative diseases, autoimmune diseases, and viral infections. [Brief explanation of the drawings]

[0022] [Figure 1] SN2 reactions between DNA bases and electrophilic chemotherapeutic agents. (A) Electrophilic species based on sp3 hybridized carbon atoms (nitrogen mustards). (B) Electrophilic species based on square planar metal centers (commonly Pt(II) based; Lg and Lg' represent leaving groups). DNA bases can be G and, to a lesser extent, A. [Figure 2] Possible adducts formed by DNA and chemotherapeutic agents from (A) SN2 attack of two DNA bases or (B) SN2 attack of three or more DNA bases in a polyelectrophilic species, represented as In. Note that in case (B), adduct formation between two DNA strands is much more likely. The bases shown in the schematic are guanine (G) units, although involvement of one or two adenine units is also possible. [Figure 3] Computational simulation (theoretical level: B3LYP-D3BJ / 6-31+G*) of the SN2 reactivity of the compound of formula (1) with the guanine (G) unit. In the simulation, chloride ions or water ligands act as leaving groups at the metal center (TS1-Pt and TS2-Pt, b-path) or at the carbon atom (TS1-C and TS2-C, a-path). Lower internal energies (ΔE) and Gibbs activation energies (ΔG) (higher reactivity) correspond to reactions at Pt(II) with the water ligand as the leaving group. Bond distances are shown in Å and energies in kcal / mol. [Figure 4]AFM (atomic force microscopy) images of a DNA sample (methylated λ phage, 103 kDa, 48 kb, expressed by E. coli W3110, panel A) in the presence of compound 1o. Images were obtained after 2 minutes (B) and 10 minutes (C) of incubation. The damage caused by compound 1g is shown, particularly in panel C. [Figure 5] TEM micrographs of lyophilized DNA from methylated λ phage (Mw 31.5103 kDa, 48 kb, Sigma-Aldrich) in E. coli (host strain W3110) at (A) baseline (0.167 mg / ml), (B) after 3 minutes of incubation with compound 1g, and (C) after 10 minutes of incubation with compound 1g. The damage caused by compound 1g is shown, particularly in panel C. [Figure 6] Cell viability in the presence of CisPt or a novel panel of compounds of formula (1). Effect of CisPt (10 μM) and the novel chemical entity of formula (1) (10 μM) on the viability of CCA (EGI-1 and HUCCT1), ovarian cancer (A2780Cis), breast cancer (MDA-453 and MDA-231), and normal human cholangiocyte (NHC) cell lines after 48 hours of incubation. Statistics of results are calculated relative to the control vehicle (DMF) and CisPt. [Figure 7] Cell viability in the presence of CisPt or a novel group of compounds (1). Effect of CisPt (20 μM) and the novel chemical entity of formula (1) (20 μM) on the viability of CCA (EGI-1 and HUCCT1), ovarian cancer (A2780Cis), breast cancer (MDA-453 and MDA-231), and normal human cholangiocyte (NHC) cell lines after 48 hours of incubation. Statistics of results are calculated relative to the control vehicle (DMF) and CisPt. [Figure 8]Early cell death in the presence of CisPt or a novel group of compounds (1). Effect of CisPt (10 μM and 20 μM) and the novel chemical entity of formula (1) (10 μM and 20 μM) on early cell death (caspase-3) assessed by flow cytometry on CisPt-sensitive CCA cell lines (EGI-1 and HUCCT1) and CisPt-resistant CCA cell lines (EGI-1R), normal human cholangiocyte (NHC) cell lines, ovarian cancer (A2780Cis) cell lines, and breast cancer (MDA-453 and MDA-231) cell lines after 48 hours of incubation. Statistics of results are calculated relative to the control vehicle (DMF) and CisPt. [Figure 9] Late-stage cell death in the presence of CisPt or a novel group of compounds (1). Effects of CisPt (10 μM and 20 μM) and the novel chemical entity of formula (1) (10 μM and 20 μM) on late-stage cell death (annexin-V / TO-PRO-3) assessed by flow cytometry on CisPt-sensitive CCA cell lines (EGI-1 and HUCCT1) and CisPt-resistant CCA cell lines (EGI-1R), normal human cholangiocyte (NHC) cell lines, ovarian cancer (A2780Cis) cell lines, and breast cancer (MDA-453 and MDA-231) cell lines after 48 hours of incubation. Statistics of results are calculated relative to the control vehicle (DMF) and CisPt. [Figure 10] DNA damage assessed by comet assay in the presence of CisPt or a novel group of compounds (1). Representative images of the comet assay and quantification of DNA damage in CCA (EGI-1 and HUCCT1) cells, normal human cholangiocyte (NHC) cells, and ovarian cancer (A2780Cis) cells incubated with representative compounds (1a), (1h), (1g), and (1d) for 48 hours. For comparison, results obtained using DMF and CisPt under the same conditions are also provided. [Figure 11]Therapeutic effect of compound 1g on a subcutaneous xenograft model using CCA cells transplanted from immunodeficient mice. (A) Schematic diagram of the subcutaneous CCA model. (B) Tumor growth of CCA cells injected subcutaneously into immunodeficient mice in the presence or absence of intraperitoneal administration of compound 1g (0.5 mg / kg). (C) Images representing the tumors. (D) Tumor weight of the xenografts after sacrifice. #p<0.05 (compared to DMF control), *p<0.05 (compared to CisPt used as a reference). [Figure 12] For compound 1a (1E-5 M in N,N-dimethylformamide), spectrum (UV-vis) A for absorption, spectrum (fluorescence) B for excitation and emission, and spectrum (C) for lifetime measurement. For compound 1a (1E-5 M in DMEM / F12 basal medium), spectrum (UV-vis) D for absorption, spectrum (fluorescence) E for excitation and emission, and spectrum (F) for lifetime measurement. [Figure 13] Effects of Compounds 1a, 1d, and 1g on OCT1-, OCT3-, OATP1A2-, OATP1B3-, and OATP2B1-mediated transport were investigated. Cells with or without overexpression of influx transporters were incubated with specific fluorescent substrates in the presence or absence of typical inhibitors of the transporters (OCT1 / 3: quinine; 1A2: Rif, rifampicin; 1B3: TC, taurocholate; 2B1: Mif, mifepristone) or 10 μM of Compound 1 at 37°C for 15 minutes. Substrate content was determined by flow cytometry, and net transporter-mediated uptake was calculated. Values ​​are the mean ± SEM of four experiments in duplicate. *, p<0.05; **, p<0.01; ***, p<0.001 compared to control (one-way ANOVA + Dukey's test for multiple comparisons). [Figure 14]The effects of the compound of formula (1) on OCT1-, OCT3-, and OATP1A2-mediated transport were compared with those of cisplatin. Cells with or without overexpression of influx transporters were incubated with specific fluorescent substrates in the presence or absence of typical inhibitors of the transporters (OCT1 / 3: quinine; 1A2: Rif, rifampicin), 10 μM of the corresponding compound (1), or 10 μM of cisplatin (CDDP) at 37°C for 15 minutes. Substrate content was determined by flow cytometry, and net transporter-mediated uptake was calculated. Values ​​are the mean ± SEM of four experiments in duplicate. *, p<0.05; **, p<0.01; ***, p<0.001 compared with control (one-way ANOVA + Dukey's test for multiple comparisons). [Figure 15] Aurki-Pt16 uptake by influx transporters. Cells with or without influx transporter overexpression were incubated with 10 μM of compound (1 g) for 60 min at 37 °C. The intracellular content of the compound was determined by HPLC-MS / MS. Data are expressed as a percentage of control cells (mock). Values ​​are the mean ± SEM of at least three experiments in triplicate. *, p<0.05; **, p<0.01 compared to mock (t-Student, unpaired data). [Figure 16] Compound (1d) uptake by influx transporters. Cells with or without overexpression of influx transporters were incubated with 10 μM Aurki-Pt18 for 60 min at 37 °C. The intracellular content of the compound was determined by HPLC-MS / MS. Data are expressed as a percentage of control cells (mock). Values ​​are the mean ± SEM of at least three experiments in triplicate. *, p < 0.05; **, p < 0.01 compared to mock (t-Student, unpaired data). DETAILED DESCRIPTION OF THE INVENTION

[0023] Detailed Description of the Invention In the context of the present invention, the following terms have the meanings detailed below.

[0024] The term "C1-C6 alkyl" refers to a straight or branched hydrocarbon chain radical containing no unsaturation and attached to the rest of the molecule by a single bond, provided that the chain consists of 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, etc.

[0025] The term "aryl" refers to an aromatic ring group containing 6 to 10 carbon atoms, more preferably 6 carbon atoms. According to certain embodiments, the aryl is a phenyl group. The aryl group can be optionally substituted with one or more substituents, in particular C1-C6 alkyl, halogen, or hydroxyl.

[0026] The term "C4-C6 cycloalkyl" refers to a saturated ring group containing between 4 and 6 carbon atoms, for example, cyclobutyl, cyclopentyl, or cyclohexyl.

[0027] The terms "halogen" or halide are used interchangeably and include fluorine, chlorine, bromine, and iodine, preferably chlorine or bromine.

[0028] The term "leaving group" refers to any functional group that has leaving group properties in a second-order nucleophilic substitution reaction, such as tosylate (p-CH3(C6H4)SO3 - ), mesylate (CH3SO3 - ), or triflate (CF3SO3 - ) etc.

[0029] The term "salt" should be understood to mean any form of the compound of formula (I) according to the invention that is or is in ionic form and is paired with a counterion (cation or anion). Preferably, the salt is a pharmaceutically acceptable salt, i.e., a physiologically tolerable salt, which means that the salt is not toxic, especially as a result of the counterion, when used in a suitable manner for treatment according to the present invention (i.e., in reasonable medical doses).

[0030] Salts can be prepared by methods known in the art. Generally, the salts are prepared by reacting the free base form of the compound of the present invention with a suitable base or acid in water, or in an organic solvent, or in a mixture of both. Non-aqueous media, such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, are generally preferred.

[0031] The term "solvate" according to the present invention should be understood to mean any compound of formula (I) according to the present invention that is non-covalently bound to another molecule (usually a polar solvent), and particularly includes hydrates and alcoholates (e.g., methanolates, etc.). Preferred solvates are hydrates. Preferably, the solvate is a pharmaceutically acceptable solvate, i.e., a physiologically tolerable solvate, which means that when used in a suitable manner for treatment according to the present invention (i.e., in a reasonable medical dose), the solvate is not toxic, especially as a result of the solvate molecule.

[0032] As used herein, the term "stereoisomer" refers to an enantiomer, diastereomer, or mixture thereof (e.g., racemate, etc.) of a compound of formula (I) according to the present invention. Likewise, this term also encompasses geometric isomers about any double bond present in the compound of formula (I), i.e., isomer (E) and isomer (Z) (trans isomer and cis isomer). Furthermore, this term also encompasses rotational isomers of the compound of formula (I).

[0033] Any compound of formula (I) according to the present invention may exist in different tautomeric forms. Specifically, the term "tautomer" refers to one of two or more structural isomers of a compound of formula (I) that exist in equilibrium and are readily converted into one isomeric form with respect to the other.

[0034] The term "prodrug" refers to a derivative of a compound of formula (I) that is converted in vivo, for example by enzymatic hydrolysis, to a compound of formula (I).

[0035] As stated above, a first aspect of the present invention relates to a compound of formula (1), or a salt, solvate or stereoisomer thereof:

[0036] In certain embodiments, in the compound of formula (1), M is Pt(II).

[0037] In another particular embodiment, in the compound of formula (1), X1 and X2 are both chloride or together represent: - O-C(O)-C(O)-O - ) and ( - OC(O)-C(R9)(R 10 )-C(O)O - ), in which an oxygen atom (O - ) is bonded to the metal center, and R9 and R 10 together with the carbon to which they are attached form a C4-C6 cycloalkyl group.

[0038] In another particular embodiment, in the compound of formula (1), Y is N or CR 12 where R 12 is H or a C1 to C6 alkyl group. Preferably, Y is N or -CH-, more preferably Y is -CH-.

[0039] In preferred embodiments of the compounds of formula (1), Z1 is hydrogen or can be taken together with Z2 to form a single covalent bond.

[0040] In another preferred embodiment of the compound of formula (1), Z2 is hydrogen, halogen, or can form a single covalent bond together with Z1, or can be attached to R5 to form a C6 aryl group. When Z2 is halogen, the halogen is preferably chloride or bromide, more preferably bromide.

[0041] In another particular embodiment, in the compound of formula (1), R1 is a C1-C6 alkyl group substituted at the end of the chain by a halogen or by a leaving functional group. Preferably, R1 is a methyl group substituted at the end of the chain by a halogen, more preferably by chloride.

[0042] In another particular embodiment, in the compound of formula (1), R2 to R4 are independently H or a C1 to C6 alkyl group, preferably H or an alkyl group, and more preferably all H.

[0043] In another specific embodiment, in the compound of formula (1), R5 to R7 can all be H, or can be joined together in an R5 to R6 pair, or R6 to R7 can form a C6 aryl group.

[0044] Preferred compounds of formula (1) are selected from: [ka] or a salt, solvate or stereoisomer thereof.

[0045] A further aspect of the present invention relates to a process for preparing a compound of formula (1), comprising reacting a compound of formula (2) as defined above with a metal salt selected from gold trichloride (AuCl), copper dichloride (CuCl), and a platinum salt of formula (3), also as defined above.

[0046] The reaction allows the incorporation of a square planar electrophilic metal center and its coordination to the corresponding nitrogen-containing heterocycle of formula (2).

[0047] Preferably, the reaction is carried out in an organic solvent (such as an alcohol, preferably methanol or ethanol) or in acetonitrile.

[0048] In a preferred embodiment, when the metal in the compound of formula (1) is Pt(II) and both X and X are chloride, the compound of formula (3) used in this reaction is the platinum salt Pt(DMSO)Cl. Said salt can be obtained from KPtCl by previously described methodology [Bar-Nahum, I. et al., J. Am. Chem. Soc., 2004, 126, 10236-10237]. Preferably, in this particular embodiment, the organic solvent used in the reaction between the compound of formula (2) and the metal salt is methanol or ethanol, more preferably methanol.

[0049] In another preferred embodiment, when the metal in the compound of formula (1) is Cu(II) and both X1 and X2 are chloride, the compound of formula (3) used in this reaction is the copper salt CuCl2. In this preferred embodiment, the organic solvent used in the reaction between the compound of formula (2) and the metal salt is preferably ethanol.

[0050] In another preferred embodiment, when the metal in the compound of formula (1) is Au(III) and both X1 and X2 are chloride, the compound of formula (3) used in this reaction is the gold salt AuCl3. In this preferred embodiment, the organic solvent used in the reaction between the compound of formula (2) and the metal salt is preferably acetonitrile.

[0051] In particular, as shown above, in the compound of formula (1), when the metal is Au(III), the compound may be Cl - , PF6 - , and R8C(O)O - where R8 is a C1-C6 alkyl group. To that end, in the process of preparing said compound of formula (1), in addition to reacting the corresponding compound of formula (2) with a gold salt in an organic solvent, a compound providing the corresponding anion (e.g., AgCl, AgPF6, and CH3C(O)Ag, respectively) must be added to the reaction mixture.

[0052] In certain embodiments, in the compound of formula (1), X1 and X2 together represent: - O-C(O)-C(O)-O - The reaction of the present invention is based on the reaction of the compound cis-[PtCl2(DMSO)2] with a salt (such as silver nitrate) that allows the elimination of chloride ions, followed by a reaction with oxalic acid to form the complex [Pt(OC(O)-C(O)-O - In this preferred embodiment, the organic solvent used in the reaction between the compound of formula (2) and the complex is preferably methanol.

[0053] In another particular embodiment, in the compound of formula (1), X1 and X2 together represent: - OC(O)-C(R9)(R 10 )-C(O)O - ) group or ( -OC(O)-CH(R 11 )O - ) group, the reaction of the present invention is - OC(O)-C(R9)(R 10 )-C(O)-O - ) / (DMSO)2] or [Pt( - OC(O)-CH(R 11 )-O - ) / (DMSO)2] was converted to the corresponding dicarboxylic acid HO-C(O)-C(R9) (R 10 )-C(O)-OH or α-hydroxycarboxylic acid HO-C(O)-CH(R 11 )OH, respectively. In this preferred embodiment, the organic solvent used in the reaction between the compound of formula (2) and the corresponding complex is preferably methanol.

