Stress granule formation promoter and broad-spectrum antiviral composition comprising same

Abstract

The present invention relates to a stress granule formation promoter and a broad-spectrum antiviral agent comprising same. Specifically, the stress granule formation promoter of the present invention promotes the formation of stress granules, which is an innate anti-viral immune response, and thus can be applied to various viruses. In addition, the stress granule formation promoter of the present invention has weaker cytotoxicity than a pre-developed stress granule formation promoting compound, thereby reducing the risk of side effects while exhibiting an improved antiviral effect, and thus is expected to be used as a broad-spectrum antiviral therapeutic agent.

Description

Stress granule formation promoter and broad-spectrum antiviral composition comprising the same

[0001] The present invention relates to a stress granule formation promoter and a broad-spectrum antiviral composition comprising the same.

[0002]

[0003] Stress granules are dynamic RNA-protein complexes that exist within the cytoplasm without forming membranes. They form in response to various external stimuli, such as oxidative stress, UV damage, nutrient deficiency, and viral infection. When stress granules are activated, cells can conserve energy required for protein synthesis while simultaneously strengthening their defense mechanisms against invasion by external pathogens (e.g., viruses). During this process, translation is temporarily halted, inhibiting the indiscriminate production of harmful proteins and RNA. At the same time, key immune sensors such as RIG-I, MDA5, and PKR gather within stress granules, promoting downstream signaling (e.g., IRF3 activation). This enhances the innate immune response by increasing the expression of interferon (IFN) and interferon-inducible genes (ISGs). By transmitting infection signals to surrounding cells, stress granules function as an immune platform that activates the overall defense system.

[0004] Despite the antiviral effects of stress granules, many viruses, including coronaviruses, maximize their own replication by interfering with stress granule formation or disrupting their internal proteins. For example, SARS-CoV-2 partially modulates intracellular translation and immune signaling processes to delay stress granule formation, exploiting the delay to initiate genome replication and protein synthesis. Because viral genomes rapidly change through mutation, existing antiviral agents that directly inhibit viral proteins are prone to developing resistance. In contrast, strategies that suppress overall viral replication by enhancing the host's stress response and innate immune mechanisms offer the potential to broadly respond to mutant viruses.

[0005] The inventors of the present invention have developed a novel antiviral strategy to overcome these limitations and promote stress granule formation, a host innate immune response. Specifically, based on compound C01 developed through prior research, they synthesized various C01 derivatives, and among them, they identified promising candidates, including compound SB2960, which exhibited significantly reduced cytotoxicity at high concentrations.

[0006]

[0007] The inventors of the present invention have developed a novel antiviral strategy to overcome these limitations and promote stress granule formation, a host innate immune response. Specifically, based on compound C01 developed through prior research, they synthesized various C01 derivatives, and among them, they identified promising candidates, including compound SB2960, which exhibited significantly reduced cytotoxicity at high concentrations.

[0008]

[0009] An object of the present invention is to provide a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof:

[0010] [Chemical Formula 1]

[0011]

[0012] In the above chemical formula 1

[0013] R 2 is substituted or unsubstituted, straight or branched C1-C6 alkyl; substituted or unsubstituted, straight or branched C1-C6 alkylacetyl; or -L2R 2A and;

[0014] R 3 is substituted or unsubstituted, straight or branched C1-C6 alkyl; substituted or unsubstituted, straight or branched C1-C6 alkylacetyl; or -L3R 3A And

[0015] R 2A is substituted or unsubstituted C6-C 10 Aryl; substituted or unsubstituted 6-10 membered heteroaryl; substituted or unsubstituted C3-C 10 Cycloalkyl; or 3 to 10 membered heterocycloalkyl;

[0016] R 3A is substituted or unsubstituted C6-C 10 Aryl; substituted or unsubstituted 6-10 membered heteroaryl; substituted or unsubstituted C3-C 10 Cycloalkyl; 3 to 10 membered heterocycloalkyl; or substituted or unsubstituted bicyclo[1.1.1]pentane;

[0017] L2 is a single bond, carbonyl (-CO-), fumaryl (-CO-CH=CH-CO-), C1-C6 alkylene (-(CH2) n -) or C1-C6 alkylenecarbonyl (-CO-(CH2) n -) and;

[0018] L3 is a single bond, carbonyl (-CO-), fumaryl (-CO-CH=CH-CO-), C1-C6 alkylene (-(CH2) n -) or C1-C6 alkylenecarbonyl (-CO-(CH2) n -) and; and

[0019] The above substituted alkyl, alkylacetyl, aryl, heteroaryl, bicyclo[1.1.1]pentane is substituted with a substituent selected from the group consisting of halogen, hydroxy, amine, carboxy, C1-C5 alkyl, C1-C5 alkoxy and C1-C5 alkoxycarbonyl;

[0020] The above heteroaryl and heterocycloalkyl comprise at least one of N, O or S.

[0021] Another object of the present invention is to provide an antiviral composition comprising a compound represented by the above chemical formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

[0022] Another object of the present invention is to provide a pharmaceutical composition for preventing or treating viral infection, comprising a compound represented by the above chemical formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

[0023] Another object of the present invention is to provide an antiviral or antiviral composition for improving viral infection, comprising a compound represented by the above chemical formula 1, a food-based acceptable salt, or a solvate thereof as an active ingredient.

[0024]

[0025] The present invention relates to a stress granule formation promoter within a cell and a broad-spectrum antiviral agent comprising the same. The compounds of the present invention have been shown to exhibit excellent effects in promoting stress granule formation within cells, and their cytotoxicity has also been shown to be significantly improved compared to previously developed compounds. Furthermore, since stress granule formation is based on innate immune function, the compounds of the present invention have been confirmed to have antiviral effects against various viruses, including SARS-CoV-2, MERS-CoV, SARS-CoV, severe fever with thrombocytopenia syndrome virus (SFTSV), and dengue virus (DENV).

[0026] Therefore, it is expected that the compounds of the present invention can be used as broad-spectrum antiviral agents applicable not only to various viruses but also to mutants that will appear in the future.

[0027]

[0028] Figure 1 is a schematic diagram showing the broad-spectrum antiviral action mechanism of a compound C01 derivative that induces stress granule formation.

[0029] Figure 2 is the chemical structure of compound C01.

[0030] Figure 3 shows R of compound C01 2 or R 3 This is the chemical structure of the derivative.

[0031] Figures 4 and 5 are compounds C01 R 2 It shows the chemical structure of the derivative and its ability to form stress granules depending on concentration.

[0032] Figures 6 to 8 are compounds C01 R 2 Immunofluorescence images of stress granules induced by the derivative.

[0033] Figures 9 and 10 are compounds C01 R 3 It shows the chemical structure of the derivative and its ability to form stress granules depending on concentration.

[0034] Figures 11 to 13 are compounds C01 R 3 Immunofluorescence images of stress granules induced by the derivative.

[0035] Figure 14 shows R in the compound C01 derivative. 2 and R 3 Shows the role of the seat.

[0036] Figure 15 shows a stress granule formation inducer prepared by combining a molecular adhesive decomposition agent moiety with a compound C01 derivative.

[0037] Figure 16 monitors the intracellular stress granule formation effect of compound SB2960 over time.

[0038] Figure 17 shows the antiviral efficacy of compound C01 derivatives against SARS-CoV-2 (initial strain, alpha, beta, gamma, delta, omicron), MERS-CoV, SARS-CoV, SFTSV, and DENV.

[0039] Figure 18 shows the antiviral efficacy of combined administration of compound SB2960 and remdesivir.

[0040] Figure 19 shows the ZIP synergy score according to co-administration of compound SB2960 and remdesivir.

[0041] Figure 20 shows the antiviral efficacy of combined administration of compound SB2935 and remdesivir.

[0042] Figure 21 shows the ZIP synergy score according to co-administration of compound SB2935 and remdesivir.

[0043] Figure 22 is an immunofluorescence image showing the results of treatment of cells infected with SARS-CoV-2 with compound C01 or compound SB2960.

[0044] Figure 23 is an immunofluorescence image showing the results of treatment with compound SB2960 at various concentrations in cells infected with SARS-CoV-2.

[0045] Figure 24 is an immunofluorescence image showing the results of treatment with compound C01 at various concentrations in cells infected with SARS-CoV-2.

[0046] Figure 25 is a blood drug concentration-time curve when compound SB2960 is administered intravenously or orally.

[0047]

[0048] Hereinafter, the present invention will be described in more detail.

[0049] One aspect of the present invention is a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, or a solvate thereof:

[0050] [Chemical Formula 1]

[0051]

[0052] In the above chemical formula 1

[0053] R 2 is substituted or unsubstituted, straight or branched C1-C6 alkyl; substituted or unsubstituted, straight or branched C1-C6 alkylacetyl; or -L2R 2A and;

[0054] R 3 is substituted or unsubstituted, straight or branched C1-C6 alkyl; substituted or unsubstituted, straight or branched C1-C6 alkylacetyl; or -L3R 3A And

[0055] R 2A is substituted or unsubstituted C6-C 10 Aryl; substituted or unsubstituted 6-10 membered heteroaryl; substituted or unsubstituted C3-C 10 Cycloalkyl; or 3 to 10 membered heterocycloalkyl;

[0056] R 3A is substituted or unsubstituted C6-C 10 Aryl; substituted or unsubstituted 6-10 membered heteroaryl; substituted or unsubstituted C3-C 10 Cycloalkyl; 3 to 10 membered heterocycloalkyl; or substituted or unsubstituted bicyclo[1.1.1]pentane;

[0057] L2 is a single bond, carbonyl (-CO-), fumaryl (-CO-CH=CH-CO-), C1-C6 alkylene (-(CH2) n -) or C1-C6 alkylenecarbonyl (-CO-(CH2) n -) and;

[0058] L3 is a single bond, carbonyl (-CO-), fumaryl (-CO-CH=CH-CO-), C1-C6 alkylene (-(CH2) n -) or C1-C6 alkylenecarbonyl (-CO-(CH2) n -) and; and

[0059] The above substituted alkyl, alkylacetyl, aryl, heteroaryl, bicyclo[1.1.1]pentane is substituted with a substituent selected from the group consisting of halogen, hydroxy, amine, carboxy, C1-C5 alkyl, C1-C5 alkoxy and C1-C5 alkoxycarbonyl;

[0060] The above heteroaryl and heterocycloalkyl comprise at least one of N, O or S.

[0061] The inventors of the present invention confirmed that the previously developed compound C01 (compound SB2601) had strong cytotoxicity and thus had some limitations in applying it to the human body. They completed the present invention by synthesizing a C01 derivative that improved both cytotoxicity and antiviral effects. Specifically, the R 2 is methyl, acetyl, 2-hydroxyethyl, trifluoroacetyl, 2-aminoacetyl, carboxymethyl, or -L2R 2A and the above R 2A is pyridine, carboxypyridine, imidazole, methylimidazole, pyrrolidine or methoxybenzene, and L2 may be, but is not limited to, a single bond, carbonyl (-CO-), fumaryl (-CO-CH=CH-CO-), methylene (-CH2-), ethylene (-CH2-CH2-) or methylenecarbonyl (-CO-CH2-).

[0062] Also, the above R 3 is methyl, acetyl, chloroacetyl, 2-hydroxyethyl or -L3R 3A and the above R 3A is benzene, methoxycarbonylbenzene, morpholine, pyridine, hydroxypyridine, carboxypyridine, pyrimidine, methylimidazole, pyrrolidine, or 1-(methoxycarbonyl)bicyclo[1.1.1]pentane, and L3 may be, but is not limited to, a single bond, carbonyl (-CO-), methylene (-CH2-), or methylenecarbonyl (-CO-CH2-).

[0063] More specifically, the compound represented by the above chemical formula 1 may be selected from those listed below.

[0064] <화합물 SB2902>

[0065]

[0066] <화합물 SB2903>

[0067]

[0068] <화합물 SB2904>

[0069]

[0070] <화합물 SB2905>

[0071]

[0072] <화합물 SB2906>

[0073]

[0074] <화합물 SB2907>

[0075]

[0076] <화합물 SB2908>

[0077]

[0078] <화합물 SB2909>

[0079]

[0080] <화합물 SB2910>

[0081]

[0082] <화합물 SB2911>

[0083]

[0084] <화합물 SB2912>

[0085]

[0086] <화합물 SB2913>

[0087]

[0088] <화합물 SB2914>

[0089]

[0090] <화합물 SB2915>

[0091]

[0092] <화합물 SB2916>

[0093]

[0094] <화합물 SB2931>

[0095]

[0096] <화합물 SB2932>

[0097]

[0098] <화합물 SB2933>

[0099]

[0100] <화합물 SB2934>

[0101]

[0102] <화합물 SB2935>

[0103]

[0104] <화합물 SB2936>

[0105]

[0106] <화합물 SB2937>

[0107]

[0108] <화합물 SB2951>

[0109]

[0110] <화합물 SB2953>

[0111]

[0112] <화합물 SB2954>

[0113]

[0114] <화합물 SB2955>

[0115]

[0116] <화합물 SB2956>

[0117]

[0118] <화합물 SB2957>

[0119]

[0120] <화합물 SB2958>

[0121]

[0122] <화합물 SB2959>

[0123]

[0124] <화합물 SB2960>

[0125]

[0126] <화합물 SB2961>

[0127]

[0128] <화합물 SB2962>

[0129]

[0130] <화합물 SB2963>

[0131]

[0132] <화합물 SB2964>

[0133]

[0134] <화합물 SB2965>

[0135]

[0136] <화합물 SB2967>

[0137]

[0138] <화합물 SB2968>

[0139]

[0140] <화합물 SB2969>

[0141]

[0142] Compound SB2991

[0143]

[0144] Compound SB2992

[0145]

[0146]

[0147] The inventors of the present invention confirmed that the compound represented by the above chemical formula 1 is a substance that promotes the formation of intracellular stress granules when administered to cells. In addition, when the compound represented by the chemical formula 1 was treated on cells infected with various viruses such as SARS-CoV-2 (initial type, alpha, beta, gamma, delta, omicron), MERS-CoV, SARS-CoV, severe fever with thrombocytopenia syndrome virus (SFTSV), and dengue virus (DENV), it was confirmed that it had a broad antiviral effect, thereby proving that the promotion of intracellular stress granule formation can exhibit a therapeutic effect on viral infections.

[0148] The compound represented by the above chemical formula 1 may have a concentration of 1 to 1000 μM, 1 to 500 μM, 1 to 300 μM, 1 to 100 μM, 1 to 50 μM, 1 to 40 μM, 1 to 30 μM, 5 to 1000 μM, 5 to 500 μM, 5 to 300 μM, 5 to 100 μM, 5 to 50 μM, 5 to 40 μM, 5 to 30 μM, 10 to 1000 μM, 10 to 500 μM, 10 to 300 μM, 10 to 100 μM, 10 to 50 μM, 10 to 40 μM or 10 to 30 μM, but is not limited thereto. Preferably, the compound represented by the above chemical formula 1 may have a concentration of 10 to 50 μM.

[0149]

[0150] Another aspect of the present invention is an antiviral composition comprising a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, or a solvate thereof:

[0151] [Chemical Formula 1]

[0152]

[0153] In the above chemical formula 1

[0154] R 2 is substituted or unsubstituted, straight or branched C1-C6 alkyl; substituted or unsubstituted, straight or branched C1-C6 alkylacetyl; or -L2R 2A and;

[0155] R 3 is substituted or unsubstituted, straight or branched C1-C6 alkyl; substituted or unsubstituted, straight or branched C1-C6 alkylacetyl; or -L3R 3A And

[0156] R 2A is substituted or unsubstituted C6-C 10 Aryl; substituted or unsubstituted 6-10 membered heteroaryl; substituted or unsubstituted C3-C 10 Cycloalkyl; or 3 to 10 membered heterocycloalkyl;

[0157] R 3A is substituted or unsubstituted C6-C 10 Aryl; substituted or unsubstituted 6-10 membered heteroaryl; substituted or unsubstituted C3-C 10 Cycloalkyl; 3 to 10 membered heterocycloalkyl; or substituted or unsubstituted bicyclo[1.1.1]pentane;

[0158] L2 is a single bond, carbonyl (-CO-), fumaryl (-CO-CH=CH-CO-), C1-C6 alkylene (-(CH2) n -) or C1-C6 alkylenecarbonyl (-CO-(CH2) n -) and;

[0159] L3 is a single bond, carbonyl (-CO-), fumaryl (-CO-CH=CH-CO-), C1-C6 alkylene (-(CH2) n -) or C1-C6 alkylenecarbonyl (-CO-(CH2) n -) and; and

[0160] The above substituted alkyl, alkylacetyl, aryl, heteroaryl, bicyclo[1.1.1]pentane is substituted with a substituent selected from the group consisting of halogen, hydroxy, amine, carboxy, C1-C5 alkyl, C1-C5 alkoxy and C1-C5 alkoxycarbonyl;

[0161] The above heteroaryl and heterocycloalkyl comprise at least one of N, O or S.

[0162] The description of the compound represented by the above chemical formula 1 is the same as that described above.

[0163] The above antiviral composition may target, but is not limited to, a virus selected from the group consisting of SARS-CoV-2, MERS-CoV, SARS-CoV, severe fever with thrombocytopenia syndrome virus (SFTSV), and dengue virus (DENV). This is because the compound of the present invention induces an innate immune response to exhibit an antiviral effect, and thus can exhibit a broad antiviral effect regardless of the type of virus.

[0164] The above antiviral composition may further comprise a known antiviral agent. The above antiviral drugs include chloroquine diphosphate, lopinavir, remdesivir, favipiravir, ritonavir, Janus kinase inhibitor, hydroxychloroquine, azithromycin, amantadine, rimantadine, ribavirin, idoxuridine, trifluridine, vidarabine, acyclovir, ganciclovir, didanosine, foscarnet, zidovudine, peramivir, zalcitabine, It may be at least one selected from the group consisting of stavudine, famciclovir, oseltamivir, zanamivir, and valacyclovir, but is not limited thereto. Preferably, the antiviral composition may further comprise remdesivir.

[0165] The molar concentration ratio of the compound represented by the above chemical formula 1 and remdesivir is 1:0.01 to 1:1000, 1:0.01 to 1:500, 1:0.01 to 1:300, 1:0.01 to 1:100, 1:0.05 to 1:1000, 1:0.05 to 1:500, 1:0.05 to 1:300, 1:0.05 to 1:100, 1:0.1 to 1:1000, 1:0.1 to 1:500, 1:0.1 to 1:300, 1:0.1 to 1:100, 1:0.3 to 1:1000, 1:0.3 to 1:500, 1:0.3 to 1:300, It may be 1:0.3 to 1:100, 1:0.5 to 1:1000, 1:0.5 to 1:500, 1:0.5 to 1:300, or 1:0.5 to 1:100, but is not limited thereto. Preferably, the molar concentration ratio of the compound represented by the above chemical formula 1 and remdesivir may be 1:0.3 to 1:300.

[0166]

[0167] Another aspect of the present invention is a pharmaceutical composition for preventing or treating viral infection, comprising a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, or a solvate thereof:

[0168] [Chemical Formula 1]

[0169]

[0170] In the above chemical formula 1

[0171] R 2 is substituted or unsubstituted, straight or branched C1-C6 alkyl; substituted or unsubstituted, straight or branched C1-C6 alkylacetyl; or -L2R 2A and;

[0172] R 3 is substituted or unsubstituted, straight or branched C1-C6 alkyl; substituted or unsubstituted, straight or branched C1-C6 alkylacetyl; or -L3R 3A And

[0173] R2A is substituted or unsubstituted C6-C 10 Aryl; substituted or unsubstituted 6-10 membered heteroaryl; substituted or unsubstituted C3-C 10 Cycloalkyl; or 3 to 10 membered heterocycloalkyl;

[0174] R 3A is substituted or unsubstituted C6-C 10 Aryl; substituted or unsubstituted 6-10 membered heteroaryl; substituted or unsubstituted C3-C 10 Cycloalkyl; 3 to 10 membered heterocycloalkyl; or substituted or unsubstituted bicyclo[1.1.1]pentane;

[0175] L2 is a single bond, carbonyl (-CO-), fumaryl (-CO-CH=CH-CO-), C1-C6 alkylene (-(CH2) n -) or C1-C6 alkylenecarbonyl (-CO-(CH2) n -) and;

[0176] L3 is a single bond, carbonyl (-CO-), fumaryl (-CO-CH=CH-CO-), C1-C6 alkylene (-(CH2) n -) or C1-C6 alkylenecarbonyl (-CO-(CH2) n -) and; and

[0177] The above substituted alkyl, alkylacetyl, aryl, heteroaryl, bicyclo[1.1.1]pentane is substituted with a substituent selected from the group consisting of halogen, hydroxy, amine, carboxy, C1-C5 alkyl, C1-C5 alkoxy and C1-C5 alkoxycarbonyl;

[0178] The above heteroaryl and heterocycloalkyl comprise at least one of N, O or S.

[0179] The description of the compound represented by the above chemical formula 1 and its antiviral properties is the same as described above.

[0180] The composition may prevent or treat viral infection by inducing intracellular granule formation.

[0181] The term “prevention” used in the present invention means any act of suppressing a disease or delaying its onset by administering a pharmaceutical composition according to the present invention.

[0182] The term “treatment” used in the present invention means any act in which symptoms of a disease are improved or beneficially changed by administration of a pharmaceutical composition according to the present invention.

[0183] The pharmaceutical composition of the present invention may further include a pharmaceutically acceptable carrier, excipient or diluent in addition to the above-mentioned effective ingredient.

[0184] The pharmaceutically acceptable carrier may be saline solution, sterile water, Ringer's solution, buffered saline solution, dextrose solution, maltodextrin solution, glycerol, ethanol, or a mixture of one or more of these components. If necessary, other conventional additives such as antioxidants, buffers, and bacteriostatic agents may be added. In addition, diluents, dispersants, surfactants, binders, and lubricants may be additionally added to formulate the composition into an injectable formulation such as an aqueous solution, suspension, or emulsion, or into a pill, capsule, granule, or tablet. Furthermore, the composition may be preferably formulated according to each disease or component using an appropriate method in the art or a method disclosed in Remington's Pharmaceutical Science (recent edition), Mack Publishing Company, Easton PA.

[0185] The above excipients and diluents include various compounds or mixtures including lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate, and mineral oil. When formulated, the composition is prepared using diluents or excipients such as commonly used fillers, extenders, binders, wetting agents, disintegrants, and surfactants.

[0186] The composition of the present invention can be administered orally or parenterally (e.g., intravenously, subcutaneously, intraperitoneally, or topically) depending on the intended method, and the pharmaceutical dosage form of the composition according to the present invention can be used alone or in combination with other pharmaceutically active compounds, as well as in an appropriate group. The pharmaceutical composition according to the present invention can be formulated and used in the form of oral formulations such as capsules, powders, granules, tablets, suspensions, emulsions, syrups, and aerosols, as well as in the form of external preparations, suppositories, and sterile injectable solutions, respectively, according to conventional methods.

[0187] Solid preparations for oral administration include tablets, pills, powders, granules, capsules, etc., and these solid preparations are prepared by mixing the compound represented by the above chemical formula 1 with at least one excipient, such as starch, calcium carbonate, sucrose or lactose, gelatin, etc. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used.

[0188] Liquid preparations for oral administration include suspensions, solutions, emulsions, and syrups. In addition to the commonly used simple diluents such as water and liquid paraffin, they may contain various excipients such as wetting agents, sweeteners, flavoring agents, and preservatives.

[0189] Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solutions, suspensions, emulsions, lyophilized preparations, and suppositories. Non-aqueous solutions and suspensions can include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate. Suppository bases include withepsol, macrogol, Tween 61, cocoa butter, laurin, and glycerogelatin.

