Ethacrynic Acid Derivatives as Inhibitors of MPRO Protease and SARS-COV-2 Replication

Abstract

The present invention relates to novel compounds of formula (I) and (II), their use as drugs, in particular for the treatment of SARS-CoV-2, COVID-19 disease and any disease associated with β-coronaviruses, and for their in vitro application to study the interaction with Mpro protease. The present invention also relates to pharmaceutical compositions comprising at least one compound of formula (I) or (II) as an active ingredient. JPEG2024517333000078.jpg81162

Description

[Background technology]

[0001] Several coronaviruses can cause respiratory infections ranging from the common cold to more severe diseases such as Middle East Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). COVID-19 disease or Severe Acute Respiratory Syndrome is also caused by a virus from the Coronaviridae family. This virus was first discovered in Wuhan, Hubei Province, China and named SARS-CoV-2 [Zhu et al, N. Engl. J. Med. 2020, 382, ​​727-73; Li et al, N. Engl. J. Med. 2020, 382, ​​1199-1207]. Sequencing of the SARS-CoV-2 genome shows that it is 79.6% identical to SARS-CoV [Wu et al, Nature 2020, 579, 265-269; Zhou et al, Nature 2020, 579, 270-273].

[0002] M pro Protease (3CL pro Also known as M, is an enzyme required for the production of proteins, which are then important for viral development and replication. This protease is currently considered to be one of the most promising targets for the development of anti-SARS-CoV-2 treatments. This includes M, whose chemical composition and X-ray diffraction structure are now well characterized. pro This will require the discovery of molecules capable of inhibiting the viral replication [Zhang et al., Science 2020, 368, 409-412]. The enzyme, in the form of a dimer, contains a catalytic site characterized by the presence of two key amino acids, namely His41 and Cys145. Moreover, this site is directly involved in the production of amino acids and proteins required for viral replication [Dai et al., Science 2020, 368, 1331-1335] (Figure 1).

[0003] Following the emergence of the SARS-CoV virus in 2002 and 2003, proSeveral studies have been conducted worldwide to develop small antiviral molecules that can inhibit M. It should be noted that this protease is also present in SARS-CoV and its structure has not changed much compared to that found in SARS-CoV-2 last year [Zhang et al., Science 2020, 368, 409-412]). pro It should also be noted that M has no homologue in humans, which is another reason why it is a major target for antiviral drug development [Kim et al., PLOS Pathog. 2016, 12, e1005531; Yang et al., PLOS Biol. 2005, 3, e324]. Furthermore, M pro is conserved in several β-coronaviruses (MERS, SARS-CoV, SARS-CoV-2), allowing the development of treatments for not only the current disease but also future diseases in the event of other health crises caused by other forms of β-coronaviruses. [Prior art documents] [Patent documents]

[0004] [Non-Patent Document 1] Zhu et al,N.Engl.J.Med.2020,382,727-73 [Non-Patent Document 2] Li et al,N.Engl.J.Med.2020,382,1199-1207 [Non-Patent Document 3] Wu et al,Nature 2020,579,265-269 [Non-Patent Document 4] Zhou et al,Nature 2020,579,270-273 [Non-Patent Document 5] Zhang et al,Science 2020,368,409-412 [Non-Patent Document 6] Dai et al.,Science 2020,368,1331-1335 Summary of the Invention

[0005] Since the beginning of the health crisis at the end of 2019, SARS-CoV-2 M pro Very interesting studies on protease inhibition have been published in very well-known journals [Jin et al, Nature 2020, 582, 289-293; Zhang et al, Science 2020, 368, 409-412; Dai et al, Science 2020, 368, 1331-135; Jin et al, Nat. Struct. Mol. Biol. 2020, 27, 529-532]. Following the analysis of these various studies, some crucial and important information for the design and development of anti-SARS-CoV-2 are summarized in the following sections. [Brief description of the drawings]

[0006] [Figure 1] The three-dimensional structure of Mpro is shown in two different views rotated by 90°. The figure also shows the location of the catalytic site composed of His41 (blue ball) and Cys145 (yellow ball), as well as the structure of the enzyme as a dimer. [Diagram 2] This includes a representation of the binding surface between the Mpro active site and the ligand (active substance). Thanks to this recent work, the team of Dai, Zhang, Jiang and Su has provided two molecules, 11a and 11b (Figure 2), each containing an aldehyde covalently bound to Cys145, a cyclohexyl or 3-fluorophenyl to occupy pocket S2, and an indole to hydrogen bond with pocket S4 [Dai et al., Science 2020, 368, 1331-1335]. The IC50 (half maximal inhibitory concentration) of compounds 11a and 11b is 0.053 and 0.040 μM, respectively. [Diagram 3] The structures of product N3 and ebselen are shown. [Figure 4] 1 shows the mode of interaction between carmofur and the active sites of Mpro. [Diagram 5]1 shows the antiviral activity of compounds GRL-1720 and 5h against SARS-CoV-2, as well as the X-ray diffraction structure of compound 5h complexed with Mpro protease. [Figure 6] The structures of the compounds synthesized and tested are shown. [Figure 7] The structures of the compounds and their binding modes with Mpro are shown. [Figure 8] Illustrative examples of cytopathic effects are shown. [Figure 9] The percentage reduction in infectious titer of molecules P7, P26 and P30 at different concentrations is shown. [Figure 10] The percentage reduction in infectious titer by molecules P7, P26 and P30 is shown. [Figure 11] An illustration of the interaction of ligand P7 with aa in the active site of Mpro is shown. [Figure 12] RT-PCR of genes RdRP, N, and E on SARS CoV-2. [Figure 13] The IC50 values ​​of three compounds, P7, P26 and P30, are shown. [Figure 14] The results of a docking analysis of the position and orientation in the active site are shown. [Figure 15] Data for each type of binding established between the ligand and an aa in the active site of MPRO are shown. [Figure 16] 1 shows a synthesis scheme for compounds of formula I and II.

[0007] Peptide mimetic compounds N3 (Figure 3) and M pro Based on the mechanism of interaction between SARS-CoV-2 M and N3, Jiang, Rao and Yang used computer-aided drug design to identify inhibitors and then synthesized SARS-CoV-2 M complexed with compound N3. pro The crystal structure of was determined. High-throughput virtual screening analyzed over 10,000 compounds, including approved drugs, drug candidates in clinical trials, and other biologically active compounds. As a result of this study, six compounds were identified with IC values ​​ranging from 0.67 to 21.4 μM. 50 Value Mpro One of these six compounds, ebselen, also showed promising antiviral activity at the cellular level (Figure 3) [Jin et al., Nature 2020, 582, 289-293].

[0008] In another study, Zhang and Yang's team used X-ray structure to identify M pro We were able to highlight the mode of interaction between β-lactamase and carmofur (which has been used since 1980 for the treatment of colorectal cancer [Sakamoto et al., Jpn J. Clin. Oncol. 2005, 35, 536-544]). This compound establishes a covalent bond with the catalytic site, i.e. Cys145, while the alkyl (hydrophobic) part occupies pocket S2 (Figure 4) [Jin et al., Nat. Struct. Mol. Biol. 2020, 27, 529-532] (Figure 3). The anti-SARS-CoV-2 activity (IC 50 = 1.82 μM) was first revealed by the same team after screening 10,000 compounds [Jin et al., Nature, 2020, 582, 289-293].