[0054] In certain embodiments, the method of the present invention further comprises reacting a compound of formula (2) with a compound of formula (4): [ka] During the ceremony, Y is N;CR 12 where R 12 is H, or a C1-C6 alkyl group optionally substituted at the chain end by halogen or hydroxyl; a leaving functional group; or C(O)OMe; R1-R4 are independently selected from H; a C1-C6 alkyl group optionally substituted at the chain end with halogen or hydroxyl; a leaving functional group; and a C(O)OMe group. and a compound of the following formula (5): [ka] (In the formula, R5 to R7 have the meanings defined in claim 1; A is H, halogen, trifluoromethylsulfonyl, or trialkylsilyl, or is attached to R5 to form an optionally substituted aryl group; B is a halogen, a trifluoromethylsulfonyl group, or a trialkylsilyl group; However, when A is a trifluoromethylsulfonyl group, B is a trialkylsilyl group, or conversely, when A is a trialkylsilyl group, B is a trifluoromethylsulfonyl group. The present invention includes a prior step of preparing the compound by a method comprising a coupling reaction or cycloaddition reaction between the compound of formula (I) and the compound of formula (II).

[0055] In certain embodiments, R1-R4 are independently selected from H; a methyl group optionally substituted with a halogen (preferably chlorine) or a hydroxyl; and a C(O)OMe group.

[0056] In another preferred embodiment, Y is N; CR 12 where R 12 is H or a methyl group optionally substituted by halogen or hydroxyl; or C(O)OMe.

[0057] In another particular embodiment, in the compound of formula (2), Z1 and Z2 together form a single covalent bond, and the compound of formula (5) has a trifluoromethylsulfonyl group as substituent A and a trialkylsilyl group as substituent B, or conversely, a trialkylsilyl group as substituent A and a trifluoromethylsulfonyl group as substituent B.

[0058] In certain of these embodiments, the cycloaddition (8+2) occurs based on 2-(pyridin-2-yl)imidazo[1,2-a]pyridine (a compound of formula (2)) in the presence of a suitable additive (e.g., 18-corona-6) that preferably incorporates the cation Cs(+), as detailed in Method E of the Examples herein.

[0059] In another particular embodiment, when in the compound of formula (2), Z1 is hydrogen and Z2 is hydrogen, halogen, or is bonded to R5 to form an optionally substituted aryl group, the compound of formula (5) has as substituent A hydrogen, halogen, or is bonded to R5 to form an aryl group and as substituent B halogen.

[0060] In another particular embodiment, once the compound of formula (2) is formed, the method may further comprise, when any of R, R, R, or R is a C(O)OMe ester group, replacing said ester with a methyl group substituted by a halogen or hydroxyl, or with a leaving functional group.

[0061] For example, the ester group can be reduced to the corresponding alcohol (methyl group replaced by a hydroxyl group) in the presence of a reducing agent (e.g., lithium aluminum hydride (LiAlH4)), as detailed in Method C in the Examples herein.

[0062] The alcohol obtained according to the preceding paragraph can then be chlorinated in the presence of a chlorinating agent (such as thionyl chloride (SOCl)) as described in Method D of the Examples herein.

[0063] In another particular embodiment, the method of the present invention further comprises reacting a compound of formula (4) with a compound of formula (6): [ka] wherein R1 and R2 are independently selected from H; a C1-C6 alkyl group optionally substituted at the chain end with a halogen or hydroxyl; a leaving functional group; and a C(O)OMe group. and a compound of the following formula (7): [ka] (In the formula, Y is N;CR 12 where R12 is H; a C1-C6 alkyl group optionally substituted at the chain end by halogen or hydroxyl; a leaving functional group; or C(O)OMe; R3 and R4 are independently selected from H; a C1-C6 alkyl group optionally substituted at the chain end with halogen or hydroxyl; a leaving functional group; and a C(O)OMe group; L is a halogen, a methylsulfonyl group, or a p-toluenesulfonyl group. or its hydrobromide salt.

[0064] Said step can be carried out, for example, as described in Method B of the Examples herein.

[0065] In certain embodiments, in the compound of formula (4), R1-R2 are independently selected from H; a C1-C6 alkyl group substituted by a halogen group or a hydroxyl; and a C(O)OMe group.

[0066] In certain embodiments, in the compound of formula (4), R3-R4 are independently selected from H and a methyl group.

[0067] In certain embodiments, in the compound of formula (4), Y is selected from N and CR 12 (In the formula, R 12 is selected from H, a methyl group substituted by a hydroxyl group or a halogen; or a C(O)OMe group.

[0068] In a particular embodiment of the process for obtaining a compound of formula (4), in the compound of formula (6), R1 and R2 are independently selected from H and a C(O)OMe group.

[0069] In another specific embodiment of the process for obtaining a compound of formula (4), in the compound of formula (7), R3 and R4 are independently selected from H; and a C1-C6 alkyl group (preferably methyl).

[0070] In a preferred embodiment of the process for obtaining the compound of formula (4), in the compound of formula (7), Y is N or CR 12 where R 12 is H or C(O)OMe.

[0071] In another preferred embodiment, L is a halogen, preferably Br.

[0072] In certain embodiments, once the compound of formula (4) is formed, the method further comprises: 12 When either is a C(O)OMe ester group, it may include substitution of said ester by a methyl group which is replaced by a halogen or hydroxyl, or by a leaving functionality.

[0073] For example, the ester group can be reduced to the corresponding alcohol (methyl group replaced by a hydroxyl group) in the presence of a reducing agent (e.g., lithium aluminum hydride (LiAlH4)), as detailed in Method C in the Examples herein.

[0074] The alcohol obtained according to the preceding paragraph can then be chlorinated in the presence of a chlorinating agent (such as thionyl chloride (SOCl)) as described in Method D of the Examples herein.

[0075] Compounds of formula (7) can be obtained from methyl 2-acetylisonicotinate, from the corresponding 1-(pyridin-2-yl)ethan-1-one, or from 1-(pyrazin-2-yl)ethan-1-one, respectively, depending on whether Y is C-COMe, C-CH, or N. These methods are described, for example, in J. Med. Chem. 2016, 59, 1388-1409 or Med. Chem. Lett., 2007, 17, 4374-4377.

[0076] A further aspect of the present invention is a compound of formula (2): [ka] or a salt, solvate or stereoisomer thereof, In equation (2), Z1 is hydrogen or can form a single covalent bond together with Z2; Z2 is hydrogen, halogen, or can be joined to Z1 to form a single covalent bond, or can be attached to R5 to form an aryl group optionally substituted with at least one C1-C6 alkyl group, halogen, or OH; Y is N or CR 12 where R 12 is H; a C1-C6 alkyl group optionally substituted at the chain end by halogen or hydroxyl; a C(O)OMe group; or a leaving functional group; R1-R4 are independently selected from H; a C1-C6 alkyl group optionally substituted at the chain end with halogen or hydroxyl; a C(O)OMe group; and a leaving functional group; R5-R7 can all be H, or taken together in an R5-R6 pair, or R6-R7 can form a C6 aryl group optionally substituted with at least one C1-C6 alkyl group, halogen, or hydroxyl; However, Z1=Z2=R 1 =R 2 =R 3 =R 4 =R5=R6=R 7 =H and Y=CR 12 Compounds where =CH are not included.

[0077] In certain embodiments, in compounds of formula (2), Z 1 is hydrogen or together with Z 2 forms a single covalent bond.

[0078] In certain embodiments, in compounds of formula (2), Z2 is hydrogen, halogen, or can be bonded to R5 to form a C6 aryl group, or together with Z1 form a single covalent bond.

[0079] In another particular embodiment, in the compound of formula (2), R1 is a C1-C6 alkyl group (preferably methyl) optionally substituted with hydroxyl or halogen; or a C(O)OMe group.

[0080] In another particular embodiment, in the compound of formula (2), R2 is H.

[0081] In another particular embodiment, in the compound of formula (2), R3 and R4 are independently H or a methyl group.

[0082] In another particular embodiment, in the compound of formula (2), R5 to R7 are H, or are joined together in an R5 to R6 pair, or R6 to R7 form a C6 aryl group.

[0083] Preferably, the compound of formula (2) is selected from: [ka] or a salt, solvate or stereoisomer thereof.

[0084] A further aspect of the present invention relates to a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and at least one pharmaceutically acceptable excipient thereof.

[0085] The term "excipient" refers to an ingredient of a pharmaceutical product other than the active ingredient (as defined by the European Medicines Agency (EMA)). Excipients preferably include "carriers, adjuvants, and / or vehicles." Carriers are forms into which substances are incorporated to improve drug administration and efficacy. Various drug carriers are used in drug delivery systems, e.g., in controlled-release technologies, to prolong the drug's action in vivo, reduce its metabolism, or reduce its toxicity. Carriers are also used to increase drug administration efficacy at the pharmacological site of action. Adjuvants are substances added to the formulation of a medicinal product that affect the action of the active ingredient in a predictable manner. Vehicles are excipients or substances, preferably without therapeutic activity, used as a means to provide a volume for administration of a medicinal product (Stedman's Medical Spellchecker (Copyright), 2006, Lippincott Williams & Wilkins). The pharmaceutical carrier, adjuvant, and / or vehicle can be a sterile liquid, such as water and various oils, including those of petroleum, animal, vegetable, or synthetic origin (e.g., peanut oil, soybean oil, mineral oil, sesame oil, and the like). Suitable pharmaceutical carriers are described in EW Martin's "Remington's Pharmaceutical Sciences." The choice of these excipients and the amounts to be used will depend on the application form of the pharmaceutical composition.

[0086] The pharmaceutical compositions according to the invention may be in any form suitable for administration in humans and / or animals, preferably in humans, including infants, children and adults, and may be prepared by conventional methods known by those skilled in the art, for example by methods described or mentioned in the Spanish Pharmacopoeia and the United States Pharmacopoeia and similar reference texts.

[0087] The pharmaceutical compositions of the present invention can be provided in any form that is suitable for drug administration (e.g., intraperitoneal, intramuscular, intraarticular, intravenous, intraarterial, intravesical, intraosseous, intracavity, pulmonary, buccal, sublingual, ophthalmic, intravitreal, intranasal, transdermal, rectal, vaginal, oral, epidural, intrathecal, intraventricular, intracerebral, intraventricular, intracisternal, intraspinal, perispinal, intracranial, or topical, etc.).

[0088] Pharmaceutical forms suitable for oral administration can be tablets and capsules, and can contain conventional excipients known in the art, such as binders (e.g., molasses, gum arabic, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone), fillers (e.g., lactose, sugar, corn starch, calcium phosphate, sorbitol, or glycine), tableting lubricants (e.g., magnesium stearate), disintegrants (e.g., starch, polyvinylpyrrolidone, sodium starch glycolate, or microcrystalline cellulose), or pharmaceutically acceptable wetting agents (e.g., sodium lauryl sulfate, etc.). Pharmaceutical forms suitable for parenteral administration can be sterile solutions, suspensions, or lyophilized preparations. Suitable excipients, such as fillers, buffers, or surfactants, can be used.

[0089] The compounds of the present invention can be used with at least one other drug to provide combination therapy, which can be part of the same composition or can be provided as separate compositions for administration at the same time or at different times.

[0090] In a further aspect, the present invention also relates to a compound of general formula (I) as defined above, or a pharmaceutically acceptable salt or stereoisomer or solvate or prodrug thereof, for use as a medicinal product, or a pharmaceutical composition as defined above.

[0091] Another aspect of the present invention relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or stereoisomer or solvate or prodrug thereof, or a pharmaceutical composition as defined in the claims, for use in the treatment of a disease selected from a proliferative disease, an autoimmune disease, and a viral infection.

[0092] In a preferred embodiment, the compounds according to the invention are suitable for the prevention and treatment of proliferative diseases or disorders.

[0093] A "proliferative disease or disorder" refers to the abnormal growth or expansion of cells as a result of mitotic proliferation. Proliferative diseases may be accompanied by 1) pathological proliferation of normal quiescent cells, 2) pathological migration of cells from their normal location (e.g., metastasis of cancer cells), 3) pathological expression of proteolytic enzymes such as matrix metalloproteinases (e.g., collagenase, gelatinase, and elastase), or 4) pathological angiogenesis, such as in proliferative retinopathies and tumor metastasis. Examples of proliferative diseases include cancer (i.e., "malignant neoplasms"), benign neoplasms, angiogenesis, and inflammatory diseases.

[0094] In certain embodiments, the proliferative disease is cancer.

[0095] The term "cancer" refers to a class of diseases characterized by the development of abnormal cells that grow in an abnormal manner and have the ability to invade and destroy normal tissues of the body. Examples of cancer include solid tumors and hematological tumors, among others.

[0096] Solid tumors that can be treated according to the present invention include, for example, breast tumors, respiratory tract tumors, brain tumors, reproductive organ tumors, gastrointestinal tumors, urogenital tract tumors, eye tumors, liver tumors, skin tumors, head and neck tumors, thyroid tumors, parathyroid tumors, bone tumors, connective tissue tumors, and metastases of these tumors. In certain embodiments, the solid tumor to be treated is a breast tumor, a reproductive organ tumor, or a liver tumor.

[0097] Liver tumors that can be treated are, for example, hepatocellular carcinoma and cholangiocarcinoma.

[0098] Hematological tumors that can be treated are, for example, multiple bone tumors, lymphoma, or leukemia.

[0099] In a preferred embodiment, the cancer to be treated is selected from intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, ovarian cancer, and breast cancer.

[0100] More specifically, the cancer or cancerous condition is produced in the A2780Cis ovarian cancer cell line, the MDA-453 and MDA-231 breast cancer cell lines, or the EGI-1 extrahepatic cholangiocarcinoma and HUCCT1 intrahepatic cholangiocarcinoma cell lines.

[0101] More particularly, the cancer to be treated is ovarian or breast cancer.

[0102] More specifically, the cancer or cancerous condition is produced in the A2780Cis ovarian cancer cell line, or in the MDA-453 and MDA-231 breast cancer cell lines.

[0103] More specifically, the cancer or cancerous condition to be treated has developed resistance to other anticancer drugs as a result of previous chemotherapy cycles, such as cisplatin, carboplatin, oxaliplatin, nedaplatin, miriplatin, and lobaplatin. More preferably, the cancer or cancerous condition to be treated has developed resistance to cisplatin as a result of previous chemotherapy cycles with this compound.

[0104] Autoimmune diseases include, among others, autoimmune diseases of the eye (e.g., autoimmune uveitis); autoimmune diseases of the blood (e.g., autoimmune hemolytic anemia, pernicious anemia, and autoimmune thrombocytopenia); autoimmune diseases of the central and peripheral nervous system (e.g., multiple sclerosis, myasthenia gravis, Eaton-Lambert myasthenic syndrome); autoimmune neuropathies (e.g., Guillain-Barré); autoimmune diseases of the vascular system (e.g., antiphospholipid syndrome, vasculitis, temporal arteritis, Behcet's disease); autoimmune diseases of the skin (e.g., dermatitis herpetiformis, pemphigus vulgaris, bullous pemphigoid, alopecia areata, psoriasis, and autoimmune diseases of the gastrointestinal tract (e.g., Crohn's disease, ulcerative colitis, celiac disease, primary biliary cirrhosis, and autoimmune hepatitis); autoimmune diseases of the adrenal glands (e.g., Addison's disease); and multisystem autoimmune diseases including diseases of the musculoskeletal system and connective tissue (e.g., systemic lupus erythematosus, scleroderma, rheumatoid arthritis, polymyositis, dermatomyositis, etc.); autoimmune diseases of the endocrine glands (e.g., type 1 diabetes, autoimmune thyroiditis, Graves' disease, Hashimoto's thyroiditis, autoimmune oophoritis and orchitis, etc.), autoimmune-mediated glomerulonephritis, inflammatory bowel disease, and type 1 autoimmune diabetes.

[0105] Viral infections or disorders include infections caused by papillomavirus, herpesvirus, influenza virus, Epstein-Barr virus, hepatitis B or C virus, and human immunodeficiency virus, among others.

[0106] Also described in the present invention is a method for the treatment of a disease selected from a proliferative disease, an autoimmune disease, and a viral infection, comprising administering to a patient in need thereof a compound of formula (I), or a stereoisomer, or a salt, solvate, or prodrug thereof.

[0107] The term "treatment" or "treating" in the context of this specification means administering a compound or pharmaceutical composition according to the invention to prevent, ameliorate, or eliminate a disease or one or more symptoms associated with said disease. "Treatment" also encompasses preventing, ameliorating, or eliminating the physiological sequelae of a disease.

[0108] The present invention also describes the use of a compound of formula (I), or a stereoisomer, or a salt, solvate, or prodrug thereof, for the manufacture of a medicinal product intended for the treatment of a disease selected from a proliferative disease, an autoimmune disease, and a viral infection. [Example]

[0109] Chemical synthesis of the compound of formula (1) and its precursors (2), (4) and (7) The following Methods A through G describe methods for obtaining the compounds described in this invention. These methods are presented as examples that can be modified by changes in the substituents according to the variables described above, as well as changes in the solvents, catalysts, treatments, and temperatures used.

