Viral protease inhibitors containing n-(substituted sulfonyl)acetamide structures, and their use in antiviral medicaments

Abstract

A kind of compound containing N-(substituted sulfonyl) acetamide structure as shown in formula I, its pharmaceutically acceptable salt, its isomer, its hydrate or its solvate, and its application as viral protease inhibitor in preparation of antiviral drugs.The provided peptide compound has strong inhibitory effect on coronavirus 3CL protease and small RNA virus (such as enterovirus EV71 virus) 3C protease.Through cell level activity test, the N-(substituted sulfonyl) acetamide structure compound has obvious inhibitory effect on small RNA virus (such as enterovirus EV71 virus) virus and coronavirus, etc., as shown in formula I, the compound containing N-(substituted sulfonyl) acetamide structure can produce viral inhibition effect on cell level by inhibiting viral protease activity, and has good antiviral drug application prospect.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of pharmaceutical chemical industry, and relates to a kind of N- (substituted sulfonyl) acetamide structural compound as viral protease inhibitor, its application in preparing antiviral drugs. Specifically, the present application relates to a kind of viral protease inhibitor containing N- (substituted sulfonyl) acetamide structure, its pharmaceutically acceptable salt, its isomer, its hydrate or its solvate, and its application in inhibiting viral protease, preparing and / or treating viral infection caused by viruses whose life cycle is mainly affected by protease, mainly including but not limited to small RNA viruses and coronaviruses. BACKGROUND

[0002] Small RNA viruses and coronaviruses belong to single-stranded RNA viruses. The small RNA virus family mainly includes enterovirus (Coxsackievirus (CV), poliovirus (PV), EV71 virus, etc.), human rhinovirus (HRV) and hepatitis A virus (HAV) etc. Enterovirus 71 and coxsackievirus infection can cause herpangina and hand, foot and mouth disease in children, which can be life-threatening. Poliovirus (PV) and hepatitis A virus (HAV) can cause poliomyelitis (usually manifested as infantile paralysis) and hepatitis A, respectively. Human rhinovirus (RhV) is a virus with the most serotypes among human viruses, and is the main pathogen causing common cold. The virus is the culprit of acute respiratory disease, and nearly half of the acute respiratory disease infections are caused by rhinovirus infection.

[0003] In the process of viral replication, the genome of some viruses first encodes a large polyprotein precursor, and then the functional proteins are generated by hydrolysis of the polyprotein, and this hydrolysis process is mainly completed by protease. The precursor protein produced by most single-stranded RNA viruses can only form functional proteins after hydrolysis by 3C or 3CL protease, and then the subsequent replication and packaging can be carried out, so 3C and 3CL proteases are the core proteases for hydrolysis of single-stranded RNA virus precursor polyprotein, and play a crucial role in the process of single-stranded RNA virus replication. For example, small RNA viruses first encode a large polyprotein precursor, and then the hydrolysis of the polyprotein precursor is completed by 3C protease, and coronaviruses first encode two polyproteins (pp1a and pp1ab), and then the functional proteins are also generated by hydrolysis of the polyproteins, and the hydrolysis process is mainly completed by 3CL protease. In the genus Flavivirus, the hydrolysis of polyprotein is mainly completed by non-structural protein NS3 / 4A. In non-single-stranded RNA viruses, such as the life cycle of human immunodeficiency virus (HIV), similar proteases are also involved.

[0004] Because there is no similar proteinase in human body, inhibiting the catalytic function of the viral proteinase can effectively inhibit the cleavage of the viral precursor protein and block the viral replication. The 3C or 3CL proteinase is an important target for the drug treatment of the single-stranded RNA virus. Although the single-stranded RNA virus gene has diversity, the 3C and 3CL proteinase substrate binding sites are highly conserved and have similar catalytic mechanisms, and are highly similar proteinases in the single-stranded RNA virus. Therefore, the research on the broad-spectrum anti-single-stranded RNA virus inhibitor targeting the 3C and 3CL proteinases has attracted extensive attention. The 3C and 3CL proteinases both belong to the cysteine proteinases and have highly conserved three-dimensional structures. Although the 3C and 3CL proteinases have low sequence homology, the sequence analysis based on the structural basis shows that the two types of proteinases have highly conserved Gly-X-Cys-Gly-Gly-Gly / Ser sequence structures, and the His-Cys in the catalytic triad of the 3C proteinase is almost completely consistent with the His-Cys of the 3CL proteinase, indicating that the two types of proteinases have highly conserved substrate binding sites and similar catalytic mechanisms.