[0009] Very recently, M pro As inhibitors, two new molecules, called GRL-1720 and 5h, were developed by Mitsuya and colleagues. Using cell-based studies on VeroE6 cells and RNA replication by qPCR, the researchers found that both compounds had EC values ​​of 15 ± 4 and 4.2 ± 0.7 μM for GRL-1720 and 5h, respectively. 50 Further studies by X-ray diffraction analysis showed that compound 5h inhibits SARS-CoV-2 infection at M values ​​through polar interactions with several amino acid residues in the active site. pro We showed that it forms covalent bonds with α-terminal β-terminal 1,2-diphenyl ether (PA) as well as other bonds (Figure 5) [Hattori et al, Nat. Commun., 2021, 12:668].

[0010] Also very recently, Rut, Drag and co-workers reported the design and synthesis of pseudopeptide inhibitors of SARS-CoV-2 from a mixture of natural and unnatural amino acids (Figure 6). The best molecule, Ac-QSS-VS (15) (Ac-Abu-dTyr-Leu-Gln-VS), had an EC 50 In addition, another molecule called B-QS1-VS (13) (Biotin-PEG(4)-Abu-Leu-Gln-VS) was used to bind to the SARS-CoV-2 M pro The fluorescence of the synthesized compound allowed the detection of SARS-CoV-2 M in nasopharyngeal epithelial cells of patients suffering from COVID-19 infection. pro monitored the interaction between the active site of and inhibitors [Rut et al, Nat. Chem. Biol. 2021, 17, 222-228].

[0011] Despite numerous recent efforts, there is still no cure for COVID-19. pro After the determination of the crystal structure of (Jin et al., Nature 2020, 582, 289-293), most of the published studies focused on M pro This is related to molecular modeling to study the interaction between the active site of M and several bioactive compounds (antivirals, anticancer drugs, etc.) that are already on the market or in clinical development (Yoshino et al., Sci. Rep. 2020, 10, 12493; Bolcato et al. Sci. Rep. 2020, 10, 20927). For example, based on the crystal structure published by Jin et al. (Jin et al., Nature, 2020, 582, 289-293), the majority of the compounds studied by molecular modeling have been shown to inhibit the action of M by mimicking the action of the peptidomimetic N3. proIt targets the inhibition of the active site (Figure 7) and its mechanism of action involves an electrophilic chemical group (Michael acceptor) that can covalently bond with Cys145 (Figure 7A). For example, in the paper reported by W. Cui, K. Yang and H. Yang, the study of carmofur (Figure 7B) by molecular modeling shows that the carboxylic acid functional group of carmofur is bound to the sulfur atom of Cys145 by a 1.8 Å covalent bond, while the fatty acid tail is inserted into pocket S2. The whole carmofur molecule is stabilized by numerous hydrogen bonds and hydrophobic interactions. In contrast, the inhibitor N3 (Figure 7A) is inserted via a different mechanism, forming a covalent bond with Cys145 by Michael addition of a thiol to the vinyl group. On the other hand, M pro and the peptidomimetic α-ketoamides GC-376 and 13b (Fig. 1C and 1D), on the other hand, M pro Regarding the binding mode between and aldehyde 11a (Figure 1E), modeling studies also showed that the carbonyl group of these compounds is covalently bound to Cys145, while other groups present on these same compounds occupy sites S1, S2, S3 and S4 of the protease, establishing hydrophobic and hydrogen interactions (Cui et al., Front. Mol. Biosci., 2020, 7, 616341).

[0012] The inventors have developed new anti-SARS-CoV-2 compounds and MHCs that are better suited to practical needs, especially due to their simplicity of preparation. pro (or 3CL pro ) protease inhibitors have been designed and prepared. These compounds may have potential use in human therapy.

[0013] This object is achieved by the compounds of formula (I) and (II) described below and which are the first object of the present invention, which have potent anti-SARS-CoV-2 and -M pro In addition, the compounds are generally easy to prepare in 2-4 steps. All compounds of formula (I) and (II) are very conveniently obtained using very simple chemical reactions well known in the literature.

[0014] The present invention relates to compounds of formulae (I) and (II) below.

[0015] [ka] During the ceremony, W and Z may be the same or different and independently represent hydrogen, a halogen atom, hydroxyl or an amine, preferably W is a hydrogen or chlorine atom and Z is a chlorine, fluorine, bromine atom or hydroxyl, V, X and Y may be the same or different and each independently represent a carbon, nitrogen, oxygen or sulfur atom, preferably V and X are nitrogen atoms and Y is a carbon or nitrogen atom. -U is a carbon atom or one or more nitrogen atoms replacing a carbon atom of a six-membered aromatic ring, preferably U is a carbon atom or one or two nitrogen atoms. -n and n' may be the same or different and independently represent the length of alkyl, hydroxy, perfluoroalkyl, alkylthio, aminoalkyl and alkoxy chains which may contain from 1 to 10 carbon atoms. -R1, R2, R3 and R4 may be the same or different and each independently represent hydrogen, a halogen atom, hydroxy, alkoxy, alkyl, aryl, heteroaryl or amine, wherein the alkyl, hydroxy, perfluoroalkyl, alkylthio, aminoalkyl and alkoxy groups may contain 1 to 10 carbon atoms.

[0016] For the purposes of this invention, the term: -Alkyl: refers to a saturated straight or branched chain hydrocarbon aliphatic group having 1 to 10 carbons, preferably 1 to 2 carbon atoms. The term "branched" means that at least one lower alkyl group, such as methyl or ethyl, is carried by a straight alkyl chain (higher alkyl). The term "lower" alkyl refers to an alkyl group having 1 or 2 carbon atoms, and the term "higher" alkyl refers to a straight or branched chain alkyl group having 3 to 10 carbon atoms. By way of example, alkyl groups include methyl, ethyl, n-propyl, isobutyl, tert-butyl, n-butyl, and n-pentyl. - halogen atom: denotes a bromine, chlorine, iodine or fluorine atom, with bromine, chlorine and fluorine being the preferred designations. - Perfluoroalkyl: an alkyl group defined below in which all hydrogen atoms are replaced with fluorine atoms. Among perfluoroalkyl groups, a trifluoromethyl group and a perfluoroethyl group are preferred. - alkoxy: denotes an O-alkyl group, in which the alkyl group may have the same meaning as above. As examples of alkoxy groups, mention may be made of methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy and pentoxy groups. -Alkylthio: denotes an S-alkyl group, in which the alkyl group may have the same meaning as above. As examples of alkylthio groups, mention may be made of methylthio, ethylthio, propylthio, isopropylthio, butylthio and pentylamino groups. -aminoalkyl: denotes an N-alkyl group, in which the alkyl group may have the same meaning as above. As examples of aminoalkyl groups, mention may be made of the aminomethyl, aminoethyl, iso-propylamino, butylamino and pentylamino groups. - Aryl: refers to an unsaturated cyclic aromatic hydrocarbon group having 4 to 6 carbon atoms, preferably 5 to 6 carbon atoms. Heteroaryl: denotes an aryl as defined above in which one or more carbon atoms are replaced by a nitrogen, oxygen or sulfur atom.As examples of heteroaryl groups, mention may be made of pyridine, pyrimidine, thiophene, furan, imidazole, pyrrole and triazole groups.

[0017] According to one preferred embodiment of the invention, the compounds of formulae (I) and (II) are selected from those in which Z and W represent halogen and alkoxy, preferably hydroxy.

[0018] According to one preferred embodiment of the invention, the compounds of formulae (I) and (II) are selected such that X and Y represent a nitrogen atom and a carbon atom or two nitrogen atoms.

[0019] According to one preferred embodiment of the invention, the compounds of formula (I) and (II) are those in which n and n' represent a chain length of 0 to 3 carbons, preferably selected from those in which n and n' are equal to 0 and 1.