[0110] Likewise, it should be noted that the decimal notation used in the examples below is based on the English language, where dots are used instead of commas.

[0111] Method A: Method A describes the preparation of platinum complexes of general formula (1) by the reaction of various 2,2'-bipyridine derivatives or 2-(pyridin-2-yl)imidazo[1,2-a]pyridine derivatives of general formula (2) with the Pt(DMSO)Cl catalyst (3a), obtained from KPtCl by previously described methodology [Bar-Nahum, I. et al., J. Am. Chem. Soc., 2004, 126, 10236-10237]. After dissolving both reagents in methanol (MeOH), the resulting mixture is left stirring at room temperature for 16 hours. Upon completion of the reaction, the mixture is placed in an ultrasonic bath for 2 hours for subsequent purification by washing with ethanol (EtOH) and ethyl ether (EtO). The final product (yellow solid) is purified by vacuum filtration.

[0112] Method B: Method B describes a method for preparing 2-(pyridin-2-yl)imidazo[1,2-a]pyridine derivatives of formula (4). The corresponding 2-bromoacetylpyridinium (7) and 2-aminopyridine (6) are dissolved in ethanol with sodium bicarbonate and refluxed for 16 hours. When the reaction is complete, the solvent is removed under vacuum. After adding water, the product is extracted with dichloromethane. The organic phase is dried over magnesium sulfate, and the solvent is evaporated again. Finally, the resulting mixture is purified by silica gel column chromatography using a 1:2 (v / v) ethyl acetate:n-hexane mixture as the mobile phase.

[0113] Method C: Method C describes a method for reducing the methyl ester of general formula (4a), the methyl ester of general formula (4d), the methyl ester of general formula (4g), and the methyl ester of general formula (2a) to the corresponding alcohols (4b), (4e), (4h), and (2b), respectively. Various 2-(pyridin-2-yl)imidazo[1,2-a]pyridine derivatives containing methyl ester-type substituents are dissolved in dry tetrahydrofuran (THF). The solution is introduced into an ice bath for the slow addition of 1 M lithium aluminum hydride (LiAlH) solution. The reaction mixture is stirred with saturated sodium bicarbonate solution at room temperature for 2 hours, followed by cooling in an ice bath. After separating the organic phase and evaporating the tetrahydrofuran, the resulting residue is redissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The organic phase is dried over magnesium sulfate, and the solvent is evaporated again. The resulting mixture is purified by silica gel column chromatography using a 1:10 (v / v) mixture of methanol:dichloromethane as the mobile phase [Selwood, DL et al., J. Med. Chem., 2001, 44, 78-93].

[0114] Method D: Method D describes the chlorination of alcohols (4b), (4e), (4h), and (2b) to obtain the corresponding methyl chlorides (4c), (4f), (4i), and (2c). Thionyl chloride is added dropwise to a solution of these different alcohols in dichloromethane in an ice bath. The mixture is heated under reflux with dichloromethane for 90 minutes. The mixture is then neutralized with saturated sodium bicarbonate solution and extracted with dichloromethane. Finally, the resulting oil is purified by silica gel column chromatography using a 1:1 (v / v) ethyl acetate:n-hexane mixture as the mobile phase [Abdelfattah, MAO et al., Bioorg. Med. Chem. Lett., 2013, 23, 5077-5081].

[0115] Method E: Method E describes a method for cycloaddition (8 + 2) based on 2-(pyridin-2-yl)imidazo[1,2-a]pyridines. The selected heterocycle, various 2-(trimethylsilyl)aryltrifluoromethanesulfonate benzyne precursors, 18-corona-6, and cesium fluoride are mixed in a microwave vial, and the resulting mixture is heated in a sealed vial at 180 °C for 15 min with 250 W and 100 psi reactor power and pressure limits. Upon completion of the reaction, the resulting mixture is dissolved in dichloromethane, filtered, and the solvent is evaporated under vacuum. The final product is purified by silica gel column chromatography using a 1:2 (v / v) ethyl acetate:n-hexane mixture as the mobile phase [Aginagalde, M. et al., J. Org. Chem., 2010, 75, 2776-2784].

[0116] Method G: Method G describes a method for arylation of methyl 2-(pyridin-2-yl)imidazo[1,2-a]pyridines at the C3 position. In a sealed microwave vial, the corresponding imidazo[1,2-a]pyridine, potassium carbonate, and Pd(PPh3)4 are mixed in N,N-dimethylformamide under argon. The selected aryl bromide is then added, and the reaction mixture is heated at 160 °C for 16 h. Upon completion of the reaction, the solvent is evaporated, and the organic reaction product is redissolved in dichloromethane and subsequently filtered. The filtrate is evaporated, and the final product is purified using silica gel column chromatography with ethyl acetate as the eluent.

[0117] Several examples for the synthesis of Compounds (1), (2), (4), and (7) are detailed below. These examples are for illustrative purposes and do not limit the structural possibilities of the corresponding heterocyclic families.

[0118] Example 1. Synthesis of methyl 2-(2-bromoacetyl)isonicotinate (7a) [ka] A reaction mixture containing methyl 2-acetylisonicotinate (8 g, 44.64 mmol) and acetic acid (56 mL) is cooled, and to this solution, a suitable amount of 48% aqueous HBr solution (44.64 mmol) is added in an ice bath. Finally, Br2 (8.16 g, 51.04 mmol) is added. The resulting mixture is stirred under an argon atmosphere at room temperature for 1 hour and then at 75 °C for an additional 1.5 hours. After this, the reaction mixture is left to cool at room temperature, diluted with THF (90 mL), and the resulting reaction mixture is left stirring for 16 hours. When the reaction is complete, the resulting solution is diluted with ethyl acetate (AcOEt) and washed successively with NaHCO3 (saturated solution) and H2O. The resulting organic phase is dried over MgSO4, filtered, and the solvent is removed under reduced pressure. Finally, the product 7a is obtained after purification by silica gel column chromatography using a 1:8 (v / v) ethyl acetate:n-hexane mixture as the eluent [Bavetsias, V. et al., J. Med. Chem., 2016, 59, 1388-1409]. Methyl 2-(2-bromoacetyl)isonicotinate (7a). Red oil. Yield: 33%. 1 H NMR (400MHz, CDCl3) δ8.84(dd, J=0.7, 5.0Hz, 1H), 8.59(dd, J=0.9, 1.7Hz, 1H), 8.07(dd, J=1.7, 5.0Hz, 1H), 4.84(s, 2H), 4.00(s, 3H).

[0119] Example 2. Synthesis of 2-bromo-1-(6-methylpyridin-2-yl)ethan-1-one hydrobromide (7b) [ka] 1-(6-Methylpyridin-2-yl)ethan-1-one (2.5 g, 18.5 mmol) is dissolved in a HBr (48%) / acetic acid mixture (1.3 / 2 mL) in an ice bath, and Br2 (0.948 mL, 18.5 mmol) is added. The mixture is left stirring at room temperature for 1 hour. Toluene is added, and the resulting solution is evaporated to give a yellow-orange solid, which is used in the next step without further purification. Yield: 75%.

[0120] Example 3. Synthesis of 2-bromo-1(pyrazin-2-yl)ethan-1-one hydrobromide (7c) [ka] 1-(Pyrazin-2-yl)ethan-1-one (4.0 g, 32.76 mmol) is dissolved in a HBr (48%) / acetic acid mixture (3.7 / 40 mL) in an ice bath, and Br2 (1.68 mL, 32.76 mmol) is added. The mixture is left stirring at 60 °C for 2 hours. Toluene is added, and the mixture is evaporated to give product (7c) as a black solid, which is used in the next step without further purification. Keith, JM; Gomez, LA; Barbier, AJ; Wilson, SJ; Boggs, JD; Lord, B.; Mazur, C.; Alisio, L.; Lovenberg, TW; Curruthers, NI, Bioorg. Med. Chem. Lett., 2007, 17, 4374-4377. Black solid. Yield: 55%.

[0121] Example 4. Synthesis of methyl 2-(2-(imidazo[1,2-a]pyridin-2-yl)pyridin-4-yl)acetate (4a) [ka] The procedure described as Method B was followed. Compound 7a (1.6 g, 6.20 mmol), 2-aminopyridine (729.4 mg, 7.75 mmol), and NaHCO3 (812.4 mg, 9.67 mmol) were dissolved in EtOH (25 mL). The reaction mixture was refluxed with EtOH for 16 hours. After cooling to room temperature, the resulting reaction mixture was filtered and the resulting solid was dried to give 4a as a brown solid. Yield: 72%; mp: 158-159 °C; IR 1721, 1604, 1355, 1297, 1115, 754 cm -1 ; 1H NMR (400MHz, CDCl3) δ8.79(dd, J=5.0, 0.9Hz, 1H), 8.73(s, 1H), 8.30(s, 1H), 8.19(dt, J=6.9, 1.2Hz, 1H), 7.80(dd, J=5. 0, 1.7Hz, 1H), 7.70(dt, J=9.1, 1.0Hz, 1H), 7.24(ddd, J=9.1, 6.7, 1.3Hz, 1H), 6.85(td, J=6.8, 1.2Hz, 1H), 4.00(s, 3H); 13 C NMR (101MHz, CDCl3) δ156.78, 155.69, 149.83, 149.34, 147.07, 137.20, 124.19, 123.08, 121.43, 120.44, 44.49;HRMS(ESI), C 14 H 11 Calculated for N3O2, [M+H] + :254.0851, actual value:254.0929.

[0122] Example 5. Synthesis of 2-(imidazo[1,2-a]pyridin-2-yl)pyridin-4-yl)methanol (4b) [ka] Following the procedure described as Method C, starting from derivative 4a (405.2 mg, 1.60 mmol), LiAlH (1 M) (3.68 mmol) and THF (20 mL), the title product was obtained as a white solid. Yield: 52%; mp: 196-197 °C; IR 3139, 2884, 1607, 1364, 1043, 826, 762 cm -1 ; 1 H NMR (400MHz, CDCl3) δ8.61(d, J=5.0Hz, 1H), 8.29(s, 1H), 8.24~8.15(m, 2H), 7.67(dd, J=9.1, 1.1 Hz, 1H), 7.39(m, 1H), 7.24(ddd, J=9.1, 6.7, 1.3Hz, 1H), 6.85(td, J=6.7, 1.2Hz, 1H), 4.85(s, 2H); 13C NMR (101MHz, CDCl3) δ152.82, 151.19, 149.49, 145.57, 145.41, 126.03, 125.18, 120.16, 117.90, 117.68, 112.86, 111.03, 63.49;HRMS(ESI), C 13 H 11 Calculated for NO, [M+H] + :226.0902, Actual value:226.0978.

[0123] Example 6. Synthesis of 2-(4-(chloromethyl)pyridin-2-yl)imidazo[1,2-a]pyridine (4c) [ka] Following the procedure described as Method D, starting from compound 4b (180.2 mg, 0.8 mmol), SOCl (190.4 mg, 1.6 mmol), and dichloromethane (10 mL), the title product was obtained as a light brown solid. Yield: 82%; mp: 129-130 °C; IR 3239, 2970, 1738, 1366, 1216, 1091, 677 cm -1 ; 1 H NMR (400MHz, CDCl3) δ8.65(d, J=5.0Hz, 1H), 8.30(s, 1H), 8.25(d, J=1.7Hz, 1H), 8.19(dt, J=6.8, 1.2Hz, 1H), 7 .69(d, J=9.1Hz, 1H), 7.32(dd, J=5.1, 1.7Hz, 1H), 7.26~7.20(m, 1H), 6.86(td, J=6.8, 1.1Hz, 1H), 4.65(s, 2H); 13 C NMR (101MHz, CDCl3) δ153.34, 149.90, 146.81, 145.60, 144.98, 126.06, 125.29, 121.87, 119.69, 117.81, 112.96, 111.19, 44.23;HRMS(ESI), C 13 H 10 Calculated for ClN3, [M+H] + :244.0563, actual value:244.0641.

[0124] Example 7. Synthesis of methyl 2-(pyridin-2-yl)imidazo[1,2-a]pyridine-7-carboxylate (4d) [ka] Following the procedure described as Method B, starting with 2-(bromoacetyl)pyridine hydrobromide (1.74 g, 6.20 mmol), methyl 2-aminoisonicotinate (1.18 g, 7.75 mmol), and NaHCO3 (812.4 mg, 9.67 mmol) dissolved in EtOH (25 mL), the reaction mixture was kept under reflux with EtOH for 16 hours. Upon cooling to room temperature, the reaction mixture was filtered and the resulting solid was dried. The title product was obtained as a reddish-white solid. Yield: 74%; mp: 225-226 °C; IR 1715, 1593, 1327, 1228, 1117, 761, 740 cm -1 ; 1 H NMR (400MHz, CDCl3) δ8.65(dd, J=4.8, 0.9Hz, 1H), 8.40(s, 1H), 8.37(s, 1H), 8.26~8.19(m, 2 H), 7.83(td, J=7.7, 1.8Hz, 1H), 7.43(dd, J=7.1, 1.7Hz, 1H), 7.31~7.26(m, 1H), 3.99(s, 3H); 13 C NMR (101MHz, CDCl3) δ165.55, 152.30, 149.45, 147.94, 144.48, 136.89, 126.32, 125.45, 123.09, 120.67, 120.46, 112.26, 112.04, 52.58; HRMS (ESI), C 14 H 11 Calculated for N3O2, [M+H] + :254.0851, Actual value:254.0932.

[0125] Example 8. Synthesis of (2-(pyridin-2-yl)imidazo[1,2-a]pyridin-7-yl)methanol (4e) [ka] Following the procedure described as Method C, starting from compound 4b (405.2 mg, 1.60 mmol), LiAlH (1 M) (3.68 mmol), and THF (20 mL), the title product was obtained as a white solid. Yield: 56%; mp: 227-228 °C; IR 3167, 2583, 1739, 1493, 1375, 1066, 787, 718 cm -1 ; 1 H NMR (500MHz, DMSO-d6) δ8.60(d, J=4.7Hz, 1H), 8.52(d, J=6.9Hz, 1H), 8.43(s, 1H), 8.10(d, J=7.8Hz, 1H), 7.88( td, J=7.7, 1.8Hz, 1H), 7.48(s, 1H), 7.32(ddd, J=7.5, 4.8, 1.2Hz, 1H), 6.87(dd, J=7.0, 1.6Hz, 1H), 4.56(s, 2H); 13 C NMR (101MHz, DMSO-d6) δ152.87, 149.44, 145.07, 144.62, 144.48, 140.76, 137.00, 126.7 0, 126.66, 122.70, 119.78, 112.46, 111.96, 111.80, 111.08, 111.03, 62.04; HRMS(ESI), C 13 H 11 Calculated for NO, [M+H] + :226.0902, Actual value:226.0978.

[0126] Example 9. Synthesis of 7-(chloromethyl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine (4f) [ka] Following the procedure described as Method D, starting from compound 4e (180.2 mg, 0.8 mmol), SOCl (190.4 mg, 1.6 mmol), and dichloromethane (10 mL), the title product was obtained as an off-white solid. Yield: 78%; mp: 292-293 °C; IR 3157, 3034, 1739, 1594, 1373, 1257, 1229, 1091, 806, 742 cm -1 ; 1H NMR (500MHz, DMSO-d6) δ8.67~8.55(m, 2H), 8.52(s, 1H), 8.12(d, J=8.0Hz, 1H), 7.90(t , J=7.7Hz, 1H), 7.72(s, 1H), 7.35(t, J=6.2Hz, 1H), 7.00(d, J=7.0Hz, 1H), 4.86(s, 2H); 13 C NMR (101MHz, DMSO-d6) δ152.32, 149.47, 145.03, 144.15, 137.11, 135.36, 127.53, 122.98, 119.92, 116.05, 113.47, 111.84, 45.47;HRMS(ESI), C 13 H 10 Calculated for ClN3, [M+H] + :244.0563, actual value:244.0641.

[0127] Example 10. Synthesis of methyl 2-(pyridin-2-yl)imidazo[1,2-a]pyridine-6-carboxylate (4g) [ka] Following the procedure described as Method B, starting with 2-(bromoacetyl)pyridine hydrobromide (1.74 g, 6.20 mmol), methyl 6-aminopyridine-3-carboxylate (1.18 mg, 7.75 mmol), NaHCO (812.4 mg, 9.67 mmol), and EtOH (30 mL), the title product was obtained as an off-white solid. Yield: 63%; mp: 233-234 °C; IR 3080, 1720, 1594, 1427, 1301, 1197, 1095, 767 cm -1 ; 1 H NMR (400MHz, CDCl3) δ8.94(s, 1H), 8.65(d, J=4.9Hz, 1H), 8.43(s, 1H), 8.24(d, J=8.0Hz, 1H), 7.8 4(t, J=7.8Hz, 1H), 7.77(d, J=9.5Hz, 1H), 7.66(d, J=9.5Hz, 1H), 7.33~7.24(m, 1H), 3.97(s, 3H); 13C NMR (101MHz, CDCl3) δ165.10, 151.71, 148.96, 146.45, 145.95, 137.50, 130.25, 124.96, 123.24, 121.03, 117.08, 116.98, 112.22, 52.53; HRMS (ESI), C 14 H 11 Calculated for N3O2, [M+H] + :254.0851, Actual value:254.0932.