[0005] Rupintrivir (AG7088) is originally developed by Agouton Pharmaceutical Company, which is a specific irreversible inhibitor of human rhinovirus and a peptide drug. Rupintrivir has a similar spatial configuration to the 3C proteinase substrate, so it can compete with the substrate to bind to the 3C proteinase and exert an inhibitory effect on the enzyme. Rupintrivir can inhibit the replication of 48 different HRV serotypes in H1-HeLA and MRC-5 cell protection tests, with an average EC50 of 0.023 μM. Rupintrivir has an immunomodulatory effect. Some literatures report that Rupintrivir has a therapeutic effect on EV71-infected animals. Another literature reports that Rupintrivir can inhibit SARS coronavirus by inhibiting the 3CL proteinase of SARS coronavirus. The above facts show that a compound can have a broad-spectrum antiviral effect on 3C proteinase or 3CL proteinase. SUMMARY

[0006] The compound having the N-(substituted sulfonyl)acetamide structure shown in formula I involved in the present application is an effective viral proteinase inhibitor. The present application provides the compound shown in formula I and a pharmaceutically acceptable salt, isomer, solvate thereof, or as a pharmaceutical composition component for inhibiting the viral proteinase, including but not limited to 3C / 3CL proteinase, or preventing / treating one or more symptoms of viral infection.

[0007] The first aspect of the present application relates to the compound of formula I, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof.

[0008]

[0009] wherein: R1is C1-C6alkyl or cycloalkyl;

[0010] R2is C1-C6alkyl or cycloalkyl, or fluorine, chlorine, bromine, iodine, C1-C6alkyl, C1-C6alkoxy, cyano, nitro substituted aromatic alkane;

[0011] R3is selected from substituted or unsubstituted alkyl, aromatic alkyl, alkoxy, wherein the substituents are C1-C6alkyl or cycloalkyl, C1-C6alkoxy, halogen (fluorine, chlorine, bromine, iodine), cyano, alkynyl, cyano, nitro;

[0012] n is 1-3.

[0013] In certain embodiments, the compound of Formula I, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof, or a solvate thereof,

[0014] wherein: R1is C1-C3alkyl or cycloalkyl;

[0015] R2is C1-C6alkyl or cycloalkyl, or fluorine substituted phenyl ring;

[0016] R3is selected from substituted or unsubstituted benzyloxy, phenyl, indol-2-yl, benzimidazol-2-yl, oxazol-5-yl, imidazolyl, benzyl. The substituents are selected from C1-C6alkyl or cycloalkyl, C1-C6alkoxy, halogen (fluorine, chlorine, bromine, iodine), cyano, alkynyl, nitro;

[0017] n is 1-2.

[0018] In certain embodiments, the compound of Formula I, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof, or a solvate thereof:

[0019] wherein: R1is selected from methyl, ethyl, propyl, and cyclopropyl;

[0020] R2is selected from cyclopropyl, cyclohexyl, 4-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl;

[0021] R3is selected from

[0022]

[0023] n is 1-2.

[0024] In certain embodiments, the cycloalkyl is C3-C6cycloalkyl.

[0025] In certain embodiments, R1is C1-C3alkyl or C3-C6cycloalkyl.

[0026] In certain embodiments, R1is selected from the group consisting of methyl, ethyl, isopropyl, and cyclopropyl.

[0027] In certain embodiments, R2is selected from the group consisting of C3-C6alkyl, C3-C6cycloalkyl, or a fluorine substituted phenyl ring.

[0028] In certain embodiments, R2is selected from the group consisting of cyclopropyl, cyclohexyl, isopropyl, 4-fluorophenyl, 3-fluorophenyl, 3,4-difluorophenyl.

[0029] In certain embodiments, R3is selected from the group consisting of C1-C6alkyl, aralkyl, C1-C6alkoxy, optionally substituted with a substituent selected from the group consisting of C1-C6alkyl, C3-C6cycloalkyl, C1-C6alkoxy, halogen (fluorine, chlorine, bromine, iodine), cyano, alkynyl, nitro.