[0020] According to one preferred embodiment of the invention, the compounds of formulae (I) and (II) are selected from those in which R1, R2, R3 and R4 represent hydrogen, alkyl, hydroxy and alkylamine, preferably hydrogen, methyl, aminomethyl and hydroxy.

[0021] Compounds of formulae (I) and (II) include the following:

[0022] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-indol-5-yl)acetamide of the following formula:

[0023] [ka] (Compound P5);

[0024] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-indazol-5-yl)acetamide of the formula:

[0025] [ka] (Compound P7);

[0026] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1H-indol-4-yl)acetamide of the formula:

[0027] [ka] (Compound P11);

[0028] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1H-indol-5-yl)acetamide of the formula:

[0029] [ka] (Compound P12);

[0030] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1H-indol-6-yl)acetamide of the formula:

[0031] [ka] (Compound P13);

[0032] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-indazol-4-yl)acetamide of the following formula:

[0033] [ka] (Compound P18);

[0034] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-indazol-6-yl)acetamide of the following formula:

[0035] [ka] (Compound P20);

[0036] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-indazol-7-yl)acetamide of the following formula:

[0037] [ka] (Compound P21);

[0038] 1-(4-(2-(1H-indazol-1-yl)-2-oxoethoxy)-2,3-dichlorophenyl)-2-methylenebutan-1-one of the following formula:

[0039] [ka] (Compound P22);

[0040] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1H-indazol-5-yl)acetamide of the formula:

[0041] [ka] (Compound P26);

[0042] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(2-methyl-2H-indazol-6-yl)acetamide of the following formula:

[0043] [ka] (Compound P29);

[0044] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(2-methyl-2H-indazol-7-yl)acetamide of the following formula:

[0045] [ka] (Compound P30);

[0046] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(2-methyl-2H-indazol-4-yl)acetamide of the following formula:

[0047] [ka] (Compound P31);

[0048] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(14(4-methoxyphenyl)-sulfonyl)-1H-indazol-5-yl)acetamide of the following formula:

[0049] [ka] (Compound P32);

[0050] tert-Butyl 5-(2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetamido)-1H-indazole-1-carboxylate of the following formula:

[0051] [ka] (Compound P33);

[0052] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-(prop-2-yn-1-yl)-1H-indazol-4-yl)acetamide of the following formula:

[0053] [ka] (Compound P34);

[0054] tert-Butyl (2-(2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetamido)ethyl)-carbamate of the formula:

[0055] [ka] (Compound P35);

[0056] tert-Butyl (1-(2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetyl)piperidin-4-yl)carbamate of the formula:

[0057] [ka] (Compound P36);

[0058] N-(2-chloroethyl)-2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetamide of the formula:

[0059] [ka] (Compound P37);

[0060] tert-Butyl 4-(2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetyl)piperazine-1-carboxylate of the following formula:

[0061] [ka] (Compound P38);

[0062] N-butyl-2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetamide of the formula:

[0063] [ka] (Compound P39);

[0064] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-((1-methyl-1H-indazol-5-yl)methyl)acetamide of the following formula:

[0065] [ka] (Compound P40);

[0066] 1-(2,3-dichloro-4-(2-(5-methyl-1H-indazol-1-yl)-2-oxoethoxy)phenyl)-2-methylene-butan-1-one of the following formula:

[0067] [ka] (Compound P41);

[0068] 1-(2,3-dichloro-4-(2-oxo-2-(1H-pyrazolo[4,3-b]pyridin-1-yl)ethoxy)phenyl)-2-methylenebutan-1-one of the formula:

[0069] [ka] (Compound P42);

[0070] 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-benzo[d]imidazol-5-yl)acetamide of the formula:

[0071] [ka] (Compound P43);

[0072] Preparation of compounds -All analogues are synthesized according to reaction scheme 1 below. - The amines used are generally prepared in two steps according to the standards of the literature [Swarna et al, J. Med. Chem. 2002, 45, 3, 740-743; Down et al, J. Med. Chem. 2015, 58, 18, 7381-7399; Usninn et al, Chem. Commun. 2012, 48, 2680-2682]. Ethacrynic acid (EA) is then treated with various amines via an amidation reaction carried out according to the procedure described in Scheme 1. This procedure was carried out at room temperature in the presence of activating agents, such as N,N'-dicyclohexylcarbodiimide (DCC), hydroxybenzotriazole (HOBt) and 4-dimethylaminopyridine (DMAP) in DCM. The desired products are obtained in satisfactory yields after purification on a silica gel column.

[0073] Synthesis protocols and characterization of various compounds according to the invention Solvents were dried according to standard methods and distilled under nitrogen before use. All reagents were used without prior purification from conventional commercial sources. 13 C carbon and 1 H proton nuclear magnetic resonance (NMR) spectra were recorded on a JEOL AC500 (500 MHz) instrument. Chemical shifts (δ) are reported in ppm relative to the residual TMS reference peak. JNM-ECZ500R / S1 FT NMR system (JEOL).

[0074] Experimental protocol Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-indol-5-yl)acetamide (P5)

[0075] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 1-methyl-1H-indol-5-amine (24.12 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (9: 1 to 8: 2 (v / v)) to give the expected product P5 as a white solid (48 mg in 67% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):8.56(s,1H),7.95(d,J=2.0 Hz,1H),7.38(dd,J=2.0,8.7 Hz,1H),7.32(d,J=8.7 Hz,1H),7.25(d,J=3.1 Hz,1H),7.38(d,J=3.1 Hz,1H),6.97(d,J=8.5 Hz,1H),6.53-6.48(m,1H),5.99(s,1H),5.64(s,1H),4.75(s,2H),3.82(s,3H),2.51(q,J=7.4 Hz,2H),1.18(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz), δ(ppm):195.50,164.30,154.41,150.27,134.53,134.33,131.55,129.90,128.95,12 8.75,128.53,127.32,115.52,112.73,111.12,109.44,101.10,68.40,32.90,23.40,12.40.

[0076] Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-indazol-5-yl)acetamide (P7)

[0077] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 1-methyl-1H-indazol-5-amine (24.29 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (4: 1 (v / v)) to give the expected product P7 as a white solid (55 mg in 77% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):8.63(s,1H),8.14(d,J=1.5 Hz,1H),8.01-7.96(m,1H),7.49(dd,J=1.5,8.9 Hz,1H),7.40(d,J=8.9 Hz,1H),7.24(d,J=8.5 Hz,1H),6.96(d,J=8.5 Hz,1H),5.99(s,1H),5.63(s,1H),4.74(s,2H),4.09(s,3H),2.50(q,J=7.4 Hz,2H),1.18(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz), δ(ppm):195.42,164.62,154.33,150.19,137.70,134.59,132.85,131.56,129.85,12 8.85,127.36,124.05,123.07,120.75,112.05,111.25,109.47,68.48,35.63,23.46,12.43.

[0078] Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1H-indol-4-yl)acetamide (P11)

[0079] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 1H-indol-4-amine (21.78 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (9: 1 (v / v)) to give the expected product P11 as a white solid (37 mg in 51% yield).

[0080] Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1H-indol-5-yl)acetamide (P12)

[0081] [ka] To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 5-aminoindole (21.81 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (4: 1 (v / v)) to give the expected product P12 as a white solid (44 mg in 64% yield). 1 H NMR (CDCl 3,500 MHz),δ(ppm):8.57(s,1H),8.36(s,1H),7.97(s,1H),7.41-7.29(m,2H),7.27-7.18(m,2H),6.92(d,J=8.7 Hz,1H),6.56(s,1H),5.99(s,1H),5.63(s,1H),4.72(s,2H),2.51(q,J=7.4 Hz,2H),1.18(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz)δ(ppm):195.54,164.53,154.44,150.23,134.33,133.54,131.55,129.24,128.86,128 .07,127.27,125.45,123.06,116.06,112.66,111.35,111.15,102.85,68.46,23.43,12.43.