[0128] Example 11. Synthesis of (2-(pyridin-2-yl)imidazo[1,2-a]pyridin-6-yl)methanol (4h) [ka] Following the procedure described as Method B, starting with 2-(bromoacetyl)pyridine hydrobromide (1.74 g, 6.20 mmol), (2-aminopyridin-4-yl)methanol (962.1 mg, 7.75 mmol), NaHCO (812.4 mg, 9.67 mmol), and EtOH (30 mL), the title product was obtained as a white solid. Yield: 52%; mp: 161-162 °C; IR 3222, 2970, 1739, 1370, 1217, 1032, 861, 824, 721 cm -1 ; 1 H NMR (500MHz, DMSO-d6) δ8.60(d, J=4.7Hz, 1H), 8.51(s, 1H), 8.49(s, 1H), 8.10(d, J=8.0Hz, 1H), 7.88(td, J=7.7 , 1.8Hz, 1H), 7.58(d, J=9.2Hz, 1H), 7.32(ddd, J=7.5, 4.8, 1.2Hz, 1H), 7.24(dd, J=9.3, 1.6Hz, 1H), 4.53(s, 2H); 13 C NMR (101MHz, DMSO-d6) δ152.87, 149.39, 144.66, 144.37, 136.98, 127.15, 125.70, 123.96, 122.69, 119.68, 116.47, 111.57, 60.46;HRMS(ESI), C 13 H 11 Calculated for NO, [M+H] +:226.0902, Actual value:226.0979.

[0129] Example 12. Synthesis of 6-(chloromethyl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine (4i) [ka] Following the procedure described as Method D, starting from compound 4h (180.2 mg, 0.8 mmol), SOCl (190.4 mg, 1.6 mmol), and dichloromethane (10 mL), the title product was obtained as an off-white solid. Yield: 65%; MP: 298-299 °C; IR 3034, 1737, 1594, 1375, 1347, 1258, 1214, 741 cm -1 ; 1 H NMR (400MHz, DMSO-d6) δ8.73(s, 1H), 8.61(dd, J=4.8, 0.9Hz, 1H), 8.50(s, 1H), 8.11(d, J=8. 0Hz, 1H), 7.89(td, J=7.7, 1.8Hz, 1H), 7.65(d, J=9.3Hz, 1H), 7.37~7.31(m, 2H), 4.85(s, 2H); 13 C NMR (101MHz, DMSO-d6) δ152.35, 149.50, 145.04, 144.11, 137.19, 126.95, 126.76, 123.05, 119.96, 117.12, 112.00, 43.95;HRMS(ESI), C 13 H 10 Calculated for ClN3, [M+H] + :244.0563, actual value:244.0640.

[0130] Example 13. Synthesis of methyl 2-(pyrazin-2-yl)imidazo[1,2-a]pyridine-7-carboxylate (4j) [ka] Following the procedure described as Method B, starting from compound 7c (3.2 g, 8.52 mmol), methyl 2-aminoisonicotinate (1.14 g, 7.5 mmol), NaHCO (0.95 g, 11.24 mmol), and EtOH (70 mL), the title product was obtained as a dark brown solid. Yield: 48%; mp: 243-244 °C; IR 3052, 1712, 1469, 1396, 1231, 1119, 745, 436, 404 cm -1 ; 1 H NMR (400MHz, CDCl3) δ9.52(d, J=1.7Hz, 1H), 8.68~8.58(m, 2H), 8.45(m, 2H), 8.27(dd, J=7.0, 1.1Hz, 1H), 7.51(dd, J=7.1, 1.7Hz, 1H), 4.05(s, 3H); 13 C NMR (101MHz, CDCl3) δ165.66, 148.17, 145.68, 145.14, 144.29, 144.13, 142.89, 127.21, 125.82, 121.02, 113.36, 112.70, 52.94;HRMS(ESI), C 13 H 10 Calculated for N4O2, [M+H] + :Calculated: 255.2490, Measured: 255.0804.

[0131] Example 14. Synthesis of methyl 2-(6-methylpyridin-2-yl)imidazo[1,2-a]pyridine-7-carboxylate (4k) [ka] Following the procedure described as Method B, starting from compound 7b (4.9 g, 16.61 mmol), methyl 2-aminoisonicotinate (2.11 g, 13.84 mmol), NaHCO (1.76 g, 20.76 mmol), and EtOH (80 mL), the title product was obtained as a light brown solid. Yield: 68%; mp: 268-269 °C; IR: 2953, 1713, 1571, 1440, 1328, 1275, 1238, 1125, 1086, 817, 767, 740 cm -1 ; 1H NMR (400MHz, CDCl3) δ8.44~8.35 (m, 2H), 8.19 (dd, J=7.0, 1.0Hz, 1H), 8.02 (d, J=7.7Hz, 1H), 7.7 1(t, J=7.7Hz, 1H), 7.42(dd, J=7.0, 1.7Hz, 1H), 7.14(d, J=7.6Hz, 1H), 3.99(s, 3H), 2.64(s, 3H); 13 C NMR (101MHz, CDCl3) 165.88, 158.57, 151.96, 148.58, 144.74, 137.30, 126.46 , 125.59, 123.00, 120.76, 118.01, 112.56, 112.26, 52.82, 24.86; HRMS(ESI), C 15 H 13 Calculated for N3O2, [M+H] + :268.2880, actual value:268.1088.

[0132] Example 15. Synthesis of methyl 1-(pyridin-2-yl)benzo[a]imidazo[5,1,2-cd]indolizine-4-carboxylate (2a) [ka] Following the procedure described as Method E, starting from compound (4d) (150 mg, 0.59 mmol), 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (176 mg, 0.59 mmol), 18-Corona-6 (156.8 mg, 0.59 mmol), and CsF (89.6 mg, 0.59 mmol), the title product was obtained as a yellow solid. Yield: 23%; mp: 214-215 °C; IR 1710, 1455, 1272, 1246, 1081, 767, 731 cm -1 ; 1H NMR (400MHz, CDCl3) δ9.07(d, J=8.1Hz, 1H), 8.95(d, J=4.8Hz, 1H), 8.79(s, 1H), 8.70(s, 1H), 8.57(d, J=7.8Hz, 1H), 8.38(d, J=8.0Hz, 1H), 7. 94(td, J=7.7, 1.8Hz, 1H), 7.86(td, J=7.9, 7.4, 1.0Hz, 1H), 7.68(td, J=7.9, 7.3, 1.1Hz, 1H), 7.40(ddd, J=7.4, 4.7, 1.2Hz, 1H), 4.12(s, 3H); 13 C NMR (101MHz, CDCl3) δ166.65, 152.92, 149.95, 148.13, 138.22, 136.81, 131.96, 130.29, 130.12, 129 .70, 128.29, 125.98, 124.46, 124.20, 123.51, 122.71, 121.91, 115.51, 109.52, 52.86; HRMS(ESI), C 20 H 13 Calculated for N3O2, [M+H] + :328.1008, Actual value:328.1090.

[0133] Example 16. Synthesis of (1-(pyridin-2-yl)benzo[a]imidazo[5,1,2-cd]indolizin-4-yl)methanol (2b) [ka] Following the procedure described as Method C, starting from compound 2a (327.4 mg, 1 mmol), LiAlH (1 M) (2.3 mmol), and THF (10 mL), the title product was obtained as a yellow solid. Yield: 49%; mp: 222-223 °C; IR 3049, 2839, 1532, 1402, 1341, 1191, 1120, 1082, 1055, 767, 735 cm -1 ; 1H NMR (400MHz, CDCl3) δ9.07(d, J=8.0Hz, 1H), 8.97(d, J=4.1Hz, 1H), 8.55(d, J=7.9Hz, 1H), 8.28(d, J=7.9Hz, 1H), 7.99(d, J=2.5H) z, 2H), 7.94(td, J=7.7, 1.8Hz, 1H), 7.84(t, J=7.6Hz, 1H), 7.63(t, J=7.6Hz, 1H), 7.39(ddd, J=7.5, 4.8, 1.2Hz, 1H), 5.12(s, 2H); 13 C NMR (101MHz, CDCl3) δ153.42, 149.95, 145.79, 141.52, 141.37, 139.04, 136.83, 131.47, 130.82 , 130.37, 129.47, 125.46, 123.91, 123.14, 122.68, 121.66, 111.30, 108.21, 65.50; HRMS(ESI), C 20 H 13 Calculated for N3O2, [M+H] + :300.1059, Actual value:300.1140.

[0134] Example 17. Synthesis of 4-(chloromethyl)-1-(pyridin-2-yl)benzo[a]imidazo[5,1,2-cd]indolizine (2c) [ka] Following the procedure described as Method D, starting with compound 2b (120 mg, 0.4 mmol), SOCl (95.2 mg, 0.8 mmol), and dichloromethane (10 mL), the title product was obtained as a yellow solid. Yield: 72%; mp: 231-232 °C; IR 3039, 1528, 1400, 1265, 1194, 1083, 765, 735, 703 cm -1 ; 1H NMR (400MHz, CDCl3) δ9.11(d, J=8.0Hz, 1H), 8.97(dt, J=4.5, 1.4Hz, 1H), 8.59(d, J=7.9Hz, 1H), 8.39(d, J=7.9Hz, 1H), 8.14(s, 1H), 8 .09(s, 1H), 7.95(td, J=8.1, 1.9Hz, 1H), 7.88(t, J=7.6Hz, 1H), 7.69(d, J=7.9Hz, 1H), 7.40(ddd, J=7.5, 4.8, 1.2Hz, 1H), 5.07(s, 2H); 13 C NMR (101MHz, CDCl3) δ150.05, 137.06, 131.57, 131.33, 130.49, 130.10, 126.45, 126.24, 124.53 , 124.36, 123.65, 122.92, 122.18, 122.03, 118.04, 113.01, 110.33, 107.13, 46.50; HRMS(ESI), C 19 H 12 Calculated for ClN3, [M+H] + :318.0720, actual value:318.0804.

[0135] Example 18. Synthesis of 4-(bromomethyl)-1-(pyridin-2-yl)benzo[a]imidazo[5,1,2-cd]indolizine (2d) [ka] Compound (2a) (101.7 mg, 0.34 mmol) is dissolved in dichloromethane (10 mL), and the resulting solution is cooled in an ice bath. PBr (184.1 mg, 0.68 mmol) is added slowly at 0-5°C. The resulting mixture is stirred at room temperature for 1 hour. Upon completion of the reaction, the pH of the reaction mixture is adjusted using saturated aqueous NaCO solution. The resulting mixture is extracted with dichloromethane and water, and the organic phase is dried over MgSO, filtered, and evaporated. The final product is purified by silica gel column chromatography using a 1:2 (v / v) ethyl acetate:n-hexane mixture as the mobile phase. The title product is obtained as a yellow solid. Yield: 74%; mp: 249-250°C; IR cm -13039, 1494, 1398, 1264, 1192, 1082, 765, 735, 664; 1 H NMR (400MHz, CDCl3) δ9.10(dt, J=8.0, 1.0Hz, 1H), 8.97(ddd, J=4.8, 1.8, 0.9Hz, 1H), 8.56(dt, J=7.9, 1.1Hz, 1H), 8.38(dt, J=8.0, 1.0Hz, 1H), 8.11(s, 1H), 8.07(s, 1H), 7.94(td, J=7.7, 1.8Hz, 1H), 7.87(td, J=7.4, 1.0Hz, 1H), 7.68(td, J=7.7, 1.1Hz, 1H), 7.39(ddd, J=7.6, 4.8, 1.2Hz, 1H), 4.98(s, 2H); 13 C-NMR (101MHz, CDCl3) δ153.21, 149.97, 138.72, 137.36, 136.83, 131.51, 131.04, 130.5 6, 129.77, 125.73, 124.10, 123.30, 122.81, 121.77, 113.73, 110.29, 33.84; HRMS(ESI), C 19 H 12 Calculated for BrN3, [M+H] + :362.0215, actual value:362.0289.

[0136] Example 19. Synthesis of methyl 1-(pyridin-2-yl)imidazo[5,1,2-cd]naphtho[2,3-a]indolizine-4-carboxylate (2e) [ka] Following the procedure described as Method E, starting from compound (4d) (150 mg, 0.59 mmol), 3-(trimethylsilyl)-2-naphthyl trifluoromethanesulfonate (205.6 mg, 0.59 mmol), 18-Corona-6 (156.8 mg, 0.59 mmol), and CsF (89.6 mg, 0.59 mmol), the title product was obtained as a dark yellow solid. Yield: 19%; mp: 263-264 °C; IR: 1713, 1456, 1293, 1233, 1220, 1070, 893, 761, 730 cm -1 ; 1H NMR (400MHz, CDCl3) δ9.49(s, 1H), 9.05(d, J=4.8Hz, 1H), 8.87(s, 1H), 8.74(s, 1H), 8.63(s, 1H), 8.57(d, J=7.9Hz, 1H), 8.28(d, J=8.2Hz, 1H), 8.17(d, J=8.1Hz, 1H), 7.96(m, 1H), 7.75~7.62(m, 3H), 7.43(dd, J=7.5, 4.9Hz, 1H), 4.13(s, 3H); 13 C NMR (101MHz, CDCl3) δ166.58, 153.15, 149.98, 138.30, 136.85, 134.05, 131.64, 131.38, 129.20, 129.02 , 128.74, 127.78, 127.04, 126.05, 123.30, 122.98, 122.81, 121.76, 116.40, 107.93, 52.88; HRMS(ESI), C 24 H 15 Calculated for N3O2, [M+H] + :378.1164, actual value:378.1243.

[0137] Example 20. Synthesis of 4-(chloromethyl)-1-(pyridin-2-yl)imidazo[5,1,2-cd]naphthol[2,3-a]indolizine (2f) [ka] First, following the procedure described as Method C, starting from compound 2e (301.7 mg, 0.8 mmol), LiAlH (1 M) (2 mmol), and THF (10 mL), the corresponding hydroxylated derivative was obtained, which was used without purification in the next reaction step according to Method D, starting from (1-pyridin-2-yl)imidazo[5,1,2-cd]naphtho[2,3-a]indolizin-4-yl)methanol (104.8 mg, 0.3 mmol), SOCl (71.4 mg, 0.6 mmol), and dichloromethane (8 mL). The title product 2f was obtained as a yellow solid. Yield: 70%; MP: 232-233°C; FTIR 3031, 1587, 1427, 1412, 1291, 1180, 1118, 883, 793, 743, 702 cm-1 ; 1 H NMR (400MHz, CDCl3) δ9.48(s, 1H), 9.05(d, J=4.8Hz, 1H), 8.84(s, 1H), 8.54(dt, J=7.8, 1.1Hz, 1H), 8.28(d, J=8.1Hz, 1H), 8.17(d, J=8.2Hz, 1H), 8.04(s, 1H), 8.00~7.92(m, 2H), 7.74~7.62(m, 2H), 7.41(ddd, J=7.5, 4.8, 1.2Hz, 1H), 5.03(s, 2H); 13 C NMR (101MHz, CDCl3) δ153.33, 149.97, 138.69, 137.52, 136.84, 134.12, 132.09, 131.36, 131.25, 129.17 , 129.00, 127.92, 127.03, 125.92, 123.05, 122.88, 122.71, 121.58, 113.77, 108.47, 46.77; HRMS(ESI), C 23 H 14 Calculated for ClN3, [M+H] + :368.0876, Actual value:368.0956.

[0138] Example 21. Synthesis of methyl 3-phenyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridine-7-carboxylate (2g) [ka] Following the procedure described as Method G, starting with compound 4d (501.5 mg, 1.98 mmol), bromobenzene (464.7 mg, 2.96 mmol), Pd(PPh) (160.6 mg, 0.14 mmol), KCO (819.6 mg, 5.93 mmol), and DMF (15 mL), the title product was obtained as a white solid. Yield: 54%; mp: 142-143 °C; IR: 1716, 1347, 1268, 1225, 1144, 1084, 752, 733, 713 cm -1 ; 1H NMR (400MHz, CDCl3) δ8.61(d, J=4.9Hz, 1H), 8.47~8.43(m, 1H), 8.04(dd, J=7.2, 1.0Hz, 1H), 7.70(dt, J=8.0, 1.2Hz, 1H), 7 .63(td, J=7.6, 1.8Hz, 1H), 7.60~7.50(m, 5H), 7.37(dd, J=7.2, 1.7Hz, 1H), 7.19(ddd, J=7.4, 4.8, 1.3Hz, 1H), 3.99(s, 3H); 13 C NMR (101MHz, CDCl3) δ165.63, 152.64, 149.69, 144.13, 143.71, 136.07, 130.57, 129.25, 129 .18, 128.97, 126.29, 124.63, 123.08, 122.84, 122.44, 120.77, 111.84, 52.55; HRMS(ESI), C 20 H 15 Calculated for N3O2, [M+H] + :330.1164, actual value:330.1245.