[0030] In certain embodiments, the aralkyl is selected from the group consisting of benzyloxy, phenyl, indol-2-yl, benzimidazol-2-yl, oxazol-5-yl, imidazolyl, benzyl, isoindolyl, [1,2,3]triazolyl, methylene-2,3-dihydrobenzo[1,4]dioxinyl, pyridyl-S-CH2-phenyl, benzyl-isoindolyl, morpholinyl-SO2-phenyl.

[0031] In certain embodiments, R3is selected from the group consisting of

[0032]

[0033] In certain embodiments, n = 1.

[0034] In certain embodiments, n = 2.

[0035] The compounds of the present application include, but are not limited to, compounds having a structure selected from the group consisting of:

[0036]

[0037]

[0038]

[0039]

[0040] The present application also provides a pharmaceutical composition comprising at least one compound of the present application, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof, or a solvate thereof; optionally, the pharmaceutical composition further comprises at least one pharmaceutically acceptable excipient, carrier, vehicle, or adjuvant.

[0041] Optionally, the pharmaceutical composition further comprises an EV71 antiviral agent; in certain embodiments, the EV71 antiviral agent is an antiviral agent selected from 3D protease inhibitors and VP1 protein inhibitors.

[0042] In certain embodiments, the pharmaceutical composition is used for preventing / treating a disease associated with viral infection in a subject, the virus is selected from the group consisting of small RNA viruses (e.g. enterovirus, human rhinovirus (HRV) and hepatitis A virus (HAV)), and coronaviruses. Among them, the enterovirus includes but is not limited to enterovirus 71 (EV71), poliovirus, coxsackievirus A, coxsackievirus B, and the coronavirus includes but is not limited to SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV and MERS-CoV. In certain embodiments, the pharmaceutical composition is used for preventing / treating a disease associated with enterovirus 71 (EV71) infection or a disease associated with SARS-CoV-2 infection in a subject. In certain embodiments, the subject is a mammal, such as a bovine, equine, porcine, canine, feline, rodent, primate. Among them, the particularly preferred subject is a human.

[0043] The present application also provides the use of the compound of the present application, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof in the preparation of a medicament, which is a viral protease inhibitor.

[0044] In certain embodiments, the virus is selected from the group consisting of small RNA viruses (e.g. enterovirus (e.g. coxsackievirus (CV), poliovirus (PV), enterovirus 71), human rhinovirus (HRV) and hepatitis A virus (HAV)), and coronaviruses (e.g. SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV and MERS-CoV).

[0045] In certain embodiments, the protease is a 3C / 3CL protease.

[0046] The present application also provides the use of the compound of the present application, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof in the preparation of a medicament, which is an antiviral drug;

[0047] Preferably, the virus against which the antiviral drug is directed is selected from the group consisting of picornaviruses (e.g. enterovirus genus (e.g. coxsackievirus (CV), poliovirus (PV), enterovirus 71), human rhinovirus genus (HRV) and hepatitis A virus genus (HAV)), and coronaviruses (e.g. SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV and MERS-CoV).

[0048] The present application also provides the use of a compound of the present application, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof or a solvate thereof in the manufacture of a medicament for preventing / treating a disease associated with viral infection in a subject, the virus being selected from the group consisting of picornaviruses (e.g. enterovirus genus, human rhinovirus genus (HRV) and hepatitis A virus genus (HAV)), and coronaviruses. Among them, the enterovirus includes but is not limited to enterovirus 71 (EV71), poliovirus, coxsackievirus A, coxsackievirus B, and the coronavirus includes but is not limited to SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV and MERS-CoV. In certain embodiments, the subject is a mammal, such as a bovine, equine, porcine, canine, feline, rodent, primate. Among them, a particularly preferred subject is a human.

[0049] In another aspect, the present application provides a method for preventing / treating a disease associated with viral infection in a subject, comprising the step of administering to the subject a prophylactically / treatingly effective amount of a compound of the present application, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof, or a solvate thereof, or a pharmaceutical composition of the present application, wherein the virus is selected from the group consisting of a picornavirus (e.g., enterovirus (e.g., coxsackievirus (CV), poliovirus (PV), enterovirus 71), human rhinovirus (HRV), and hepatitis A virus (HAV)), and a coronavirus (e.g., SARS-CoV-2, HCoV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-CoV, and MERS-CoV). In certain embodiments, the subject is a mammal, such as a bovine, equine, porcine, canine, feline, rodent, primate. Among them, a particularly preferred subject is a human. The present application also provides a pharmaceutical composition comprising a compound of Formula I according to any one of the first aspect of the present application, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof, or a solvate thereof, preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient, in particular, the pharmaceutical composition is a solid preparation, an injection, a topical preparation, a spray, a liquid preparation, or a compound preparation.