[0082] Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1H-indol-6-yl)acetamide (P13)

[0083] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 1H-indole-6-amine (21.78 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (9: 1 (v / v)) to give the expected product P13 as a white solid (35 mg in 49% yield).

[0084] Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-indazol-4-yl)acetamide (P18)

[0085] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 1-methyl-1H-indazol-4-amine (24.29 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (4: 1 (v / v)) to give the expected product P18 as a white solid (41 mg in 58% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):8.96(s,1H),8.07(d,J=1.0 Hz,1H),7.90(d,J=7.5 Hz,1H),7.40(dd,J=8.4,7.6 Hz,1H),7.26-7.19(m,1H),6.94(d,J=8.5 Hz,1H),5.97(s,1H),5.60(s,1H),4.82-4.75(m,1H),4.77(s,2H),4.09(s,3H),2.47(q,J=7.4 Hz,2H),1.15(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz), δ(ppm):195.59,164.73,154.14,150.27,140.95,134.66,131.82,129.44,129.09,12 9.02,127.48,127.38,122.95,116.70,111.13,110.95,106.02,68.14,35.92,23.48,12.47.

[0086] Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-indazol-6-yl)acetamide (P20)

[0087] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 1-methyl-1H-indazol-6-amine (24.29 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (4: 1 (v / v)) to give the expected product P20 as a white solid (55 mg in 77% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):8.74(s,1H),8.24-8.13(m,1H),7.93(d,J=1.0 Hz,1H),7.68(dd,J=8.5,0.8 Hz,1H),7.23(d,J=8.5 Hz,1H),6.93(d,J=1.6 Hz,1H),5.97(s,1H),5.60(s,1H),4.74(s,2H),4.11(s,1H),4.07(s,3H),2.35(q,J=7.4 Hz,2H),1.13(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz), δ(ppm):195.40,164.92,156.89,137.16,132.80,131.75,129.07,127.46,1 21.86,121.41,119.04,114.40,111.28,99.64,68.43,49.26,35.78,23.48,12.47.

[0088] Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-indazol-7-yl)acetamide (P21)

[0089] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 1-methyl-1H-indazol-7-amine (24.29 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (4: 1 (v / v)) to give the expected product P21 as a white solid (34 mg in 44% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):7.98(s,1H),7.66(dd,J=8.1,1.0 Hz,1H),7.50(dt,J=7.5,1.0 Hz,1H),7.25(d,J=8.5 Hz,1H),7.19-7.13(m,1H),6.97(d,J=8.5 Hz,1H),5.97(s,1H),5.60(s,1H),4.82(s,2H),4.36(s,1H),4.27(s,3H),2.47(t,J=7.4 Hz,2H),1.15(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz), δ(ppm):195.52,166.41,156.88,150.28,135.04,134.82,133.22,131.85,129.07,12 7.48,126.97,124.55,121.13,120.64,118.98,111.09,68.41,49.25,38.47,23.47,12.47.

[0090] Preparation of 1-(4-(2-(1H-indazol-1-yl)-2-oxoethoxy)-2,3-dichlorophenyl)-2-methylenebutan-1-one (P22)

[0091] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 1H-indazole (19.47 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with DCM to give the expected product P22 as a white solid (41 mg in 62% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):8.44(d,J=8.4 Hz,1H),8.23(s,1H),7.97(d,J=8.4 Hz,1H),7.65-7.63(m,1H),7.46-7.44(m,1H),7.15(d,J=8.5 Hz,1H),6.94(d,J=8.7 Hz,1H),5.96(s,1H),5.71(s,2H),5.65(s,1H),2.49(q,J=7.4 Hz,2H),1.17(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz)δ(ppm):195.80,166.41,155.46,155.60,150.10,141.20,139.00,133.84,131.55, 130.12,128.50,126.00,125.21,123.41,121.20,115.11,111.00,67.40,23.41,12.40.

[0092] Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1H-indazol-5-yl)acetamide (P26)

[0093] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 1H-indazol-5-amine (21.91 mg, 0.165 mmol) at 0 °C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (4:1 (v / v)) to give the expected product P26 as a white solid (34 mg in 50% yield). RMN 1 H(CDCl 3 ,500 MHz),δ(ppm):13.01(s,1H),10.19(s,1H),8.11(s,1H),8.03(s,1H),7.51(d,J=8.9 Hz,1H),7.45(d,J=8.9 Hz,1H),7.36(d,J=8.6 Hz,1H),7.20(d,J=8.6 Hz,1H),6.08(s,1H),5.59(s,1H),4.98(s,2H),2.38(q,J=7.4 Hz,2H),1.08(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz), δ(ppm):195.60,165.60,156.10,149.80,137.05,133.09,132.90,131.70,130.00 ,129.80,128.00,123.10,121.60,120.80,112.04,110.70,110.60,68.40,23.40,12.80.

[0094] Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(2-methyl-2H-indazol-6-yl)acetamide (P29)

[0095] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 2-methyl-2H-indazol-6-amine (24.29 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (4: 1 (v / v)) to give the expected product P29 as a white solid (41 mg in 58% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):8.65(s,1H),7.92-7.82(m,1H),7.71-7.58(m,1H),7.59(d,J=2.8 Hz,1H),7.35(d,J=8.5 Hz,2H),7.23-7.10(m,1H),6.90(d,J=8.5 Hz,1H),5.95(d,J=1.6 Hz,1H),5.59(s,1H),5.28(s,1H),4.69(s,2H),4.18(s,3H),2.44(q,7.4 Hz,2H),0.98(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz), δ(ppm):201.31,164.57,150.23,134.64,133.00,130.88,129.93,128.82,127.97,12 6.97,125.26,124.17,121.09,117.09,115.29,111.26,110.90,68.29,48.24,23.47,11.06.

[0096] Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(2-methyl-2H-indazol-7-yl)acetamide (P30)

[0097] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 2-methyl-2H-indazol-7-amine (24.29 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (4: 1 (v / v)) to give the expected product P30 as a white solid (33 mg in 46% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):9.59(s,1H),8.17(dd,J=7.3,0.8 Hz,1H),7.86(s,1H),7.38(dd,J=8.4,0.8 Hz,1H),7.19(d,J=8.4 Hz,1H),7.07(dd,J=8.5,7.3 Hz,1H),6.92(d,J=8.5 Hz,1H),5.95(t,J=1.5 Hz,1H),5.59(d,J=1.0 Hz,1H),4.75(s,2H),4.20(s,3H),2.47(q,J=7.4 Hz,2H),1.14(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz), δ(ppm):195.81,165.00,154.65,150.30,141.98,134.28,131.60,128.94,127.26,12 6.37,124.25,123.59,122.48,122.44,115.82,113.22,111.00,68.39,40.57,23.50,12.48.

[0098] Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(2-methyl-2H-indazol-4-yl)acetamide (P31)

[0099] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 2-methyl-2H-indazol-4-amine (24.29 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (4: 1 (v / v)) to give the expected product P31 as a white solid (40 mg in 56% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):8.72(s,1H),7.98(d,J=0.9 Hz,1H),7.55-7.50(m,2H),7.30-7.20(m,2H),6.93(d,J=8.5 Hz,1H),5.97(s,1H),5.59(s,1H),4.74(s,2H),4.22(s,3H),2.47(q,J=7.4 Hz,2H),1.14(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz), δ(ppm):195.56,164.45,154.20,150.27,149.99,134.63,131.70,129.08,128.30,12 7.57,126.33,122.84,121.96,116.44,114.78,112.25,111.11,68.24,40.70,23.48,12.47.