[0190] The pharmaceutical composition of the present invention is administered in a pharmaceutically effective amount. As used herein, "pharmaceutically effective amount" means an amount sufficient to treat a disease with a reasonable benefit / risk ratio applicable to medical treatment. The effective dosage level may be determined based on factors including the type and severity of the patient's disease, the activity and sensitivity of the drug to the drug, the time of administration, the route of administration and the excretion rate, the duration of treatment, concurrently used drugs, and other factors well known in the medical field. The composition according to one embodiment of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to administer an amount that achieves the maximum effect with the minimum amount without causing side effects by taking all of the above factors into consideration, and this can be easily determined by those skilled in the art.

[0191] Specifically, the effective amount of the pharmaceutical composition according to the present invention may vary depending on the patient's age, sex, and weight, and is generally 0.1 mg to 1,000 mg, 1 mg to 100 mg, or 3 mg to 10 mg per 1 kg of body weight, administered daily or every other day, or divided into 1 to 3 times a day. However, the dosage may increase or decrease depending on the route of administration, severity of the disease, sex, weight, age, etc., and thus the above dosage does not limit the scope of the present invention in any way.

[0192]

[0193] Another aspect of the present invention is a food composition for improving antiviral or viral infection properties, comprising a compound represented by the following chemical formula 1, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient:

[0194] [Chemical Formula 1]

[0195]

[0196] In the above chemical formula 1

[0197] R 2 is substituted or unsubstituted, straight or branched C1-C6 alkyl; substituted or unsubstituted, straight or branched C1-C6 alkylacetyl; or -L2R 2A and;

[0198] R 3 is substituted or unsubstituted, straight or branched C1-C6 alkyl; substituted or unsubstituted, straight or branched C1-C6 alkylacetyl; or -L3R 3A And

[0199] R 2A is substituted or unsubstituted C6-C 10 Aryl; substituted or unsubstituted 6-10 membered heteroaryl; substituted or unsubstituted C3-C 10 Cycloalkyl; or 3 to 10 membered heterocycloalkyl;

[0200] R 3A is substituted or unsubstituted C6-C 10 Aryl; substituted or unsubstituted 6-10 membered heteroaryl; substituted or unsubstituted C3-C 10 Cycloalkyl; 3 to 10 membered heterocycloalkyl; or substituted or unsubstituted bicyclo[1.1.1]pentane;

[0201] L2 is a single bond, carbonyl (-CO-), fumaryl (-CO-CH=CH-CO-), C1-C6 alkylene (-(CH2) n -) or C1-C6 alkylenecarbonyl (-CO-(CH2) n -) and;

[0202] L3 is a single bond, carbonyl (-CO-), fumaryl (-CO-CH=CH-CO-), C1-C6 alkylene (-(CH2) n -) or C1-C6 alkylenecarbonyl (-CO-(CH2) n -) and; and

[0203] The above substituted alkyl, alkylacetyl, aryl, heteroaryl, bicyclo[1.1.1]pentane is substituted with a substituent selected from the group consisting of halogen, hydroxy, amine, carboxy, C1-C5 alkyl, C1-C5 alkoxy and C1-C5 alkoxycarbonyl;

[0204] The above heteroaryl and heterocycloalkyl comprise at least one of N, O or S.

[0205] The description of the compound represented by the above chemical formula 1 is the same as that described above.

[0206] The above food composition includes processed forms of all natural materials, such as foods, functional foods, nutritional supplements, health feeds, and food additives. The above type of food composition can be manufactured in various forms according to conventional methods known in the art.

[0207] The term "food" used in the present invention includes dairy products including meat, sausage, bread, chocolate, candy, snacks, confectionery, pizza, ramen, other noodles, gum, ice cream, various soups, spices, beverages, tea, drinks, alcoholic beverages, vitamin complexes, health functional foods, and health foods, and includes all foods in the conventional sense, and is not limited thereto, as long as the compound represented by the chemical formula 1 may be included.

[0208] In addition, the food composition may include additional ingredients commonly used in food compositions to improve odor, taste, sight, etc. For example, it may include vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, pantothenic acid, etc. In addition, it may include minerals such as zinc (Zn), iron (Fe), calcium (Ca), chromium (Cr), magnesium (Mg), manganese (Mn), copper (Cu), chromium (Cr), etc. In addition, it may include amino acids such as lysine, tryptophan, cysteine, and valine.

[0209] In addition, the food composition may include food additives such as preservatives (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), sterilizers (bleaching powder and high-purity bleaching powder, sodium hypochlorite, etc.), antioxidants (butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), etc.), coloring agents (tar color, etc.), coloring agents (sodium nitrite, sodium nitrite, etc.), bleaching agents (sodium sulfite), seasonings (MSG, etc.), sweeteners (dulcin, cyclamate, saccharin, sodium, etc.), flavorings (vanillin, lactones, etc.), leavening agents (alum, D-potassium hydrogen tartrate, etc.), reinforcing agents, emulsifiers, thickeners (glutinating agents), film-forming agents, gum-forming agents, foam suppressants, solvents, and improvers. The additives may be selected depending on the type of food and used in an appropriate amount.

[0210]

[0211] Hereinafter, the composition and effects of the present invention will be described in more detail through examples. These examples are intended solely to illustrate the present invention, and the scope of the present invention is not limited by these examples.

[0212]

[0213] Manufacturing Example 1. Reagents and Equipment

[0214] Unless otherwise specified, all reagents used in organic synthesis were purchased from Sigma-Aldrich, Tokyo Chemical Industry Co., Ltd., or ThermoFisher Scientific and used without further purification. Solvents were commercially available unless otherwise specified, and dry solvents were prepared using the ultimate solvent purification system CT-SPS-SA [Glass Contour]. The reaction progress was monitored by silica gel 60, F 254 (0.25 mm) thin-layer chromatography (TLC) or liquid chromatography-mass spectrometry (LC-MS) using LCMS-2020 [Shimadzu] were identified. Compounds on TLC were visualized by irradiation with UV light (254 and 365 nm) or treatment with KMnO4 or phosphomolybdic acid reagent and then heating. Purification of compounds was performed using medium-pressure liquid chromatography (MPLC) Isolera One (Biotage) or reversed-phase preparative high-performance liquid chromatography (HPLC) LC-6AD [Shimadzu] with YMC-Pack ODS-A AA20S05-2520WT (S-5 μm, 12 nm, 20 X 250 mm) [YMC]. Eluents used for purification are indicated in parentheses as needed.

[0215]

[0216] Manufacturing Example 2. Compound Characterization

[0217] 1 H and 13C NMR spectra were measured using an Agilent 400-MR DD2 nuclear magnetic resonance system (400 MHz, Agilent, USA), a Varian / Oxford As-500 (500 MHz, Varian Assoc., Palo Alto, USA), and a Bruker AVANCE III HD 500 (500 MHz, Bruker, Germany) instrument. Chemical shifts are expressed in ppm (δ). 1 H NMR spectra were calibrated using tetramethylsilane (TMS, 0.00 ppm) as an internal standard. 13 C NMR spectrum shows residual solvent peak (CDCl3 13 C: 77.00 ppm; (CD3)2CO 13 C: 29.84 ppm; CD3OD 13 C: 49.00 ppm; (CD3)2SO 13 C: 39.52 ppm) was used as the standard. Multiplicity was expressed as follows: s(singlet), d(doublet), t(triplet), q(quartet), m(multiplet), dd(doublet of doublet), dt(doublet of triplet), tt(triplet of triplet), br s(broad singlet), etc. Coupling constants were expressed in Hz. Low-resolution mass spectrometry (LRMS) was performed using electron spray ionization (ESI) technique on LCMS-2020 [Shimadzu], and high-resolution mass spectrometry (HRMS) was performed using ESI technique on Orbitrap Exploris 120 [ThermoFisher Scientific] at the Research Support Center of the Department of Chemistry, Seoul National University.

[0218]

[0219] Manufacturing Example 3. Synthesis method and characterization of compound -R 2 derivative

[0220] Manufacturing Example 3-1. Synthesis procedure and characterization of compound 3-8.

[0221] The synthesis of compounds 3 to 8 was carried out according to the procedure of Scheme 1 below.

[0222] [Reaction Formula 1]

[0223]

[0224] The starting material, compound 1, was synthesized according to the method reported by Park et al. (2009). Compound 1 (1.11 g, 1.83 mmol, 1.0 equiv) was dissolved in a mixed solvent of tetrahydrofuran (THF, 13.0 mL) and ethanol (EtOH, 13.0 mL), and aqueous KOH (40%, 1.03 g, 18.3 mmol, 10.0 equiv) was added at room temperature. The mixture was then stirred at 100°C for 4 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched by adding saturated aqueous NaHCO3 solution (to stop the reaction), and extracted three times with dichloromethane (DCM). The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography (MPLC) using silica gel, using a gradient of 0% to 17% methanol (MeOH) in ethyl acetate (EtOAc). As a result, compound 2 was obtained in the form of a yellow solid.

[0225] Yield: 75% (648 mg, 1.37 mmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 7.82 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.59 (s, 1H), 7.53 (s, 1H), 6.65 (s, 1H), 3.09-3.00 (m, 8H), 1.69 (s, 6H); 13C NMR (100 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 157.7, 148.9, 142.6, 135.2, 134.8, 131.1 (d, 2 J C,F = 33.1 Hz), 130.7, 126.8 (q, 3 J C,F = 3.7 Hz), 125.8, 125.3, 123.2, 121.5, 108.7, 107.6, 79.2, 52.4, 45.7, 29.0; C 23 H 23 F3N5O3[M+H] + LRMS (ESI) m / z Theoretical: 474.2, Measured: 474.1.

[0226] Compound 3

[0227]

[0228] Paraformaldehyde (4.84 mg, 0.161 mmol, 1.5 equiv), acetic acid (12.3 μL, 0.215 mmol, 2.0 equiv), and sodium triacetoxyborohydride (68.3 mg, 0.322 mmol, 3.0 equiv) were sequentially added to a solution of compound 2 (50.8 mg, 0.107 mmol, 1.0 equiv) in 1,2-dichloroethane (2.0 mL) at room temperature, and the mixture was stirred at 40 °C for 3 h. Then, sodium triacetoxyborohydride (45.5 mg, 0.215 mmol, 2.0 equiv) was additionally added, and the mixture was further stirred at 70 °C for 12 h. To ensure complete reaction, sodium borohydride (8.13 mg, 0.215 mmol, 2.0 equiv) was added and stirred at 70°C for 2 h. After confirming the completion of the reaction by TLC and LC-MS, the reaction mixture was quenched by adding saturated aqueous NaHCO3 solution and extracted three times with dichloromethane (DCM). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography (MPLC) using silica gel, using a gradient of 0% to 3% MeOH in DCM. As a result, compound 3 was obtained in the form of a yellow solid.

[0229] Yield: 73% (38.5 mg, 78.9 μmol); 1 H NMR (400 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 7.82 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.59 (s, 1H), 7.53 (s, 1H), 6.67 (s, 1H), 3.12 (t, J = 4.8 Hz, 4H), 2.60 (t, J = 4.7 Hz, 4H), 2.37 (s, 3H), 1.69 (s, 6H); 13C NMR (100 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 157.6, 148.5, 142.5, 135.2, 134.7, 131.0 (d, 2 J C,F = 33.3 Hz), 130.6, 126.7 (q, 3 J C,F = 3.7 Hz), 125.8, 123.6 (d, 1 J C,F = 272.4 Hz), 123.1, 121.5, 108.7, 107.5, 79.2, 54.6, 51.1, 45.9, 29.0; C 24 H 25 F3N5O3[M+H] + LRMS (ESI) m / z Theoretical: 488.2, Measured: 488.2.

[0230] Compound 4

[0231]

[0232] To a solution of compound 2 (50.8 mg, 0.107 mmol, 1.0 equiv) in dry dichloromethane (2.0 mL) at 0°C, triethylamine (20.9 μL, 0.150 mmol, 1.5 equiv) and acetyl chloride (7.85 μL, 0.110 mmol, 1.1 equiv) were sequentially added, and the mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction by TLC and LC-MS, the reaction mixture was quenched with water and extracted three times with dichloromethane. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography (MPLC) using silica gel using a gradient of 0% to 5% MeOH in dichloromethane. As a result, compound 4 was obtained in the form of a yellow solid.

[0233] Yield: 99% (51.0 mg, 98.9 μmol); 1H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 7.83 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.64 (s, 1H), 7.55 (s, 1H), 6.66 (s, 1H), 3.79 (t, J = 4.9 Hz, 2H), 3.64 (t, J = 4.9 Hz, 2H), 3.11-3.06 (m, 4H), 2.13 (s, 3H), 1.70 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 169.0, 157.7, 148.2, 142.5, 135.2, 135.1, 131.1 (d, 2 J C,F = 32.9 Hz), 130.4, 126.7 (q, 3 J C,F = 3.8 Hz), 125.9, 123.5 (d, 1 J C,F = 272.3 Hz), 123.3, 121.4, 109.2, 108.4, 79.4, 51.9, 50.9, 46.0, 41.1, 29.0, 21.2; C 25 H 25 F3N5O4[M+H] + LRMS (ESI) m / z Theoretical: 516.2, Measured: 516.2.

[0234] Compound 5

[0235]

[0236] Compound 2 (35.7 mg, 75.5 μmol, 1.0 equivalent) was dissolved in dichloromethane (2.0 mL) at room temperature, and 3-pyridylacetic acid hydrochloride (15.7 mg, 90.6 μmol, 1.2 equivalent), 4-(dimethylamino)pyridine (DMAP, 12.0 mg, 98.1 μmol, 1.3 equivalent), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 17.4 mg, 90.6 μmol, 1.2 equivalent) were sequentially added, and the mixture was stirred at room temperature for 3 hours. After confirming the completion of the reaction by TLC and LC-MS, the reaction mixture was quenched by adding saturated aqueous NaHCO3 solution, and extracted three times with ethyl acetate (EtOAc). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography (MPLC) using silica gel, using a gradient of 0% to 5% MeOH in dichloromethane. As a result, compound 5 was obtained in the form of a yellow solid.

[0237] Yield: 99% (44.4 mg, 74.8 μmol); 1 H NMR (400 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.62-8.43 (m, 2H), 7.82 (d, J = 8.1 Hz, 2H), 7.69-7.61 (m, 4H), 7.54 (s, 1H), 7.30 (d, J = 6.3 Hz, 1H), 6.62 (s, 1H), 3.83 (t, J = 4.9 Hz, 2H), 3.76 (s, 2H), 3.67 (t, J = 4.7 Hz, 2H), 3.07 (t, J = 5.0 Hz, 2H), 2.96 (t, J = 4.7 Hz, 2H), 1.69 (s, 6H); 13C NMR (100 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 168.6, 157.8, 149.91, 149.89, 148.5, 148.1, 142.4, 136.5, 135.2, 135.1, 131.0, 130.3, 126.8 (q, 3 J C,F = 3.8 Hz), 125.9, 124.9, 123.6, 123.4, 121.5, 109.3, 108.6, 79.6, 51.9, 50.9, 45.8, 41.7, 37.7, 29.1; C 30 H 28 F3N6O4[M+H] + LRMS (ESI) m / z Theoretical: 593.2, Measured: 593.2.

[0238] Compound 6

[0239]

[0240] To a solution of compound 2 (47.3 mg, 0.100 mmol, 1.0 equiv) in acetonitrile (4.0 mL) at room temperature, 2-bromoethanol (2-bromoethanol, 14.2 μL, 0.200 mmol, 2.0 equiv) and potassium carbonate (K2CO3, 27.6 mg, 0.200 mmol, 2.0 equiv) were sequentially added, and the mixture was stirred at 80°C for 4 h. After confirming the completion of the reaction by TLC and LC-MS, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography (MPLC) using silica gel, using a gradient of 0% to 2% MeOH in dichloromethane. As a result, compound 6 was obtained in the form of a yellow oily substance.

[0241] Yield: 89% (46.0 mg, 88.9 μmol); 1H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 7.82 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.59 (s, 1H), 7.54 (s, 1H), 6.66 (s, 1H), 3.66 (t, J = 5.3 Hz, 2H), 3.11 (t, J = 4.9 Hz, 4H), 2.69 (t, J = 4.8 Hz, 4H), 2.63 (t, J = 5.4 Hz, 2H), 2.19 (br s, 1H), 1.69 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 157.7, 148.5, 142.5, 135.2, 134.7, 131.1 (q, 2 J C,F = 33.1 Hz), 130.6, 126.8 (q, 3 J C,F = 3.7 Hz), 125.8, 123.6 (d, 1 J C,F = 272.6 Hz), 123.2, 121.5, 108.7, 107.7, 79.3, 59.2, 57.7, 52.5, 51.3, 29.0; C 25 H 27 F3N5O4[M+H] + LRMS (ESI) m / z Theoretical: 518.2, Measured: 518.2.

[0242] Compound 7

[0243]

[0244] To a solution of compound 2 (47.3 mg, 0.100 mmol, 1.0 equiv) in dichloromethane (4.0 mL) at 0°C, triethylamine (TEA, 27.9 μL, 0.200 mmol, 2.0 equiv) and trifluoroacetic anhydride (20.9 μL, 0.150 mmol, 1.5 equiv) were added dropwise, and the mixture was stirred at room temperature for 0.5 h. After confirming the completion of the reaction by TLC and LC-MS, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography (MPLC) using silica gel, using a gradient of 0% to 1% MeOH in dichloromethane. As a result, compound 7 was obtained in the form of a yellow oily substance.

[0245] Yield: 91% (52.0 mg, 91.3 μmol); 1 H NMR (400 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 7.83 (d, J = 8.1 Hz, 2H), 7.69-7.62 (m, 3H), 7.55 (s, 1H), 6.68 (s, 1H), 3.87 (t, J = 4.8 Hz, 2H), 3.79 (t, J = 4.7 Hz, 2H), 3.17-3.10 (m, 4H), 1.70 (s, 6H); 13 C NMR (100 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 157.9, 155.6 (q, 2 J C,F = 36.0 Hz), 147.9, 142.4, 135.5, 135.2, 131.2 (q, 2 J C,F = 33.2 Hz), 130.2, 126.8 (q, 3 J C,F = 3.7 Hz), 125.9, 123.5 (q, 1 J C,F = 272.4 Hz), 123.5, 121.4, 116.3 (q, 1 J C,F= 288.2 Hz), 109.7, 109.2, 79.7, 51.9, 51.1, 45.7, 43.2, 29.1; C 25 H 22 F6N5O4[M+H] + LRMS (ESI) m / z Theoretical: 570.2, Measured: 570.2.

[0246] Compound 8

[0247]

[0248] To a solution of compound 2 (49.2 mg, 0.104 mmol, 1.0 equiv) dissolved in dichloromethane (4.0 mL) at room temperature, N,N-dimethylglycine (N,N-dimethylglycine, 12.9 mg, 0.125 mmol, 1.2 equiv), 4-(dimethylamino)pyridine (DMAP, 16.5 mg, 0.135 mmol, 1.3 equiv), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 23.9 mg, 0.125 mmol, 1.2 equiv) were sequentially added, and the mixture was stirred at room temperature for 16 hours. After confirming the completion of the reaction by TLC and LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted three times with ethyl acetate (EtOAc). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography (MPLC) using silica gel, using a gradient of 0% to 7% MeOH in dichloromethane. As a result, compound 8 was obtained in the form of a yellow oily substance.

[0249] Yield: 86% (49.7 mg, 89.0 μmol); 1H NMR (500 MHz, CDCl3 peak TMS 0.00 ppm): δ 7.82 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.64 (s, 1H), 7.55 (s, 1H), 6.67 (s, 1H), 3.83-3.76 (m, 4H), 3.16 (s, 2H), 3.11-3.05 (m, 4H), 2.29 (s, 6H), 1.70 (s, 6H); 13 C NMR (100 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 168.5, 157.7, 148.3, 142.4, 135.2, 134.9, 131.0 (q, 2 J C,F = 33.2 Hz), 130.4, 126.8 (q, 3 J C,F = 3.7 Hz), 125.8, 123.5 (d, 1 J C,F = 272.4 Hz), 123.3, 121.5, 109.1, 108.3, 79.4, 62.5, 52.1, 51.2, 45.4, 45.3, 41.5, 29.0; C 27 H 30 F3N6O4[M+H] + LRMS (ESI) m / z Theoretical: 559.2, Measured: 559.2.

[0250]

[0251] Manufacturing Example 3-2. Synthetic Procedure for Compounds SB2902-SB2907

[0252] Compounds SB2902 to SB2907 were prepared according to the procedure of Scheme 2 below.

[0253] [Reaction Formula 2]

[0254]

[0255] At room temperature, 20 wt% palladium-activated carbon catalyst (Pd / C) was added to a solution of compounds 3 to 8 (1.0 equiv) in methanol (0.015 M), and the mixture was stirred at room temperature under 1 atm of hydrogen. After confirming the completion of the reaction by TLC and LC-MS, the reaction mixture was filtered through Celite and washed with ethanol. The obtained filtrate was concentrated under reduced pressure. The resulting crude amine was dissolved in dry dichloromethane (0.030 M), and N,N-diisopropylethylamine (DIPEA, 2.0 equiv) and benzoyl chloride (1.5 equiv) were sequentially added at 0°C, and the mixture was stirred at room temperature. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with a saturated aqueous NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified using medium-pressure liquid chromatography (MPLC) or reverse-phase preparative HPLC to obtain compounds SB2902-SB2907.

[0256] Compound SB2902

[0257]

[0258] Compound 3 (52.0 mg, 0.107 mmol) synthesized according to the above procedure was used as a starting material and purified through medium-pressure liquid chromatography using silica gel (MPLC, gradient from 0% to 4% MeOH in dichloromethane) to obtain compound SB2902 in the form of a white solid.

[0259] Step 2 reaction total yield: 15% (9.01 mg, 16.0 μmol); 1H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.70 (br s, 1H), 8.07 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.78 (d, J = 7.7 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.56-7.47 (m, 4H), 6.90 (s, 1H), 3.09 (s, 4H), 2.99-2.62 (m, 4H), 2.54 (s, 3H), 1.67 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 163.9, 149.4, 142.8, 142.6, 134.9, 134.7, 132.6, 131.7, 130.6 (q, 2 J C,F = 33.0 Hz), 128.8, 126.8 (q, 3 J C,F = 3.8 Hz), 126.73, 126.66, 126.1, 123.9 (d, 1 J C,F = 272.1 Hz), 123.7, 114.4, 111.8, 110.8, 77.4, 55.3, 50.8, 45.3, 28.4; C 31 H 31 F3N5O2[M+H] + LRMS (ESI) m / z Theoretical: 562.2, Measured: 562.2.

[0260] Compound SB2903

[0261]

[0262] Compound 4 (51.0 mg, 98.9 μmol) synthesized according to the above procedure was used as a starting material and purified through reverse-phase preparative HPLC (water / acetonitrile mixed solvent containing 0.1% trifluoroacetic acid, gradient from 20% to 100% acetonitrile) to obtain compound SB2903 in the form of a white solid.

[0263] Step 2 reaction total yield: 17% (10.0 mg, 17.0 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.77 (br s, 1H), 8.10 (s, 1H), 7.86 (d, J = 8.1 Hz, 2H), 7.78 (d, J = 7.6 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.56-7.46 (m, 4H), 6.81 (s, 1H), 3.78 (t, J = 4.8 Hz, 2H), 3.62 (t, J = 5.0 Hz, 2H), 2.92-2.86 (m, 4H), 2.15 (s, 3H), 1.67 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 169.4, 163.9, 149.3, 142.7, 142.6, 134.8, 134.6, 132.5, 131.8, 130.6 (q, 2 J C,F = 33.0 Hz), 128.9, 126.9 (q, 3 J C,F = 3.7 Hz), 126.8, 126.6, 126.1, 123.9 (q, 1 J C,F = 272.7 Hz), 123.6, 114.4, 111.9, 110.6, 77.4, 52.1, 51.8, 46.8, 42.1, 28.4, 21.3; C 32 H 31 F3N5O3[M+H] + LRMS (ESI) m / z Theoretical: 590.2, Measured: 590.1.