[0050] The present application also provides the use of a compound of Formula I according to any one of the first aspect of the present application, a pharmaceutically acceptable salt thereof, an isomer thereof, a hydrate thereof, or a solvate thereof, as a viral protease inhibitor in the preparation of an antiviral drug.

[0051] The use of the drug comprising at least one compound of Formula I or a pharmaceutically acceptable salt, isomer, solvate thereof and at least one other excipient, in the preparation of a drug for treating enterovirus infection diseases, wherein the enterovirus includes: enterovirus 71 (EV71), poliovirus, coxsackievirus A, coxsackievirus B.

[0052] The use of the drug comprising at least one compound of Formula I or a pharmaceutically acceptable salt, isomer, solvate thereof and at least one other excipient, as a viral protease inhibitor in the preparation of an antiviral drug against picornavirus and coronavirus.

[0053] The use of the drug comprising at least one compound of Formula I or a pharmaceutically acceptable salt, isomer, solvate thereof and at least one other excipient, in the preparation of an antiviral drug against EV71 virus, SARS-CoV-2 virus, SARS virus, Middle East respiratory syndrome coronavirus (MERS-CoV).

[0054] A pharmaceutical composition comprising an effective amount of an inhibitor of Formula I and a pharmaceutically acceptable carrier medium or adjuvant therefor.

[0055] The above pharmaceutical composition, further comprising an EV71 antiviral agent, said EV71 antiviral agent is an antiviral agent selected from 3D protease inhibitors and VP1 protein inhibitors.

[0056] Use of the above pharmaceutical composition in the preparation of an antiviral drug for treating enterovirus 71 (EV71) and SARS-CoV-2 infection diseases.

[0057] Use of the above pharmaceutical composition in the manufacture of a medicament for treating EV71 and SARS-CoV-2 viral infection in mammals.

[0058] Definitions of terms

[0059] As described herein, the following definitions shall apply in the present application, unless otherwise indicated: In this application, the use of "or" in the context of a list of items prefaced by "for example" or "such as" indicates a non-exclusive alternatives, unless otherwise indicated (i.e., "or" is merely an abbreviation for "and / or"). Unless otherwise indicated, the terms (whether in the context of a dependency claim or otherwise) shall have their generally accepted meanings as understood by those of ordinary skill in the art. However, for better understanding of the present application, definitions for certain terms are provided below. In the event that any definition provided herein conflicts with the generally accepted meaning of a term, the definition provided herein shall control.

[0060] In referring to the examples, (R) or (S) is used to indicate the absolute configuration of an asymmetric center, which indicates the description for the whole compound rather than the description for the individual substituent.

[0061] The term "C1-C6alkyl" means straight or branched chain alkyl groups having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and the like; C1-C3alkyl is also to be so construed. Preferred is C1-C3alkyl.

[0062] The term "cycloalkyl" means a cycloalkyl group having from 3 to 6 carbon atoms.

[0063] "C1-C6alkoxy" as used herein means straight or branched chain alkoxy groups having from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, t-butoxy, pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and the like; C1-C3alkoxy is also to be so construed. Preferred is C1-C3alkoxy.

[0064] The term "solvate" as used herein means a compound associated with a molecule of solvent, such as an organic solvent (e.g., methanol, ethanol, propanol, acetonitrile, etc.), and the like.

[0065] The term "hydrate" as used herein means a compound associated with a molecule of water.