[0139] Example 22. Synthesis of 7-(chloromethyl)-3-phenyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridine (2h) [ka] First, the method described as Method C was followed, starting from compound (2g) (329.4 mg, 1 mmol), LiAlH (1 M) (2.3 mmol) and THF (15 mL). The corresponding hydroxylated derivative was obtained, which was used without purification in the next reaction step according to Method D, starting from (3-phenyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-7-yl)methanol (120.5 mg, 0.4 mmol), SOCl (95.2 mg, 0.8 mmol), dichloromethane (10 mL). The title product was obtained as a yellowish oil. Yield: 68%; IR 3053, 1589, 1508, 1365, 1217, 794, 720, 699 cm -1 ; 1H NMR (400MHz, CDCl3) δ8.61(d, J=4.7Hz, 1H), 8.01(d, J=7.1Hz, 1H), 7.72~7.68(m, 1H), 7.67~7.61(m, 2H), 7.60~7.51(m, 5H), 7.17(ddd, J=7.2, 4.8, 1.5Hz, 1H), 6.84(dd, J=7.2, 1.8Hz, 1H), 4.67(s, 2H); 13 C NMR (101MHz, CDCl3) δ153.03, 149.65, 144.23, 142.54, 136.00, 134.64, 130.72, 129.41 , 129.21, 128.97, 123.89, 123.54, 122.71, 122.19, 117.08, 113.07, 45.42; HRMS(ESI), C 20 H 14 Calculated for ClN3, [M+H] + :320.0876, Actual value:320.0958.

[0140] Example 23. Synthesis of methyl 3-(2-bromophenyl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine-7-carboxylate (2i) [ka] Following the procedure described as Method G, starting with compound 4d (501.5 mg, 1.98 mmol), 1,2-dibromobenzene (698.3 mg, 2.96 mmol), Pd(PPh) (160.6 mg, 0.14 mmol), KCO (819.6 mg, 5.93 mmol), and DMF (15 mL), the title product was obtained as a white solid. Yield: 49%; mp: 162-163 °C; IR 1712, 1333, 1244, 1231, 1144, 1085, 754, 736 cm -1 ; 1 H NMR (400MHz, CDCl3) δ8.55(d, J=4.9Hz, 1H), 8.50(s, 1H), 7.84(d, J=7.9Hz, 1H), 7.77(d, J=7.9 Hz, 1H), 7.71~7.62(m, 2H), 7.54~7.39(m, 4H), 7.18(ddd, J=7.5, 4.8, 1.2Hz, 1H), 4.00(s, 3H);13 C NMR (101MHz, CDCl3) δ165.66, 152.45, 149.70, 144.61, 143.76, 136.17, 133.68, 133.34, 131.08, 130 .78, 127.99, 126.54, 125.66, 123.60, 123.52, 122.48, 122.16, 120.67, 111.87, 52.60; HRMS(ESI), C 20 H 14 Calculated for BrN3O2, [M+H] + :408.0269, actual value:408.0392.

[0141] Example 24. Synthesis of 3-(2-bromophenyl)-7-(chloromethyl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine (2j) [ka] First, the method described as Method C was followed, starting from compound (2i) (408.3 mg, 1 mmol), LiAlH (1 M) (2.3 mmol), and THF (15 mL). The corresponding hydroxylated derivative was obtained, which was used without purification in the next reaction step according to Method D, starting from 3-(2-bromophenyl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-7-yl)methanol (152 mg, 0.4 mmol), SOCl (95.2 mg, 0.8 mmol), and dichloromethane (10 mL). The title product was obtained as a yellowish oil. Yield: 73%; IR 3026, 1738, 1424, 1336, 1229, 1217, 794, 744 cm -1 ; 1 H NMR (400MHz, CDCl3) δ8.55(d, J=4.8Hz, 1H), 7.83(d, J=7.9Hz, 1H), 7.78~7.67(m, 2H), 7.70~7.58(m, 2H), 7.55~7.37(m, 4H), 7.16(ddd, J=7.5, 4.8, 1.3Hz, 1H), 6.88(dd, J=7.1, 1.8Hz, 1H), 4.68(s, 2H); 13C NMR (101MHz, CDCl3) δ152.58, 149.65, 144.14, 142.85, 136.11, 134.96, 133.83, 133.73, 133.32, 131 .03, 130.94, 127.98, 125.85, 124.33, 122.39, 122.26, 122.04, 116.91, 113.13, 45.38; HRMS(ESI), C 19 H 13 Calculated for BrClN3, [M+H] + :399.9952, Actual value:400.0044.

[0142] Example 25. Synthesis of methyl 3-(naphthalen-1-yl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine-7-carboxylate (2k) [ka] Following the procedure described as Method G, starting with compound 4d (501.5 mg, 1.98 mmol), 1-bromonaphthalene (612.9 mg, 2.96 mmol), Pd(PPh) (160.6 mg, 0.14 mmol), KCO (819.6 mg, 5.93 mmol), and DMF (15 mL), the title product was obtained as a white solid. Yield: 51%; mp: 80-81 °C; IR 1715, 1331, 1226, 1145, 1088, 756, 739 cm -1 ; 1 H NMR (400MHz, CDCl3) δ8.58 (d, J=4.6Hz, 1H), 8.55~8.52 (m, 1H), 8.11 (dd, J=7.6, 2.0Hz, 1H), 8.04 (d, J=8.2Hz, 1H), 7.74 ~7.65(m, 2H), 7.60~7.46(m, 4H), 7.42~7.33(m, 2H), 7.32~7.29(m, 1H), 7.11(ddd, J=6.7, 4.8, 1.9Hz, 1H), 4.00(s, 3H); 13C NMR (101MHz, CDCl3) δ165.71, 152.27, 149.93, 144.14, 136.03, 134.03, 132.13, 132.03, 131.92, 1 30.28, 130.04, 128.82, 128.54, 128.42, 127.32, 126.62, 126.47, 125.94, 124.82, 123.70, 122.38.

[0143] Example 26. Synthesis of 7-(chloromethyl)-3-(naphthalen-1-yl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine (2l) [ka] First, following the procedure described as Method C, starting from compound (2k) (379.4 mg, 1 mmol), LiAlH (1 M) (2.3 mmol), and THF (15 mL), the corresponding hydroxylated derivative was obtained, which was used without purification in the next reaction step according to Method D, starting from 3-(naphthalen-1-yl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-7-yl)methanol (140.5 mg, 0.4 mmol), SOCl (95.2 mg, 0.8 mmol), and dichloromethane (10 mL). The title product was obtained as a yellow solid. Yield: 73%; mp: 153-154 °C; IR 3051, 1587, 1375, 1348, 1247, 1147, 775, 744 cm -1 ; 1 H NMR (400MHz, CDCl3) δ8.56(d, J=4.8Hz, 1H), 8.08(dd, J=7.8, 1.8Hz, 1H), 8.02(d, J=8.2Hz, 1H), 7.78(s, 1H), 7.68~7.60( m, 2H), 7.59~7.53(m, 1H), 7.50~7.36(m, 5H), 7.07(ddd, J=7.3, 4.8, 1.5Hz, 1H), 6.75(dd, J=7.1, 1.8Hz, 1H), 4.66(s, 2H); 13C NMR (101MHz, CDCl3) δ152.48, 149.81, 144.52, 143.59, 135.91, 134.71, 133.99, 132.17, 130.09, 130.05, 128.71 , 127.20, 126.82, 126.51, 125.91, 124.94, 124.37, 122.18, 122.05, 121.50, 117.04, 113.03, 45.41; HRMS(ESI), C 23 H 16 Calculated for ClN3, [M+H] + :370.1033, actual value:370.1112.

[0144] Example 27. Synthesis of methyl 3-(naphthalen-2-yl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine-7-carboxylate (2m) [ka] Following the procedure described as Method G, starting from compound 4d (501.5 mg, 1.98 mmol), 2-bromonaphthalene (612.9 mg, 2.96 mmol), Pd(PPh) (160.6 mg, 0.14 mmol), KCO (819.6 mg, 5.93 mmol), and DMF (15 mL), the title product was obtained as a light brown solid. Yield: 58%; mp: 172-173 °C; IR: 1713, 1331, 1225, 1141, 1088, 816, 755, 737 cm -1 ; 1 H NMR (400MHz, CDCl3) δ8.59(ddd, J=4.8, 1.8, 0.9Hz, 1H), 8.49(dd, J=1.7, 1.0Hz, 1H ), 8.11(dd, J=7.2, 1.0Hz, 1H), 8.10~8.03(m, 1H), 8.03(d, J=8.4Hz, 1H), 7.97(dd, J=7.5, 2.6Hz, 1H), 7.92(d, J=7.4Hz, 1H), 7.75(dt, J=8.0, 1.1Hz, 1H), 7.66~7.53( m, 4H), 7.39(dd, J=7.4, 1.8Hz, 1H), 7.19(ddd, J=7.5, 4.9, 1.2Hz, 1H), 4.01(s, 3H); 13C NMR (101MHz, CDCl3) δ165.65, 152.68, 149.71, 144.41, 143.86, 136.15, 136 .09, 133.46, 133.36, 130.60, 129.86, 129.27, 129.01, 128.24, 127.97, 127. 88, 127.07, 126.66, 126.47, 126.41, 124.63, 123.14, 122.86, 122.51, 122.4 6, 120.84, 111.96, 111.87, 77.31, 77.20, 76.99, 76.68, 52.59; HRMS(ESI), C 24 H 17 Calculated for N3O2, [M+H] + :380.1321, actual value:380.1401.

[0145] Example 28. Synthesis of 7-(chloromethyl)-3-(naphthalen-2-yl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine (2n) [ka] First, following the procedure described as Method C, starting from compound (2m) (379.4 mg, 1 mmol), LiAlH (1 M) (2.3 mmol), and THF (15 mL), the corresponding hydroxylated derivative was obtained, which was used without purification in the next reaction step according to Method D, starting from 3-(naphthalen-2-yl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-7-yl)methanol (140.5 mg, 0.4 mmol), SOCl (95.2 mg, 0.8 mmol), and dichloromethane (10 mL). The title product was obtained as a yellow oil. Yield: 69%; IR 3051, 1738, 13655, 1229, 1217, 794, 748 cm -1 ; 1H NMR (400MHz, CDCl3) δ8.58 (ddd, J=4.9, 1.8, 1.0Hz, 1H), 8.11~7.95 (m, 4H), 7.91 (dd, J=7.4, 1.8Hz, 1H), 7.79 ~7.69(m, 2H), 7.67~7.53(m, 4H), 7.17(ddd, J=7.5, 4.8, 1.2Hz, 1H), 6.87(dd, J=7.2, 1.8Hz, 1H), 4.68(s, 2H); 13 C NMR (101MHz, CDCl3) δ152.66, 149.67, 144.15, 136.13, 135.08, 133.50, 133.31, 129.90, 128.97, 128 .21, 128.16, 127.87, 126.98, 126.62, 123.97, 122.72, 122.34, 116.97, 113.36, 45.35; HRMS(ESI), C 23 H 16 Calculated for ClN3, [M+H] + :370.1033, actual value:369.1968.

[0146] Example 29. Synthesis of methyl 3-(3-bromonaphthalen-2-yl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine-7-carboxylate (2o) [ka] Following the procedure described as Method G, starting from compound 4d (501.5 mg, 1.98 mmol), 2,3-dibromonaphthalene (846.4 mg, 2.96 mmol), Pd(PPh) (160.6 mg, 0.14 mmol), KCO (819.6 mg, 5.93 mmol), and DMF (15 mL), the title product was obtained as a pale yellow solid. Yield: 55%; mp: 118-120 °C; IR 1716, 1331, 1268, 1228, 1143, 1087, 751, 739 cm -1 ; 1H NMR (400MHz, CDCl3) δ8.54~8.49(m, 2H), 8.36(s, 1H), 8.00(s, 1H), 7.92(d, J=7.7Hz, 1H), 7.87(d, J=7.7Hz, 1H), 7.79(d, J=7.9Hz , 1H), 7.72(dd, J=7.2, 1.0Hz, 1H), 7.69~7.58(m, 3H), 7.41(dd, J=7.2, 1.7Hz, 1H), 7.15(ddd, J=7.5, 4.8, 1.2Hz, 1H), 4.01(s, 3H); 13 C NMR (101MHz, CDCl3) δ165.69, 152.51, 149.73, 145.05, 143.79, 136.20, 134.69, 133.14, 132.27, 132.01, 128.67 , 128.26, 128.06, 127.00, 126.93, 126.59, 123.57, 122.48, 122.41, 122.20, 120.69, 111.97, 52.61; HRMS(ESI), C 24 H 16 Calculated for BrN3O2, [M+H] + :460.0405, Actual value:460.0492.

[0147] Example 30. Synthesis of 3-(3-bromonaphthalen-2-yl)-7-(chloromethyl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine (2p) [ka] First, the method described as Method C was followed, starting from compound (2o) (458.3 mg, 1 mmol), LiAlH (1 M) (2.3 mmol), and THF (15 mL). The corresponding hydroxylated derivative was obtained, which was used without purification in the next reaction step according to Method D, starting from 3-(3-bromonaphthalen-2-yl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridin-7-yl)methanol (172.1 mg, 0.4 mmol), SOCl (95.2 mg, 0.8 mmol), and dichloromethane (10 mL). The title product was obtained as a yellow oil. Yield: 70%; IR 3049, 1736, 1420, 1385, 1350, 1230, 1217, 783, 743, 713 cm -1 ; 1 H NMR (400MHz, CDCl3) δ8.49(d, J=4.9Hz, 1H), 8.35(s, 1H), 7.99(s, 1H), 7.92(d, J=8.4Hz, 1H), 7.87~7.78(m, 2H), 7.75( dt, J=7.9, 1.1Hz, 1H), 7.71~7.55(m, 4H), 7.13(ddd, J=7.5, 4.8, 1.2Hz, 1H), 6.89(dd, J=7.2, 1.8Hz, 1H), 4.68(s, 2H); 13 C NMR (101MHz, CDCl3) δ152.36, 149.64, 143.98, 142.94, 136.18, 135.23, 134.60, 133.23, 132.25, 131.95, 128 .20, 128.08, 127.98, 126.93, 126.87, 124.28, 122.59, 122.30, 122.07, 116.77, 113.35, 45.31;HRMS(ESI), C 23 H 15 Calculated for BrClN3, [M+H] + :450.0117, Actual value:450.0200.

[0148] Example 31. Synthesis of methyl 3-(3-bromonaphthalen-2-yl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine-7-carboxylate (2q) [ka] Following the procedure described as Method G, starting from compound 4k (1.6 mg, 6.25 mmol), 1-bromonaphthalene (1.9 mg, 9.36 mmol), Pd(PPh) (489 mg, 0.44 mmol), KCO (2.59 mg, 18.73 mmol), and DMF (15 mL), the title product was obtained as a yellowish solid. Yield: 44%; mp: 163-164 °C; IR 2963, 1797, 1589, 1573, 1431, 1329, 1273, 1247, 1084, 797, 751, 734 cm -1 ; 1 H NMR (400MHz, CDCl3) δ8.50(s, 1H), 8.12(dd, J=7.2, 0.9Hz, 1H), 8.10(d, J=1.6Hz, 1H), 8.00(d, J=8.5Hz, 1H), 7.97~7.95(m, 1H), 7.91(dd, J=7.7, 1.5Hz, 1H), 7.65~7.55(m, 3H), 7.48(d, J=4.9Hz, 1H), 7.38(dd, J=7.2, 1.7Hz, 1H), 7.05(t, J=4.3Hz, 1H), 4.00(s, 3H), 2.48(s, 3H); 13 C NMR (101MHz, CDCl3) δ165.95, 158.73, 152.12, 149.96, 145.01, 144.11, 136.59, 133.65, 133.58, 130.29, 128.99, 128.44 , 128.35, 128.10, 127.25, 126.87, 126.76, 126.53, 123.36, 122.40, 121.15, 120.34, 112.16, 52.83, 24.73; HRMS(ESI), C 25 H 19 Calculated for N3O2, [M+H] + :394.1321, actual value:394.1553.