[0264] Compound SB2904

[0265]

[0266] Compound 5 (59.4 mg, 0.100 mmol) synthesized according to the above procedure was used as a starting material and purified through reverse-phase preparative HPLC (water / acetonitrile mixed solvent containing 0.1% trifluoroacetic acid, gradient from 20% to 100% acetonitrile) to obtain compound SB2904 in the form of a white solid.

[0267] Total yield of the two-step reaction: 22% (14.5 mg, 21.8 μmol); 1 H NMR (500 MHz, CD3OD / CDCl3(1:1, v / v), reference peak TMS 0.00 ppm): δ 8.73-8.68 (m, 2H), 8.38-8.32 (m, 1H), 7.94-7.88 (m, 3H), 7.84 (d, J = 7.0 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.62 (s, 1H), 7.60-7.54 (m, 2H), 7.53-7.48 (m, 2H), 6.86 (s, 1H), 4.08 (s, 2H), 3.82-3.76 (m, 4H), 3.02 (t, J = 5.0 Hz, 2H), 2.96 (t, J = 5.0 Hz, 2H), 1.67 (s, 6H); 13 C NMR (125 MHz, CD3OD / CDCl3(1:1, v / v), reference peak CD3OD 49.00 ppm): δ 169.3, 167.1, 162.4 (TFA, q, 2 J C,F = 35.3 Hz), 151.9, 147.3, 146.9, 144.9, 143.8, 142.2, 136.9, 136.0, 135.3, 133.8, 132.9, 131.8 (q, 2 J C,F = 32.9 Hz), 129.7, 127.9 (q, 3 J C,F = 3.8 Hz), 127.8, 127.4, 127.2, 126.5, 124.5, 123.9 (q, 1 J C,F= 272.3 Hz), 118.7, 117.6 (TFA, d, 1 J C,F = 298.2 Hz), 111.7, 111.3, 78.4, 52.6, 52.2, 47.0, 43.5, 37.0, 28.7; C 37 H 34 F3N6O3[M+H] + LRMS (ESI) m / z Theoretical: 667.3, Measured: 667.1.

[0268] Compound SB2905

[0269]

[0270] Compound 6 (46.0 mg, 88.9 μmol) synthesized according to the above procedure was used as a starting material and purified through medium-pressure liquid chromatography using silica gel (MPLC, gradient from 0% to 4% MeOH in dichloromethane) to obtain compound SB2905 in the form of a white solid.

[0271] Total yield of the two-step reaction: 72% (38.0 mg, 64.2 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.82 (br s, 1H), 8.11 (s, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.81-7.78 (m, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.55-7.46 (m, 4H), 6.86 (s, 1H), 3.67 (t, J = 5.3 Hz, 2H), 2.95 (t, J = 4.8 Hz, 4H), 2.85-2.58 (m, 6H), 2.10 (br s, 1H), 1.67 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 163.8, 149.3, 143.2, 142.8, 134.8, 134.7, 132.7, 131.6, 130.5 (q, 2J_C,F = 32.9 Hz), 128.8, 126.9, 126.8 (q, 1 J_C,F = 3.7 Hz), 126.7, 126.1, 123.9 (q, 3 J_C,F = 272.1 Hz), 123.5, 114.1, 111.4, 110.6, 77.3, 59.3, 57.8, 53.6, 52.0, 28.4; C 32 H 33 F3N5O3[M+H] + LRMS (ESI) m / z Theoretical: 592.3, Measured: 592.2.

[0272] Compound SB2906

[0273]

[0274] Compound 7 (52.0 mg, 91.3 μmol) synthesized according to the above procedure was used as a starting material and purified through medium-pressure liquid chromatography using silica gel (MPLC, gradient from 1% to 20% ethyl acetate in hexane) to obtain compound SB2906 in the form of a white solid.

[0275] Total yield of the two-step reaction: 88% (52.0 mg, 80.8 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.69 (br s, 1H), 8.09 (s, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 7.3 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.58-7.45 (m, 4H), 6.83 (s, 1H), 3.85 (t, J = 5.0 Hz, 2H), 3.76 (t, J = 4.9 Hz, 2H), 3.00-2.94 (m, 4H), 1.67 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 163.9, 155.6 (q, 2 J C,F= 36.1 Hz), 149.4, 142.7, 141.9, 134.9, 134.5, 132.4, 131.9, 130.6 (q, 2 J C,F = 32.9 Hz), 128.9, 126.9 (q, 1 J C,F = 3.7 Hz), 126.7, 126.5, 126.2, 123.9 (q, 1 J C,F = 272.4 Hz), 123.7, 116.3 (q, 1 J C,F = 287.9 ​​Hz), 114.7, 112.3, 110.7, 77.5, 51.9, 51.6, 46.3, 43.8, 28.4;C 32 H 28 LRMS (ESI) m / z for F6N5O3[M+H]+: Theoretical: 644.2, Measured: 644.2.

[0276] Compound SB2907

[0277]

[0278] Compound 8 (20.0 mg, 35.8 μmol) synthesized according to the above procedure was used as a starting material and purified through reverse-phase preparative HPLC (water / acetonitrile mixed solvent containing 0.1% trifluoroacetic acid, gradient from 15% to 90% acetonitrile) to obtain compound SB2907 in the form of a white solid.

[0279] Step 2 reaction total yield: 25% (5.70 mg, 9.01 μmol); 1H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.64 (br s, 1H), 8.07 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.76 (d, J = 7.2 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.56-7.46 (m, 4H), 6.80 (s, 1H), 4.07 (s, 2H), 3.84-3.70 (m, 2H), 3.56-3.47 (m, 2H), 3.06 (s, 6H), 2.97-2.88 (m, 4H), 1.67 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 163.9, 162.3, 149.4, 142.7, 142.0, 134.9, 134.5, 132.4, 131.9, 130.7 (d, 2 J C,F = 33.3 Hz), 128.9, 126.9 (q, 3 J C,F = 3.4 Hz), 126.64, 126.56, 126.2, 123.9 (d, 1 J C,F = 272.5 Hz), 123.7, 114.8, 112.3, 110.5, 77.6, 55.4, 51.6, 45.6, 42.9, 42.4, 28.5; C 34 H 36 LRMS (ESI) m / z for F3N6O3[M+H]+: Theoretical: 633.3, Found: 633.4.

[0280]

[0281] Manufacturing Example 3-3. Synthetic Procedure for Compound SB2908

[0282] Compound SB2908 was prepared according to the procedure of Scheme 3 below.

[0283] [Reaction Formula 3]

[0284]

[0285] At 0℃, a solution of SB2905 (17.0 mg, 28.7 μmol, 1.0 equiv) in dichloromethane (2.0 mL) was sequentially added with triethylamine (TEA, 40.0 μL, 0.287 mmol, 10.0 equiv), 4-(dimethylamino)pyridine (DMAP, 0.351 mg, 2.87 μmol, 0.1 equiv), and methanesulfonyl chloride (8.90 μL, 0.115 mmol, 4.0 equiv). The mixture was stirred at room temperature for 0.5 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with water and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude amine was dissolved in acetonitrile (4.0 mL) at room temperature, and potassium carbonate (K2CO3, 16.5 mg, 0.115 mmol, 4.0 equiv) and morpholine (morpholine, 7.81 mg, 86.2 μmol, 3.0 equiv) were added, and the mixture was stirred at 60°C for 12 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through cotton and washed with DCM / MeOH (9:1, v / v) and EtOAc. Then, it was concentrated under reduced pressure and purified by reverse-phase preparative HPLC (water / ACN mixed solvent containing 0.1% TFA, gradient from 20% to 65% ACN) to obtain a white solid compound SB2908 in the form of a TFA salt.

[0286] Total yield of the two-step reaction: 72% (13.6 mg, 20.6 μmol); 1H NMR (400 MHz, (CD3)2SO, reference peak TMS 0.00 ppm): δ 9.26 (br s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.82 (d, J = 7.6 Hz, 2H), 7.80-7.74 (m, 3H), 7.61-7.56 (m, 1H), 7.54-7.48 (m, 2H), 7.43 (s, 1H), 6.86 (s, 1H), 3.81-3.71 (m, 4H), 3.25-3.15 (m, 4H), 3.15-3.07 (m, 8H), 3.06-3.00 (m, 4H), 1.63 (s, 6H); 13 C NMR (100 MHz, (CD3)2SO, reference peak (CD3)2SO 39.52 ppm): δ 164.3, 158.3 (TFA, d, 2 J C,F = 32.7 Hz), 149.8, 145.4, 142.8, 135.5, 134.3, 131.70, 131.65, 128.9, 128.6, 127.0, 126.8 (q, 3 J C,F = 3.8 Hz), 126.3, 125.2, 124.0 (d, 1 J C,F = 272.4 Hz), 123.1, 118.1, 109.75, 109.68, 77.3, 64.1, 52.2, 52.0, 51.5, 50.7, 48.7, 28.2; C 36 H 40 LRMS (ESI) m / z for F3N6O3[M+H]+: Theoretical: 661.3, Measured: 661.3.

[0287]

[0288] Manufacturing Example 3-4. Synthetic Procedure for Compound SB2909

[0289] Compound SB2909 was prepared according to the procedure of Scheme 4 below.

[0290] [Reaction Formula 4]

[0291]

[0292] At room temperature, a solution of compound 2 (23.7 mg, 50.0 μmol, 1.0 equivalent) in ACN (2.0 mL) was added with potassium carbonate (K2CO 3, 34.6 mg, 0.250 mmol, 5.0 equiv) and ethyl chloroacetate (9.19 mg, 75.0 μmol, 1.5 equiv) were added and stirred at 60°C for 8 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through cotton and washed with DCM / MeOH (9:1, v / v) and EtOAc. The product was concentrated under reduced pressure and purified by medium-pressure liquid chromatography using silica gel (MPLC, gradient from 0% to 3% MeOH in DCM) to obtain compound 9 as a yellow solid.

[0293] Yield: 75% (21.0 mg, 37.5 μmol); 1 H NMR (400 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 7.81 (d, J = 8.1 Hz, 2H), 7.65 (d, J = 8.2 Hz, 2H), 7.58 (s, 1H), 7.53 (s, 1H), 6.65 (s, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.27 (s, 2H), 3.18-3.11 (m, 4H), 2.79-2.72 (m, 4H), 1.69 (s, 6H), 1.29 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 170.1, 157.7, 148.5, 142.6, 135.2, 134.8, 131.1 (d, 2 J C,F = 33.2 Hz), 130.7, 126.8 (q, 3 J C,F = 3.7 Hz), 125.8, 123.6 (d, 1 J C,F= 272.7 Hz), 123.2, 121.5, 108.8, 107.7, 79.3, 60.7, 59.3, 52.7, 51.1, 29.0, 14.2; C 27 H 29 LRMS (ESI) m / z for F3N5O5[M+H]+: Theoretical: 560.2, Measured: 560.2.

[0294] Compound 9 (21.0 mg, 37.5 μmol, 1.0 equiv) was dissolved in methanol (MeOH, 6.0 mL) at room temperature. Pd / C (20 wt%) was added to the solution, and the mixture was stirred at room temperature under 1 atm of hydrogen for 7 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through Celite and washed with ethanol (EtOH). The resulting filtrate was concentrated under reduced pressure. The resulting crude amine product was dissolved in dry dichloromethane (2.0 mL), and N,N-diisopropylethylamine (DIPEA, 13.1 μL, 75.0 μmol, 2.0 equiv) and benzoyl chloride (6.54 μL, 56.3 μmol, 1.5 equiv) were added at 0°C, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography using silica gel (MPLC, gradient from 0% to 2% MeOH in dichloromethane) to obtain compound 10 as a yellow solid.

[0295] Total yield of the two-step reaction: 85% (20.2 mg, 31.9 μmol); 1H NMR (400 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.88 (br s, 1H), 8.11 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.81 (d, J = 7.4 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.55-7.45 (m, 4H), 6.86 (s, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.32 (s, 2H), 3.02-2.92 (m, 4H), 2.86-2.75 (m, 4H), 1.67 (s, 6H), 1.29 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 170.0, 163.8, 149.2, 143.3, 142.8, 134.8, 134.7, 132.7, 131.6, 130.5 (d, 2 J C,F = 33.1 Hz), 128.7, 127.0, 126.8 (q, 3 J C,F = 3.8 Hz), 126.7, 126.1, 124.0 (d, 1 J C,F = 272.4 Hz), 123.6, 114.0, 111.5, 110.7, 60.7, 59.2, 53.4, 51.8, 28.4, 14.3; C 34 H 35 F3N5O4[M+H] + LRMS (ESI) m / z Theoretical: 634.3, Measured: 634.2.

[0296] Lithium hydroxide monohydrate (5.35 mg, 0.127 mmol, 4.0 equiv) was added to a solution of compound 10 (20.2 mg, 31.9 μmol, 1.0 equiv) in a mixed solvent of water (1.0 mL), ethanol (EtOH, 1.0 mL), and tetrahydrofuran (THF, 1.0 mL) at room temperature, and the mixture was stirred at 60°C for 1 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was concentrated under reduced pressure, diluted with water, and washed with ether. The product was then neutralized with citric acid monohydrate (53.6 mg, 0.255 mmol, 8.0 equiv) and extracted twice with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 20% to 70% ACN in a water / ACN mixture containing 0.1% TFA) to obtain SB2909 as a white solid in the form of a TFA salt.

[0297] Yield: 44% (8.50 mg, 14.0 μmol); 1 H NMR (400 MHz, (CD3)2SO, reference peak TMS 0.00 ppm): δ 9.25 (s, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.82-7.74 (m, 5H), 7.61-7.55 (m, 1H), 7.54-7.49 (m, 2H), 7.47 (s, 1H), 6.86 (s, 1H), 3.83 (s, 2H), 3.20-3.12 (m, 4H), 3.12-3.06 (m, 4H), 1.63 (s, 6H); 13 C NMR (100 MHz, (CD3)2SO, reference peak (CD3)2SO 39.52 ppm): δ 167.7, 164.4, 157.9 (TFA, q, 2 J C,F= 32.0 Hz), 149.8, 145.0, 142.8, 135.6, 135.1, 134.3, 131.7, 128.9, 128.6, 127.1, 126.9 (q, 3 J C,F = 3.8 Hz), 126.4, 125.3, 124.0 (d, 1 J C,F = 272.3 Hz), 123.2, 118.1, 110.0, 109.8, 77.4, 55.3, 52.1, 47.7, 43.3, 40.4, 28.3; C 32 H 31 F3N5O4[M+H] + LRMS (ESI) m / z Theoretical: 606.2, Measured: 606.2.

[0298]

[0299] Manufacturing Example 3-5. Synthetic Procedure for Compounds SB2910-SB2916

[0300] Compounds SB2910 to SB2916 were prepared according to the procedure of Scheme 5 below.

[0301] [Reaction Formula 5]

[0302]

[0303] Compound 1 (280 mg, 0.485 mmol, 1.0 equiv) was dissolved in N,N-dimethylformamide (DMF, 5.0 mL), tin chloride dihydrate (767 mg, 3.40 mmol, 7.0 equiv) was added, and the mixture was stirred at room temperature for 3 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with a saturated aqueous potassium sodium tartrate tetrahydrate solution and extracted three times with dichloromethane (DCM). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The remaining N,N-dimethylformamide was removed three times by azeotropic evaporation using toluene. The obtained crude amine product was dissolved in dry dichloromethane (23.5 mL), and N,N-diisopropylethylamine (DIPEA, 170 μL, 0.976 mmol, 2.0 equiv) and benzoyl chloride (84.6 μL, 0.728 mmol, 1.5 equiv) were added at 0°C, and the mixture was stirred at room temperature for 1.5 h. After confirming the completion of the reaction by TLC and LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography on silica gel (MPLC, gradient from 0% to 5% MeOH in dichloromethane) to obtain compound 11 in the form of a yellow solid.

[0304] Step 2 reaction total yield: 93% (308 mg, 0.453 mmol); 1H NMR (400 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.78 (br s, 1H), 8.10 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 6.8 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.56-7.42 (m, 5H), 7.40-7.35 (m, 4H), 6.81 (s, 1H), 5.17 (s, 2H), 3.70-3.62 (m, 4H), 2.92-2.82 (m, 4H), 1.67 (s, 6H); 13 C NMR (100 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 163.9, 155.2, 149.3, 142.9, 142.7, 136.4, 134.9, 134.6, 132.6, 131.8, 130.6 (d, 2 J C,F = 32.8 Hz), 130.1, 128.9, 128.6, 128.4, 128.2, 128.1, 126.9 (q, 3 J C,F = 3.7 Hz), 126.6, 126.2, 123.6, 114.3, 111.8, 110.6, 77.4, 67.5, 51.8, 44.5, 28.4; C 38 H 35 F3N5O4[M+H] + LRMS (ESI) m / z Theoretical: 682.3, Measured: 682.2.

[0305] To a solution of compound 11 (150 mg, 0.221 mmol, 1.0 equiv) in a mixed solvent of tetrahydrofuran (THF, 0.6 mL) and ethanol (EtOH, 2.4 mL) at room temperature, 40% aqueous potassium hydroxide (KOH, 124 mg, 2.21 mmol, 10.0 equiv) was added, and the mixture was stirred at 100°C for 3 h. After confirming the completion of the reaction by TLC and LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with dichloromethane (DCM). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography on silica gel (MPLC, gradient from 0% to 12% MeOH in dichloromethane) to obtain compound 12 as a yellow solid.

[0306] Yield: 55% (66.9 mg, 0.122 mmol); 1 H NMR (400 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.91 (br s, 1H), 8.13 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.84-7.77 (m, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.58-7.43 (m, 4H), 6.86 (s, 1H), 3.07 (t, J = 4.7 Hz, 4H), 2.88 (t, J = 4.7 Hz, 4H), 1.67 (s, 6H); 13 C NMR (100 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 163.7, 149.2, 143.7, 143.2, 142.8, 134.9, 134.8, 132.7, 131.6, 130.5 (d, 2 J C,F = 32.9 Hz), 128.8, 127.0, 126.8 (q, 3 J C,F= 3.7 Hz), 126.7, 126.1, 123.5, 114.0, 111.4, 110.7, 53.2, 46.8, 28.4; C 30 H 29 F3N5O2[M+H] + LRMS (ESI) m / z Theoretical: 548.2, Measured: 548.1.

[0307] Compound SB2910

[0308]

[0309] To a solution of compound 12 (20.1 mg, 36.7 μmol, 1.0 equiv) in dry tetrahydrofuran (0.80 mL) at room temperature, 3-pyridinecarboxaldehyde (19.7 mg, 0.184 mmol, 5.0 equiv), dibutyltin dichloride (11.5 mg, 37.9 μmol, 1.0 equiv), and phenylsilane (23.0 μL, 0.187 mmol, 5.0 equiv) were added, and the mixture was stirred at 65°C for 4 hours. After confirming the completion of the reaction by TLC and LC-MS, the reaction mixture was concentrated under reduced pressure and purified using reverse-phase preparative HPLC (gradient from 10% to 75% ACN in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2910 as a white solid in the form of a TFA salt.

[0310] Yield: 76% (17.78 mg, 27.8 μmol); 1H NMR (400 MHz, CD3OD / CDCl3(1:10, v / v), reference peak TMS 0.00 ppm): δ 8.69 (br s, 1H), 8.14 (d, J = 7.9 Hz, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.79 (d, J = 8.0 Hz, 3H), 7.69 (d, J = 8.2 Hz, 2H), 7.60-7.47 (m, 5H), 7.35 (s, 2H), 6.88 (s, 1H), 4.25 (s, 2H), 3.26-3.11 (m, 8H), 1.67 (s, 6H); 13 C NMR (100 MHz, CD3OD / CDCl3 (1:10, v / v), reference peak CD3OD 49.00 ppm): δ 165.0, 150.1, 149.3, 148.8, 142.8, 142.5, 140.8, 134.9, 134.3, 132.5, 132.0, 130.8 (d, 2 J C,F = 32.9 Hz), 128.8, 126.8 (q, 3 J C,F = 3.7 Hz), 126.7, 126.2, 125.9, 123.8 (d, 1 J C,F = 272.1 Hz), 123.7, 116.2, 111.8, 110.7, 77.5, 57.6, 52.2, 28.3; C 36 H 34 LRMS (ESI) m / z for F3N6O2[M+H]+: Theoretical: 639.3, Found: 639.5.

[0311] Compound SB2911

[0312]

[0313] To a solution of compound 12 (12.8 mg, 23.4 μmol, 1.0 equiv) dissolved in dichloromethane (0.90 mL) at room temperature, pyridine-3-carboxylic acid (3.74 mg, 30.4 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 4.28 mg, 35.1 μmol, 1.5 equiv) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 5.82 mg, 30.4 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC and LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted three times with ethyl acetate (EtOAc). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 15% to 85% ACN in a water / ACN mixture containing 0.1% TFA) to obtain SB2911 as a white solid.

[0314] Yield: 86% (13.2 mg, 20.2 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.84 (s, 1H), 8.76 (s, 1H), 8.71 (s, 1H), 8.11-8.05 (m, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.79-7.75 (m, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.67-7.62 (m, 1H), 7.57-7.47 (m, 4H), 6.84 (s, 1H), 4.14-3.78 (m, 2H), 3.78-3.44 (m, 2H), 3.13-2.81 (m, 4H), 1.67 (s, 6H); 13C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 166.3, 164.0, 149.5, 147.8, 145.1, 142.5, 142.2, 138.6, 134.8, 134.5, 132.63, 132.55, 131.9, 130.8 (d, 2 J C,F = 33.1 Hz), 129.0, 126.9 (q, 3 J C,F = 3.7 Hz), 126.7, 126.6, 126.2, 125.1, 123.9 (d, 1 J C,F = 272.4 Hz), 123.6, 114.7, 112.1, 110.7, 77.5, 51.9, 48.5, 28.5; C 36 H 32 LRMS (ESI) m / z for F3N6O3[M+H]+: Theoretical: 653.2, Found: 653.3.

[0315] Compound SB2912

[0316]

[0317] To a solution of compound 12 (18.2 mg, 33.3 μmol, 1.0 equiv) dissolved in dichloromethane (1.3 mL) at room temperature, pyridine-4-carboxylic acid (5.33 mg, 43.3 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 6.10 mg, 49.9 μmol, 1.5 equiv) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 8.30 mg, 43.3 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted three times with ethyl acetate (EtOAc). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 20% to 90% ACN in a water / ACN mixture containing 0.1% TFA) to obtain SB2912 as a white solid.

[0318] Yield: 53% (11.5 mg, 17.6 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.84-8.74 (m, 2H), 8.69 (s, 1H), 8.08 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 7.7 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.57-7.52 (m, 2H), 7.51-7.46 (m, 4H), 6.84 (s, 1H), 4.07-3.86 (m, 2H), 3.61-3.42 (m, 2H), 3.06-2.82 (m, 4H), 1.67 (s, 6H); 13C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 167.0, 163.9, 149.4, 148.4, 145.1, 142.6, 142.1, 134.9, 134.5, 132.4, 131.9, 130.7 (d, 2 J C,F = 32.9 Hz), 128.9, 126.9 (q, 3 J C,F = 3.8 Hz), 126.7, 126.6, 126.2, 123.9 (d, 1 J C,F = 272.2 Hz), 123.7, 122.2, 114.7, 112.2, 110.6, 77.5, 52.1, 51.8, 48.0, 42.7, 28.5; C 36 H 32 LRMS (ESI) m / z for F3N6O3[M+H]+: Theoretical: 653.2, Found: 653.0.