[0066] The term "pharmaceutically acceptable salt" as used herein refers to a salt of a compound of Formula I which is suitable for use in normal medical therapy and which is not toxic, injurious, or allergenic to the tissues of humans and animals at the dosages recommended for use. It is generally water or oil soluble, or is readily dispersible, and is effective for its use. This term includes both pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. The term "pharmaceutically acceptable acid addition salt" means a salt with an inorganic acid such as sulfuric, nitric, phosphoric, hydrochloric, hydrobromic, sulfamic, and organic acid such as acetic, trifluoroacetic, trichloroacetic, cinnamic, citric, maleic, adipic, alginic, ascorbic, aspartic, benzoic, benzenesulfonic, glycolic, malic, lactic, malonic, oxalic, nicotinic, succinic, salicylic, stearic, tartaric, p-aminobenzoic, trimethylbenzoic, p-toluenesulfonic, mandelic, galacturonic, picric, propionic, and the like. The term "pharmaceutically acceptable base addition salt" means a salt with an inorganic base such as ammonia or ammonium or metal cations such as sodium, magnesium, copper, zinc, calcium, potassium, aluminum, and the like, particularly preferred are the ammonium, potassium, sodium, calcium, and magnesium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include primary, secondary, and tertiary amines, quaternary ammonium compounds, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, tripropylamine, isopropylamine, tributylamine, ethanolamine, diethanolamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, choline, betaine, ethylenediamine, glucosamine, methylglucosamine, theobromine.

[0067] The present application also relates to a medicament comprising at least one compound according to the application, which preferably also comprises one or more pharmacologically acceptable excipients or carriers, and to its use for the above-mentioned purposes. The pharmaceutical carriers here include, but are not limited to, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerol, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylates, beeswax, lanolin.

[0068] The active ingredients can have systemic and / or local action and can therefore be administered in suitable ways, such as orally, parenterally, pulmonarily, nasally, sublingually, lingually, buccally, rectally, transdermally, conjunctivally, topically or in the form of implants.

[0069] The active ingredients can also be administered in the form of administration forms suitable for these administration routes.

[0070] Suitable for oral administration are the known administration forms which rapidly and / or in a modified manner release the active ingredients, such as solid preparations, such as tablets (uncoated tablets or coated tablets, such as tablets with enteric or moro coatings), capsules, sugar-coated tablets, granules, pellets, powders, liquid preparations, such as emulsions, suspensions, and aerosols. Parenteral administration is possible either without an absorption step (intravenous, intraarterial, intracardiac, intraspinal or intrathecal administration) or with an absorption step (intramuscular, subcutaneous, intracutaneous, transdermal or intraperitoneal administration). Suitable for parenteral administration are in particular solutions, suspensions, emulsions, freeze-dried materials and sterile powders for injection and infusion. Suitable for other administration routes are, for example, drugs for inhalation (in particular powder inhalation, spray), nasal drops / solutions, sprays; tablets or capsules for lingual, sublingual or buccal administration, suppositories, preparations for the ear and eye, vaginal capsules, aqueous suspensions (lotions, shake-mixtures), lipophilic suspensions, ointments, creams, emulsions, pastes, powders for sprinkling or implants, such as stents.

[0071] The active ingredients can be converted to the stated dosage forms by processes known per se. They can be achieved with inert, nontoxic, suitable pharmaceutical excipients. These include carriers (for example microcrystalline cellulose), solvents (for example liquid polyethylene glycols), emulsifiers (for example sodium dodecyl sulfate), dispersants (for example polyvinylpyrrolidone), synthetic and natural biopolymers (for example proteins), stabilizers (for example antioxidants and ascorbic acid), colorants (for example inorganic pigments such as iron oxides) or flavorings and / or taste-masking agents. If appropriate, the active ingredients can be present in microencapsulated form in one or more of the above-mentioned carriers. DETAILED DESCRIPTION

[0072] The experimental methods used in the following examples are conventional unless otherwise stated. The materials, reagents, etc. used are commercially available unless otherwise stated. The following examples are preferred illustrative preferred embodiments of the present application and do not constitute any limitation on the present application.

[0073] Example 1 Synthesis of N-sulfonylamide compound (1)

[0074] Step 1 Synthesis of (2S,4R)-2-tert-butoxycarbonylamino-4-cyanomethyl-pentane-dicarboxylic acid dimethyl ester (1-2)

[0075]