[0100] Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(14(4-methoxyphenyl)sulfonyl)-1H-indazol-5-yl)acetamide (P32)

[0101] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 1((4-methoxyphenyl)sulfonyl)-1H-indazol-5-amine (50.06 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (4:1 (v / v)) to give the expected product P32 as a white solid (49 mg in 51% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):8.69(s,1H),8.22-8.14(m,3H),7.93-7.86(m,2H),7.53(dd,J=8.9,2.1 Hz,1H),7.22(d,J=8.5 Hz,1H),6.93(d,J=8.5 Hz,1H),6.92-6.86(m,2H),5.97(s,1H),5.59(s,1H),4.72(s,2H),3.80(s,3H),2.47(q,J=7.4 Hz,2H),1.14(t,J=7.5 Hz,3H). 13 C NMR (CDCl 3,126 MHz), δ(ppm):195.55,165.02,164.29,154.25,150.25,141.31,137.72,134.78,133.18,131.75,129.99,12 9.07,128.79,127.46,126.43,123.10,122.74,114.57,113.95,112.15,111.33,68.39,55.80,23.48,12.47.

[0102] Preparation of tert-butyl 5-(2-(2,3-dichloro-4-(2-methylenebutanoyl)-phenoxy)acetamido)-1H-indazole-1-carboxylate (P33)

[0103] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added tert-butyl 5-amino-1H-indazole-1-carboxylate (38.49 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (4: 1 (v / v)) to give the expected product P33 as a white solid (49 mg in 57% yield). 1 H NMR (CDCl 3,500 MHz),δ(ppm):8.70(s,1H),8.28-8.24(m,1H),8.19-8.13(m,2H),7.52(dd,J=9.0,2.1 Hz,1H),7.22(d,J=8.5 Hz,1H),6.93(d,J=8.5 Hz,1H),5.96(t,J=1.5 Hz,1H),5.59(d,J=1.0 Hz,1H),4.73(s,2H),2.47(q,J=7.4 Hz,2H),1.72(s,9H),1.14(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz), δ(ppm):195.56,164.93,154.32,150.26,149.16,139.61,137.19,134.73,132.77,131.74,12 9.05,127.47,126.35,123.11,122.29,115.27,111.84,111.31,85.23,68.41,28.25,23.47,12.46.

[0104] Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-(prop-2-yn-1-yl)-1H-indazol-4-yl)acetamide (P34)

[0105] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 1-(prop-2-yn-1-yl)-1H-indazol-4-amine (28.22 mg, 0.165 mmol) at 0 ° C. The mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (9: 1 (v / v)) to give the expected product P34 as a white solid (41 mg in 55% yield).1 H NMR (CDCl 3 ,500 MHz),δ(ppm):8.97(s,1H),8.11(dd,J=4.4,1.0 Hz,1H),7.94-7.91(m,1H),7.42-7.39(m,1H),7.25-7.22(m,1H),6.94(d,J=8.5 Hz,1H),5.96(s,1H),5.60(s,1H),5.19(s,2H),5.06-4.99(m,1H),4.77(s,2H),2.47(q,J=7.4 Hz,2H),2.41(t,J=2.6 Hz,1H),1.15(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz)δ(ppm):195.59,164.73,154.12,150.27,140.29,134.68,132.55,131.83,130.34,129.63,12 9.05,127.88,127.49,118.16,111.78,111.32,110.94,106.36,74.02,68.12,39.24,23.48,12.47.

[0106] Preparation of tert-butyl (2-(2-(2,3-dichloro-4-(2-methylenebutanoyl)-phenoxy)acetamido)ethyl)-carbamate (P35)

[0107] [ka] To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added tert-butyl (2-aminoethyl)carbamate (26.44 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (4: 1 (v / v)) to give the expected product P35 as a white solid (48 mg in 66% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):7.20(d,J=8.6 Hz,1H),6.68(d,J=8.6 Hz,1H),5.97(s,1H),5.60(s,1H),4.88(br,1H),4.59(s,2H),3.55-3.51(m,2H),3.36-3.32(m,2H),2.49(q,J=7.4 Hz,2H),1.44(s,9H),1.17(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz), δ(ppm):195.52,172.46,167.33,154.63,150.22,134.24,131.55,130.9 7,128.78,127.19,123.19,110.97,68.26,40.36,39.75,28.35,23.45,12.35.

[0108] Preparation of tert-butyl (1-(2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetyl)piperidin-4-yl)carbamate (P36)

[0109] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added tert-butyl piperidin-4-ylcarbamate (33.05 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (4: 1 (v / v)) to give the expected product P36 as a white solid (39 mg in 49% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):7.16(d,J=8.6 Hz,1H),6.99(d,J=8.6 Hz,1H),5.96(s,1H),5.62(s,1H),4.93-4.73(m,2H),3.47-3.42(m,2H),4.04- 4.02(m,1H),3.70(br,1H),3.26-3.16(m,1H),2.90-2.79(m,1H),2.49(q,J=7.4 Hz,2H),2.09-1.98(m,2H),1.46(s,9H),1.37-1.25(m,2H),1.16(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz), δ(ppm):198.01,195.81,165.04,155.23,155.03,150.26,133.76,128.75,127.14 ,110.64,68.83,44.43,41.33,33.95,33.13,32.05,28.35,25.63,24.95,23.43,12.41.

[0110] Preparation of N-(2-chloroethyl)-2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetamide (P37)

[0111] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol), triethylamine (0.033 mL, 0.248 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 2-chloroethylamine hydrochloride (19.14 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred overnight at room temperature. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with DCM to give the expected product P37 as a white solid (33 mg in 55% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):7.24(br,1H),7.22(d,J=8.6 Hz,1H),6.89(d,J=8.6 Hz,1H),5.98(s,1H),5.61(s,1H),4.62(s,2H),3.84-3.66(m,4H),2.50(q,J=7.4 Hz,2H),1.17(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz),δ(ppm):195.50,166.09,154.40,150.20,134.30,131.50,128.70,127.02,110.09,110.08,68.10,43.05,40.70,23.40,12.40.

[0112] Preparation of tert-butyl 4-(2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetyl)piperazine-1-carboxylate (P38)

[0113] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added tert-butyl piperazine-1-carboxylate (30.69 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (9: 1 to 8: 2 (v / v)) to give the expected product P38 as a white solid (43 mg in 56% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):7.17(d,J=8.5 Hz,1H),6.99(d,J=8.5 Hz,1H),5.96(s,1H),5.61(s,1H),4.85(s,2H),3.62-3.55(m,4H),3.47-3.45(m,4H),2.55-2.41(m,2H),1.49(s,9H),1.16(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz), δ(ppm):195.77,165.40,155.08,154.42,150.18,133.85,131.48,128.72,127 .10,110.64,80.52,68.77,45.48,42.13,33.97,29.70,28.37,23.42,12.40,12.39.

[0114] Preparation of N-butyl-2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetamide (P39)

[0115] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added n-butylamine (12.05 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (9: 1 (v / v)) to give the expected product P39 as a white solid (39 mg in 65% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):7.19(d,J=8.6 Hz,1H),6.87(d,J=8.6 Hz,1H),6.79(br,1H),5.96(s,1H),5.59(s,1H),4.57(s,2H),3.39(q,J=7.4 Hz,2H),2.47(q,J=7.4 Hz,2H),1.63-1.53(m,2H),1.47-1.32(m,2H),1.15(t,J=7.4 Hz,3H),0.95(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz), δ(ppm):195.50,166.51,154.50,150.10,134.10,131.40,128.70,1 27.20,122.80,110.80,68.20,38.80,31.40,23.40,19.90,13.70,12.30.