[0319] Compound SB2913

[0320]

[0321] Lithium 1-methylimidazole-2-carboxylate (10.8 mg, 81.7 μmol, 1.5 eq), 4-(dimethylamino)pyridine (DMAP, 6.66 mg, 54.5 μmol, 1.0 eq), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 13.6 mg, 70.8 μmol, 1.3 eq) were added to a solution of compound 12 (29.8 mg, 54.5 μmol, 1.0 eq) in dichloromethane (3.0 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. Afterwards, lithium 1-methylimidazole-2-carboxylate (7.19 mg, 54.5 μmol, 1.0 equiv), DMAP (9.98 mg, 81.7 μmol, 1.5 equiv), EDC, HCl (13.6 mg, 70.8 μmol, 1.3 equiv) were further added, and the mixture was stirred at room temperature for 48 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with ethyl acetate (EtOAc). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 10% to 80% ACN in a water / ACN mixture containing 0.1% TFA) to obtain SB2913 as a white solid in the form of a TFA salt.

[0322] Yield: 20% (7.10 mg, 10.8 μmol); 1H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.79 (br s, 1H), 8.09 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.80-7.76 (m, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.56-7.52 (m, 2H), 7.51-7.46 (m, 2H), 7.28-7.26 (m, 1H), 7.08-7.05 (m, 1H), 6.83 (s, 1H), 4.04-3.88 (m, 7H), 3.04-2.91 (m, 4H), 1.67 (s, 6H); 13 C NMR (150 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 164.0, 160.8 (TFA, q, 2 J C,F = 38.5 Hz), 157.4, 149.4, 142.6, 142.5, 138.2, 134.8, 134.4, 132.6, 131.9, 130.7 (q, 2 J C,F = 32.9 Hz), 128.9, 126.9 (q, 3 J C,F = 3.7 Hz), 126.8, 126.6, 126.2, 125.0, 123.9, 123.7, 123.0 (q, 1 J C,F = 272.3 Hz), 115.7 (TFA, q, 1 J C,F = 289.0 Hz), 114.6, 112.0, 110.7, 77.4, 52.3, 51.7, 47.9, 43.0, 35.4, 28.4; C 35 H 33 LRMS (ESI) m / z for F3N7O3[M+H]+: Theoretical: 656.3, Observed: 656.1

[0323] Compound SB2914

[0324]

[0325] Compound 12 (20.1 mg, 36.6 μmol, 1.0 equiv) was dissolved in dichloromethane (DCM, 1.8 mL), and 2,6-pyridinedicarboxylic acid (2,6-pyridinedicarboxylic acid, 7.96 mg, 47.6 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 6.71 mg, 55.0 μmol, 1.5 equiv), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 9.13 mg, 47.6 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 3 hours. The completion of the reaction was confirmed by LC-MS. The reaction mixture was quenched with saturated aqueous NaHCO3, extracted three times with ethyl acetate (EtOAc), and the combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (water / ACN mixed solvent containing 0.1% TFA, gradient from 10% to 100% ACN) to obtain SB2914 as a white solid.

[0326] Yield: 35% (9.00 mg, 12.9 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.74 (br s, 1H), 8.31 (d, J = 7.8 Hz, 1H), 8.14-8.09 (m, 1H), 8.08 (s, 1H), 7.92 (d, J = 7.8 Hz, 1H), 7.86 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 7.6 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.57-7.52 (m, 2H), 7.51-7.47 (m, 2H), 6.85 (s, 1H), 4.08-3.93 (m, 2H), 3.75-3.63 (m, 2H), 3.10-3.01 (m, 2H), 2.97-2.88 (m, 2H), 1.67 (s, 6H); 13C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 166.0, 164.0, 163.4, 152.4, 149.5, 145.1, 142.5, 142.4, 139.9, 134.8, 134.5, 132.6, 131.9, 130.8 (q, 2 J C,F = 33.0 Hz), 128.9, 128.0, 126.9 (q, 3 J C,F = 3.7 Hz), 126.7, 126.6, 126.2, 125.1, 123.9 (q, 1 J C,F = 272.4 Hz), 123.6, 114.6, 112.0, 110.7, 77.5, 52.2, 51.8, 47.9, 43.0, 28.5; C 37 H 32 LRMS (ESI) m / z for F3N6O5[M+H]+: Theoretical: 697.2, Found: 697.2.

[0327] Compound SB2915

[0328]

[0329] To a solution of compound 12 (18.2 mg, 33.2 μmol, 1.0 equiv) dissolved in dichloromethane (1.6 mL) at room temperature, N-(tert-butoxycarbonyl)-L-proline (9.30 mg, 43.2 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 6.09 mg, 49.8 μmol, 1.5 equiv), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 8.28 mg, 43.2 μmol, 1.3 equiv) were added, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by TLC and LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with ethyl acetate (EtOAc). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude product was dissolved in dichloromethane (0.50 mL), trifluoroacetic acid (TFA, 0.10 mL) was added, and the mixture was stirred at room temperature for 1 hour. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 10% to 80% ACN in a water / ACN mixture containing 0.1% TFA) to obtain SB2915 as a white solid in the form of a TFA salt.

[0330] Total yield of the two-step reaction: 82% (17.5 mg, 27.2 μmol); 1H NMR (500 MHz, CDCl3, 기준 피크 TMS 0.00 ppm): δ 8.66 (br s, 1H), 8.07 (s, 1H), 7.85 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 7.6 Hz, 2H), 7.69 (d, J = 8.2 Hz, 2H), 7.54-7.51 (m, 2H), 7.50-7.46 (m, 2H), 6.81 (s, 1H), 4.92 (t, J = 7.7 Hz, 1H), 3.89-3.71 (m, 2H), 3.68-3.59 (m, 2H), 3.53-3.43 (m, 2H), 3.03 (dt, J = 10.0, 4.2 Hz, 1H), 2.95 (dt, J = 9.7, 4.0 Hz, 1H), 2.91-2.84 (m, 2H), 2.56-2.46 (m, 1H), 2.22-2.12 (m, 1H), 2.10-2.01 (m, 1H), 1.99-1.91 (m, 1H), 1.66 (s, 6H); 13 C NMR (125 MHz, CDCl3, 기준 피크 CDCl377.00 ppm): δ 167.5, 163.9, 162.4 (TFA, d, 2 J C,F = 35.4 Hz), 149.4, 142.7, 142.0, 134.9, 134.5, 132.4, 131.9, 130.6 (q, 2 J C,F = 33.2 Hz), 128.9, 126.9 (q, 3 J C,F = 3.8 Hz), 126.6, 126.5, 126.1, 123.9 (q, 1 J C,F = 272.4 Hz), 123.7, 116.5 (TFA, d, 1 J C,F = 285.7 Hz), 114.8, 112.2, 110.6, 77.5, 57.6, 51.6, 51.5, 46.4, 45.9, 43.4, 29.8, 28.4, 24.9; C 35 H 36LRMS (ESI) m / z for F3N6O3[M+H]+: Theoretical: 645.3, Found: 645.2.

[0331] Compound SB2916

[0332]

[0333] To a solution of compound 12 (41.3 mg, 75.4 μmol, 1.0 equiv) in dry N,N-dimethylformamide (1.0 mL) at room temperature were added 4-imidazoleacetic acid hydrochloride (15.9 mg, 98.0 μmol, 1.3 equiv), N,N-diisopropylethylamine (DIPEA, 65.6 μL, 0.377 mmol, 5.0 equiv), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 57.4 mg, 0.151 mmol, 2.0 equiv), and the mixture was stirred at room temperature for 3 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted three times with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 10% to 75% ACN in a water / ACN mixture containing 0.1% TFA) to obtain SB2916 as a white solid in the form of a TFA salt.

[0334] Yield: 12% (6.01 mg, 9.17 μmol); 1H NMR (500 MHz, CD3OD, reference peak TMS 0.00 ppm): δ 8.83 (s, 1H), 7.91 (d, J = 8.2 Hz, 2H), 7.85 (d, J = 7.7 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H), 7.66 (s, 1H), 7.60-7.56 (m, 1H), 7.53-7.49 (m, 2H), 7.46 (s, 1H), 7.39 (s, 1H), 6.86 (s, 1H), 4.01 (s, 2H), 3.79-3.72 (m, 4H), 3.03-2.98 (m, 2H), 2.97-2.92 (m, 2H), 1.66 (s, 6H); 13 C NMR (125 MHz, CD3OD, reference peak CD3OD 49.00 ppm): δ 168.6, 167.6, 163.0 (TFA, q, 2 J C,F = 34.5 Hz), 152.4, 147.9, 144.2, 136.3, 135.6, 135.0, 134.0, 133.1, 132.0 (q, 2 J C,F = 32.8 Hz), 129.9, 129.5, 128.13, 128.12 * (q, 3 J C,F = 3.7 Hz), 127.8, 126.6, 125.4 (q, 1 J C,F = 271.5 Hz), 124.8, 119.6, 118.8, 118.2 (TFA, d, 1 J C,F = 293.6 Hz), 111.7, 111.4, 78.6, 52.8, 52.3, 47.2, 43.6, 29.9, 28.7; C 35 H 33 LRMS (ESI) m / z for F3N7O3[M+H]+: Theoretical: 656.3, Found: 656.1.

[0335] *Half of the peak overlaps with the adjacent peak (δ = 128.13 ppm), so a multiplet is inferred based on the half signal.

[0336]

[0337] Manufacturing Example 3-6. Synthetic Procedure for Compounds SB2921-SB2924

[0338] Compounds SB2921 to SB2924 were prepared according to the procedure of Scheme 6 below.

[0339] [Reaction Formula 6]

[0340]

[0341] Compound 13, the starting material, was synthesized according to the method reported by Park et al. (2009). To a solution of compound 13 (1.50 g, 6.27 mmol, 1.0 equiv) in acetonitrile (ACN, 18.6 mL) at room temperature, potassium carbonate (K2CO3, 3.47 g, 25.1 mmol, 4.0 equiv) and morpholine (morpholine, 1.08 mL, 12.5 mmol, 2.0 equiv) were added. The mixture was stirred at 60°C for 3 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through cotton and washed with DCM / MeOH (9:1, v / v) and ethyl acetate (EtOAc). The product was concentrated under reduced pressure and purified by MPLC using silica gel (gradient from 2% to 30% ethyl acetate in hexane) to obtain compound 14 in the form of a yellow viscous substance (gum).

[0342] Yield: 83% (1.60 g, 5.22 mmol); 1 H NMR (400 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.45 (s, 1H), 6.44 (s, 1H), 3.85 (t, J = 4.5 Hz, 4H), 3.13 (t, J = 4.6 Hz, 4H), 2.71 (s, 2H), 1.49 (s, 6H); 13C NMR (100 MHz, CDCl3, reference peak CDCl3 77.00 ppm): δ 189.4, 163.3, 151.7, 135.5, 127.4, 112.7, 106.60, 106.56, 80.8, 66.3, 51.1, 48.3, 26.7; C 15 H 29 N2O5[M+H] + LRMS (ESI) m / z Theoretical: 307.1, Measured: 307.1.

[0343] To a solution of triethyl orthoformate (2.61 mL, 15.7 mmol, 3.0 equiv) in dry dichloromethane (5.0 mL) at -10°C was added boron trifluoride diethyl etherate (1.93 mL, 15.7 mmol, 3.0 equiv) under argon gas, and the mixture was stirred for 10 minutes. The reaction mixture was slowly warmed to 0°C and stirred for an additional 15 minutes. The mixture was then cooled to -78°C, and a solution of compound 14 (1.60 g, 5.22 mmol, 1.0 equiv) in dry dichloromethane (3.0 mL) and N,N-diisopropylethylamine (DIPEA, 3.18 mL, 18.3 mmol, 3.5 equiv) were slowly added over 30 minutes. The mixture was warmed to room temperature and stirred for an additional 2 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was diluted with dichloromethane, quenched with a saturated aqueous solution of NaHCO3, and extracted three times with dichloromethane. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC using silica gel (gradient from 2% to 15% ethyl acetate in hexane) to obtain compound 15 as a yellow solid.

[0344] Yield: 94% (2.00 g, 4.90 mmol); 1H NMR (400 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.42 (s, 1H), 6.42 (s, 1H), 4.90 (d, J = 5.5 Hz, 1H), 3.88-3.82 (m, 4H), 3.76-3.61 (m, 2H), 3.56-3.38 (m, 2H), 3.16-3.08 (m, 4H), 2.82 (d, J = 5.4 Hz, 1H), 1.57 (s, 3H), 1.43 (s, 3H), 1.19 (t, J = 7.0 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H); 13 C NMR (100 MHz, CDCl3, reference peak CDCl3 77.00 ppm): δ 189.1, 162.6, 151.6, 135.6, 127.5, 113.3, 106.4, 106.3, 99.6, 99.5, 82.5, 66.3, 63.0, 61.8, 58.31, 58.29, 51.1, 26.5, 25.6, 15.1, 15.0; C 20 H 29 N2O7[M+H] + LRMS (ESI) m / z Theoretical: 409.2, Measured: 409.2.

[0345] To a solution of compound 15 (2.00 g, 4.90 mmol, 1.0 equiv) in acetone (75.0 mL) at room temperature was added iodine (249 mg, 0.979 mmol, 0.2 equiv), and the mixture was stirred at 35°C for 14 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with a saturated aqueous sodium thiosulfate pentahydrate solution and extracted three times with dichloromethane. The combined organic layers were dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC on silica gel (gradient from 2% to 15% ethyl acetate in hexane) to obtain compound 16 as a yellow solid.

[0346] Yield: 76% (1.24 g, 3.71 mmol); 1 H NMR (400 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.45 (s, 1H), 7.88 (s, 1H), 6.41 (s, 1H), 3.85 (t, J = 4.5 Hz, 4H), 3.15 (t, J = 4.5 Hz, 4H), 1.63 (s, 6H); 13 C NMR (100 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 179.7, 169.3, 169.2, 162.2, 151.5, 135.5, 127.2, 127.1, 113.3, 111.7, 106.5, 106.3, 80.2, 66.4, 66.2, 66.1, 51.1, 28.55, 28.48; C 16 H 19 N2O6[M+H] + LRMS (ESI) m / z Theoretical: 335.1, Measured: 335.1.

[0347] To a solution of compound 16 (400 mg, 1.20 mmol, 1.0 equiv) in acetic acid (12.0 mL) was added 4-(trifluoromethyl)phenylhydrazine (253 mg, 1.44 mmol, 1.2 equiv), and the mixture was stirred at 35°C for 2 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous Na2CO3 solution and extracted three times with dichloromethane. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by MPLC on silica gel (gradient from 0% to 3% methanol in dichloromethane) to obtain compound 17 (SB2925) as a yellow solid.

[0348] Yield: 93% (530 mg, 1.12 mmol); 1H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 7.82 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H), 7.61 (s, 1H), 7.54 (s, 1H), 6.66 (s, 1H), 3.87-3.83 (m, 4H), 3.10-3.05 (m, 4H), 1.70 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 157.8, 148.5, 142.5, 135.2, 134.9, 131.3 (q, 2 J C,F = 33.1 Hz), 130.5, 126.8 (q, 3 J C,F = 3.7 Hz), 125.9, 123.6 (d, 1 J C,F = 272.3 Hz), 123.2, 121.5, 108.7, 108.0, 79.4, 66.6, 51.7, 29.1; C 23 H 22 F3N4O4[M+H] + LRMS (ESI) m / z Theoretical: 475.2, Measured: 475.2.

[0349] Compound 17 (170 mg, 0.358 mmol, 1.0 equivalent) was dissolved in methanol (12.0 mL) at room temperature. Pd / C (10 wt%) was added to the solution, and the mixture was stirred at room temperature for 6 h under 1 atm of hydrogen. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through Celite, washed with ethanol, and concentrated under reduced pressure. The resulting compound 18 was unstable and was used in the next reaction without purification. C 23 H 24 F3N4O2[M+H] + LRMS (ESI) m / z Theoretical: 445.2, Measured: 445.2.

[0350] Compound SB2921

[0351]

[0352] To a solution of compound 18 (30.0 mg, <67.5 μmol, 1.0 equiv) in dry dichloromethane (2.0 mL) at 0°C, N,N-diisopropylethylamine (DIPEA, 23.5 μL, 0.135 mmol, 2.0 equiv) and benzoyl chloride (11.8 μL, 0.101 mmol, 1.5 equiv) were sequentially added, and the mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 20% to 100% ACN in a water / ACN mixture containing 0.1% TFA) to give SB2921 as a yellow solid.

[0353] Step 2 Overall yield: 54% (20.0 mg, 36.5 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.84 (br s, 1H), 8.11 (s, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.81-7.76 (m, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.55-7.50 (m, 2H), 7.49-7.45 (m, 2H), 6.85 (s, 1H), 3.89-3.83 (m, 4H), 2.93-2.88 (m, 4H), 1.67 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 163.8, 149.4, 143.0, 142.8, 134.9, 134.7, 132.7, 131.7, 130.7 (d, 2 J C,F = 32.7 Hz), 128.8, 127.0, 126.9 (d, 3 JC,F = 4.0 Hz), 126.6, 126.2, 124.0 (d, 1 J C,F = 272.5 Hz), 123.6, 114.3, 111.7, 110.6, 77.4, 67.5, 52.4, 28.5; C 30 H 28 F3N4O3[M+H] + LRMS (ESI) m / z Theoretical: 549.2, Measured: 549.2.

[0354] Compound SB2922

[0355]

[0356] To a solution of compound 18 (30.0 mg, <67.5 μmol, 1.0 equiv) in dry dichloromethane (2.0 mL) at 0°C were added N,N-diisopropylethylamine (DIPEA, 35.3 μL, 0.203 mmol, 3.0 equiv) and nicotinic acid chloride hydrochloride (nicotinoyl chloride hydrochloride, 15.62 mg, 87.8 μmol, 1.3 equiv), and the mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 20% to 75% ACN in a water / ACN mixture containing 0.1% TFA) to give compound SB2922 as a white solid.

[0357] Step 2 Overall yield: 26% (9.64 mg, 17.5 μmol); 1H NMR (500 MHz, (CD3)2SO, reference peak TMS 0.00 ppm): δ 9.51 (s, 1H), 8.98-8.94 (m, 1H), 8.76-8.71 (m, 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.93 (d, J = 8.3) Hz, 2H), 7.79-7.76 (m, 3H), 7.59-7.54 (m, 1H), 7.37 (s, 1H), 6.82 (s, 1H), 3.74-3.70 (m, 4H), 2.91-2.85 (m, 4H), 1.63 (s, 6H); 13 C NMR (125 MHz, (CD3)2SO, reference peak (CD3)2SO 39.52 ppm): δ 162.8, 152.1, 150.1, 148.1, 146.6, 142.8, 135.5, 134.7, 131.8, 129.9, 128.7 (d, 2 J C,F = 32.2 Hz), 126.8 (q, 3 J C,F = 3.8 Hz), 126.4, 124.7, 124.0 (d, 1 J C,F = 272.1 Hz), 123.6, 123.0, 118.2, 109.5, 109.3, 77.3, 66.4, 51.2, 28.2; C 29 H 27 F3N5O3[M+H] + LRMS (ESI) m / z Theoretical: 550.2, Measured: 550.2.

[0358] Compound SB2923

[0359]

[0360] To a solution of compound 18 (30.0 mg, <67.5 μmol, 1.0 equiv) dissolved in dichloromethane (2.0 mL) at room temperature, lithium 1-methylimidazole-2-carboxylate (13.4 mg, 0.101 mmol, 1.5 equiv), N,N-diisopropylethylamine (DIPEA, 58.8 μL, 0.338 mmol, 5.0 equiv), 1-hydroxybenzotriazole (HOBt, 9.12 mg, 67.5 μmol, 1.0 equiv), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC HCl, 15.7 mg, 0.101 mmol, 1.5 equiv) were sequentially added, and then the mixture was stirred at 40°C. The mixture was stirred for 20 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 20% to 70% ACN in a water / ACN mixture containing 0.1% TFA) to obtain compound SB2923 as a white solid.

[0361] Step 2 Overall yield: 40% (15.0 mg, 27.2 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 9.77 (br s, 1H), 7.87-7.83 (m, 3H), 7.71 (d, J = 8.2 Hz, 2H), 7.54 (s, 1H), 7.08 (d, J = 1.1 Hz, 1H), 6.99 (d, J = 1.1 Hz, 1H), 6.78 (s, 1H), 4.00 (s, 3H), 3.94-3.90 (m, 4H), 2.92-2.88 (m, 4H), 1.68 (s, 6H); 13C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 155.8, 149.6, 144.1, 142.6, 138.8, 134.8, 132.8, 130.5 (q, 2 J C,F = 32.8 Hz), 127.2, 126.9 (q, 3 J C,F = 3.7 Hz), 126.4, 125.8, 125.8, 124.0 (d, 1 J C,F = 272.2 Hz), 123.1, 114.3, 110.5, 110.0, 77.4, 67.2, 52.1, 35.5, 28.6; C 28 H 28 F3N6O3[M+H] + LRMS (ESI) m / z Theoretical: 553.2, Measured: 553.2.

[0362] Compound SB2924

[0363]

[0364] To a solution of compound 18 (30.0 mg, <67.5 μmol, 1.0 equiv) dissolved in dichloromethane (4.0 mL) at room temperature, cyclohexanecarboxylic acid (13.0 mg, 0.101 mmol, 1.5 equiv), N,N-diisopropylethylamine (DIPEA, 58.8 μL, 0.338 mmol, 5.0 equiv), 1-hydroxybenzotriazole (HOBt, 9.12 mg, 67.5 μmol, 1.0 equiv) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 15.7 mg, 0.101 mmol, 1.5 equiv) were sequentially added, and the mixture was stirred at 40°C for 20 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 20% to 100% ACN in a water / ACN mixture containing 0.1% TFA) to obtain compound SB2924 as a white solid.

[0365] Step 2 Overall yield: 48% (18.0 mg, 32.5 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.01 (br s, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.77 (s, 1H), 7.65 (d, J = 8.0 Hz, 2H), 7.53 (s, 1H), 6.79 (s, 1H), 3.91-3.79 (m, 4H), 2.93-2.79 (m, 4H), 2.19 (tt, J = 11.4, 3.4 Hz, 1H), 1.92-1.85 (m, 2H), 1.84-1.77 (m, 2H), 1.73-1.68 (m, 1H), 1.65 (s, 6H), 1.43-1.29 (m, 4H), 1.24-1.16 (m, 1H); 13C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 173.7, 149.5, 143.1, 142.5, 134.7, 132.8, 130.8 (q, 2 J C,F = 32.7 Hz), 126.8 (q, 3 J C,F = 3.7 Hz), 126.3, 126.2, 123.8 (q, 1 J C,F = 272.3 Hz), 123.4, 115.2, 111.3, 110.2, 77.3, 67.3, 52.2, 46.1, 29.7, 28.4, 25.7, 25.6; C 30 H 34 F3N4O3[M+H] + LRMS (ESI) m / z Theoretical: 555.3, Measured: 555.3.

[0366]

[0367] Manufacturing Example 4. Synthesis method and characterization of compound -R 3 derivative

[0368] Manufacturing Example 4-1. Synthetic Procedure for Compounds SB2931-SB2937

[0369] The synthesis of compounds SB2931 to SB2937 was carried out according to the procedure of Scheme 7 below.

[0370] [Reaction Formula 7]

[0371]

[0372] To a solution of the starting material, compound 5 (284 mg, 0.479 mmol, 1.0 equiv) in N,N-dimethylformamide (4.7 mL), tin chloride (SnCl2·2H2O, 756 mg, 3.35 mmol, 7.0 equiv) was added, and the mixture was stirred at room temperature for 3 h. After confirming the completion of the reaction through LC-MS, the reaction mixture was quenched with a saturated potassium-sodium tartrate hydrate solution and extracted three times with ethyl acetate (EtOAc). The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The remaining N,N-dimethylformamide was removed three times by azeotropic distillation with toluene, and finally compound 19 was obtained as a yellow solid.