[0076] N-Boc-L-glutamic acid dimethyl ester 1-1 (12.0 g, 43.6 mmol) was dissolved in anhydrous THF (100 mL) solution, cooled to -78 °C, and a solution of lithium bis(trimethylsilyl)amide (LiHDMS) (94 mL, 1 M in THF) was added dropwise. The mixture was stirred at -78 °C for 1 h, and then bromoacetonitrile (3.24 mL, 46.6 mmol) was added dropwise at -78 °C. The reaction was allowed to proceed at -78 °C for 4 h. After the raw material was completely reacted, saturated NH4Cl solution (40 mL) was added to quench, and the temperature was raised to room temperature. Ethyl acetate (50 mL x 3) was used to extract. The organic phase was collected, dried, filtered, and rotary evaporated. The residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 4 / 1) to obtain the product 1-2 (7.58 g, 55%) as a colorless oil. 1 H NMR (600 MHz, CDC13) δ 5.11 (d, J = 7.5 Hz, 1H), 4.38 (s, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 2.92-2.82 (m, 1H), 2.81-2.71 (m, 2H), 2.24-2.08 (m, 2H), 1.44 (s, 9H). ESI-MS m / z 215.1 [M-Boc+H] + .

[0077] Step 2. Synthesis of (S)-methyl 2-(tert-butoxycarbonylamino)-3-((S)-2- oxopyrrolidin-3-yl)propanoate (1-3)

[0078]

[0079] Compound 1-2 (6.0 g, 19.09 mmol) was dissolved in anhydrous MeOH (100 mL), cooled to 0 °C, CoCl2-6H2O (2.72 g, 11.45 mmol) was added, then NaBH4(4.35 g, 114.78 mmol) was added portionwise, the reaction mixture was raised to room temperature and stirred for 12 h. After the raw material reacted completely, saturated NH4Cl solution (30 mL) was added to quench. The MeOH was removed by rotary evaporation, and the residue was extracted with ethyl acetate (50 mL x 3). The organic layer was washed with saturated NH4Cl solution (100 mL x 3) and brine (100 mL x 3), the organic phase was collected, dried, filtered, rotary evaporated, and the residue was purified by flash column chromatography (petroleum ether / ethyl acetate = 1 / 2) to give the product 1-3 (2.18 g, 40%) as a white solid. 1 H NMR (600 MHz, CDC13) δ 6.64 (s, 1H), 5.56 (s, 1H), 4.29 (d, J = 9.1 Hz, 1H), 3.71 (s, 3H), 3.37-3.26 (m, 2H), 2.47-2.42 (m, 2H), 2.13-2.08 (m, 1H), 1.84-1.81 (m, 2H), 1.41 (s, 9H). ESI-MS m / z 187.7 [M-Boc+H] + .

[0080] Step 3. Synthesis of (S)-methyl 2-((S)-2-((tert-butoxycarbonyl)amino)-3- cyclohexylpropanamide)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (1-6)

[0081]

[0082] Compound 1-3 (1.0 g, 3.5 mmol) was dissolved in 10 mL of dry DCM, and HCl (9 mL, 4M in indioxane) was added. The reaction was stirred at room temperature for 12 h, and concentrated in vacuo to give the Boc-deprotected product 1-3 as a white solid. Boc-L-Cyc-OH 1-4 (0.95 g, 3.5 mmol) was dissolved in dry DCM (40 mL) and cooled to -20 °C. HATU (1.9 g, 4.9 mmol) was added and maintained at -20 °C for 20 min, followed by the addition of the Boc-deprotected product 1-3 (0.77 g 3.5 mmol). After 30 min at -20 °C, DIPEA (1.7 mL, 10.5 mmol) was added dropwise. The reaction mixture was then stirred at -20 °C for 12 h. After the reaction was complete, the reaction was washed with saturated NH4Cl solution (100 mL x 3), saturated NaHCO3 solution (100 mL x 3), and brine (100 mL x 3). The organic phase was dried over Na2SO4 and concentrated in vacuo, and the residue was purified by flash column chromatography (DCM / MeOH = 50 / 1) to give the product 1-5 (1.23 g, 80%) as a white solid. 1 H NMR (600 MHz, DMSO-d6) δ 8.29 (d, J = 8.1 Hz, 1H), 7.60 (s, 1H), 6.83 (d, J = 8.1 Hz, 1H), 4.39-4.28 (m, 1H), 3.97-3.93 (m, 1H), 3.60 (s, 3H), 3.13 (t, J = 9.0 Hz, 1H), 3.06-3.04 (m, 1H), 2.36-2.24 (m, 1H), 2.11-2.02 (m, 2H), 1.70-1.55 (m, 7H), 1.47-1.38 (m, 1H), 1.35 (s, 9H), 1.32-1.19 (m, 2H), 1.17-1.04 (m, 3H), 0.85-0.81 (m, 2H). ESI-MS m / z 440.2 [M+H] + .