[0116] Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-((1-methyl-1H-indazol-5-yl)methyl)acetamide (P40)

[0117] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added (1-methyl-1H-indazol-5-yl)methanamine (26.56 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (9: 1 (v / v)) to give the expected product P40 as a white solid (37 mg in 51% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):7.94(d,J=1.0 Hz,1H),7.69(dd,J=8.3,0.8 Hz,1H),7.33(t,J=1.0 Hz,1H),7.17(d,J=8.5 Hz,1H),7.08(dd,J=8.3,1.4 Hz,1H),6.86(d,J=8.5 Hz,1H),5.93(s,1H),5.55(s,1H),4.71(d,J=6.0 Hz,2H),4.64(s,2H),4.23(br,1H),4.05(s,3H),2.45(q,J=7.4 Hz,2H),1.12(t,J=7.4 Hz,3H).RMN 13 C(CDCl 3 ,126 MHz)δ(ppm):195.64,166.87,156.96,154.51,150.25,140.14,136.07,134.39,132.77,131.61 ,128.96,127.34,123.62,121.77,120.59,111.05,107.86,68.36,43.60,35.69,23.47,12.46.

[0118] Preparation of 1-(2,3-dichloro-4-(2-(5-methyl-1H-indazol-1-yl)-2-oxoethoxy)phenyl)-2-methylenebutan-1-one (P41)

[0119] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 5-methyl-1H-indazole (21.78 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred overnight at room temperature. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with DCM to give the expected product P41 as a white solid (40 mg in 58% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):8.26(d,J=8.5 Hz,1H),8.11(s,1H),7.55-7.49(m,1H),7.41(dd,J=8.5,1.6 Hz,1H),7.11(d,J=8.5 Hz,1H),6.89(d,J=8.5 Hz,1H),5.93(s,1H),5.66(s,2H),5.62(s,1H),2.48(s,3H),2.47-2.42(m,2H),1.13(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz)δ(ppm):196.07,166.34,155.78,150.25,141.09,137.55,135.34,133.83,131.93,129 .17,128.80,126.92,126.58,123.47,120.74,114.79,111.02,67.45,23.51,21.42,12.47.

[0120] Preparation of 1-(2,3-dichloro-4-(2-oxo-2-(1H-pyrazolo[4,3-b]pyridin-1-yl)ethoxy)phenyl)-2-methylenebutan-1-one (P42)

[0121] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 1H-pyrazolo[4,3-b]pyridine (19.64 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred at room temperature overnight. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (9: 1 (v / v)) to give the expected product P42 as a white solid (35 mg in 53% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):8.77(dd,J=4.6,1.4 Hz,1H),8.67(dt,J=8.4,1.4 Hz,1H),8.43(d,J=0.9 Hz,1H),7.52(dd,J=8.4,4.6 Hz,1H),7.13(d,J=8.4 Hz,1H),6.91(d,J=8.4 Hz,1H),5.94(t,J=1.5 Hz,1H),5.70(s,2H),5.61(s,1H),2.46(q,J=7.4,2H),1.13(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz):195.97,166.81,155.54,150.25,149.26,144.20,141.89,134.14,132.72 ,131.74,128.86,126.89,124.03,123.62,123.01,111.08,67.27,23.49,12.47.

[0122] Preparation of 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-benzo[d]imidazol-5-yl)acetamide (P43)

[0123] [ka] - To a solution of DCC (37.45 mg, 0.182 mmol), HOBt (30.32 mg, 0.198 mmol), DMAP (2.02 mg, 0.017 mmol) and EA (50 mg, 0.165 mmol) in DCM (5 mL) is added 1-methyl-1H-benzo[d]imidazol-5-amine (24.26 mg, 0.165 mmol) at 0 ° C. The reaction mixture is stirred overnight at room temperature. After extraction with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated under pressure. The obtained residue is purified by column chromatography eluting with a mixture (DCM / EtOAc (9: 1 (v / v)) to give the expected product P43 as a white solid (56 mg in 79% yield). 1 H NMR (CDCl 3 ,500 MHz),δ(ppm):8.66(s,1H),8.05(d,J=1.8 Hz,1H),7.98(s,1H),7.63(dd,J=1.8,8.6 Hz,1H),7.40(d,J=8.6 Hz,1H),7.25(d,J=8.5 Hz,1H),6.97(d,J=8.5 Hz,1H),5.99(s,1H),5.63(s,1H),4.76(s,2H),3.88(s,3H),2.51(q,J=7.4 Hz,2H),1.18(t,J=7.4 Hz,3H). 13 C NMR (CDCl 3 ,126 MHz):195.41,164.52,154.32,150.10,144.51,143.91,134.51,132.20,131.70,131.61 ,128.82,127.31,123.10,116.81,112.10,111.21,109.50,68.41,31.11,23.41,12.42.

[0124] biological activity protocol The fastest way to find an effective drug against COVID-19 is to conduct clinical trials with drugs already used for other diseases, because we know how to administer them and know their effective doses (drug repositioning strategy). However, inhibitors of a given protease are not necessarily effective at blocking another protease with different structural and functional properties. pro Molecules from the family of α,β-unsaturated ketones (Michael acceptors) capable of blocking proteases represent a real hope for treating patients. Some, such as telaprevir and boceprevir, which were among the first protease inhibitors prescribed in 2011 to treat patients with hepatitis C, are already in clinical use. The development of protease inhibitors should benefit from a substantial source in order to rapidly develop effective treatments against COVID-19.

[0125] We used the microneutralization test described by Amanat F et al [Amanat et al, Curr Protoc Microbiol 2020, 58, e108] to quantitatively evaluate whether antibodies or drugs are able to block SARS-CoV-2 entry and / or replication in vitro. To do this, we perform the microneutralization test in a 96-well format that allows a medium throughput. While the test first described by Amanat et al. [Amanat et al., Curr Protoc Microbiol 2020, 58, e108] is based on the staining of the viral nucleoprotein (NP) by an Elisa test, we chose a test based on RT-PCR with the amplification of the genes encoding the viral nucleoprotein (N), the RNA-dependent polymerase (R) and the envelope gene (E), respectively. This approach was also used by David et al [David et al, Nature 2020, 583, 459-468] and allows for a quantitative assessment of inhibition, thus substantiating the visual observation of cytopathic effect (CPE).

[0126] Experimental Department biology The anti-SARS-CoV-2 activity of the candidate molecules has been studied in vitro in Vero cells. The characteristics of the infection of Vero cells by SARS-CoV-2 have been described by Yajing [Yao et al, Virol Sin. 2020, 35, 348-350]. The Vero cell line is derived from green monkey kidney cells isolated in 1962. The Vero-E6 and Vero cells used in this study were obtained at 39 and 159 passages, respectively, from two cell banks (INRA Toulouse, France) and (Societe Biopharma, Rabat, Morocco). Culture medium formulations containing glucose and L-glutamine were used.

[0127] Culture of Vero-E6 and Vero cells Cell culture and infection with SARS-CoV-2 virus were performed in a biosafety level 3 (BSL-3) laboratory. Cells were cultured in a culture medium containing 6% fetal calf serum (FCS) and 2% donor serum (DS), hereafter referred to as reference medium (RM). The first step of cell expansion was to culture 30,000 cells.cm for Vero-E6 cells. -2 , and 40,000 cells.cm for Vero cells. -2 175cm 2 These cultures are maintained at 37 °C and 5% CO 2 Place in a 37°C controlled incubator. For cell passage, cells were trypsinized and the cell suspension was collected and used for subsequent seeding. The culture volume was then adjusted with fresh ECM that had been previously brought to 37°C.