[0373] Yield: quantitative (269 mg, 0.479 mmol); 1 H NMR (400 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.57-8.49 (m, 2H), 7.77 (d, J = 8.2 Hz, 2H), 7.67 (d, J = 8.4 Hz, 3H), 7.49 (s, 1H), 7.34-7.25 (m, 3H), 6.61 (s, 1H), 6.26 (s, 1H), 3.77 (s, 4H), 3.64-3.59 (m, 2H), 2.92-2.86 (m, 2H), 2.85-2.79 (m, 2H), 1.61 (s, 6H); 13 C NMR (100 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 168.5, 149.9, 148.4, 145.8, 143.2, 139.9, 136.70, 136.69, 135.2, 134.9, 132.8, 130.7, 130.3 (d, 2 J C,F = 33.4 Hz), 126.4 (q, 3 J C,F= 3.9 Hz), 125.7, 124.4, 123.6, 111.4, 110.2, 108.8, 76.5, 50.8, 50.5, 46.5, 42.4, 37.7, 28.0; C 30 H 30 F3N6O2[M+H] + LRMS (ESI) m / z Theoretical: 563.2, Measured: 563.3.

[0374] Compound SB2931

[0375]

[0376] To a solution of compound 19 (48.9 mg, 86.9 μmol, 1.0 equiv) in 1,4-dioxane (1.1 mL) at room temperature, copper(II) acetate (39.5 mg, 0.217 mmol, 2.5 equiv) and pyridine (24.8 μL, 0.304 mmol, 3.5 equiv) were added, and the mixture was stirred at room temperature for 0.5 h. Subsequently, methylboronic acid (13.0 mg, 0.217 mmol, 2.5 equiv) was added, and the mixture was stirred at 100°C for 1.5 h. After confirming the completion of the reaction through TLC and LC-MS, the reaction mixture was cooled to room temperature, filtered through Celite, and the filtrate was concentrated under reduced pressure. The residue was purified using reverse phase preparative HPLC (gradient from 10% to 75% ACN in a water / ACN mixture containing 0.1% TFA) to obtain compound SB2931 as a white solid in the form of a TFA salt.

[0377] Yield: 51% (25.4 mg, 44.0 μmol); 1H NMR (500 MHz, CD3OD, reference peak TMS 0.00 ppm): δ 8.78 (s, 1H), 8.76 (d, J = 5.5 Hz, 1H), 8.48 (d, J = 8.1 Hz, 1H), 8.02 (dd, J = 8.1, 5.8 Hz, 1H), 7.93 (d, J = 8.2 Hz, 2H), 7.76 (d, J = 8.2 Hz, 2H), 7.66 (s, 1H), 6.93 (s, 1H), 6.43 (s, 1H), 4.15 (s, 2H), 3.88-3.72 (m, 4H), 2.98 (t, J = 4.9 Hz, 2H), 2.88 (t, J = 5.0 Hz, 2H), 2.60 (s, 3H), 1.64 (s, 6H); 13 C NMR (125 MHz, CD3OD, reference peak CD3OD 49.00 ppm): δ 169.4, 162.5 (TFA, q, 2 J C,F = 35.0 Hz), 150.6, 148.8, 145.1, 144.41, 144.39, 144.37, 141.5, 138.0, 136.5, 134.2, 134.0, 132.1 (q, 2 J C,F = 33.0 Hz), 128.1, 127.9 (q, 3 J C,F = 3.9 Hz), 127.7, 125.4, 125.3 (q, 1 J C,F = 271.6 Hz), 118.0 (TFA, d, 1 J C,F = 290.8 Hz), 113.3, 110.6, 78.5, 53.1, 52.8, 47.0, 43.5, 37.1, 33.9, 28.5; C 31 H 32 F3N6O2[M+H] + LRMS (ESI) m / z Theoretical: 577.3, Measured: 577.3.

[0378] Compound SB2932

[0379]

[0380] To a solution of compound 19 (36.0 mg, 64.0 μmol, 1.0 equiv) in dry dichloromethane (1.2 mL) at 0°C, TEA (17.9 μL, 0.128 mmol, 2.0 equiv) and acetyl chloride (6.83 μL, 96.1 μmol, 1.5 equiv) were sequentially added, and the mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse phase preparative HPLC (gradient from 10% to 80% ACN in a water / ACN mixture containing 0.1% TFA) to obtain compound SB2932 as a white solid in the form of a TFA salt.

[0381] Yield: 77% (29.8 mg, 49.2 μmol); 1 H NMR (500 MHz, CD3OD, reference peak TMS 0.00 ppm): δ 8.77 (s, 1H), 8.75 (d, J = 5.6 Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.99 (dd, J = 8.1, 5.7 Hz, 1H), 7.88 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.64 (s, 1H), 7.27 (s, 1H), 6.78 (s, 1H), 4.13 (s, 2H), 3.82 (t, J = 4.9 Hz, 2H), 3.78 (t, J = 4.9 Hz, 2H), 2.97 (t, J = 4.9 Hz, 2H), 2.89 (t, J = 5.0 Hz, 2H), 2.06 (s, 3H), 1.63 (s, 6H); 13 C NMR (125 MHz, CD3OD, reference peak CD3OD 49.00 ppm): δ 171.5, 169.5, 162.5 (TFA, q,2 J C,F = 35.2 Hz), 152.3, 148.5, 147.8, 144.6, 144.2, 141.7, 137.8, 136.4, 134.0, 131.8 (q, 2 J C,F = 32.6 Hz), 128.0 (q, 3 J C,F = 3.7 Hz), 127.64, 127.58, 126.3, 125.3 (q, 1 J C,F = 271.5 Hz), 124.9, 120.0, 118.1 (TFA, d, 1 J C,F = 286.1 Hz), 111.4, 111.0, 78.5, 52.6, 52.2, 47.0, 43.5, 37.1, 28.6, 23.4; C 32 H 32 F3N6O3[M+H] + LRMS (ESI) m / z Theoretical: 605.2, Measured: 605.3.

[0382] Compound SB2933

[0383]

[0384] To a solution of compound 19 (38.8 mg, 68.9 μmol, 1.0 equiv) in methanol (MeOH, 1.3 mL) at room temperature, sodium sulfate (Na2SO4, 29.4 mg, 0.207 mmol, 3.0 equiv) and benzaldehyde (benzaldehyde, 10.4 μL, 0.103 mmol, 1.5 equiv) were added, and the mixture was stirred at room temperature for 3 h. After confirming complete consumption of the starting material by TLC, sodium borohydride (NaBH4, 13.0 mg, 0.344 mmol, 5.0 equiv) was added, and the mixture was stirred at 60°C for an additional 3 h. To ensure complete reaction progression, sodium borohydride (2.61 mg, 68.9 μmol, 1.0 equiv) was additionally added at 2-h intervals. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 10% to 85% ACN in a water / ACN mixture containing 0.1% TFA), and compound SB2933 was obtained as a TFA salt.

[0385]

[0386] Yield: 54% (24.4 mg, 37.3 μmol); 1H NMR (500 MHz, CD3OD, reference peak TMS 0.00 ppm): δ 8.77-8.75 (m, 1H), 8.74 (d, J = 5.7 Hz, 1H), 8.45-8.42 (m, 1H), 8.00-7.96 (m, 1H), 7.77 (d, J = 8.2 Hz, 2H), 7.60-7.56 (m, 3H), 7.23-7.15 (m, 3H), 6.99-6.94 (m, 2H), 6.75 (s, 1H), 6.04 (s, 1H), 4.12 (s, 2H), 4.00 (s, 2H), 3.89-3.69 (m, 4H), 2.98 (t, J = 5.1 Hz, 2H), 2.89 (t, J = 5.8 Hz, 2H), 1.57 (s, 6H); 13 C NMR (125 MHz, CD3OD, reference peak CD3OD 49.00 ppm): δ 169.5, 162.6 (TFA, q, 2 J C,F = 35.6 Hz), 148.3, 146.8, 144.7, 144.5, 142.3, 141.9, 140.3, 137.8, 137.5, 136.4, 134.7, 131.7 (q, 2 J C,F = 32.8 Hz), 129.5, 128.0, 127.8 (q, 3 J C,F = 3.6 Hz), 127.72, 127.70, 127.6, 125.33 (q, 1 J C,F = 271.6 Hz), 125.30, 118.0 (TFA, d, 1 J C,F = 291.7 Hz), 112.2, 111.7, 106.6, 77.6, 52.4, 52.0, 47.2, 43.7, 37.2, 28.3; C 37 H 36 F3N6O2[M+H] + LRMS (ESI) m / z Theoretical: 653.3, Measured: 653.3.

[0387] Compound SB2934

[0388]

[0389] To a solution of compound 19 (38.5 mg, 68.4 μmol, 1.0 equiv) in dichloromethane (3.4 mL) at room temperature, morpholinoacetic acid hydrochloride (16.1 mg, 88.9 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 12.5 mg, 0.103 mmol, 1.5 equiv), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 17.0 mg, 88.9 μmol, 1.3 equiv) were sequentially added, and the reaction mixture was stirred at room temperature for 2 h. After confirming the completion of the reaction through LC-MS, the reaction mixture was quenched by adding saturated aqueous NaHCO3 solution, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 10% to 60% ACN in water / ACN containing 0.1% TFA) to obtain compound SB2934 as a white solid in the form of a TFA salt.

[0390] Yield: 72% (33.9 mg, 49.1 μmol); 1H NMR (500 MHz, CD3OD, 기준 피크 TMS 0.00 ppm): δ 8.77 (s, 1H), 8.75 (d, J = 5.6 Hz, 1H), 8.44 (d, J = 8.0 Hz, 7. = 1H), Hz, 1H), 7.90 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.66 (s, 1H), 7.58 (s, 1H), 6.85 (s, 1H), 4.15 (s. 4, 2H), 3.98–3.91 (m, 4H), 3.85 (t, J = 4.9 Hz, 2H), 3.82 (t, J = 5.0 Hz, 2H), 3.41–3.32 (m, 4H), 2.97 (t, J = 4.7 Hz 2. Hz, = 2H), 1.64 (s, 6H); 13 C NMR (125 MHz, CD3OD, 기준 피크 CD3OD 49.00 ppm): δ 169.5, 163.7, 62.7 (TFA, q, 2 J C,F = 35.3 Hz), 152.3, 148.2, 146.9, 144.7, 144.3, 141.9, 137.7, 136.4, 133.8, 131.5 (q, 2 J C,F = 32.6 Hz), 128.1 (q, 3 J C,F = 3.7 Hz), 27.7, 127.6, 125.9, 125.5 (q, 1 J C,F = 271.4 Hz), 125.0, 118.3, 118.1 (TFA, d, 1 J C,F = 294.4 Hz), 111.7, 111.5, 78.6, 65.0, 58.8, 54.0, 52.7, 52.6, 46.9, 43.4, 37.2, 28.6; C 36 H 39 F3N7O4[M+H] +LRMS (ESI) m / z Theoretical: 690.3, Measured: 690.3.

[0391] Compound SB2935

[0392]

[0393] To a solution of compound 19 (29.7 mg, 52.7 μmol, 1.0 equiv) in dichloromethane (2.1 mL) at room temperature, pyridine-2-carboxylic acid (8.43 mg, 68.5 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 9.66 mg, 79.1 μmol, 1.5 equiv), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 13.1 mg, 68.5 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 2 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched by adding saturated aqueous NaHCO3 solution, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 10% to 65% ACN in water / ACN containing 0.1% TFA) to give SB2935 as a white solid in the form of a TFA salt.

[0394] Yield: 76% (26.6 mg, 39.9 μmol); 1H NMR (500 MHz, CD3OD, reference peak TMS 0.00 ppm): δ 8.76-8.69 (m, 2H), 8.63 (d, J = 4.7 Hz, 1H), 8.35 (d, J = 8.0 Hz, 1H), 8.07-8.03 (m, 2H), 8.00-7.96 (m, 1H), 7.91 (d, J = 8.3 Hz, 3H), 7.70 (d, J = 8.1 Hz, 2H), 7.64 (s, 1H), 7.58-7.54 (m, 1H), 6.85 (s, 1H), 4.11 (s, 2H), 3.90 (t, J = 4.9 Hz, 2H), 3.87 (t, J = 5.3 Hz, 2H), 2.99 (t, J = 4.8 Hz, 2H), 2.92 (t, J = 4.9 Hz, 2H), 1.64 (s, 6H); 13 C NMR (125 MHz, CD3OD, reference peak CD3OD 49.00 ppm): δ 169.9, 162.8 (TFA, d, 2 J C,F = 35.2 Hz), 162.7, 151.2, 151.1, 149.7, 146.9, 145.7, 145.2, 144.2, 144.1, 142.9, 139.1, 137.1, 136.2, 134.2, 132.0 (q, 2 J C,F = 32.7 Hz), 128.2 (q, 3 J C,F = 3.8 Hz), 127.94, 127.87, 127.2, 125.5 (q, 1 J C,F = 271.6 Hz), 124.8, 123.0, 115.1, 112.0, 111.5, 78.5, 52.9, 52.5, 47.4, 43.8, 37.3, 28.7; C 36 H 33 LRMS (ESI) m / z for F3N7O3[M+H]+: Theoretical: 668.3, Found: 668.1.

[0395] Compound SB2936

[0396]

[0397] To a solution of compound 19 (29.7 mg, 52.7 μmol, 1.0 equiv) in dichloromethane (2.1 mL) at room temperature, 3-hydroxypyridine-2-carboxylic acid (9.53 mg, 68.5 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 9.66 mg, 79.1 μmol, 1.5 equiv) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 13.1 mg, 68.5 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 20 h. After confirming the completion of the reaction through LC-MS, the reaction mixture was quenched by adding saturated aqueous NaHCO3 solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 10% to 65% ACN in water / ACN containing 0.1% TFA) to give SB2936 as a white solid in the form of a TFA salt.

[0398] Yield: 76% (20.8 mg, 30.4 μmol); 1H NMR (500 MHz, CDCl3, TMS 0.00 ppm 기준): δ 11.66 (br s, 1H), 10.54 (s, 1H), 8.88 (s, 1H), 8.70 (d, J = 5.5 Hz, 1H), 8.28 (d, J = 7.9 Hz, 1H), 8.09 (dd, J = 4.1, 1.7 Hz, 1H), 7.98 (s, 1H), 7.87 (d, J = 8.2 Hz, 2H), 7.81 (dd, J = 8.0, 5.4 Hz, 1H), 7.70 (d, J = 8.3 Hz, 2H), 7.54 (s, 1H), 7.38-7.33 (m, 2H), 6.78 (s, 1H), 3.95 (s, 2H), 3.93-3.85 (m, 2H), 3.85-3.80 (m, 2H), 3.00 (t, J = 4.8 Hz, 2H), 2.95 (t, J = 5.0 Hz, 2H), 1.69 (s, 6H); 13 C NMR (125 MHz, CDCl3, CDCl377.00 ppm 기준): δ 166.6, 165.8, 161.9 (TFA, d, 2 J C,F = 35.6 Hz). (q, 3 J C,F = 3.6 Hz), 126.59, 126.56, 125.7, 125.2, 123.9 (q, 1 J C,F = 272.4 Hz), 123.2, 116.0 (TFA, d, 1 J C,F = 290.1 ​​Hz), 113.9, 111.3, 110.3, 77.7, 51.7, 51.5, 46.2, 42.7, 36.5, 28.6; C 36 H 33 F3N7O4[M+H]+에 대한 LRMS (ESI) m / z 이론값: 684.3, 측정값: 684.1.

[0399] Compound SB2937

[0400]

[0401] Lithium 1-methylimidazole-2-carboxylate (10.9 mg, 82.7 μmol, 1.3 equiv), N,N-diisopropylethylamine (DIPEA, 55.4 μL, 0.318 mmol, 5.0 equiv), and 3-oxide hexafluorophosphate (HATU, 48.4 mg, 0.127 mmol, 2.0 equiv) were sequentially added to a solution of compound 19 (35.8 mg, 63.6 μmol, 1.0 equiv) in dry N,N-dimethylformamide (3.0 mL) at room temperature, and the mixture was stirred at room temperature for 3 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched by adding saturated aqueous NaHCO3 solution, and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 20% to 80% ACN in water / CAN containing 0.1% TFA) to give SB2937 as a white solid in the form of a TFA salt.

[0402] Yield: 45% (19.4 mg, 28.9 μmol); 1H NMR (based on 500 MHz, CD3OD, TMS 0.00 ppm): δ 8.78 (s, 1H), 8.76 (d, J = 5.7 Hz, 1H), 8.50-8.44 (m, 1H), 8.01 (dd, J = 8.1, 5.7 Hz, 1H), 7.95-7.89 (m, 3H), 7.71 (d, J = 8.2 Hz, 2H), 7.64 (s, 1H), 7.23 (s, 1H), 7.02 (s, 1H), 6.85 (s, 1H), 4.14 (s, 2H), 3.98 (s, 3H), 3.90 (t, J = 4.9 Hz, 2H), 3.86 (t, J = 4.9 Hz, 2H), 2.99 (t, J = 4.9 Hz, 2H), 2.90 (t, J = 5.0 Hz, 2H), 1.65 (s, 6H); 13 C NMR (125 MHz, CD3OD, reference CD3OD = 49.00 ppm): δ 169.6, 162.3 (TFA, 2 J C,F = 36.2 Hz), 157.5, 151.1, 148.7, 144.9, 144.5, 144.1, 141.6, 140.2, 138.0, 136.2, 134.2, 131.9 (q, 2 J C,F = 32.4 Hz), 128.7, 128.2 (q, 3 J C,F = 4.0 Hz), 128.1, 127.8, 127.7, 127.3, 125.5 (q, 1 J C,F = 271.6 Hz), 124.7, 115.0, 111.9, 111.5, 78.5, 52.9, 52.6, 47.2, 43.7, 37.2, 35.7, 28.8; C 35 H 34 LRMS (ESI) m / z for F3N8O5[M+H]+: Theoretical: 671.3, Measured: 671.3.

[0403]

[0404] Manufacturing Example 4-2. Synthetic Procedures for Compounds SB2951-SB2965 and Compounds SB2967-SB2969

[0405] The synthesis of compounds SB2951 to SB2965 and compounds SB2967 to SB2969 was carried out according to the procedure of Scheme 8 below.

[0406] [Reaction Formula 8]

[0407]

[0408] Lithium 1-methylimidazole-2-carboxylate (138 mg, 1.04 mmol, 1.3 equiv), N,N-diisopropylethylamine (DIPEA, 699 μL, 4.01 mmol, 5.0 equiv), and 3-oxide hexafluorophosphate (HATU, 610 mg, 1.60 mmol, 2.0 equiv) were sequentially added to a solution of compound 2 (380 mg, 0.803 mmol, 1.0 equiv) in anhydrous N,N-dimethylformamide (11.0 mL) at room temperature, and the mixture was stirred at room temperature for 1.5 h. After confirming the completion of the reaction by TLC and LC-MS, the reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed three times with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography using silica gel (MPLC, gradient from 20% to 75% ethyl acetate in hexane) to obtain compound 20 as a yellow solid.

[0409] Yield: 80% (374 mg, 0.644 mmol); 1H NMR (400 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 7.83 (d, J = 8.2 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.64 (s, 1H), 7.54 (s, 1H), 7.05 (s, 1H), 6.96 (s, 1H), 6.68 (s, 1H), 4.29 (t, J = 4.8 Hz, 2H), 3.98-3.92 (m, 2H), 3.91 (s, 3H), 3.23-3.14 (m, 4H), 1.70 (s, 6H); 13 C NMR (100 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 159.5, 157.8, 148.4, 142.5, 139.4, 135.6, 135.2, 135.0, 130.5, 129.2, 127.4, 126.8 (q, 3 J C,F = 3.8 Hz), 125.8, 124.1, 123.3, 121.5, 109.2, 108.3, 79.4, 52.0, 51.4, 47.1, 42.2, 35.2, 29.1; C 28 H 27 F3N7O4[M+H] + LRMS (ESI) m / z Theoretical: 582.2, Measured: 582.2.

[0410] To a solution of compound 20 (364 mg, 0.626 mmol, 1.0 equiv) in N,N-dimethylformamide (DMF, 6.0 mL) was added tin chloride dihydrate (989 mg, 4.38 mmol, 7.0 equiv), and the mixture was stirred at room temperature for 1.5 h. After confirming the completion of the reaction through LC-MS, the reaction mixture was quenched with a saturated aqueous potassium sodium tartrate tetrahydrate solution and extracted three times with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. N,N-dimethylformamide was then removed through azeotropic distillation with toluene three times, obtaining compound 21 in the form of a yellow solid.

[0411] Yield: Quantitative (345 mg, 0.626 mmol); 1 H NMR (400 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 7.77 (d, J = 8.3 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.49 (s, 1H), 7.05 (s, 1H), 6.96 (s, 1H), 6.69 (s, 1H), 6.28 (s, 1H), 4.22 (s, 2H), 3.95-3.85 (m, 5H), 3.45 (br s, 2H), 3.02-2.95 (m, 4H), 1.61 (s, 6H); 13 C NMR (100 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 159.4, 145.7, 143.2, 140.2, 139.5, 135.2, 134.9, 132.8, 130.1 (d, 2 J C,F = 32.6 Hz), 127.3, 126.3 (q, 3 J C,F = 3.7 Hz), 125.7, 124.3, 124.0, 123.7 (d, 1 J C,F= 272.5 Hz), 111.2, 110.3, 108.7, 76.3, 51.2, 50.6, 47.8, 42.7, 35.1, 27.9; C 28 H 29 F3N7O2[M+H] + LRMS (ESI) m / z Theoretical: 552.2, Measured: 552.2.

[0412] Compound SB2951

[0413]

[0414] To a solution of compound 21 (45.0 mg, 81.7 μmol, 1.0 equiv) in acetonitrile (0.81 mL) at room temperature were added K2CO3 (16.9 mg, 0.122 mmol, 1.5 equiv) and methyl iodide (6.10 μL, 98.0 μmol, 1.2 equiv), and the mixture was stirred at 80°C for 1 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through cotton and washed with ethyl acetate. The product was concentrated under reduced pressure and purified by reverse-phase preparative HPLC (gradient from 10% to 60% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2951 as a white solid in the form of a TFA salt.

[0415] Yield: 19% (8.90 mg, 15.7 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 7.80 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.52 (s, 1H), 7.33 (d, J = 1.5 Hz, 1H), 7.10 (d, J) = 1.4 Hz, 1H), 6.75 (s, 1H), 6.26 (s, 1H), 5.41 (br s, 1H), 4.04-3.71 (m, 7H), 3.02-2.88 (m, 4H), 2.50 (s, 3H), 1.63 (s, 6H); 13C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 166.6, 161.3 (TFA, d, 2 J C,F = 36.1 Hz), 156.5, 147.2, 142.9, 141.3, 138.0, 135.05, 134.98, 132.8, 130.9 (q, 2 J C,F = 33.2 Hz), 126.4 (q, 3 J C,F = 3.8 Hz), 123.99, 123.95, 123.68, 123.65 (q, 1 J C,F = 272.4 Hz), 115.9 (TFA, d, 1 J C,F = 290.2 Hz), 112.0, 111.2, 107.0, 77.0, 51.8, 51.0, 47.6, 42.9, 35.4, 32.0, 28.2; C 29 H 31 LRMS (ESI) m / z for F3N7O2[M+H]+: Theoretical: 566.2, Found: 566.3.

[0416] Compound SB2952

[0417]

[0418] To a solution of compound 21 (18.6 mg, 33.7 μmol, 1.0 equiv) in acetonitrile (0.33 mL) at room temperature were added K2CO3 (9.31 mg, 67.3 μmol, 2.0 equiv) and methyl iodide (4.19 μL, 67.3 μmol, 2.0 equiv), and the mixture was stirred at 80°C for 1 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was filtered through cotton and washed with ethyl acetate. The product was concentrated under reduced pressure and purified by reverse-phase preparative HPLC (gradient from 10% to 60% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2952 as a white solid.