[0149] Example 32. Synthesis of 3-(3-bromonaphthalen-2-yl)-7-(chloromethyl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine (2r) [ka] First, the method described as Method C was followed, starting from compound (2q) (700 mg, 1.78 mmol), LiAlH (1 M) (4.10 mmol), and THF (20 mL). The corresponding hydroxylated derivative was obtained, which was used without purification in the next reaction step according to Method D, starting from 2-(6-methylpyridin-2-yl)-3-(naphthalen-2-yl)imidazo[1,2-a]pyridin-7-yl)methanol (400 mg, 1.09 mmol), SOCl (391 mg, 3.28 mmol), and dichloromethane (30 mL). The title product was obtained as a yellowish oil. Yield: 53%; IR 3048, 1560, 1375, 1349, 1252, 1147, 1050, 780, 742 cm -1 ; 1 H NMR (400MHz, CDCl3) δ8.10~8.07(m, 2H), 7.98(d, J=8.4Hz, 1H), 7.95(dd, J=7.8, 1.5Hz, 1H), 7.89(dd, J=7.5, 1.6Hz, 1H), 7.73(s, 1H), 7.62~7.55(m, 3H), 7.45(d, J=5.6Hz, 2H), 7.02(dd, J=5.3, 3.3Hz, 1H), 6.84(dd, J=7.2, 1.8Hz, 1H), 4.66(s, 2H), 2.48(s, 3H); 13 C NMR (101MHz, CDCl3) δ158.59, 152.42, 144.56, 143.33, 136.48, 134.82, 133.67, 133.46, 130.23, 128.87, 128.57, 12 8.38, 128.06, 127.12, 127.08, 126.76, 124.12, 123.67, 122.09, 120.16, 117.41, 113.32, 45.70, 24.74; HRMS(ESI), C 24 H 18 Calculated for ClN3, [M+H] + :384.1189, actual value:384.1244.

[0150] Example 33. Synthesis of dichloro(4-(chloromethyl)-1-(pyridin-2-yl)benzo[a]imidazo[5,1,2-cd]indolizine)platinum(II) (1a) [ka] Following the procedure described as Method A, starting from compound 2c (63.6 mg, 0.2 mmol), Pt(DMSO)Cl (75 mg, 0.18 mmol), and MeOH (5 mL), the title product was obtained as a yellow solid. Yield: 70%; mp: >410 °C; IR 3038, 1529, 1400, 1265, 1194, 1138, 1083, 765, 734, 703 cm -1 ; 1 H NMR (500MHz, DMF-d7) δ9.29 (dt, J=8.1, 1.0Hz, 1H), 9.23 (dt, J=4.7, 1.2Hz, 1H), 8.90 (d, J=7.8Hz, 1H), 8.79~8.74 (m, 2H), 8. 56(s, 1H), 8.29(td, J=7.7, 1.8Hz, 1H), 8.13(t, J=7.0Hz, 1H), 7.96(td, J=7.7, 1.1Hz, 1H), 7.73(ddd, J=7.5, 4.7, 1.2Hz, 1H); 13 C NMR (126MHz, DMF-d7) δ153.57, 150.51, 146.60, 138.99, 138.63, 137.52, 131.81, 131. 00, 130.31, 129.90, 126.11, 123.97, 123.95, 123.83, 121.76, 114.31, 111.40, 46.99; 195 Pt NMR(107MHz, DMF-d7) -2204.00;HRMS(ESI), C 19 H 12 Calculated for Cl3N3Pt, [M+Na] + :605.9642, Actual value:605.9611.

[0151] Example 34. Synthesis of dichloro(4-(bromomethyl)-1-(pyridin-2-yl)benzo[a]imidazo[5,1,2-cd]indolizine)platinum(II) (1b) [ka] Following the procedure described as Method A, starting from compound (2d) (54.3 mg, 0.15 mmol), Pt(DMSO)Cl (58.3 mg, 0.14 mmol), and MeOH (5 mL), the title product was obtained as a yellow solid. Yield: 76%; mp > 410 °C; IR 3057, 1610, 1491, 1462, 1402, 1211, 1133, 788, 762, 732, 664 cm -1 ; 1 H NMR 500MHz, DMF-d7) δ9.69(d, J=6.2Hz, 1H), 9.16(s, 1H), 8.86~8.78(m, 5H), 8.56(td, J=7.7, 1.6Hz, 1H), 7.94(t, J=7.6Hz, 1H), 7.90~7.83(m, 1H), 5.41(d, J=2.2Hz, 2H); 13 C NMR (126MHz, DMF-d7) δ149.37, 143.59, 140.64, 132.69, 131.16, 128.50, 126.34, 124.69, 124.37, 123.46, 114.06, 113.42, 45.99; 195 Pt NMR (107MHz, DMF-d7) -2207.29;HRMS (ESI), C 19 H 12 Calculated value for BrCl2N3Pt, [M+K] + :667.8856, Actual value:667.8838.

[0152] Example 35. Synthesis of dichloro(4-(chloromethyl)-1-(pyridin-2-yl)imidazo[5,1,2-cd]naphtho[2,3-a]indolizine)platinum(II) (1c) [ka] Following the procedure described as Method A, starting from compound 2f (55.2 mg, 0.15 mmol), Pt(DMSO)Cl (58.3 mg, 0.14 mmol), and MeOH (5 mL), the title product was obtained as a yellow solid. Yield: 73%; mp: >410 °C; IR 3058, 1633, 1488, 1456, 1257, 1148, 1075, 878, 770, 734 cm -1 ; 1H NMR (500MHz, DMF-d7) δ9.90(d, J=6.0Hz, 1H), 9.58(s, 1H), 9.56(s, 1H), 9.27(s, 1H), 9.08(d, J=8.0Hz, 1H), 8.87( s, 1H), 8.69(td, J=7.8, 1.5Hz, 1H), 8.62(d, J=8.0Hz, 1H), 8.55(d, J=8.0Hz, 1H), 8.07~7.97(m, 4H), 5.51(s, 2H); 13 C NMR 126MHz, DMF-d7)δ149.58, 140.44, 129.58, 128.50, 127.92, 126.01, 125.25, 124.01, 123.24, 113.98, 111.78, 46.07;HRMS(ESI), C 23 H 14 Calculated for Cl3N3Pt, [M+H] + :655.9799, Actual value:655.9790.

[0153] Example 36. Synthesis of dichloro(7-(chloromethyl)-3-phenyl-2-(pyridin-2-yl)imidazo[1,2-a]pyridine)platinum(II) (1d) [ka] Following the procedure described as Method A, starting from compound 2h (48 mg, 0.15 mmol), Pt(DMSO)Cl (58.3 mg, 0.14 mmol), and MeOH (5 mL), the title product was obtained as a yellow solid. Yield: 77%; mp: >410 °C; IR 3066, 1620, 1510, 1252, 778, 695 cm -1 ; 1 H NMR (500MHz, DMF-d7) δ9.62(d, J=5.6Hz, 1H), 9.26(s, 1H), 8.20(dd, J=7.2, 1.0Hz, 1H), 8.12(td, J=7.8, 1.5 Hz, 1H), 7.92~7.86(m, 2H), 7.84~7.80(m, 2H), 7.68~7.58(m, 1H), 7.39~7.31(m, 2H), 4.98(d, J=0.8Hz, 2H); 13C NMR (126MHz, DMF-d7) δ153.27, 148.92, 145.67, 141.17, 139.64, 131.44, 131.35, 130.37, 126.26, 125.31, 125.06, 121.56, 116.01, 114.65, 44.86; 195 Pt NMR (107MHz, DMF-d7) -2178.24;HRMS (ESI), C 19 H 14 Calculated for Cl3N3Pt, [M+Na] + :607.9799, Actual value:607.9785.

[0154] Example 37. Synthesis of dichloro(3-(2-bromophenyl)-7-(chloromethyl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine)platinum(II) (1e) [ka] Following the procedure described as Method A, starting from compound (2j) (59.5 mg, 0.15 mmol), Pt(DMSO)Cl (58.3 mg, 0.14 mmol), and MeOH (5 mL), the title product was obtained as a yellow solid. Yield: 76%; mp: >410 °C; IR 065, 1618, 1509, 1252, 778, 696 cm -1 ; 1 H NMR (500MHz, DMF-d7) δ9.60(d, J=5.9Hz, 1H), 9.23(s, 1H), 8.20(d, J=7.1Hz, 1H), 8.11(td, J=7.9, 1.5Hz, 1 H), 7.94~7.87(m, 1H), 7.83~7.80(m, 3H), 7.62(d, J=7.6Hz, 1H), 7.35(dd, J=7.3, 1.8Hz, 2H), 4.97(s, 2H); 13 C NMR (126MHz, DMF-d7) δ153.49, 149.06, 145.83, 141.24, 139.73, 131.58, 131.56, 130. 49, 128.35, 127.39, 126.46, 126.22, 125.41, 125.32, 121.75, 116.13, 114.86, 45.04; 195Pt NMR (107MHz, DMF-d7) -2177.53;HRMS (ESI), C 19 H 13 Calculated for BrCl3N3Pt, [M+Na] + :685.8904, Actual value:685.8892.

[0155] Example 38. Synthesis of dichloro(7-(chloromethyl)-3-(naphthalen-1-yl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine)platinum(II) (1f) [ka] Following the procedure described as Method A, starting from compound (2l) (55.5 mg, 0.15 mmol), Pt(DMSO)Cl (58.3 mg, 0.14 mmol), and MeOH (5 mL), the title product was obtained as a yellow solid. Yield: 74%; mp: >410 °C; IR 3054, 1628, 1506, 1247, 1138, 792, 779, 769 cm -1 ; 1 H NMR (500MHz, DMF-d7) δ9.63~9.56(m, 1H), 9.29(dd, J=1.8, 0.9Hz, 1H), 8.43(d d, J=8.4, 1.2Hz, 1H), 8.28~8.23(m, 1H), 8.15(dd, J=7.0, 1.2Hz, 1H), 8.01~7.9 5(m, 2H), 7.91(dd, J=8.3, 7.0Hz, 1H), 7.72(dd, J=7.9, 6.5Hz, 2H), 7.65~7.53 (m, 2H), 7.31(dd, J=7.2, 1.8Hz, 1H), 6.96(dd, J=7.7, 1.2Hz, 1H), 5.02(s, 2H); 13 C NMR (126MHz, DMF-d7) 153.07, 148.83, 146.14, 142.56, 141.21, 139.77, 134.26, 132.15, 131.82, 131.48, 1 29.21, 128.33, 127.35, 126.62, 126.51, 125.37, 124.44, 123.75, 121.91, 121.76, 116.11, 114.75, 44.90; 195Pt NMR (107MHz, DMF-d7) -2175.67;HRMS (ESI), C 23 H 16 Calculated for Cl3N3Pt, [M+Na] + :657.9955, Actual value:657.9953.

[0156] Example 39. Synthesis of dichloro(7-(chloromethyl)-3-(naphthalen-2-yl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine)platinum(II) (1g) [ka] Following the procedure described as Method A, starting from compound (2n) (55.5 mg, 0.15 mmol), Pt(DMSO)Cl (58.3 mg, 0.14 mmol), and MeOH (5 mL), the title product was obtained as a yellow solid. Yield: 71%; mp: >410 °C; IR 3032, 1639, 1509, 1245, 1017, 774, 744, 698 cm -1 ; 1 H NMR (500MHz, DMF-d7) δ9.81(d, J=5.2Hz, 1H), 9.46(s, 1H), 8.75(s, 1H), 8.58(d, J= 7.2Hz, 1H), 8.54(d, J=8.4Hz, 1H), 8.39(d, J=8.0Hz, 1H), 8.32(d, J=8.1Hz, 1H), 8.2 7(td, J=7.9, 1.5Hz, 1H), 8.15(dd, J=8.4, 1.7Hz, 1H), 8.01~7.89(m, 2H), 7.82(td, J=6.1, 1.5Hz, 1H), 7.61(d, J=8.1Hz, 1H), 7.54(dd, J=7.2, 1.8Hz, 1H), 5.22(s, 2H); 13 C NMR (126MHz, DMF-d7) δ153.26, 148.86, 145.65, 141.56, 141.24, 139.76, 134.37, 133.76, 131.99, 130.22, 128.82, 128.23, 128.15, 127.41, 127.28, 126.75, 125.85, 125.34, 122.46, 121.82, 115.98, 114.58, 44.92; 195Pt NMR (107MHz, DMF-d7) -2177.42; HRMS (ESI), C 23 H 16 Calculated for Cl3N3Pt, [M+Na] + :657.9955, Actual value:657.9954.

[0157] Example 40. Synthesis of dichloro(3-(3-bromonaphthalen-2-yl)-7-(chloromethyl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine)platinum(II) (1h) [ka] Following the procedure described as Method A, starting from compound (2p) (67 mg, 0.15 mmol), Pt(DMSO)Cl (58.3 mg, 0.14 mmol), and MeOH (5 mL), the title product was obtained as a yellow solid. Yield: 70%; mp: >410 °C; IR 3052, 1622, 1505, 1395, 1129, 1029, 949, 765, 752, 694 cm -1 ; 1 H NMR (500MHz, DMF-d7) δ9.64(d, J=6.0Hz, 1H), 9.33(s, 1H), 8.73(s, 1H), 8. 70(s, 1H), 8.38(d, J=7.1Hz, 1H), 8.24(d, J=8.2Hz, 1H), 8.17~8.09(m, 2H), 7.87(ddd, J=8.3, 6.8, 1.3Hz, 1H), 7.82~7.78(m, 1H), 7.69(ddd, J=7.6, 5. 9, 1.5Hz, 1H), 7.44(dd, J=7.2, 1.7Hz, 1H), 7.32~7.27(m, 1H), 5.06(s, 2H); 13 C NMR (126MHz, DMF-d7)) δ152.72, 148.98, 141.76, 140.20, 135.75, 135.17, 132.91, 132.63, 129 .33, 128.88, 127.90, 127.47, 126.98, 125.80, 122.91, 122.12, 120.59, 116.41, 114.61, 44.82; 195 Pt NMR (107MHz, DMF-d7) -2179.79;HRMS (ESI), C23 H 15 Calculated for BrCl3N3Pt, [M+Na] + :735.9060, actual value:735.9053.

[0158] Example 41. Synthesis of dichloro(7-(chloromethyl)-2-(6-methylpyridin-2-yl)3-(naphthalen-2-yl)imidazo[1,2-a]pyridine)platinum(II) (1i) [ka] Following the procedure described as Method A, starting from compound (2r) (48 mg, 0.13 mmol), Pt(DMSO)Cl (52 mg, 0.13 mmol), and MeOH (5 mL), the title product was obtained as a yellow solid. Yield: 52%; mp: >410 °C; IR 3044, 1711, 591, 1505, 1418, 1299, 1195, 1126, 750, 478 cm -1 ; 1 H NMR (500MHz, DMF-d7) δ8.57(s, 1H), 8.13(s, 1H), 7.96~7.92(m, 2H), 7.80(d, J=8.3Hz, 1H), 7.74(d, J=8.2Hz, 1H), 7.52(d, J=8.4,Hz, 1H), 7.47~7.4 3(m, 1H), 7.40~7.36(m, 1H), 7.34~7.30(m, 1H), 7.06(d, J=7.7Hz, 1H), 6.9 3(dd, J=7.2, 1.6Hz, 1H), 6.85(d, J=8.0Hz, 2H), 4.62(s, 2H), 2.93(s, 3H); 13 C NMR (126MHz, DMF) 153.07, 148.83, 146.14, 142.56, 141.21, 139.77, 134.26, 132.15, 131.82, 131.48, 12 9.21, 128.33, 127.35, 126.62, 126.51, 125.37, 124.44, 123.75, 121.91, 121.76, 116.11, 114.75, 44.90; 195 Pt NMR (107MHz, DMF-d7) -1931.50; HRMS (ESI), C 24 H 18Calculated for Cl3N3Pt, [M+Na] + :671.0112, Actual value:671.0150.

[0159] Example 42. Synthesis of cyclobutane-1,1-dicarboxylate (7-(chloromethyl)-3-(naphthalen-2-yl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine)platinum(II) (1k) [ka] The title product was prepared in two steps detailed below.