[0128] Isolation and confirmation of SARS-CoV-2 SARS-CoV-2 virus isolation was performed in a biosafety laboratory L3 (BSL-3) from two nasopharyngeal and oropharyngeal samples found positive in a female patient admitted to the Centre de Virologie et Maladies Infectieuses Tropicales (CVMIT), Hôpital Militaire d'Instruction Mohammed V, Rabat (279CC). Virus isolation is performed according to the protocol described in (Harcourt et al., bioRxiv, 2020) using a conservation medium called INOC. Cytopathic effect (CPE) is visible from the first passage (Figure 8). Confirmatory tests of virus growth in Vero cells were performed on cell supernatants extracted with a Viral RNA Mini Kit (QIAGEN, Hilden, Germany) and amplified by qRT-PCR using the IVD GeneFinder™ COVID-19 PLUS RealAmp Assay Kit (Korea).

[0129] Whole genome sequencing of isolated SARS-CoV-2 viruses in culture Sequencing of the complete viral genome was performed using NGS (Ion proton, ThermoFisher) and Sanger sequencing. The viral genetic material used for sequencing is extracted from passage P4 of the 279CC strain on Vero-E6. The sequence of the complete genome obtained by Sanger sequencing has been deposited in the international GISAID database under the reference hCoV-19 / Morocco / HMIMV-279CC / 2020 Accession ID: EPI-ISL-971451.

[0130] Virus adaptation, growth, production and recovery The 279CC virus isolated from Vero-E6 on INOC medium is then adapted to Vero cells from passage 2 (P2). Virus growth and production were performed on T500cm plates containing INOC medium. 2It is carried out in stationary culture flasks. Virus production continues for 5 days after infection. Daily aliquots allow monitoring the increase in virus titer and monitoring cell growth and metabolism. Virus is harvested 5 days after infection. Culture supernatants are then clarified by centrifugation, aliquoted and frozen at -80°C.

[0131] Viral titer determination Infectious titers were determined in the culture supernatant of infected cells and calculated according to the Reed-Münch method (1938). They were obtained using the limiting dilution infection technique and were expressed as TCID 50 / mL (50% tissue culture infectious dose) or log TCID 50 It is expressed as / mL.

[0132] As examples of compounds of formula (1) or (2), compounds P7, P26 and P30 are selected to illustrate the biological tests carried out.

[0133] Screening synthetic molecules to assess their antiviral efficacy Molecular concentration determination The three compounds are solubilized in DMSO according to their molar concentrations.

[0134] Cytotoxicity Testing Cytotoxicity tests consisted mainly of the assessment of cell viability by the fluorescent dye propidium iodide (logos, Biosystems, USA) after 24 and 48 h of incubation using an automated cell counter integrated with fluorescence optics and image analysis software (Luma, logos, Biosystems, USA).

[0135] The cytotoxicity of the different compounds was determined by the average cell number of each test in a plate of uninfected cells. The results are shown in Figure 1A and are expressed as a percentage (%).

[0136] Determination of the antiviral effect of molecules Antiviral screening of molecules: Cultures were 2.5 x 10 5The infections are carried out in 96-well culture plates with a volume of 100 μl of MEC medium at a density of 100 cells / mL. The protocol used follows a preventive approach (in vitro infection after 4 hours of incubation). In fact, the cells are incubated for 4 hours with or without the compounds to be tested, then incubated at 37 °C, 5% CO at an MOI (multiplicity of infection) of 0.04. 2 Infect in INOC for 48 hours under RT.

[0137] The effect on in vitro virus production (antiviral effect) was assessed by qRT-PCR after 48 h of incubation and by measuring the infectious titer in Vero cells (logDITC 50 / mL or DITC 50 The ratio of the infectious titers in each condition is expressed as a function of the infectious titer measured in the control condition (untreated).

[0138] The infectious titer measured in the experimental conditions in which the compound being tested is present is significantly reduced compared to the control conditions in which the cells are infected but untreated.

[0139] Indeed, the molecules P7 (16.6 μM), P26 (16.6 μM) and P30 (5.54 μM) allow a reduction of the infectious titer of 100%, 97.96% and 96.75%, respectively, compared to the control (see FIG. 9).

[0140] Based on these results, the effective concentration range was determined and therefore the IC 50 To determine the half-maximal inhibitory concentration (HAI), i.e., the dose required to obtain 50% inhibition of virus production, a wider range of concentrations was tested for each of the three compounds on Vero cells under the same experimental conditions (see FIG. 10).

[0141] Indeed, at 10 μM, the molecules P7, P26 and P30 allow a reduction in the infectious titer of 100%, 93.09% and 100%, respectively, compared to the control (see FIG. 2). At 8 μM, the inhibition rates of these molecules are of the order of 96.70%, 52.14% and 99.67%, respectively. At 6 μM, only P26 and P30 inhibited viral replication by about 30%, while P7 did not inhibit viral replication at all at this concentration.

[0142] The inhibitory effect of the three molecules on the replication of SARS-CoV-2 strains was confirmed by RT-PCR against three viral genes, namely gene RdRP, gene N and gene E (Table 1).

[0143] The IC of these three compounds 50 The values ​​are listed in the following table (Table 2): These ICs 50 These values ​​are relatively low compared to the usual concentrations known for non-infectious applications of these compounds. These values ​​are the cytotoxic concentrations (CC 50 ) is also far away.

[0144] SARS-CoV-2 M pro Protein Structure 3CL pro (M pro The structure of SARS-CoV-2 3CL was downloaded from the Protein Data Bank (PDB ID: 6LU7). pro and its inhibitor covalently bound to Cys145 [Jin et al, Nature 2020, 582, 289-293]. This structure has been energy minimized in Rosetta [Leaver-Fay et al, Methods Enzymol. 2011, 487, 545-574].

[0145] Docking Steps: 1-3CL pro (M proThe structure of 6LU7 (PDB ID: 6LU7) was optimized by adding its polar hydrogens as well as partial charges of all its atoms. The protein backbone was fixed during minimization. The model with the lowest score out of 1000 models was selected. MGLTools (version 1.5.6) was used to generate the PDBQT file for docking.

[0146] Compound P7 is chosen as an example of a compound of formula (1) or (2) to illustrate molecular modeling studies.

[0147] 2-Ligand optimization: Ligands selected for molecular docking were optimized by adding partial charges and hydrogen atoms followed by energy minimization using the PRODRG server (http: / / davapcl.bioch.dundee.ac.uk / cgi-bin / prodrg / ).

[0148] 3- Preparation of configuration file and potential grid calculation. A configuration file was prepared to run AutoDock Vina. AutoDockTools was used to pro Prepare an "input.PDBQT" file for and define the location and dimensions of the box (X;Y;Z). The size of the grid is set to 20x20x20 points (x, y and z) and the center of the grid is set to -10.729204, 12.417653 and 68.816122 in the x, y and z dimensions, respectively. The prepared file was saved in the ".PDBQT" format.

[0149] 4-Molecular Docking A molecular docking process is used to explore possible ligand positions and orientations, taking full advantage of the specificity of the docking site and the potential interactions of the docked ligands. AutoDock Vina (version 1.1.2) [Trott et al, J. Comput. Chem. 2010, 31, 455-461; Zhang et al, J. Mol. Recognit. 2016, 29, 520-527] is used to match the synthesized molecules to the M pro The ligand docking simulations keep the receptor rigid yet flexible.