[0419] Yield: 18% (3.42 mg, 5.90 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 7.83 (d, J = 8.4 Hz, 2H), 7.70 (d, J = 8.3 Hz, 2H), 7.54 (s, 1H), 7.29 (d, J = 1.4 Hz, 1H), 7.06 (d, J) = 1.3 Hz, 1H), 6.92 (s, 1H), 6.60 (s, 1H), 3.90 (s, 7H), 3.10 (s, 4H), 2.76 (s, 6H), 1.67 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 164.0, 156.9, 146.2, 142.87, 142.86, 138.5, 135.3, 131.6, 131.2 (d, 2 J C,F = 33.3 Hz), 126.56 (q, 3 J C,F = 3.7 Hz), 126.50, 124.4, 124.0, 123.50 (d, 1 J C,F = 272.5 Hz), 123.47, 113.3, 112.9, 112.2, 78.2, 52.1, 51.5, 47.0, 44.9, 42.5, 35.2, 28.6; C 30 H 33 LRMS (ESI) m / z for F3N7O2[M+H]+: Theoretical: 580.3, Found: 580.1.

[0420] Compound SB2953

[0421]

[0422] To a solution of compound 21 (24.6 mg, 44.6 μmol, 1.0 equiv) in anhydrous dichloromethane (0.90 mL) at 0°C, triethylamine (TEA, 12.4 μL, 89.1 μmol, 2.0 equiv) and acetyl chloride (4.75 μL, 66.9 μmol, 1.5 equiv) were sequentially added, and the mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 20% to 75% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2953 as a white solid in the form of a TFA salt.

[0423] Yield: 77% (29.8 mg, 49.2 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 7.89 (s, 1H), 7.82 (s, 2H), 7.80 (d, J = 2.5 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.53 (s, 1H), 7.36 (s, 1H), 7.13 (s, 1H), 6.76 (s, 1H), 3.98-3.86 (m, 7H), 3.01-2.85 (m, 4H), 2.09 (s, 3H), 1.64 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 168.3, 160.7 (TFA, d, 2 J C,F = 37.6 Hz), 156.4, 149.6, 142.54, 142.52, 142.4, 137.7, 134.8, 132.5, 130.6 (q, 2 J C,F = 33.3 Hz), 126.7 (q, 3 J C,F= 3.7 Hz), 126.2, 126.0, 123.9, 123.79 (q, 1 J C,F = 272.2 Hz), 123.76, 115.3, 111.8, 110.5, 77.4, 52.2, 51.3, 47.6, 42.9, 35.5, 28.3, 24.2; C 30 H 31 LRMS (ESI) m / z for F3N7O3[M+H]+: Theoretical: 594.2, Found: 594.3.

[0424] Compound SB2954

[0425]

[0426] To a solution of compound 21 (23.1 mg, 41.8 μmol, 1.0 equiv) in anhydrous dichloromethane (0.80 mL) at 0°C, triethylamine (TEA, 11.7 μL, 83.6 μmol, 2.0 equiv) and chloroacetyl chloride (5.00 μL, 62.7 μmol, 1.5 equiv) were sequentially added, and the mixture was stirred at room temperature for 1 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with dichloromethane. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 20% to 80% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2954 as a white solid in the form of a TFA salt.

[0427] Yield: 72% (18.9 mg, 30.1 μmol); 1H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 9.25 (s, 1H), 7.92 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.66 (d, J = 8.2 Hz, 2H), 7.54 (s, 1H), 7.36 (d, J = 1.4 Hz, 1H), 7.11 (d, J = 1.4 Hz, 1H), 6.82 (s, 1H), 4.11 (s, 2H), 3.99-3.84 (m, 7H), 3.01-2.92 (m, 4H), 1.65 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 162.9, 160.7 (TFA, d, 2 J C,F = 36.2 Hz), 156.6, 150.0, 142.6, 142.5, 137.8, 134.8, 132.5, 130.6 (q, 2 J C,F = 33.2 Hz), 126.8 (q, 3 J C,F = 3.8 Hz), 126.1, 125.7, 124.2, 123.80, 123.79 (d, 1 J C,F = 272.2 Hz), 123.78, 113.8, 111.9, 111.0, 77.4, 52.0, 51.5, 47.7, 43.2, 43.0, 35.4, 28.3; C 30 H 31 LRMS (ESI) m / z for F3N7O3[M+H]+: Theoretical: 628.2, Found: 628.2.

[0428] Compound SB2955

[0429]

[0430] To a solution of compound 21 (19.9 mg, 36.2 μmol, 1.0 equiv) in N,N-dimethylformamide (DMF, 0.36 mL) at room temperature were added K2CO3 (6.00 mg, 43.4 μmol, 1.2 equiv), tetrabutylammonium iodide (4.01 mg, 10.9 μmol, 0.3 equiv), and 2-bromoethanol (3.06 μL, 43.4 μmol, 1.2 equiv), and the mixture was stirred at 120°C for 6 h. After confirming the completion of the reaction by TLC and LC-MS, the reaction mixture was filtered through cotton and washed with ethyl acetate. After concentrating the product under reduced pressure, the product was purified by reverse phase preparative HPLC (gradient from 20% to 65% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2955 as a white solid in the form of a TFA salt.

[0431] Yield: 18% (3.94 mg, 6.62 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 7.79 (d, J = 8.2 Hz, 2H), 7.68 (d, J = 8.3 Hz, 2H), 7.51 (s, 1H), 7.24 (d, J = 1.4 Hz, 1H), 7.06 (d, J) = 1.3 Hz, 1H), 6.75 (s, 1H), 6.24 (s, 1H), 4.56 (br s, 1H), 4.07-3.84 (m, 7H), 3.66 (t, J = 5.2 Hz, 2H), 3.04-2.90 (m, 4H), 2.86 (t, J = 5.1 Hz, 2H), 1.63 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 157.4, 147.0, 143.0, 141.4, 138.5, 135.1, 134.4, 132.8, 130.7 (d, 2 J C,F = 33.2 Hz), 126.5 * (q,3 J C,F = 3.3 Hz), 126.4, 124.9, 124.0, 123.8, 123.7 (d, 1 J C,F = 272.1 Hz), 111.8, 111.1, 107.1, 59.9, 51.8, 51.0, 47.64, 47.63, 42.9, 35.3, 28.2; C 30 H 33 LRMS (ESI) m / z for F3N7O3[M+H]+: Theoretical: 596.3, Found: 596.3.

[0432] *Half of the peak overlaps with the adjacent peak (δ = 128.13 ppm), so a multiplet is inferred based on the half signal.

[0433] Compound SB2956

[0434]

[0435] To a solution of compound 21 (25.4 mg, 46.1 μmol, 1.0 equiv) in methanol (0.90 mL) at room temperature, sodium sulfate (Na2SO4, 19.6 mg, 0.138 mmol, 3.0 equiv) and benzaldehyde (5.60 μL, 55.4 μmol, 1.2 equiv) were added, and the mixture was stirred at room temperature for 5 h. After confirming complete consumption of the starting material by TLC, sodium borohydride (NaBH4, 5.23 mg, 0.138 mmol, 3.0 equiv) was added, and the mixture was further stirred at room temperature for 2.5 h. To ensure complete reaction, sodium borohydride (3.49 mg, 92.2 μmol, 2.0 equiv) and sodium sulfate (13.1 mg, 92.2 μmol, 2.0 equiv) were further added and stirred at 40°C for 5 h. Then, sodium borohydride (8.72 mg, 0.230 mmol, 5.0 equiv) and benzaldehyde (4.70 μL, 46.5 μmol, 1.0 equiv) were added again and stirred at 60°C for 15 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 15% to 85% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2956 as a white solid in the form of a TFA salt.

[0436] Yield: 37% (10.8 mg, 16.9 μmol); 1H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 7.67 (d, J = 8.5 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.50 (s, 1H), 7.36 (d, J = 1.5 Hz, 1H), 7.26-7.22 (m, 3H), 7.10 (d, J = 1.4 Hz, 1H), 7.02-6.98 (m, 2H), 6.73 (s, 1H), 6.20 (s, 1H), 3.98 (s, 2H), 3.96-3.67 (m, 7H), 2.98-2.87 (m, 4H), 1.61 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 161.2 (TFA, d, 2 J C,F = 36.6 Hz), 156.4, 142.8, 140.5, 138.0, 135.0, 134.5, 133.0, 130.6 (d, 2 J C,F = 32.1 Hz), 129.8, 129.0, 128.6, 127.4, 126.9, 126.4 (q, 3 J C,F = 3.8 Hz), 126.1, 124.2, 124.0, 123.7 (d, 1 J C,F = 272.3 Hz), 123.6, 111.9, 111.1, 106.3, 77.3, 51.5, 50.9, 48.9, 47.7, 43.0, 35.4, 28.1; C 35 H 35 LRMS (ESI) m / z for F3N7O2[M+H]+: Theoretical: 642.3, Found: 642.1.

[0437] Compound SB2957

[0438]

[0439] To a solution of compound 21 (42.2 mg, 76.5 μmol, 1.0 equiv) dissolved in dichloromethane (3.5 mL) at room temperature, 3-(methoxycarbonyl)bicyclo[1.1.1]pentane-1-carboxylic acid (15.6 mg, 91.8 μmol, 1.2 equiv), 4-(dimethylamino)pyridine (DMAP, 14.0 mg, 0.115 mmol, 1.5 equiv) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 19.1 mg, 99.5 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 1.5 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 10% to 85% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2957 as a white solid in the form of a TFA salt.

[0440] Yield: 40% (21.5 mg, 30.5 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.06 (br s, 1H), 7.84 (s, 1H), 7.81 (d, J = 8.3 Hz, 2H), 7.64 (d, J = 8.2 Hz, 2H), 7.52 (s, 1H), 7.32 (s, 1H), 7.10 (d, J = 1.2 Hz, 1H), 6.78 (s, 1H), 3.98-3.87 (m, 7H), 3.70 (s, 3H), 3.00-2.88 (m, 4H), 2.30 (s, 6H), 1.64 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 169.5, 166.3, 160.7 (TFA, d, 2 J C,F= 35.7 Hz), 157.1, 149.6, 142.5, 142.1, 137.9, 134.8, 132.6, 130.8 (q, 2 J C,F = 33.2 Hz), 126.8 (q, 3 J C,F = 3.7 Hz), 126.1, 125.9, 124.7, 123.9, 123.8 (d, 1 J C,F = 272.4 Hz), 123.7, 114.3, 111.9, 110.7, 77.4, 52.3, 52.0, 51.9, 51.4, 47.8, 43.0, 39.9, 36.7, 35.4, 28.3; C 36 H 37 LRMS (ESI) m / z for F3N7O5[M+H]+: 704.3, found: 704.1.

[0441] Compound SB2958

[0442]

[0443] To a solution of compound 21 (42.2 mg, 76.5 μmol, 1.0 equiv) in dichloromethane (3.5 mL) at room temperature, monomethyl terephthalate (17.9 mg, 99.5 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 14.0 mg, 0.115 mmol, 1.5 equiv), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 19.1 mg, 99.5 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 2.5 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 15% to 90% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2958 as a white solid in the form of a TFA salt.

[0444] Yield: 45% (24.8 mg, 34.8 μmol); 1 H NMR (500 MHz, CD3OD / CDCl3(1:10, v / v), reference peak TMS 0.00 ppm): δ 8.18-8.14 (m, 2H), 7.96 (s, 1H), 7.90-7.84 (m, 4H), 7.71 (d, J = 8.2 Hz, 2H), 7.54 (s, 1H), 7.11 (d, J = 1.2 Hz, 1H), 7.07 (d, J = 1.2 Hz, 1H), 6.87 (s, 1H), 4.13-4.05 (m, 2H), 3.99-3.92 (m, 5H), 3.90 (s, 3H), 3.04-2.97 (m, 4H), 1.68 (s, 6H); 13 C NMR (125 MHz, CD3OD / CDCl3 (1:10, v / v), reference peak CD3OD 49.00 ppm): δ 166.5, 163.6, 159.6 (TFA, d, 2 J C,F= 36.3 Hz), 159.1, 150.0, 143.4, 142.5, 138.8, 138.4, 134.9, 132.9, 132.7, 130.9 (d, 2 J C,F = 33.1 Hz), 130.2, 127.0 (q, 3 J C,F = 3.7 Hz), 126.8, 126.7, 126.3, 126.2, 124.3, 123.9 (d, 1 J C,F = 272.1 Hz), 123.6, 115.0, 111.6, 110.9, 77.5, 52.5, 52.4, 51.7, 47.9, 42.9, 35.0, 28.4; C 37 H 35 LRMS (ESI) m / z for F3N7O5[M+H]+: Theoretical: 714.3, Found: 714.2.

[0445] Compound SB2959

[0446]

[0447] To a solution of compound 21 (24.6 mg, 44.5 μmol, 1.0 equiv) in dichloromethane (2.2 mL) at room temperature, morpholinoacetic acid hydrochloride (10.5 mg, 57.9 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 8.16 mg, 66.8 μmol, 1.5 equiv), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 11.1 mg, 57.9 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 1.5 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 10% to 60% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2959 as a white solid in the form of a TFA salt.

[0448] Yield: 73% (22.0 mg, 32.4 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 9.04 (s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.67 (d, J = 8.2 Hz, 2H), 7.51 (d, J = 3.5 Hz, 2H), 7.27 (s, 1H), 7.13 (d, J = 1.6 Hz, 1H), 6.71 (s, 1H), 3.99-3.87 (m, 11H), 3.86 (s, 2H), 3.43-3.14 (m, 4H), 3.01-2.94 (m, 2H), 2.90-2.79 (m, 2H), 1.64 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 162.0, 161.8 (TFA, q, 2 J C,F= 36.0 Hz), 155.6, 150.5, 144.1, 142.7, 137.8, 134.9, 132.2, 130.1 (q, 2 J C,F = 32.8 Hz), 126.7 (q, 3 J C,F = 3.7 Hz), 126.3, 124.5, 123.9 (q, 1 J C,F = 272.4 Hz), 123.7, 123.4, 122.8, 116.6, 116.2 (TFA, d, 1 J C,F = 289.6 Hz), 111.0, 110.2, 77.6, 64.2, 58.6, 52.9, 52.4, 50.4, 47.4, 42.6, 35.5, 28.5; C 34 H 38 LRMS (ESI) m / z for F3N8O4[M+H]+: Theoretical: 679.3, Found: 679.2.

[0449] Compound SB2960

[0450]

[0451] To a solution of compound 21 (27.6 mg, 50.0 μmol, 1.0 equiv) in dichloromethane (2.4 mL) at room temperature, pyridine-2-carboxylic acid (8.00 mg, 65.0 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 9.16 mg, 75.0 μmol, 1.5 equiv), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 12.5 mg, 65.0 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 2 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 20% to 75% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2960 as a white solid in the form of a TFA salt.

[0452] Yield: 75% (24.6 mg, 37.5 μmol); 1 H NMR (500 MHz, CD3OD / CDCl3(10:1, v / v), reference peak TMS 0.00 ppm): δ 8.70-8.65 (m, 1H), 8.09-8.05 (m, 1H), 8.05 (s, 1H), 8.00-7.94 (m, 1H), 7.90 (d, J = 8.4 Hz, 2H), 7.71 (d, J = 8.2 Hz, 2H), 7.61 (s, 1H), 7.58-7.52 (m, 1H), 7.46 (d, J = 1.6 Hz, 1H), 7.35 (d, J = 1.6 Hz, 1H), 6.87 (s, 1H), 4.12-3.98 (m, 2H), 3.97-3.87 (m, 5H), 3.09-2.97 (m, 4H), 1.66 (s, 6H); 13C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 161.2, 160.8 (TFA, d, 2 J C,F = 38.4 Hz), 157.0, 150.0, 149.5, 148.3, 142.9, 142.7, 138.2, 137.6, 134.8, 132.8, 130.7 (q, 2 J C,F = 32.8 Hz), 126.9 (q, 3 J C,F = 3.7 Hz), 126.32, 126.28, 126.2, 124.6, 124.0 (q, 1 J C,F = 272.4 Hz), 123.7, 123.4, 122.2, 115.8 (TFA, d, 1 J C,F = 289.0 Hz), 114.1, 111.2, 110.2, 77.4, 52.1, 51.4, 47.8, 43.0, 35.3, 28.4; C 34 H 32 HRMS (ESI) m / z for F3N8O3[M+H]+: Theoretical: 657.2544, Found: 657.2544.

[0453] Compound SB2961

[0454]

[0455] Lithium 1-methylimidazole-2-carboxylate (lithium 1-methylimidazole-2-carboxylate, 7.25 mg, 54.9 μmol, 1.3 eq), N,N-diisopropylethylamine (DIPEA, 36.8 μL, 0.211 mmol, 5.0 eq) and 3-oxide hexafluorophosphate (HATU, 32.1 mg, 84.5 μmol, 2.0 eq) were sequentially added to a solution of compound 21 (23.3 mg, 42.2 μmol, 1.0 eq) in anhydrous N,N-dimethylformamide (DMF, 2.0 mL) at room temperature, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 20% to 65% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2961 as a white solid in the form of a TFA salt.

[0456] Yield: 47% (13.1 mg, 19.8 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 9.79 (s, 1H), 7.87 (s, 1H), 7.85 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.53 (s, 1H), 7.30 (d, J = 1.5 Hz, 1H), 7.08 (d, J = 1.1 Hz, 1H), 7.06 (d, J = 1.5 Hz, 1H), 6.99 (d, J = 1.1 Hz, 1H), 6.76 (s, 1H), 4.05-3.95 (m, 7H), 3.92 (s, 3H), 3.03-2.95 (m, 4H), 1.67 (s, 6H); 13C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 161.0 (TFA, q, 2 J C,F = 38.8 Hz), 157.1, 155.7, 149.7, 143.2, 142.7, 138.7, 138.3, 134.8, 132.7, 130.5 (q, 2 J C,F = 32.8 Hz), 127.2, 126.9 (q, 3 J C,F = 3.7 Hz), 126.4, 125.8, 125.7, 124.6, 124.0 (d, 1 J C,F = 272.4 Hz), 123.6, 123.3, 115.7 (TFA, d, 1 J C,F = 290.7 Hz), 114.4, 111.0, 110.3, 77.4, 51.8, 51.3, 47.6, 42.9, 35.6, 35.3, 28.5; C 33 H 33 LRMS (ESI) m / z for F3N9O3[M+H]+: Theoretical: 660.3, Found: 660.1.

[0457] Compound SB2962

[0458]

[0459] To a solution of compound 21 (24.6 mg, 44.6 μmol, 1.0 equiv) in dichloromethane (2.2 mL) at room temperature, pyridine-3-carboxylic acid (7.14 mg, 58.0 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 8.17 mg, 66.9 μmol, 1.5 equiv) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 11.1 mg, 58.0 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 2.5 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 10% to 65% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2962 as a white solid in the form of a TFA salt.

[0460] Yield: 51% (14.8 mg, 22.6 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 9.17 (s, 1H), 9.09 (s, 1H), 8.76 (d, J = 4.1 Hz, 1H), 8.40-8.34 (m, 1H), 8.07 (s, 1H), 7.86 (d, J) = 8.5 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.66-7.62 (m, 1H), 7.54 (s, 1H), 7.22 (d, J = 1.3 Hz, 1H), 7.04 (d, J = 1.4 Hz, 1H), 6.90 (s, 1H), 4.14-3.93 (m, 4H), 3.92 (s, 3H), 3.04-2.98 (m, 4H), 1.67 (s, 6H); 13C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 160.6, 157.9, 150.0, 149.7, 144.9, 142.7, 142.6, 138.5, 137.9, 134.9, 132.4, 131.4, 130.7 (q, 2 J C,F = 33.3 Hz), 126.9 (q, 3 J C,F = 3.8 Hz), 126.30, 126.25, 125.4, 124.9, 123.91 (d, 1 J C,F = 272.5 Hz), 123.85, 123.8, 114.1, 112.2, 111.3, 77.6, 52.4, 51.8, 47.6, 42.8, 35.2, 28.5; C 34 H 32 LRMS (ESI) m / z for F3N8O3[M+H]+: Theoretical: 657.3, Found: 657.1.

[0461] Compound SB2963

[0462]

[0463] To a solution of compound 21 (24.6 mg, 44.6 μmol, 1.0 equiv) in dichloromethane (2.2 mL) at room temperature, pyridine-2-carboxylic acid (7.14 mg, 58.0 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 8.17 mg, 66.9 μmol, 1.5 equiv) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 11.1 mg, 58.0 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 2 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 10% to 65% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2963 as a white solid in the form of a TFA salt.

[0464] Yield: 57% (16.7 mg, 25.5 μmol); 1 H NMR (500 MHz, (CD3)2CO, reference peak TMS 0.00 ppm): δ 8.86-8.82 (m, 2H), 8.10 (s, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.89-7.85 (m, 2H), 7.82 (d, J = 8.2) Hz, 2H), 7.69 (s, 1H), 7.37 (d, J = 1.3 Hz, 1H), 7.19 (d, J = 1.3 Hz, 1H), 6.96 (s, 1H), 4.25-4.21 (m, 2H), 4.18-4.11 (m, 2H), 3.94 (s, 3H), 3.09-3.01 (m, 4H), 1.66 (s, 6H); 13C NMR (125 MHz, (CD3)2CO, reference peak (CD3)2CO 29.84 ppm): δ 162.6, 158.8, 150.8, 145.1, 144.30, 144.29, 143.3, 140.1, 136.1, 133.0, 131.7, 130.6 (q, 2 J C,F = 32.6 Hz), 127.7 (q, 3 J C,F = 3.8 Hz), 127.4, 127.3, 127.2, 125.8, 125.20 (d, 1 J C,F = 271.7 Hz), 125.17, 124.8, 122.0, 115.7, 112.3, 112.0, 78.2, 53.1, 52.5, 48.3, 43.3, 35.4, 28.7; C 34 H 32 LRMS (ESI) m / z for F3N8O3[M+H]+: Theoretical: 657.3, Found: 657.1.

[0465] Compound SB2964

[0466]

[0467] To a solution of compound 21 (22.2 mg, 40.3 μmol, 1.0 equiv) dissolved in dichloromethane (2.0 mL) at room temperature, pyridin-3-ylacetic acid hydrochloride (3-pyridylacetic acid hydrochloride, 9.10 mg, 52.4 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 7.39 mg, 60.5 μmol, 1.5 equiv) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 10.1 mg, 52.4 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 1.5 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 10% to 50% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2964 as a white solid in the form of a TFA salt.

[0468] Yield: 97% (26.3 mg, 39.2 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.88 (s, 1H), 8.64 (d, J = 5.5 Hz, 1H), 8.48 (s, 1H), 8.38 (d, J = 8.0 Hz, 1H), 7.80 (dd, J = 8.1, 5.5 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.65 (s, 1H), 7.62 (d, J = 8.2 Hz, 2H), 7.50 (s, 1H), 7.34 (s, 1H), 7.16 (s, 1H), 6.73 (s, 1H), 3.93 (s, 3H), 3.93-3.83 (m, 6H), 3.02-2.92 (m, 2H), 2.88-2.78 (m, 2H), 1.63 (s, 6H); 13C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 165.6, 161.7 (TFA, q, 2 J C,F = 36.5 Hz), 155.9, 150.0, 145.8, 143.1, 142.7, 142.6, 140.5, 137.7, 135.3, 134.9, 132.3, 130.3 (q, 2 J C,F = 32.8 Hz), 126.7 (q, 3 J C,F = 4.1 Hz), 126.2, 125.9, 125.6, 124.0, 123.9 (q, 1 J C,F = 272.2 Hz), 123.5, 122.9, 116.2 (TFA, d, 1 J C,F = 289.5 Hz), 115.6, 111.5, 110.5, 77.5, 52.4, 50.7, 47.3, 42.6, 39.6, 35.4, 28.4; C 35 H 34 LRMS (ESI) m / z for F3N8O3[M+H]+: Theoretical: 671.3, Found: 671.2.