[0160] Cyclobutane-1,1-dicarboxylic acid (CBDCA) (138 mg, 0.96 mmol) is dissolved in HO (20 mL) and neutralized with AgO (223 mg, 0.96 mmol). The solution is stirred in the dark at room temperature for 20 min, and cis-[PtCl(DMSO)] (400 mg, 0.99 mmol) is added. The mixture is left at 70 °C for 10 min and then at room temperature for 24 h. A suspension forms, from which an AgCl precipitate is obtained by filtration to concentrate the solution to approximately 5 mL. Finally, the mixture is left at 0 °C until a white precipitate forms. The white precipitate is washed with cold water and dried under vacuum. The complex [Pt(CBDCA)(DMSO)] is obtained as a whitish solid [Ranaldo, R. et al., Inorg. Chem. 2008, 47, 2820-2830].

[0161] [Pt(CBDCA)(DMSO)2] (72 mg, 0.15 mmol) was dissolved in MeOH (10 mL) along with compound (2n) (55 mg, 0.15 mmol), and the resulting mixture was stirred under reflux (65 °C) overnight. The methanol was evaporated, and the resulting yellow solid was washed successively with HO and diethyl ether, and finally redissolved in DCM to give the title product as a yellow solid. Yield: 75%; MP: 310-311 °C; IR: 2944, 1736, 1649, 1618, 1519, 1348, 1218, 1113, 778, 697, 477 cm -1 ; 1H NMR (500MHz, CDCl3) δ9.09(d, J=5.6Hz, 1H), 8.91(s, 1H), 8.74(m, 2H), 8.60~8.52(m, 1H), 8.50(td, J=7.9, 1.6Hz, 1H), 8.33(d, J=1.4Hz, 1H), 8. 28(dd, J=8.4, 1.8Hz, 1H), 8.21~8.10(m, 3H), 8.02(ddd, J=7.4, 5.8, 1.5Hz, 1H), 7.81(d, J=8.3Hz, 1H), 7.67(dd, J=7.2, 1.8Hz, 1H), 5.38(s, 2H); 13 C NMR (101MHz, CDCl3) δ178.74, 153.06, 147.88, 140.98, 138.53, 134.27, 132.09, 131.53, 130.62, 128.86, 128.51 , 128.24, 128.04, 127.73, 126.94, 126.33, 125.17, 124.40, 121.36, 115.98, 114.02, 44.58, 31.47, 30.35, 15.57; 195 Pt NMR(107MHz, CDCl3) -1942.63;HRMS(ESI), C 25 H 16 Calculated for ClN3Pt, [M+H] + :708.0947, Actual value:708.0999.

[0162] Example 43. Synthesis of oxalato(7-(chloromethyl)-3-(naphthalen-2-yl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine)platinum(II) (1l) [ka] The title product was prepared in two steps detailed below.

[0163] cis-[PtCl2(DMSO)2] (250 mg, 0.59 mmol) was dissolved in HO (125 mL) and AgNO3 (196 mg, 1.15 mmol) was added. The resulting mixture was heated in the dark at 50 °C for 6 h and then at room temperature overnight. The resulting suspension was filtered through Celite, and the filtrate was treated with an aqueous solution (1.5 mL) of oxalic acid (74.6 mg, 0.59 mmol) neutralized with KOH (66.4 mg, 1.18 mmol). The resulting mixture was stirred for 24 h until a precipitate formed. The solvent was evaporated under reduced pressure, washed with 1 mL of cold water, and dried in vacuo. [Pt(OXA)(DMSO)2] was obtained as a white solid [Papadia, P. et al., RSC Adv., 2019, 9, 32448-32452].

[0164] [Pt(OXA)(DMSO)] (58 mg, 0.13 mmol) was dissolved in MeOH (10 mL) along with compound (2n) (50 mg, 0.13 mmol). The resulting mixture was stirred under reflux (65 °C) overnight. The solvent was evaporated, and the yellow solid was washed successively with HO and diethyl ether to give the title product as a yellow solid. Yield: 68%; mp: 333-334 °C; IR 3487, 3054, 1699, 1615, 1520, 1350, 1218, 776, 703, 478 cm -1 ; 1 H NMR (500MHz, CDCl3) δ8.75(d, J=5.7Hz, 1H), 8.47(s, 1H), 8.28(s, 1H), 8.21(d, J=8.4Hz, 1H), 8.17(d, J=7.2Hz, 1H), 8.04(d, J=7.7Hz, 1H), 7.97(d, J=7.2Hz, 1H), 7.77~7.68(m, 2H) ), 7.58(dd, J=7.2, 1.6Hz, 1H), 7.53~7.47(m, 1H), 7.38(d, J=8.0Hz, 1H), 7.22(ddd, J=7. 2, 5.6, 1.4Hz, 1H), 7.08(dd, J=7.3, 1.8Hz, 1H), 4.68(s, 2H), 2.83(m, 4H), 1.88(m, 2H).); 195 Pt NMR (107MHz, DMF-d7) -1821.61; HRMS (ESI), C 29 H 22Calculated for ClN3O4Pt, [M+H] + :654.0477, actual value:654.0522.

[0165] Example 44. Synthesis of [dichloro(7-(chloromethyl)-3-(naphthalen-2-yl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine)gold(III)]PF6(1m) [ka] Compound (2n) (50 mg, 0.13 mmol) is dissolved in MeCN (3 mL) and a solution of AuCl3 (40 mg, 0.13 mmol) and AgPF6 (37 mg, 0.14 mmol) in MeCN (5 mL) is added. The resulting solution is stirred at room temperature for 15 minutes. The mixture thus obtained is then filtered to remove AgCl, and the solvent is removed under reduced pressure. Finally, the product is obtained as a reddish solid by precipitation with n-hexane from a DCM solution. Yield: 82%; mp: 182-183 °C; IR 2970, 1703, 1648, 1613, 1502, 1352, 128, 834, 775, 557, 480 cm -1 ; 1 H NMR (500MHz, CD3CN) δ9.56(d, J=6.0Hz, 1H), 9.18(s, 1H), 8.49~8.41(m, 3H), 8.32~8.23(m, 3H), 7.98~7. 86(m, 3H), 7.82(dd, J=8.4, 1.8Hz, 1H), 7.72(d, J=8.0Hz, 1H), 7.57(dd, J=7.2, 1.7Hz, 1H), 5.06(s, 2H); 13 C NMR (126MHz, CD3CN) δ151.00, 147.87, 146.63, 145.62, 145.02, 138.94, 135.30, 134.22, 132.56, 131.44, 1 29.40, 129.35, 128.75, 128.26, 128.00, 127.97, 127.84, 126.89, 124.89, 120.51, 118.51, 113.26, 44.71.

[0166] Example 45. Synthesis of dichloro(7-(chloromethyl)-3-(naphthalen-2-yl)-2-(pyridin-2-yl)imidazo[1,2-a]pyridine)copper(II) (1n) [ka] Dissolve CuCl2 (24 mg, 0.17 mmol) in EtOH (2 mL) and add a solution of compound (2n) (33 mg, 0.09 mmol) in EtOH (1.5 mL). The resulting mixture is left under stirring at room temperature. A pale gray precipitate forms after 15-20 minutes. This is washed with EtOH and dried to give the final product, which is isolated as a pale gray solid. Yield: 46%; mp: 170-171 °C; IR 2970, 1737, 1609, 1505, 1458, 1354, 1217, 1093, 783, 748, 706, 478 cm -1 Due to the paramagnetic nature of this compound, it was not possible to record an NMR spectrum.

[0167] Characterization of the binding of compounds of the present invention to DNA The interaction between molecules of formula (1) and DNA with broken strands was clearly demonstrated by AFM (atomic force microscopy) and TEM (transmission electron microscopy).

[0168] DNA (0.167 mg / ml) from E. coli infected with λ phage was incubated in the presence of Pt(II) compound (10 μM) of formula (1) for 2 to 10 minutes and then analyzed by AFM (Figure 4) and TEM (Figure 5). The behavior of compound (1g) is shown below as an example. Similar results were observed for the other tested compounds, although the incubation times varied.

[0169] Our results show a striking difference between unincubated DNA (Figures 4A and 5A) and DNA after incubation in the presence of compound 1g, especially after 10 minutes of exposure (Figures 4C and 5C). In the AFM recordings, complete degradation is observed after exposure to the metal complex, along with double breaks in the DNA strands. In the TEM images, a significant decrease in DNA density was observed in the samples after incubation with 1g, indicating the presence of multiple damage in the DNA strands.

[0170] These results indicate that in the absence of a cellular barrier, compounds of formula (1) react with DNA within minutes, causing irreversible damage in the two complementary strands in addition to covalent distortion.

[0171] Effect of compounds of formula (1) on cell viability The cell viability of various (tumor or normal) cell cultures was analyzed in the absence or presence of the compound of formula (1) at two different concentrations (10 μM and 20 μM) in static culture medium over 48 h (Figure 6). The cell cultures assayed were extrahepatic and intrahepatic cholangiocarcinoma CCA (EGI-1 and HUCCT1), ovarian cancer (A2780Cis), breast cancer (MDA-453 and MDA-231), and normal human cholangiocyte (NHC) cell cultures. Cell viability was analyzed using the WST-1 cell proliferation assay (Roche) according to the manufacturer's instructions. Cells (2–5 x 10) 4 The cells (800 cells / well) were seeded in their corresponding culture medium onto a collagen-coated 96-well plate and incubated overnight at 37°C. Treatment with the compound of formula (1) and, for comparison, treatment with cisplatin (CisPt) were then added. Cells incubated with vehicle solution were considered the control group. Finally, 10 μL of WST-1 was added to each well and incubated at 37°C for 1 hour. The signal was measured at 450 nm using a Halo LED 96® plate reader (Dynamic Scientific Ltd., UK).

[0172] The data show that compounds 1d, 1e, 1f, 1g, and 1h significantly reduced cell viability in all tumor cell lines (CCA, breast, and ovarian) compared to CisPt or untreated cells (control). Moreover, compound 1a also significantly reduced viability in breast and ovarian tumor cells compared to CisPt.

[0173] It is important to note that the tested compounds did not have any significant effect on the viability of normal bile duct cells. These results were obtained at both 10 μM (FIG. 6) and 20 μM concentrations (FIG. 6) for each molecular entity. Therefore, it can be concluded that these novel synthesized chemotherapeutic compounds are highly potent and selective for tumor cells, but do not affect the viability of normal cells.

[0174] Effect of the compound of formula (1) on cell death (early apoptosis) in different cell cultures Caspase-3 activation is an early cellular event associated with cell death, and therefore its detection by flow cytometry (PhiPhiLux®-G2D2, OncoImmunin, Inc.) is a very useful assay for analyzing one of the first biochemical events associated with apoptosis.

[0175] cells (1~3x10 4 Cells (depending on the cell line) were seeded into 24-well plates in their corresponding culture medium. Once cells adhered, they were incubated with chemotherapeutic agents (at concentrations of 10 μM and 20 μM) or fresh medium (according to the assay). After 48 hours, the supernatant was collected, and the cells were trypsinized and centrifuged at 1500 rpm for 5 minutes at room temperature. The cell pellet was then washed once with cold DPBS 1X (Gibco-Thermo Fisher Scientific). The cells were then irradiated with radioactive caspase-3 substrate (catalog #A304R2G) at 75 μL / 10 6 The cells were labeled at a concentration of 1000kJ / ml and incubated in the dark at 37°C for 60 minutes. After incubation, the cells were 6The cells were washed with flow cytometry dilution buffer at a concentration of 400 cells / mL and centrifuged at 1500 rpm for 5 minutes at room temperature. Finally, the cell pellet was resuspended in flow cytometry dilution buffer at the recommended concentration (400 cells / μL) according to the manufacturer's instructions. Finally, differentially labeled cell populations were distinguished by placing the appropriate filters (532 nm, 543 nm, 561 nm, or 568 nm) on a Guava Easycyte 8HT flow cytometer (Merck Millipore). Labeled but untreated samples were used to establish fluorescence compensation levels. Results are shown relative to vehicle-treated cells or controls.

[0176] The data shown in Figure 8 indicate that Examples 1d, 1g, and 1h caused significantly more early death than CisPt in extrahepatic CCA cells (EGI-1) and intrahepatic CCA cells (HUCCT1), as well as in cisplatin-resistant ovarian cancer cells (at both 10 μM and 20 μM). Furthermore, Compound 1a also induced more death in ovarian tumor cells compared to CisPt. Cell death in breast cancer lines was also increased with Compound 1h compared to CisPt. It is important to note that none of these four compounds induced cell death in normal human cholangiocytes.

[0177] Effect of the compound of formula (1) on cell death (late apoptosis) in different cell cultures Late apoptosis was determined by flow cytometry using dual fluorescent staining with FITC-annexin V (BioLegend) and TO-PROTM-3 iodide (Invitrogen-Thermo Fisher Scientific). FITC-labeled annexin V fluorescent dye (Ex 494 nm / Em 520 nm; green) has a high affinity for Ca, a phospholipid (phosphatidylserine) that is transported to the outer portion of the plasma membrane during early apoptosis. 2+It is a dependent phospholipid-binding protein, whereas the TO-PROTM-3 iodide fluorescent dye (Ex 642 nm / Em 661 nm; red) has a very high affinity for dsDNA after loss of membrane and nuclear integrity, which indicates late apoptosis.

[0178] cells (1~3x10 4 Cells (depending on the cell line) were seeded into 24-well plates in their corresponding culture medium. Once cells adhered, they were incubated with chemotherapeutic agents (at concentrations of 10 μM and 20 μM) or fresh medium (according to the assay). In parallel, a positive cell death control was included by adding 2 μg / mL of puromycin dihydrochloride (Sigma-Aldrich). After 48 h, the supernatant was collected, and cells adhering to the plate were trypsinized and centrifuged at 1500 rpm for 5 min at room temperature. The cell pellet was then washed once with cold DPBS 1X (Gibco-Thermo Fisher Scientific) and diluted 1:10 in Annexin V binding buffer (BioLegend) diluted 1:10 in deionized water (dH2O). 6 The cells were resuspended at a concentration of 100 μg / mL cells / mL. The cells were then placed in a U-bottom 96-well plate (Falcon) and labeled with 100 μg / mL FITC Annexin V fluorescent dye (5 μL / well) for 15 minutes at room temperature in the dark. The cells were then incubated with 1 μM TO-PRO™-3 iodide fluorescent dye (5 μL / well) on ice for 15 minutes in the dark, according to the manufacturer's instructions, and then diluted with Annexin V binding buffer at the recommended concentration. Finally, differentially labeled cell populations were distinguished by placing appropriate filters (525 / 30 nm and 661 / 15 nm) on a Guava Easycyte 8HT flow cytometer (Merck Millipore). The percentage of apoptosis was analyzed using Incyte™ 3.1 software (Merck Millipore). Single-stained samples were used to establish fluorescence compensation levels. The results are shown in FIG. 9 in comparison to cells incubated with vehicle (control).

[0179] The present data revealed that compounds 1d and 1g significantly increased the rate of cell death compared with CisPt in extrahepatic CCA cells (both cisplatin-sensitive and cisplatin-resistant), cisplatin-resistant ovarian cancer cells, and cells from CisPt-resistant breast cancer cell lines. Furthermore, compound 1h had a significant effect on cell death compared with CisPt in intrahepatic CCA cells, CisPt-resistant ovarian cancer cells, and partially CisPt-resistant breast cancer cell lines. Compound 1a induced significantly more death than CisPt in CisPt-resistant ovarian cells. In a related manner, none of these four compounds induced apoptosis in normal human cholangiocytes, as shown in the second right panel of Figure 9.

[0180] Effect of compounds of formula (1) on DNA damage in different cell cultures The cellular DNA damage in various cell cultures caused by a group of novel chemical entities was evaluated using the COMET assay (Comet Assay Kit-ab238544). The assay, also known as single-cell gel electrophoresis (SCGE), is a rapid and sensitive technique for quantifying and analyzing DNA damage in individual cells. As such, the comet assay is one of the techniques used in cancer research to evaluate the genotoxicity and efficacy of chemotherapeutic agents.

[0181] cells (1~3x10 4 Cells (1x10, depending on the cell line) were seeded into 24-well plates in their corresponding culture medium. Once the cells adhered, chemotherapy was added at a concentration of 10 μM, or fresh medium was added (depending on the assay). After 48 hours, the supernatant was discarded, and cells that adhered to the plate were trypsinized and centrifuged at 1500 rpm for 5 minutes. The cell pellet was then washed once with cold 1X DPBS (Gibco-Thermo Fisher Scientific), centrifuged at 1500 rpm for 5 minutes, and the supernatant was discarded. The pellet was then resuspended in 1x10 cells. 5were resuspended in cold 1X DPBS (Gibco-Thermo Fisher Scientific) at a concentration of 100 cells / mL.

[0182] In parallel, the agarose was heated in a bath at 90-95°C for 20 minutes, or until the agarose was liquefied, and then cooled in a bath at 37°C for an additional 20 minutes. Next, 75 μL of agarose per well was added to the slide to create the base. Complete coverage of the wells was ensured by spreading the agarose solution with a pipette tip. The slide was stored horizontally at 4°C for 15 minutes.