[0150] 5- Search for docking solutions The best docking solution takes into account the various ways each ligand binds to the receptor, and calculates the kcal.mol -1 The aim is to find the most likely position and orientation for the active pocket that has the lowest energy in units (Table 3).

[0151] 5-Analyzing the results The best solution or pose was then evaluated by Discovery Studio Biovia 2021 software (Dassault Systemes, San Diego, California, USA) and investigated using PyMOL by docking score, ranking and distance between the reactive atom of Cys145 and the sulfur atom in the original structure described previously [Ai et al., J. Chem. Inf. Model. 2016, 56, 1563-1575].

[0152] Post-docking analysis showed the size and location of the binding site, hydrogen bond interactions, hydrophobic interactions, and binding distance as an interaction radius of <5 Å from the fixed ligand position. The compounds were docked into the active site, and then the binding pose of each ligand was observed, their interactions with the protein were characterized, and the most energetically favorable conformation of each ligand was selected ( FIG. 11 ).

[0153] The physicochemical properties of the synthesized molecules (Table 4) fulfilled the criteria of Lipinski's rule of five, also known as Lipinski's druglikeness rules. These rules allow the assessment of the structural similarity of a compound to that of an active oral drug, based on its physicochemical profile. Molecular weight and hydrogen bond interactions between donors and acceptors are important structural determinants of protein targets and ligand binding sites [Lipinski et al, Adv. Drug Deliv. Rev. 2016, 101, 34-41; Lipinski et al, Adv. Drug Deliv. Rev. 2001, 46, 3-26; Zhang et al, Curr. Opin. Biotechnol. 2007, 18, 478-88]. In particular, compounds are more likely to be permeable and active as ligands if they have 5 or fewer hydrogen bond donors and 10 or fewer hydrogen bond acceptors, a molecular mass less than 500, and a calculated log P value (CLog P) less than 5 [Lipinski et al., Adv. Drug Deliv. Rev. 2001, 46, 3-26; Zhang et al, Curr. Opin. Biotechnol. 2007, 18, 478-88].

Claims

1. A compound characterized by having the following formulae (I) and (II): 【Chemistry 1】 During the ceremony, W and Z may be the same or different and independently represent hydrogen, a halogen atom, hydroxyl or an amine, preferably W is hydrogen or a chlorine atom and Z is chlorine, fluorine, bromine or hydroxyl; V, X and Y may be the same or different and each independently represent a carbon, nitrogen, oxygen or sulfur atom, preferably V and X are nitrogen atoms and Y is a carbon or nitrogen atom; U is a carbon atom or one or more nitrogen atoms replacing said carbon atoms of a 6-membered aromatic ring, preferably U is a carbon atom or one or two nitrogen atoms; n and n' may be the same or different and independently represent the length of alkyl, hydroxy, perfluoroalkyl, alkylthio, aminoalkyl and alkoxy chains, which may contain from 1 to 10 carbon atoms; Compounds in which R1, R2, R3 and R4 may be the same or different and independently represent hydrogen, a halogen atom, hydroxy, alkoxy, alkyl, aryl, heteroaryl or amine, said alkyl, hydroxy, perfluoroalkyl, alkylthio, aminoalkyl and alkoxy groups may contain 1 to 10 carbon atoms.

2. As compounds of formula (I) or (II), mention may be made in particular of the following: 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-indol-5-yl)acetamide of the following formula: 【Chemistry 2】 (Compound P5); 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-indazol-5-yl)acetamide of the following formula: 【Chemistry 3】 (Compound P7); 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1H-indol-4-yl)acetamide of the following formula: 【Chemistry 4】 (Compound P11); 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1H-indol-5-yl)acetamide of the following formula: 【Chemistry 5】 (Compound P12); 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1H-indol-6-yl)acetamide of the following formula: 【Chemistry 6】 (Compound P13); 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-indazol-4-yl)acetamide of the following formula: 【Chemistry 7】 (Compound P18); 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-indazol-6-yl)acetamide of the following formula: 【Chemistry 8】 (Compound P20); 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-indazol-7-yl)acetamide of the following formula: 【Chemistry 9】 (Compound P21); 1-(4-(2-(1H-indazol-1-yl)-2-oxoethoxy)-2,3-dichlorophenyl)-2-methylenebutan-1-one of the following formula: 【Chemistry 10】 (Compound P22); 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1H-indazol-5-yl)acetamide of the following formula: 【Chemistry 11】 (Compound P26); 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(2-methyl-2H-indazol-6-yl)acetamide of the following formula: 【Chemistry 12】 (Compound P29); 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(2-methyl-2H-indazol-7-yl)acetamide of the following formula: 【Chemistry 13】 (Compound P30); 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(2-methyl-2H-indazol-4-yl)acetamide of the following formula: 【Chemistry 14】 (Compound P31); tert-Butyl 5-(2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetamido)-1H-indazole-1-carboxylate of the following formula: 【Chemistry 15】 (Compound P33); 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-(prop-2-yn-1-yl)-1H-indazol-4-yl)acetamide of the following formula: 【Chemistry 16】 (Compound P34); tert-Butyl (2-(2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetamido)ethyl)-carbamate of the formula: 【Chemistry 17】 (Compound P35); tert-Butyl (1-(2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetyl)piperidin-4-yl)carbamate of the formula: 【Chemistry 18】 (Compound P36); N-(2-chloroethyl)-2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetamide of the formula: 【Chemistry 19】 (Compound P37); tert-Butyl 4-(2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetyl)piperazine-1-carboxylate of the following formula: 【Chemistry 20】 (Compound P38); N-butyl-2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)acetamide of the formula: 【Chemistry 21】 (Compound P39); 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-((1-methyl-1H-indazol-5-yl)methyl)acetamide of the following formula: 【Chemical 22】 (Compound P40); 1-(2,3-dichloro-4-(2-(5-methyl-1H-indazol-1-yl)-2-oxoethoxy)phenyl)-2-methylenebutan-1-one of the following formula: 【Chemistry 23】 (Compound P41); 1-(2,3-dichloro-4-(2-oxo-2-(1H-pyrazolo[4,3-b]pyridin-1-yl)ethoxy)phenyl)-2-methylenebutan-1-one of the following formula: 【Chemistry 24】 (Compound P42); 2-(2,3-dichloro-4-(2-methylenebutanoyl)phenoxy)-N-(1-methyl-1H-benzo[d]imidazol-5-yl)acetamide of the following formula: 【Chemistry 25】 (Compound P43).

3. A compound of formula (I) or (II) as defined in claim 1 or claim 2 for application as a medicament.

4. A compound of formula (I) or (II) as claimed in claim 3 for application as a drug for the treatment of COVID-19 disease.

5. A compound of formula (I) or (II) as claimed in claim 3 for application as a drug for the treatment of pathologies caused by β-coronavirus.

6. A compound of formula (I) or (II) as claimed in claim 3 for in vitro application to inhibit SARS-CoV-2 replication.

7. M ｐｒｏ A compound of formula (I) or (II) according to claim 3 for in vitro application to inhibit proteases.

8. As a research tool, especially M ｐｒｏ 4. Use of a labeled compound of formula (I) or (II) according to claim 3 for the identification of molecules capable of interacting with the active site of a protease.

9. A compound of formula (I) or (II) as defined in claim 1 or claim 2 for use as an active ingredient in a pharmaceutical composition.

10. 3. A compound of formula (I) or (II) as defined in claim 1 or claim 2 for use in combination with other drugs in a pharmaceutical composition.

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