[0469] Compound SB2965

[0470]

[0471] To a solution of compound 21 (23.2 mg, 42.0 μmol, 1.0 equiv) in dichloromethane (2.1 mL) at room temperature, 3-hydroxypyridine-2-carboxylic acid (7.60 mg, 54.6 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 7.70 mg, 63.0 μmol, 1.5 equiv), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 10.5 mg, 54.6 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 20 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 10% to 75% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2965 as a white solid in the form of a TFA salt.

[0472] Yield: 55% (15.5 mg, 23.1 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 11.61 (br s, 1H), 10.60 (s, 1H), 8.14 (dd, J = 4.1, 1.6 Hz, 1H), 7.98 (s, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.2 Hz, 2H), 7.55 (s, 1H), 7.38-7.32 (m, 3H), 7.10 (d, J = 1.5 Hz, 1H), 6.78 (s, 1H), 4.13-3.99 (m, 2H), 3.99-3.91 (m, 5H), 3.06-3.00 (m, 2H), 3.00-2.93 (m, 2H), 1.68 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 165.9, 160.9 (TFA, d, 2 JC,F = 37.7 Hz), 158.1, 156.5, 149.9, 143.0, 142.5, 139.9, 137.9, 134.7, 132.6, 131.5, 131.1 (q, 2 J C,F = 33.0 Hz), 128.9, 126.9 (q, 3 J C,F = 3.8 Hz), 126.6, 126.5, 125.3, 124.1, 123.9 (d, 1 J C,F = 272.3 Hz), 123.7, 123.2, 115.7 (TFA, d, 1 J C,F = 288.7 Hz), 113.8, 111.2, 110.4, 77.6, 52.0, 51.4, 47.7, 43.0, 35.4, 28.6; C 34 H 32 LRMS (ESI) m / z for F3N8O4[M+H]+: Theoretical: 673.2, Found: 673.2.

[0473] Compound SB2967

[0474]

[0475] To a solution of compound 21 (25.2 mg, 45.7 μmol, 1.0 equiv) in dichloromethane (2.2 mL) at room temperature, pyrazinecarboxylic acid (7.37 mg, 59.4 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 8.38 mg, 68.6 μmol, 1.5 equiv), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 11.4 mg, 59.4 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 5 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 10% to 70% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2967 as a white solid in the form of a TFA salt.

[0476] Yield: 94% (28.3 mg, 43.0 μmol); 1 H NMR (500 MHz, CD3OD / CDCl3(1:1, v / v), reference peak TMS 0.00 ppm): δ 9.27 (d, J = 1.5 Hz, 1H), 8.81 (d, J = 2.5 Hz, 1H), 8.76-8.71 (m, 1H), 8.06 (d, J = 1.7 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H), 7.58 (d, J = 1.2 Hz, 1H), 7.19-7.15 (m, 1H), 7.09 (s, 1H), 6.88 (s, 1H), 4.16-4.08 (m, 2H), 4.07-3.99 (m, 2H), 3.90 (s, 3H), 3.09-2.98 (m, 4H), 1.69 (s, 6H); 13C NMR (125 MHz, CD3OD / CDCl3(1:1, v / v), reference peak CD3OD 49.00 ppm): δ 160.5, 160.3, 150.8, 148.0, 145.6, 144.5, 144.3, 144.0, 143.2, 139.9, 135.5, 133.6, 131.7 (d, 2 J C,F = 32.6 Hz), 127.6 (q, 3 J C,F = 3.9 Hz), 127.4, 127.2, 126.3, 124.9, 124.6 (q, 1 J C,F = 272.0 Hz), 124.0, 114.6, 111.7, 111.3, 52.8, 52.2, 43.4, 35.1, 28.7; C 33 H 31 LRMS (ESI) m / z for F3N9O3[M+H]+: Theoretical: 658.2, Found: 658.0.

[0477] Compound SB2968

[0478]

[0479] To a solution of compound 21 (32.3 mg, 58.6 μmol, 1.0 equiv) dissolved in dichloromethane (2.9 mL) at room temperature, N-(tert-butoxycarbonyl)-L-proline (N-(tert-butoxycarbonyl)-L-proline, 16.4 mg, 76.2 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 10.7 mg, 87.9 μmol, 1.5 equiv), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 14.6 mg, 76.2 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 3 hours. After confirming the completion of the reaction by TLC and LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified first by medium-pressure liquid chromatography using silica gel (MPLC, gradient from 0% to 65% ethyl acetate in hexane). The purified crude product was dissolved in dichloromethane (0.90 mL). TFA (90 μL) was added to the solution, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by LC-MS, TFA was removed three times by azeotropic distillation using toluene. The residue was purified by reverse-phase preparative HPLC (gradient from 10% to 55% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2968 as a white solid in the form of a TFA salt.

[0480] Step 2 Total yield: 40% (15.2 mg, 23.4 μmol); 1H NMR (500 MHz, CDCl3, 기준 피크 TMS 0.00 ppm): δ 9.28 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.51 (s, 1H), 7.31 (s, 1H), 7.18 (s, 1H), 7.02 (d, J = 1.3 Hz, 1H), 6.69 (s, 1H), 4.91 (dd, J = 8.6, 5.2 Hz, 1H), 4.15-4.03 (m, 4H), 3.87 (s, 3H), 3.85-3.79 (m, 1H), 3.71-3.64 (m, 1H), 3.41 (dt, J = 11.1, 7.0 Hz, 1H), 3.33 (dt, J = 11.2, 7.0 Hz, 1H), 2.99-2.94 (m, 2H), 2.73-2.65 (m, 1H), 2.45-2.34 (m, 1H), 2.09-1.98 (m, 1H), 1.99-1.89 (m, 1H), 1.90-1.80 (m, 1H), 1.65 (d, J = 5.1 Hz, 6H); 13 C NMR (125 MHz, CDCl3, 기준 피크 CDCl377.00 ppm): δ 167.1, 162.0 (TFA, d, 2 J C,F = 35.7 Hz), 157.3, 150.7, 144.9, 142.8, 138.6, 135.0, 132.2, 130.2 (q, 2 J C,F = 32.7 Hz), 126.6 (q, 3 J C,F = 3.6 Hz), 126.3, 124.9, 124.4, 123.9 (d, 1 J C,F = 272.1 Hz), 123.7, 123.4, 117.3, 110.7, 110.1, 77.6, 59.7, 52.3, 50.6, 47.2, 46.4, 42.1, 35.1, 30.5, 28.5, 24.1; C 33 H 36LRMS (ESI) m / z for F3N8O3[M+H]+: Theoretical: 649.3, Found: 649.1.

[0481] Compound SB2969

[0482]

[0483] To a solution of compound 21 (26.8 mg, 48.6 μmol, 1.0 equiv) dissolved in dichloromethane (2.4 mL) at room temperature, 2,6-pyridinedicarboxylic acid (2,6-pyridinedicarboxylic acid, 10.6 mg, 63.2 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 8.91 mg, 72.9 μmol, 1.5 equiv) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 12.1 mg, 63.2 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 1.5 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 20% to 75% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2969 as a white solid in the form of a TFA salt.

[0484] Yield: 64% (21.9 mg, 31.2 μmol); 1H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 11.02 (s, 1H), 8.32 (d, J = 7.7 Hz, 1H), 8.28-8.26 (m, 1H), 8.18 (s, 1H), 8.03 (t, J = 7.8 Hz, 1H), 7.87 (d, J = 8.3 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H), 7.55 (s, 2H), 7.28 (d, J = 1.8 Hz, 1H), 6.75 (s, 1H), 4.32-4.03 (m, 2H), 4.03-3.85 (m, 5H), 3.04-2.89 (m, 4H), 1.67 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 165.7, 162.1 (TFA, d, 2 J C,F = 36.2 Hz), 160.4, 153.9, 149.6, 149.3, 147.4, 142.5, 142.4, 138.9, 137.6, 134.7, 132.7, 130.9 (q, 2 J C,F = 33.0 Hz), 127.6, 127.0 (q, 3 J C,F = 3.7 Hz), 126.7, 126.4, 124.9, 123.9 (d, 1 J C,F = 272.2 Hz), 123.7, 123.4, 121.5, 113.5, 111.8, 110.5, 77.5, 52.3, 51.7, 47.6, 42.9, 35.6, 28.5; C 35 H 32 LRMS (ESI) m / z for F3N8O5[M+H]+: Theoretical: 701.2, Found: 701.1.

[0485]

[0486] Manufacturing Example 5. Synthetic procedure of compounds SB2960-Deg and SB2961-Deg, which are molecular adhesive decomposers.

[0487] To synthesize compounds with even better antiviral efficacy, a molecular adhesive decomposition moiety reported by Toriki et al. (2023) was conjugated to the R2 derivative of compound C01, and the synthesis of compounds SB2960-Deg and SB2961-Deg was carried out according to the procedure of Scheme 9 below.

[0488] [Reaction Formula 9]

[0489]

[0490] To a solution of compound 2 (30.4 mg, 64.1 μmol, 1.0 equiv) dissolved in dichloromethane (1.3 mL) at room temperature, trans-3-(4-methoxybenzoyl)acrylic acid (17.2 mg, 83.4 μmol, 1.3 equiv), 4-(dimethylamino)pyridine (DMAP, 11.8 mg, 96.2 μmol, 1.5 equiv), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 16.0 mg, 83.4 μmol, 1.3 equiv) were sequentially added, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by medium-pressure liquid chromatography using silica gel (MPLC, gradient 0 to 70% ethyl acetate in hexane) to obtain compound 22 as a yellow solid.

[0491] Yield: 78% (32.9 mg, 49.8 μmol); 1H NMR (400 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 8.05 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 14.9 Hz, 1H), 7.83 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.4 Hz, 3H), 7.55 (s, 1H), 7.49 (d, J = 14.9 Hz, 1H), 6.99 (d, J = 8.4 Hz, 2H), 6.67 (s, 1H), 4.01-3.88 (m, 5H), 3.83 (t, J = 4.8 Hz, 2H), 3.19-3.08 (m, 4H), 1.71 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl3 77.00 ppm): δ 187.6, 164.19, 164.17, 157.8, 148.1, 142.4, 135.20, 135.15, 134.8, 131.3, 131.1, 131.0, 130.3, 129.8, 126.8 (q, 3 J C,F = 3.8 Hz), 125.9, 124.9, 123.4, 121.5, 114.1, 109.3, 108.7, 79.5, 55.5, 52.0, 51.1, 45.8, 42.1, 29.1; C 34 H 31 LRMS (ESI) m / z for F3N5O6[M+H]+: Theoretical: 662.2, Found: 662.0.

[0492] Compound SB2991 (SB2961-Deg)

[0493]

[0494] Tin(II) chloride dihydrate (55.7 mg, 247 μmol, 7.0 eq) was added to a solution of compound 22 (23.3 mg, 35.3 μmol, 1.0 eq) in N,N-dimethylformamide (DMF, 0.35 mL) at room temperature, and the mixture was stirred at room temperature for 3 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with a saturated aqueous solution of potassium sodium tartrate tetrahydrate and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residual N,N-dimethylformamide was removed three times by azeotropic distillation using toluene. The obtained crude amine product was dissolved in dry N,N-dimethylformamide (DMF, 1.7 mL), and lithium 1-methylimidazole-2-carboxylate (6.05 mg, 45.9 μmol, 1.3 equiv), N,N-diisopropylethylamine (DIPEA, 30.7 μL, 0.176 mmol, 5.0 equiv), and 3-oxide hexafluorophosphate (HATU, 26.8 mg, 70.6 μmol, 2.0 equiv) were sequentially added, and the mixture was stirred at room temperature for 2 hours. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated NaHCO3 aqueous solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. N,N-dimethylformamide was removed three times by azeotropic distillation with toluene. The residue was purified by reverse-phase preparative HPLC (gradient from 30% to 100% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to obtain SB2991 (SB2961-Deg) as a white solid.

[0495] Step 2 Total yield: 13% (3.50 mg, 4.73 μmol); 1H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 9.79 (s, 1H), 8.09-8.03 (m, 2H), 7.99 (d, J = 14.9 Hz, 1H), 7.93 (s, 1H), 7.86 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H), 7.54-7.50 (m, 2H), 7.02-6.96 (m, 4H), 6.73 (s, 1H), 4.03-3.96 (m, 5H), 3.91-3.88 (m, 5H), 3.01-2.87 (m, 4H), 1.67 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl377.00 ppm): δ 187.7, 164.3, 164.2, 156.2, 149.3, 142.9, 142.8, 139.1, 134.9, 134.6, 132.6, 131.4, 131.3, 130.4 (d, 2 J C,F = 32.9 Hz), 129.9, 127.9, 126.9 (d, 3 J C,F = 3.6 Hz), 126.4, 126.0, 125.9, 125.1, 123.2, 114.1, 114.0, 111.0, 110.0, 77.5, 55.6, 52.0, 51.4, 46.4, 42.6, 35.3, 28.6; C 39 H 37 LRMS (ESI) m / z for F3N7O5[M+H]+: Theoretical: 740.3, Found: 740.0.

[0496] Compound SB2992 (SB2960-Deg)

[0497]

[0498] Tin(II) chloride dehydrate (39.3 mg, 174 μmol, 7.0 equiv) was added to a solution of compound 22 (16.5 mg, 24.9 μmol, 1.0 equiv) in N,N-dimethylformamide (0.25 mL) at room temperature, and the mixture was stirred at room temperature for 3 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with a saturated aqueous potassium sodium tartrate tetrahydrate solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residual N,N-dimethylformamide was removed by azeotropic distillation with toluene three times. The obtained crude amine product was dissolved in dichloromethane (1.3 mL), and pyridine-2-carboxylic acid (3.98 mg, 32.4 μmol, 1.3 equivalents), 4-(dimethylamino)pyridine (DMAP, 4.56 mg, 37.3 μmol, 1.5 equivalents), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl, 6.20 mg, 32.4 μmol, 1.3 equivalents) were sequentially added, followed by stirring at room temperature for 6 hours. To ensure complete reaction, pyridine-2-carboxylic acid (4.60 mg, 37.3 μmol, 1.5 equiv) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.16 mg, 37.3 μmol, 1.5 equiv) were added and stirred at room temperature for an additional 15 h. After confirming the completion of the reaction by LC-MS, the reaction mixture was quenched with saturated aqueous NaHCO3 solution and extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by reverse-phase preparative HPLC (gradient from 30% to 100% acetonitrile in a water / acetonitrile mixture containing 0.1% TFA) to give SB2992 (SB2960-Deg) as a white solid.

[0499] Step 2 Total yield: 26% (4.81 mg, 6.53 μmol); 1 H NMR (500 MHz, CDCl3, reference peak TMS 0.00 ppm): δ 10.55 (s, 1H), 8.62-8.53 (m, 1H), 8.15 (d, J = 7.8 Hz, 1H), 8.14 (s, 1H), 8.09-8.04 (m, 2H), 8.01 (d, J = 14.9 Hz, 1H), 7.90 (dd, J = 7.6, 1.7 Hz, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.56-7.50 (m, 2H), 7.49-7.42 (m, 1H), 7.02-6.96 (m, 2H), 6.76 (s, 1H), 4.11-3.93 (m, 2H), 3.93-3.87 (m, 5H), 3.07-2.88 (m, 4H), 1.68 (s, 6H); 13 C NMR (125 MHz, CDCl3, reference peak CDCl3 77.00 ppm): δ 187.6, 164.3, 164.2, 161.1, 150.2, 149.4, 148.1, 143.0, 142.8, 137.7, 134.9, 134.8, 134.7, 132.7, 131.32, 131.31, 129.9, 126.9 (q, 3 J C,F = 3.6 Hz), 126.32, 126.26, 126.1, 125.9, 123.4, 122.4, 114.2, 114.1, 111.2, 110.1, 77.5, 55.6, 51.9, 51.4, 46.5, 42.7, 28.5; C 40 H 36 LRMS (ESI) m / z for F3N6O5[M+H]+: Theoretical: 737.3, Found: 737.0.

[0500]

[0501] Experimental Example 1. Cell Culture and Transfection

[0502] Vero (CCL-81) cells were purchased from the American Type Culture Collection (ATCC, Manassas, VA, USA). Huh-7 (JCRB0403) cells were purchased from the Japanese Collection of Research Bioresources Cell Bank (JCRB, Tokyo, Japan). G3BP1-GFP-expressing U-2 OS human sarcoma epithelial cells were provided by Professor Jin-Ah Lee of Hannam University. Calu-3 human airway epithelial cells and Vero kidney epithelial cells from African green monkeys were obtained from the Korea Cell Line Bank [KCLB] (KCLB No. 30055 and No. 10081, respectively).

[0503]

[0504] Vero cells were seeded at 1.0 x10 per well in DMEM medium supplemented with 2% FBS and 1X antibiotic-antimycotic solution (Gibco / Thermo Fisher Scientific) 24 hours prior to infection. 4 Cells were aliquoted into black 384-well μClear plates (Greiner Bio-One, Kremsmiunster, Austria). To generate dose-response curves (DRCs), compounds were serially diluted 10-fold and 2-fold. The concentration ranges were 0.2–100 μM for the test compounds, 0.3–150 μM for chloroquine, and 2–1000 μM for ribavirin. Serially diluted compounds were added to the cells approximately 30 minutes before infection. For virus infection, the plates were transferred to a BSL-3 isolation facility and inoculated with SFTSV at an MOI of 1. Infected cells were fixed at 24 hpi, and the fixed cells were further analyzed by immunofluorescence analysis. Image analysis and DRC generation methods were identical to those for the coronavirus assay.

[0505]

[0506] Huh-7 cells were seeded at 5.0 х 10 per well in DMEM medium supplemented with 2% FBS and 1X antibiotic-antimycotic solution (Gibco / Thermo Fisher Scientific) in black 384-well μClear plates (Greiner Bio-One, Kremsmünster, Austria) 24 h before infection. 3 Cells were seeded with 10-point, 2-fold serial dilutions of compounds to generate dose-response curves (DRCs). The concentration ranges were 0.2–100 μM for test compounds, 0.01–5 μM for remdesivir, 0.2–100 μM for sofosbuvir, 1–500 μM for favipiravir, and 0.1–50 μM for ribavirin. Serially diluted compounds were added to the cells approximately 30 minutes before infection. For virus infection, DENV-2 was infected at an MOI of 0.08. Infected cells were fixed 48 hpi, and the fixed cells were further analyzed by immunofluorescence analysis. Image analysis and DRC generation methods were the same as for coronaviruses.

[0507]

[0508] G3BP1-GFP expressing U-2 OS cells, Calu-3 cells, and Vero cells were maintained and cultured in DMEM medium [Welgene] supplemented with 10% heat-inactivated fetal bovine serum (FBS) [Gibco] and 1% antibiotic-antimycotic solution [Gibco]. Poly(I:C)(HMW) / LyoVec was cultured at 37°C and 5% CO2. TM Cells were transfected using reagent [InvivoGen].

[0509] Calu-3 cells used for SARS-CoV-2 experiments were a clonal isolate that exhibited higher growth rates than the parental Calu-3 obtained from the American Type Culture Collection [ATCC] [ATCC HTB-55]. Calu-3 cells were maintained and cultured in EMEM [ATCC] supplemented with 20% heat-inactivated FBS, 1% MEM non-essential amino acid solution [Gibco], and 2% antibiotic-antimycotic solution [Gibco] at 37°C and 5% CO2.

[0510]

[0511] Experimental Example 2. Imaging Stress Granules by Immunofluorescence

[0512] Calu-3 cells 4 Х 10 4 Cells / well were seeded in 96-well black-sided clear-bottom plates at a density of 1 Х 10 4Cells were seeded at a density of 10 cells / well in 96-well black-sided clear-bottom plates. Poly(I:C) was treated for 5 h prior to compound treatment. After washing with PBS, cells were fixed with 4% paraformaldehyde (PFA) in PBS for 20 min at room temperature and permeabilized with 0.5% Triton X-100 for 20 min at 4°C. Cells were then washed three times with PBS, blocked with 3% BSA in PBS for 1 h, and treated with anti-G3BP1 primary antibody (Santa Cruz, #sc-81940) overnight at 4°C. After washing with PBS, Alexa 488-conjugated anti-mouse secondary antibody (Abcam, #ab150113) was applied to the cells, and nuclei were stained with Hoechst 33342 in PBS (1:5000) for 30 min. Cells were imaged using an IN Cell Analyzer 2000 or IN Cell Analyzer 2500 [GE Healthcare]. Images were analyzed using Developer software [GE Healthcare] to quantify stress granule puncta per cell. All data are expressed as the mean ± standard deviation (SD) of two independent biological replicates, each consisting of at least two technical replicates.

[0513]

[0514] Experimental Example 3. Stress Granule Monitoring Using G3BP1-GFP Expressing U-2 OS Cell Line

[0515] G3BP1-GFP expressing U-2 OS cells were cultured at 1.0 Х 10 for 24 h 4 Cells were seeded in 96-well black-sided clear-bottom plates at a density of 10 cells / well. Cells were plated in the order of well imaging with 1.25 μg / mL poly(I:C)(HMW) / LyoVec TMwere transfected. After 5 h of incubation, nuclei were stained with medium dilution Hoechst 33342 [ThermoFisher] for 30 min. GFP fluorescence was measured at λ in an IN Cell Analyzer 2000 [GE Healthcare]. ex / λ em = 490 / 525 nm (for FITC channel) and λ for nuclei ex / λ em = Plates were scanned at 350 / 455 nm (for the DAPI channel). Compounds were then treated with a multichannel pipette (10 μM concentration, 0.5% DMSO), and the plates were scanned after 40, 100, 160, 220, 280, 460, 1230, and 1440 minutes. Brightfield images were also captured to examine cell morphology and compound aggregates. Images were analyzed to quantify the total number of stress granules per cell using Developer software [GE Healthcare]. Each value for total stress granules per cell was normalized to the values ​​at 0 minute and the DMSO control. The change in the number of stress granules over time and with each compound was plotted using Prism 8.0.1 [GraphPad].

[0516]

[0517] Experimental Example 4. Virus

[0518] The SARS-CoV-2 variants used in the present invention are as follows: ancestor virus (βCoV / KOR / KCDC03 / 2020, NCCP43326), alpha variant (hCoV-19 / Korea / KDCA51463 / 2021, NCCP43381), beta variant (hCoV-19 / Korea / KDCA55905 / 2021, NCCP43382), gamma variant (hCoV-19 / Korea / KDCA95637 / 2021, NCCP43388), delta variant (hCoV-19 / Korea / KDCA119861 / 2021, NCCP43390), and omicron (BA.1) variant (hCoV-19 / Korea / KDCA447321 / 2021, NCCP43408). SARS-CoV-1 (HK39849) was a gift from Dr. Malik Peiris, University of Hong Kong. MERS-CoV (MERS-CoV / KOR / KNIH / 002-05-2015) was provided by the National Institutes of Health (KNIH), Republic of Korea. SFTSV KADGH strain (NCCP43261) was a gift from the KDCA, and DENV-2 BR / 01-01 (GenBank JX073928) was a gift from Dr. Claudia N. Duarte dos Santos, Instituto Carlos Chagas.