[0183] Once the slides were prepared with agarose and the cells were procured, the cells were combined with agarose at a ratio of 1:10, and 75 μL / well of the dilution was transferred to the top portion of the previously prepared agarose layer. Complete coverage of the wells was ensured by carefully spreading the suspension with a pipette tip without disturbing the base layer. The slides were stored horizontally in the dark at 4°C for 15 minutes.

[0184] The slides were carefully submerged in a small container with pre-chilled lysis buffer (approximately 25 mL / slide) for 30-60 minutes at 4°C in the dark. The lysis buffer was carefully aspirated from the container and replaced with pre-chilled alkaline solution (approximately 25 mL / slide) for 30 minutes at 4°C in the dark. This was done to obtain "nucleoids" containing supercoiled DNA bound to the nuclear matrix.

[0185] The slide was then transferred, held horizontally, to an electrophoresis chamber filled with cold alkaline solution. Electrophoresis was performed for 15–30 minutes at a voltage of 1 volt / cm and 300 mA. Thus, cells with broken DNA would lose their supercoiled state and have a greater ability to migrate toward the anode, resulting in the formation of a discontinuity resembling a comet tail—hence the name comet (Figure 10) for this type of experiment. The comet head reflects undamaged DNA, whereas the comet tail reflects damaged cellular DNA. The comet-shaped distribution was visualized by confocal fluorescence microscopy. Therefore, the relative fluorescence of the comet tail relative to the head provides a measure of DNA damage.

[0186] After electrophoresis, the slides were washed with deionized water (dH2O, approximately 25 mL per slide) for 2 minutes. After three washes, the slides were incubated with cold 70% ethanol (approximately 25 mL per slide) for 5 minutes and then air-dried. Once the agarose and slides were completely dry, 100 μL / well of a 1:10,000 dilution of View Green DNA dye in Tris-EDTA (TE) buffer was added and incubated for 15 minutes at room temperature. Finally, the slides were visualized under an LS900 ZEISS confocal microscope.

[0187] Approximately 50-100 comets were visualized and quantified for each condition in each cell type. To quantify DNA damage, the displacement between the genetic material in the nucleus (the comet head) and the resulting tail was measured. The two most common parameters for analyzing comet assay results are tail moment and head DNA %, according to the following formula: Tail DNA%=100×tail DNA intensity / cell DNA intensity Tail moment = tail DNA% × tail moment length

[0188] Our data revealed greater DNA damage in CCA cells treated with the novel compound of formula (1) compared to CisPt, as measured by an increase in the relative amount of DNA in the comet tail, as well as by increased migration of genetic material. This result can be seen both in confocal microscopy images, where greater amounts of genetic material are observed in the comet tail, and in their quantification (Figure 10). Both of the two parameters used, tail moment and tail DNA %, are increased in CCA cells incubated with novel compound (1) compared to CisPt and DMF controls (Figure 10a). Also, in ovarian cancer cells, dissociation of genetic material is observed in the microscopy images (Figure 10b). At the quantitative level, both tail DNA % and tail moment also increased in all four experiments, but this increase was more significant in cells treated with compound (1a) compared to CisPt and the control. This result is consistent with previous results, suggesting that 1a has a more specific effect on CisPt-resistant ovarian cancer cells. In a related manner, none of these four compounds 1a, 1d, 1g, and 1h induced cellular DNA damage in normal human cholangiocytes (Figure 10b).

[0189] Therapeutic effect of the compound of formula (1) on a subcutaneous xenograft model in immunodeficient mice using CCA cells The therapeutic efficacy of the most promising novel compounds was evaluated in a subcutaneous xenograft model of CCA. For that purpose, subcutaneous tumors were grown in a subcutaneous xenograft model of CCA with human CCA cells (EGI-1, 1x10 cells / mL) in each hind flank of mice. 6 Tumors were generated by injecting human tumor cells (1000 cells / 10000 cells) into immunodeficient mice (CD1-Foxn1 un). Immunodeficient mice were used to avoid immunological rejection of the mice against the human tumor cells. Tumor size was then assessed using caliper measurements every two days. Once tumors reached a minimum size of 0.5 cm in diameter, the compound was administered as monotherapy for 4 to 6 weeks. The compound was administered intraperitoneally once a week at a concentration of 0.5 mg / kg.

[0190] In this assay, tumor burden in mice treated with compound 1g stabilized from day 35 (FIG. 11), whereas tumor burden in mice treated with CisPt increased similarly to the control group (DMF) at that concentration. Similarly, when tumors were removed after sacrifice, both tumor burden and weight of tumors treated with compound 1g were significantly lower than those of tumors treated with DMF and CisPt.

[0191] Fluorescence properties of the compound of formula (1) For example, a solution of compound (1a) in DMF at 1:10 -3 at a concentration of 1·10 in DMEM / F12 (modified Eagle's medium:nutrient mixture). -5 The latter was prepared by dissolving compound (1a) in DMF (1.8 10 -3 M). The most relevant photophysical properties of this compound when measured in both media are shown in the table below: [Table 1]

[0192] In the table, λ(exc) and λ(em) are the excitation and emission wavelengths, respectively, expressed in nm; φ is the quantum yield of the fluorescence emission corresponding to λ(em); τ(1 / 2) is the half-life of said emission, expressed in ns, at λ(exc)=340 nm; ε is the M -1 ·cm -1 is the molar extinction coefficient expressed in units; σ is Å 2 is the effective absorption cross section corresponding to ε, expressed in units; finally, B(λ) is expressed as B(λ) = φ × ε, and M -1 ·cm -1 is the intensity of the fluorescent radiation expressed in units.

[0193] As can be seen in the table, compound (1a) exhibited fluorescence in the visible range (FIG. 12), along with useful photophysical properties for monitoring by confocal microscopy.

[0194] Elucidation of the mechanism of uptake and release of the compound of formula (1) To determine the molecular mechanisms underlying the uptake and release of a novel group of chemical entities, we obtained tools consisting of monoclonal or polyclonal cell sublines with homologous or heterologous expression of human proteins involved in hepatic drug transport by lentiviral transduction. In most cases, cells derived from an induced Chinese hamster ovary carcinoma (CHO) were used as the starting cell line due to their homogeneity, ease of manipulation in transport studies, and good plasma membrane expression of transduced constructs. In some cases, cell sublines derived from human liver carcinomas (HepG2 and PLC / PRF / 5), including CCA (TFK1), were also obtained. Transporters were selected because they are involved in the uptake of various antitumor drugs by hepatocytes. These include OATP1B1, OATP1B3, OATP1A2, OATP2B1, OCT1, OCT3, and CTR1. Transporter expression was verified by RT-qPCR, WB, IF, and by transport assays using representative substrates.

[0195] To elucidate the involvement of each transporter in the uptake of these platinized compounds, we performed competition and accumulation experiments. In competition experiments, control and transporter-expressing cells were exposed to a known fluorescent substrate of the transporter in the presence or absence of a typical inhibitor of the transporter or the compound of formula (1), and the intracellular loading of the substrate was determined by end-time flow cytometry. In the second type of experiment, cells were exposed to the corresponding compound (1) for a given time, after which the cells were processed to determine the intracellular content of the compound (1) under study by HPLC-MS / MS.

[0196] The results obtained allowed us to exclude the involvement of OATP1B3 and OATP2B1 from the organic anion transporting polypeptide (OATP) family in the transport of the compound of formula (1). Despite the fact that the presence of the compound stimulates transport mediated by both proteins (which may reflect some interaction of the compound of formula (1) with transporter proteins) (Figure 13), increased accumulation of the compound was observed in cells expressing OATP1B3 or OATP2B1 compared to cells expressing control (pWPI or Mock) (Figures 15 and 16). However, OCT1 and OCT3 (organic cation transporters) mediate the uptake of compounds 1d and 1g, as well as OATP1A2. Co-incubation with the novel compound 1 partially inhibits transport mediated by OCT1, OCT3 (Figure 13), and OATP1A2 (Figure 13), with compound 1d in particular inhibiting OATP1A2. Furthermore, CHO-OCT1, CHO-OCT3, and CHO-OATP1A2 cells took up significantly more 1d and 1g than control cells (Figures 15 and 16). It is important to note that OCT1-, OCT3-, and OATP1A2-mediated transport were not inhibited by cisplatin (Figure 14). This result, together with previously described evidence (PMID: 16914559), suggests that perhaps none of the transporters for the novel compound of formula 1 transports cisplatin.

Claims

1. A compound of the following formula (1): 【Chemistry 1】 During the ceremony, M is a metal center selected from Pt(II), Cu(II) and Au(III), with the proviso that when M is Au(III), formula (I) is Cl － , P.F. ６ － , and R ８ C(O)O － (In the formula, R ８ is C １ ~C ６ an anion selected from the group consisting of alkyl groups; X １ and X ２ are both chlorides, or together, ( － OC(O)-C(O)-O － ), ( － OC(O)-C(R ９ ) (R １０ )-C(O)O － ) and ( － OC(O)-CH(R １１ ) O － ) in which an oxygen atom (O － ) is attached to the metal center, and R ９ and R １０ is independently C １ ~C ６ alkyl group, or both together with the carbon to which they are attached form a C ４ ~C ６ forms a cycloalkyl group, and R １１ is C １ ~C ６ is an alkyl group; Z １ is hydrogen, or Z ２ can form a single covalent bond together with Z ２ is hydrogen, halogen, or Z １ and can form a single covalent bond together, or at least one C １ ~C ６ R forming an aryl group optionally substituted with alkyl groups, halogens, or OH ５ can be bonded to; Y is N or CR １２ where R １２ is H, or C optionally substituted at the end of the chain by halogen or hydroxyl １ ~C ６ an alkyl group; or a leaving functional group; R １ ~R ４ are independently H; C optionally substituted at the chain end by halogen or hydroxyl １ ~C ６ an alkyl group; and a leaving functional group; R ５ ~R ７ are all H, or R ５ ~R ６ Versus or R ６ ~R ７ At least one C １ ~C ６ C optionally substituted with alkyl groups, halogens, or hydroxyl ６ An aryl group can be formed.

2. 2. The compound of formula (1) according to claim 1, wherein M is Pt(II).

3. X １ and X ２ are both chlorides, or together, ( － OC(O)-C(O)-O － ) and ( － OC(O)-C(R ９ ) (R １０ )-C(O)-O － ) in which an oxygen atom (O － ) is attached to the metal center, and R ９ and R １０ together with the carbon to which they are connected to form C ４ ~C ６ 3. The compound according to claim 1 or 2, which forms a cycloalkyl group.

4. Y is N or CR １２ and R １２ is H or C １ ~C ６ The compound according to any one of claims 1 to 3, which is an alkyl group.

5. The compound of claim 4, wherein Y is -CH-.

6. Z ２ is hydrogen, halogen, or Z １ can form a single covalent bond together with C ６ R forming an aryl group ５ The compound according to any one of claims 1 to 5, which is capable of binding to

7. R １ A compound according to any one of claims 1 to 6, wherein is a methyl substituted at the end of the chain by a halogen or is a leaving functionality.

8. R ５ ~R ７ are all H, or R ５ ~R ６ Versus or R ６ ~R ７ In pairs, they are united as one, C ６ A compound according to any one of claims 1 to 7, capable of forming an aryl group.

9. The following compound: 【Chemistry 2】 or a salt, solvate or stereoisomer thereof A compound of formula (1) selected from:

10. A method for preparing a compound of formula (1), comprising reacting a compound of formula (2): 【Transformation 3】 (In the formula, Y, Z １ , Z ２ , R １ ~R ７ has the meaning defined in claim 1) The compound Gold trichloride (AuCl ３ ), copper dichloride (CuCl ２ ), and the following formula (3): 【Chemistry 4】 (In the formula, X １ and X ２ has the meaning defined in claim 1, and DMSO represents the dimethyl sulfoxide ligand. with a metal salt selected from the group consisting of platinum salts of

11. The compound of formula (2) is reacted with the compound of formula (4): 【Transformation 5】 (In the formula, Y is N;CR １２ where R １２ is H, or C optionally substituted at the end of the chain by halogen or hydroxyl １ ~C ６ an alkyl group; a leaving functional group; or C(O)OMe; R １ ~R ４ are independently H; C optionally substituted at the chain end by halogen or hydroxyl １ ~C ６ an alkyl group; a leaving functional group; and a C(O)OMe group. and a compound of the following formula (5): 【Transformation 6】 (In the formula, R ５ ~R ７ has the meaning defined in claim 1; A is H, a halogen, a trifluoromethylsulfonyl group, or a trialkylsilyl group; B is a halogen, a trifluoromethylsulfonyl group, or a trialkylsilyl group; provided that one of A and B is a trifluoromethylsulfonyl group or a trialkylsilyl group.

11. The method of claim 10, further comprising the prior step of preparing by a process comprising a coupling reaction or cycloaddition reaction between a compound of formula (I) and a compound of formula (II).

12. The compound of formula (4) is reacted with the compound of formula (6): 【Transformation 7】 (In the formula, R １ and R ２ are independently H; C optionally substituted at the chain end by halogen or hydroxyl １ ~C ６ an alkyl group; a leaving functional group; and a C(O)OMe group. and a compound of the following formula (7): 【Transformation 8】 (In the formula, Y is N;CR １２ where R １２ is H; C optionally substituted at the chain end by halogen or hydroxyl １ ~C ６ an alkyl group; a leaving functional group; or C(O)OMe; R ３ and R ４ are independently H; C optionally substituted at the chain end by halogen or hydroxyl １ ~C ６ an alkyl group; a leaving functional group; and a C(O)OMe group; L represents a halogen, a methylsulfonyl group, or a p-toluenesulfonyl group.

12. The method of claim 11, further comprising the prior step of preparing by a process comprising a condensation reaction between the compound of formula (I) or its hydrobromide salt.

13. R １ , R ２ , R ３、 or R ４ 13. The method of claim 11 or 12, wherein when either of the formula (I) is a C(O)OMe ester group, it further comprises replacing the ester with a methyl group substituted at the end of the chain by a halogen or hydroxyl, or by a leaving functional group.

14. The following formula (2): 【Chemistry 9】 or a salt, solvate or stereoisomer thereof, However, in the formula, Z １ is hydrogen, or Z ２ can form a single covalent bond together with Z ２ is hydrogen, halogen, or Z １ and can form a single covalent bond together, or at least one C １ ~C ６ R forming an aryl group optionally substituted with alkyl groups, halogens, or OH ５ can be bonded to; Y is N or CR １２ where R １２ is H; C optionally substituted at the chain end by halogen or hydroxyl １ ~C ６ an alkyl group; or a leaving functional group; R １ ~R ４ are independently H; C optionally substituted at the chain end by halogen or hydroxyl １ ~C ６ an alkyl group; a C(O)OMe group; and a leaving functional group; R ５ ~R ７ are all H, or R ５ ~R ６ Pair or R ６ ~R ７ At least one C １ ~C ６ C optionally substituted with alkyl groups, halogens, or hydroxyl ６ can form an aryl group; However, Z １ =Z ２ =R １ =R ２ =R ３ =R ４ =R ５ =R ６ =R ７ = H and Y = CR １２ Compounds where =CH are not included.

15. The following compound: 【Chemistry 10】 15. The compound of formula (2) according to claim 14, or a salt, solvate or stereoisomer thereof, selected from:

16. A pharmaceutical composition comprising a compound of formula (1) as defined in any one of claims 1 to 9, or a pharmaceutically acceptable salt, solvate or stereoisomer thereof, and a pharmaceutically acceptable excipient or vehicle thereof.

17. A compound of general formula (1) as defined in any of claims 1 to 9, or a pharmaceutically acceptable salt, or stereoisomer, or solvate, or prodrug thereof, for use as a medicinal product, or a pharmaceutical composition as defined in claim 16.

18. A compound of formula (1) as defined in any of claims 1 to 9, or a pharmaceutically acceptable salt, or stereoisomer, or solvate, or prodrug thereof, or a pharmaceutical composition as defined in claim 16, for use in the treatment of proliferative diseases, autoimmune diseases, and viral infections.

19. 19. The compound or composition for use according to claim 18, wherein the proliferative disease is a cancer selected from intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, ovarian cancer, and breast cancer.

20. 20. The compound or composition for use according to claim 19, wherein the cancer is caused in the A2780Cis ovarian cancer cell line, the MDA-453 breast cancer cell line and the MDA-231 breast cancer cell line, or the EGI-1 extrahepatic cholangiocarcinoma cell line and the HUCCT1 intrahepatic cholangiocarcinoma cell line.

21. 21. The compound or composition for use according to claim 19 or 20, wherein the cancer has developed resistance to other anti-cancer drugs as a result of previous chemotherapy cycles.

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