[0519]

[0520] Experimental Example 5. Antiviral Experiment by Immunofluorescence

[0521] Vero cells were plated at 1.2 Х 10 per well in black, 384-well, μClear plates [Greiner Bio-One] in DMEM [Welgene] supplemented with 2% heat-inactivated FBS and 2% antibiotic-antimycotic solution [Gibco]. 4 Calu-3 cells were seeded with 2.0 × 10 cells per well in EMEM [ATCC] supplemented with 20% heat-inactivated FBS, 1% MEM non-essential amino acid solution [Gibco], and 2% antibiotic-antimycotic solution [Gibco] for 24 h before the experiment. 4Cells were seeded 24 h prior to the experiment in black, 384-well, μClear plates [Greiner Bio-One]. A 10-point DRC was generated by two-fold dilution of compound concentrations ranging from 0.1 to 50 μM. For virus infection, plates were transferred to a BSL-3 containment facility, and viruses were added at a multiplicity of infection (MOI) of 0.0125 for Vero cells and 0.2 for Calu-3 cells. The MOIs for each virus were as follows: 0.03 MOI for SARS-CoV-2 ancestral, gamma, and delta variants; 0.05 MOI for SARS-CoV-2 alpha, beta, and SARS-CoV-1; 0.1 MOI for SARS-CoV-2 omicron (BA.1) variant; and 0.06 MOI for MERS-CoV. Infected cells were fixed at 24 hpi, except for the Omicron mutants, which were fixed at 48 hpi. Plates were incubated at 37°C for 24 hpi. Cells were fixed 24 hpi with 4% PFA permeabilized with 0.25% Triton X-100 solution. Anti-SARS-CoV-2 nucleocapsid (N) primary antibody (Sino Biological, #40143-T62), Alexa 488-conjugated goat anti-rabbit IgG secondary antibody (Molecular Probes, #MOP-A-11034), and Hoechst 33342 [Molecular Probes] were treated to the tested cells for immunofluorescence. Images acquired with an Operetta high-throughput imaging device [Perkin Elmer] were analyzed using Columbus software [Perkin Elmer] to quantify cell number and infection percentage. The infection rate of each well was normalized by setting the average infection rate of the infected control group (0.5% DMSO) and the average infection rate of the non-infected control group (Mock) as 0% and 100% infection inhibition, respectively. Dose-response curves (DRCs) were generated using Prism7 software [GraphPad]. Half-maximal inhibitory concentrations (IC) were calculated using XLfit 4 software. 50) values ​​were calculated. All IC 50 and 50% cytotoxic concentration (CC 50 ) values ​​were measured in duplicate, and the quality of each analysis was controlled by the Z'-factor and percent coefficient of variation (%CV).

[0522]

[0523] Experimental Example 6. Co-immunofluorescence

[0524] Vero cells were seeded at 3.5 x 10 per well in 96-well plates, μClear plates [Greiner Bio-One] 24 hours before the experiment. 4 Cells were seeded at a density of 10 μg / mL. Compounds were added to the cells in each well. Subsequently, cells were infected with each virus at an MOI of 5. At 5 hpi, cells were fixed with 16% PFA, permeabilized with 0.25% Triton X-100 solution, and stained with a mouse monoclonal antibody against G3BP1 (Santa Cruz, #sc-81940) and a rabbit polyclonal antibody against each virus (Sino Biological, #40143-T62). Cells were then treated with Alexa 488-conjugated goat anti-rabbit IgG secondary antibody (Molecular Probes, #MOPA-11034), Alexa Fluor Plus 555-conjugated goat anti-mouse IgG secondary antibody (Invitrogen, #A32728), and Hoechst 33342 [Molecular Probes]. Cells were imaged with an Operetta high-throughput imaging device [Perkin Elmer].

[0525]

[0526] Experimental Example 7. Drug Combination Analysis

[0527] 24 h before the experiment, Vero cells were seeded at 1.2 Х 10 per well in black, 384-well, μClear plates [Greiner Bio-One] with DMEM [Welgene] supplemented with 2% heat-inactivated FBS and 2% antibiotic-antimycotic solution [Gibco]. 4Cells were seeded with 10-point DRCs. 10-point DRCs were generated by 2 / 3-fold serial dilutions with compound concentrations ranging from 0.78 to 30 μM. Final 10 and 15 μM remdesivir or DMSO were added. For virus infection, plates were transferred to a BSL-3 isolation facility and added at an MOI of 0.03 for SARS-CoV-2 and 0.1 for SARS-CoV-2 omicron. Plates were incubated at 37°C for 24 hpi. Cells were fixed with 4% PFA and permeabilized with 0.25% Triton X-100 solution at 48 hpi for SARS-CoV-2 omicron variant and 24 hpi for SARS-CoV-2. Each virus was treated with primary antibody (Sino Biological, #40143-T62), Alexa 488-conjugated goat anti-rabbit IgG secondary antibody (Molecular Probes, #MOP-A-11034), and Hoechst 33342. Immunofluorescence cells. Images acquired with an Operetta high-throughput imaging device [Perkin Elmer] were analyzed using Columbus software [Perkin Elmer] to quantify cell number and infection ratio. The infection ratio of each well was normalized by setting the average infection ratio of the infected control group (1% DMSO) and the average infection ratio of the non-infected control group (Mock) as 0% and 100% infection inhibition, respectively. DRC was generated using Prism7 software (GraphPad). IC 50 The values ​​are calculated using XLfit4 software as Y = Bottom + (Top - Bottom) / (1 + (IC 50 / X)Hillslope) equation was calculated. All IC 50 and CC 50 The values ​​were measured in duplicate.

[0528]

[0529] Experimental Example 8. Microsome Stability Confirmation Experiment

[0530] The liver microsomal stability of the compounds was investigated in both mouse and human systems. SB2960 and reference compounds were prepared as 500 μM spiking solutions by dissolving them in a 10 mM stock solution. To prepare a 1.5 μM spiking solution for microsomes (0.75 mg / mL), the 500 μM spiking solution, 20 mg / mL liver microsomes, and PBS were used. A 6 mM NADPH stock solution diluted in PBS was also prepared. At each time point (0, 5, 13, 50, and 45 min), 30 μL of the 1.5 μM spiking solution was dispensed into the designated assay plate. The assay plate was pre-incubated at 37°C for 5 min. 15 μL of the NADPH stock solution was added to each well to initiate the reaction and measure the reaction time. The reaction was stopped by adding 150 μL of ACN:MeOH (1:1) containing internal standards to each sample at the specified times (0, 5, 15, 30, and 45 min). The assay plate was shaken at 600 rpm for 10 min, and the samples were centrifuged at 6000 rpm for 15 min. 80 μL of the supernatant from each well was transferred to a 96-well plate (Shimadzu, Japan) containing 140 μL of purified water for LC-MS / MS using positive spray ionization and a reversed-phase column (ACQUITY UPLC HSS T3 1.8 μm, 50 mm X 2.10 mm) (Waters, USA).

[0531]

[0532] Experimental Example 9. Pharmacodynamic Characteristics Evaluation

[0533] Male ICR mice were randomly assigned to two groups and administered compound SB2960 via intravenous (IV, 5 mg / kg) or oral (PO, 10 mg / kg) route. Blood samples were collected 5 min, 0.5 h, 1 h, 2 h, 4 h, 8 h, and 24 h after administration. Plasma was separated by centrifugation and analyzed using LC-MS / MS method to quantify the concentration of compound SB2960. Noncompartmental analysis (NCA) was used to quantify T 1 / 2 , Tmax , C max , AUC t , AUC ∞ , V ss Pharmacokinetic parameters including CL were calculated. Oral bioavailability (BA) was estimated by comparing the AUC values ​​between the IV and PO groups.

[0534]

[0535] Example 1. Structure-activity relationship study on the induction of stress granule formation by compound C01 derivatives.

[0536] Compound C01, discovered in a previous study, exhibited antiviral effects against SARS-CoV-2 early strains by inducing intracellular stress granule formation in a viral RNA-dependent manner. However, its high cytotoxicity limited its use alone (Fig. 2). Therefore, we aimed to improve the antiviral efficacy and cytotoxicity of C01 to develop a broad-spectrum antiviral therapeutic agent effective against various viruses. Structure-activity relationship (SAR) experiments were performed on C01 derivatives (Fig. 3).

[0537] To confirm the structure-activity correlation based on stress granule formation activity, Vero cells expressing G3BP1 tagged with green fluorescent protein (GFP), a marker protein of stress granules, were used. Poly(I:C), a synthetic dsRNA analogue, is known to induce stress granule formation and activate the innate antiviral response when viral dsRNA is recognized by PKR, so poly(I:C) was used to mimic virus-infected cells. Vero cells were transfected with poly(I:C) / LyoVec TMAfter treatment with 2.5 μg / mL for 5 hours, the derivatives of compound C01 were treated at the designated concentrations (10 μM, 20 μM, 40 μM) for 5 hours and fixed with a PBS solution containing 4% paraformaldehyde for 20 minutes. The cells were permeabilized with a PBS solution containing 0.5% Triton X-100 for 20 minutes. After blocking with a 3% BSA solution for 1 hour, the cells were treated with the primary antibody against G3BP1 at 4°C for 1 day. After washing three times with PBS, the cells were treated with the secondary antibody, washed three times with PBS again, and the nuclei were stained with Hoechst 33342. After that, the number of stress granules and the number of cells were quantified using an InCell2500 Analyzer.

[0538] First, R of compound C01 2 S in place N 2 or amide coupling reaction was performed to obtain 16 derivatives with substituted nitrogen of piperazine (Fig. 4). Small substituents such as methyl, acetyl, and trifluoroacetyl groups as well as substituents such as ethyl alcohol were used as R. 2 Even when introduced into the site, the water solubility was greatly reduced, making it difficult to verify activity at low concentrations. When morpholine and carboxylic acid groups were introduced, solubility was good, but stress granule-forming activity was lost. When dimethylamino, proline, and imidazole acetyl groups were introduced, activity was maintained or improved, but high cytotoxicity was still observed. When pyridine acetyl or methylimidazole groups were introduced, it was confirmed that efficacy was improved and cytotoxicity was significantly improved (SB2904 and SB2913 in Figures 4 and 5).

[0539] However, the above two compounds had poor solubility in water at high concentrations, and to improve this, S N 2 or R via amide coupling reaction 3 Derivatives with altered positions were obtained. R2 Seven derivatives in which the position is a pyridine acetyl group, R 2 Eighteen derivatives were obtained in which the methylimidazole group was the benzoyl group (Fig. 9). The activity disappeared when methyl, dimethyl, acetyl, ethyl alcohol, or morpholine groups were introduced instead of the benzoyl group. The activity also disappeared when the bicyclo[1.1.1]pentane group, a bioisostere of benzyl, benzoate, or benzene, was introduced. However, R 3 When 2-pyridine was introduced into the site, both activity and solubility improved. In the case of 3-pyridine, the potency decreased compared to 2-pyridine, and in the case of 4-pyridine, the activity decreased significantly. When methylimidazole was introduced, the activity was maintained, but cytotoxicity was observed at high concentrations, and when pyrazine was introduced, the solubility decreased significantly. Meanwhile, R, a structure in which piperazine of compound C01 was substituted with morpholine, 3 Four derivatives were also identified, but their solubility was significantly reduced or their activity was lost. Through these structure-activity correlation studies, nine derivatives with improved stress granule formation and reduced cytotoxicity compared to C01 were identified, of which SB2935 and SB2960 showed the most improved cytotoxicity-to-activity ratio (Figs. 9 to 14).

[0540] Also, R 2 , R 3 Based on the results of structure-activity correlation studies showing that the introduction of an aromatic ring structure at the site is important for activity and cytotoxicity, a molecular adhesive degrader SB2991 was synthesized (Fig. 15). 2 The site contains a para-methoxyphenyl fumarate group (ACS Cent. Sci. 2023, 9(5), 915-926.), which, when substituted with a recently reported piperazine, can act as a molecular glue degrader that recruits RNF126 E3 ligase and degrades the target protein. 3A methylimidazole group was introduced to improve solubility. Consistent with the previously identified structure-activity correlation, SB2991 was found to promote stress granule formation.

[0541]

[0542] Example 2. Monitoring intracellular stress granule formation over time.

[0543] To determine the effect of compound SB2960 on stress granule formation in virus-infected cells according to the concentration, intracellular stress granules were monitored over time. U-2 OS cells expressing G3BP1-GFP were infected with poly(I:C) and then treated with compound SB2960 at designated concentrations (1.25 μM, 2.5 μM, 5 μM, 10 μM, and 20 μM), and changes in intracellular stress granules were monitored based on images at eight different times (Fig. 16). As a result, the stress granule formation effect was not evident at low concentrations, but it was confirmed that the stress granule formation promotion effect increased significantly from concentrations above 10 μM. When treated with a concentration of 20 μM, the maximum value of stress granules was slightly lower than when treated with a concentration of 10 μM, but it was confirmed that it lasted longer.

[0544]

[0545] Example 3. Confirmation of broad-spectrum antiviral efficacy

[0546] Next, we performed a broad-spectrum antiviral efficacy test on compound C01 derivatives, including compounds SB2935 and SB2960. In collaboration with the Institut Pasteur Korea, the antiviral effects against SARS-CoV-2 (initial strain, alpha, beta, gamma, delta, and omicron), MERS-CoV, SARS-CoV, severe fever with thrombocytopenia syndrome virus (SFTSV), and dengue virus (DENV) were confirmed based on immunofluorescence. The experiments for SARS-CoV-2 variants (initial strain, alpha, beta, gamma, delta, and omicron), SARS-CoV, MERS-CoV, and SFTSV were performed in Vero cells, for DENV, they were performed in Huh7 cells, and for SARS-CoV-2 initial strains and omicron, they were also performed in Calu-3 cells, which are human lung cells. For each virus, the multiplicity of infection (MOI) was determined through independent experiments to determine the maximum infectivity and cell viability. The inhibitor was diluted by half from 100 μM to a total of 10 concentrations, and infected cells were imaged using immunofluorescence to determine the IC. 50 were analyzed. All substances that promote stress granule formation showed a wide range of antiviral effects, and the specific figures are as shown in Figure 17.

[0547] Compound C01 and its derivatives exhibiting stress granule-forming activity exhibited broad antiviral effects. However, improved derivatives compared to C01, particularly SB2935 and SB2960, exhibited significantly less cytotoxicity and had very high IC50 values ​​against SFTSV. 50 / CC 50 was shown.

[0548] IC for compound SB2960 50 The value was around several μM, and CC 50The values ​​were all greater than 100 μM in the remaining experiments except for DENV (Table 1). The selectivity index (SI) was 19.5 for the SARS-CoV-2 early strain, 24.6 for the SARS-CoV-2 alpha variant, 22.5 for the SARS-CoV-2 beta variant, 26.5 for the SARS-CoV-2 gamma variant, 23.6 for the SARS-CoV-2 delta variant, 18.4 for the SARS-CoV-2 omicron variant, 25.7 for MERS-CoV, 22.5 for SARS-CoV, and 33.2 for SFTSV. This verified that compound SB2960 has a broad-spectrum antiviral efficacy based on the host. In Calu-3 cells, the IC for the SARS-CoV-2 early strain and omicron variant 50 were 5.202 μM and 1.830 μM, respectively, and CC 50 showed values ​​greater than 100 μM in both species. The SI was confirmed to have a value of 19.2 for the SARS-CoV-2 initial species and 54.6 for the SARS-CoV-2 omicron variant.

[0549] SB2960IC 50 CC 50 SISARS-CoV-2 variants in vero cellOriginal5.128>10019.5Alpha4.07>10024.6Beta4.45>10022.5Gamma3.774>10026.5Delta4.234>10023.6Omicr on5.449>10018.4MERS-CoV3.888>10025.7SARS-CoV4.436>10022.5SFTSV3.01>10033.2DENV1.985.252.7SARS-CoV-2 variants in Calu-3Origianl5.202>10019.2Omicron1.83>10054.6

[0550] Example 4. Drug Combination Analysis In a preliminary study, it was confirmed that the combination of compound C01 and lopinavir (LPV) enhanced antiviral activity. Therefore, in the present invention, an experiment was conducted to confirm the synergistic effect of the combination of remdesivir, a representative viral protein targeting drug, and compound SB2960 or compound SB2935 (Figs. 18 to 21). The ZIP energy scores for the SARS-CoV-2 initial strain and omicron variants are as shown in Figs. 19 and 21.

[0551] Compound SB2960 showed a very large ZIP synergy score against SARS-CoV-2 in Vero cells at concentrations ranging from 0.04 to 3.33 μM with remdesivir (0.78 to 12.50 μM), and compound SB2935 also showed a very large ZIP synergy score against SARS-CoV-2 in Vero cells at concentrations ranging from 0.04 to 3.33 μM with remdesivir (0.78 to 12.50 μM). This suggests that the drug combination of the stress granule promoter of the present invention and an antiviral agent with a different mode of action can effectively treat viral diseases, including COVID-19.

[0552]

[0553] Example 5. Results of pharmacodynamic (PK / PD) experiments

[0554] To determine the hepatic metabolic stability of compound SB2960, an in vitro microsomal stability assay was conducted, which aimed to predict the in vivo persistence of compound SB2960. As a result, Phase I exhibited a half-life of 16 minutes in humans and 42 minutes in mice, indicating low metabolic stability in humans and moderate metabolic stability in mice (Table 3). In contrast, Phase II exhibited a half-life of 37 minutes in mice and 39 minutes in humans, indicating moderate metabolic stability in both species. Additionally, the microsomal stability of other derivatives of compound C01 was determined, and the results are presented in Table 2 below.

[0555]

[0556] CompoundSB2960MSMouseHumanPhase I(T 1 / 2 , min)42(44%)16(13%)Phase II(T 1 / 2 , min)37(40%)39(41%)

[0557]

[0558] In order to evaluate the pharmacokinetic characteristics, a single intravenous (IV) and oral (PO) administration was administered, and the changes in blood drug concentration over time were measured (Table 3 and Figure 25). The results of the main pharmacokinetic parameters are shown in Table 4 below. It showed a relatively long half-life of 4.82 h when administered intravenously and 4.59 h when administered orally, and T when administered orally max It was confirmed that absorption was continuous for up to 1 hour, as shown by the CL value of 1.00 h. In addition, as a result of intravenous administration, a low CL value of 4.92 L / min / kg was shown, indicating that initial metabolism was relatively fast but stability was maintained thereafter. In addition, the peak blood concentration (C max ) is administered intravenously. max 7642.25 ng / mL when administered orally, 3407.78 ng / mL when administered orally, and the duration of effect (AUC t) was confirmed to have a value of 16535.91 h·ng / mL when administered intravenously and 22434.98 h·ng / mL when administered orally. Accordingly, it appears that absorption in the gastrointestinal tract occurs well when administered orally, and it was confirmed that the bioavailability (BA) is high at approximately 68%.

[0559] Time (h)SB2960 Plasma Concentration (ng / mL)IVPO0.0837642.253059.160.53852.713407.7812438.012969.2021432.821952.9941041.311340.298493.46725.762457.3997.17

[0560]

[0561] Code nameSB2960MW656.67Microsomal stability(t 1 / 2 , min)MouseNADPH 42(44%)UDPGA 37(40%)HumanNADPH 16(13%)UDPGA 39(41%)PK parameter(ICR mouse)Admin.IV5 mpkPO10 mpkT 1 / 2 (h)4.824.59T max (h)0.081.00C max (ng / mL)7642.253407.78AUC t (h·ng / mL)16535.9122434.98AUC ∞ (h·ng / mL)16958.7423119.44V ss (L / kg)1.47CL (mL / min / kg)4.92F (%)67.84

[0562]

[0563] The present invention has been described above, focusing on preferred embodiments thereof. Those skilled in the art will appreciate that the present invention can be implemented in modified forms without departing from its essential characteristics. Therefore, the disclosed embodiments should be considered illustrative rather than limiting. The scope of the present invention is set forth in the claims, not the foregoing description, and all differences within the scope equivalent thereto should be construed as being encompassed by the present invention.

Claims

1. A compound represented by the following chemical formula 1, a pharmaceutically acceptable salt, or solvate thereof: [Chemical Formula 1] In the above chemical formula 1 R 2 is substituted or unsubstituted, straight or branched C1-C6 alkyl; substituted or unsubstituted, straight or branched C1-C6 alkylacetyl; or -L2R 2A and; R 3 is substituted or unsubstituted, straight or branched C1-C6 alkyl; substituted or unsubstituted, straight or branched C1-C6 alkylacetyl; or -L3R 3A And R 2A is substituted or unsubstituted C6-C 10 Aryl; substituted or unsubstituted 6-10 membered heteroaryl; substituted or unsubstituted C3-C 10 Cycloalkyl; or 3 to 10 membered heterocycloalkyl; R 3A is substituted or unsubstituted C6-C 10 Aryl; substituted or unsubstituted 6-10 membered heteroaryl; substituted or unsubstituted C3-C 10 Cycloalkyl; 3 to 10 membered heterocycloalkyl; or substituted or unsubstituted bicyclo[1.1.1]pentane; L2 is a single bond, carbonyl (-CO-), fumaryl (-CO-CH=CH-CO-), C1-C6 alkylene (-(CH2) n -) or C1-C6 alkylenecarbonyl (-CO-(CH2) n -) and; L3 is a single bond, carbonyl (-CO-), fumaryl (-CO-CH=CH-CO-), C1-C6 alkylene (-(CH2) n -) or C1-C6 alkylenecarbonyl (-CO-(CH2) n -) and; and The above substituted alkyl, alkylacetyl, aryl, heteroaryl, bicyclo[1.1.1]pentane is substituted with a substituent selected from the group consisting of halogen, hydroxy, amine, carboxy, C1-C5 alkyl, C1-C5 alkoxy and C1-C5 alkoxycarbonyl; The above heteroaryl and heterocycloalkyl comprise at least one of N, O or S.

2. In paragraph 1, The above R 2 is methyl, acetyl, 2-hydroxyethyl, trifluoroacetyl, 2-aminoacetyl, carboxymethyl, or -L2R 2A and; The above R 3 is methyl, acetyl, chloroacetyl, 2-hydroxyethyl or -L3R 3A And The above R 2A is pyridine, carboxypyridine, imidazole, methylimidazole, pyrrolidine or methoxybenzene; The above R 3A is benzene, methoxycarbonylbenzene, morpholine, pyridine, hydroxypyridine, carboxypyridine, pyrimidine, methylimidazole, pyrrolidine, or 1-(methoxycarbonyl)bicyclo[1.1.1]pentane; wherein L2 is a single bond, carbonyl (-CO-), fumaryl (-CO-CH=CH-CO-), methylene (-CH2-), ethylene (-CH2-CH2-), or methylenecarbonyl (-CO-CH2-); A compound, a pharmaceutically acceptable salt, or a solvate thereof, wherein the above L3 is a single bond, carbonyl (-CO-), methylene (-CH2-), or methylenecarbonyl (-CO-CH2-).

3. In paragraph 1, The compound represented by the above chemical formula 1 is a compound, a pharmaceutically acceptable salt, or a solvate thereof, selected from the following: Compound SB2902 Compound SB2903 Compound SB2904 Compound SB2905 Compound SB2906 Compound SB2907 Compound SB2908 Compound SB2909 Compound SB2910 Compound SB2911 Compound SB2912 Compound SB2913 Compound SB2914 Compound SB2915 Compound SB2916 Compound SB2931 Compound SB2932 Compound SB2933 Compound SB2934 Compound SB2935 Compound SB2936 Compound SB2937 Compound SB2951 Compound SB2953 Compound SB2954 Compound SB2955 Compound SB2956 Compound SB2957 Compound SB2958 Compound SB2959 Compound SB2960 Compound SB2961 Compound SB2962 Compound SB2963 Compound SB2964 Compound SB2965 Compound SB2967 Compound SB2968 Compound SB2969 Compound SB2991 Compound SB2992 .

4. An antiviral composition comprising a compound represented by the chemical formula 1 of paragraph 1, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

5. A pharmaceutical composition for preventing or treating viral infection, comprising a compound represented by Chemical Formula 1 of Article 1, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

6. In paragraph 5, A pharmaceutical composition comprising the compound, a pharmaceutically acceptable salt, or a solvate thereof, at a concentration of 10 to 100 μM.

7. In paragraph 5, A pharmaceutical composition that prevents or treats viral infection by inducing intracellular granule formation.

8. In paragraph 5, A pharmaceutical composition, wherein the viral infection is selected from the group consisting of coronavirus disease-19 (COVID-19), Middle East respiratory syndrome (MERS), severe acute respiratory syndrome (SARS), severe fever with thrombocytopenia syndrome (SFTSV), and dengue fever.

9. A food composition for improving antiviral or viral infection properties, comprising a compound represented by the chemical formula 1 of paragraph 1, a food-based acceptable salt thereof, or a solvate thereof as an active ingredient.

Images