[0083] Step 4. Synthesis of (S)-methyl 2-((S)-3-cyclohexyl-2-(lH-indole-2-carboxamido) propanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (1-9)

[0084]

[0085] To a solution of 1-5 (1.05 g, 2.4 mmol) in dry DCM, HCl (6 mL, 4 M in dioxane) was added and the reaction was stirred at room temperature for 12 h. The reaction was concentrated in vacuo to give the de-Boc product of 1-5. Indole-2-carboxylic acid 1-6 (0.78 g, 2.4 mmol) was dissolved in dry DCM and cooled to -20 °C. HATU (1.09 g, 2.88 mmol) was added and the reaction was kept at -20 °C for 20 min before the addition of the de-Boc product of 1-5. After 30 min at -20 °C, DIPEA (1.17 mL, 7.2 mmol) was added dropwise. The reaction mixture was then stirred at -20 °C for 12 h. After the complete consumption of the starting material, the reaction was washed with saturated NH4Cl solution (100 mL x 3), saturated NaHCO3solution (100 mL x 3) and brine (100 mL x 3). The organic phase was dried over Na2SO4and concentrated in vacuo. The residue was purified by flash column chromatography (DCM / MeOH = 30 / 1) to give the product 1-7 (0.98 g, 85%) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 8.57 (d, J = 7.9 Hz, 1H), 8.42 (d, J = 8.0 Hz, 1H), 7.64 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.2 Hz, 1H), 7.26 (d, J = 1.5 Hz, 1H), 7.18 (t, J = 7.5 Hz, 1H), 7.03 (t, J = 7.5 Hz, 1H), 4.59-4.57 (m, 1H), 4.40-4.31 (m, 1H), 3.62 (s, 3H), 3.16-3.08 (m, 2H), 2.37-2.35 (m, 1H), 2.14-2.04 (m, 2H), 1.76-1.72 (m, 2H), 1.70-1.55 (m, 8H), 1.45-1.35 (m, 1H), 1.20-1.12 (m, 2H), 0.97-0.88 (m, 2H). ESI-MS m / z 483.1 [M+H] + .

[0086] Step 5 Synthesis of N-sulfonyl amide compound (1)

[0087]

[0088] To a solution of 1-7 (0.96 g, 2.0 mmol) in THF, cooled to 0 °C, LiOH .H20 solution, the reaction solution was stirred at room temperature for 1.5 hours, THF was removed by rotary evaporation, Ph was adjusted to 4, and a white solid was obtained by filtration. The white solid was dissolved in anhydrous DCM, cooled to 0 °C, and HATU (1.08 g, 2.9 mmol) was added. The mixture was kept at 0 °C for 20 minutes, and then ethyl sulfonamide (0.62 g, 5.7 mmol) was added. After keeping at 0 °C for 30 minutes, DIPEA (0.99 mL, 5.7 mmol) was added dropwise. Then the reaction mixture was stirred at 0 °C for 12 h. After the raw material reaction was completed, the reaction solution was washed with saturated NH4Cl solution (50 mL x 3) and brine (50 mL x 3). The organic phase was dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography (DCM / MeOH = 40 / 1) to obtain the product 1 (0.23 g, 22%) as a white solid. 1 H NMR (400 MHz, Methanol-d4) δ 7.59 (dq, J = 8.1, 1.2 Hz, 1H), 7.45 - 7.38 (m, 1H), 7.24 - 7.15 (m, 2H), 7.04 (ddt, J = 8.1, 7.0, 1.4 Hz, 1H), 4.62 (dt, J = 15.8, 7.8 Hz, 1H), 4.39 (td, J = 13.0, 12.2, 4.2 Hz, 1H), 3.42 - 3.30 (m, 2H), 3.28 - 3.19 (m, 2H), 2.59 (qd, J = 9.6, 4.6 Hz, 1H), 2.33 - 2.13 (m, 2H), 1.91 - 1.56 (m, 9H), 1.45 (td, J = 7.2, 3.6 Hz, 1H), 1.33 - 1.16 (m, 6H), 0.98 (p, J = 12.2 Hz, 2H).

[0089] 13 C NMR (151 MHz, Methanol-d4) δ 121.49, 119.84, 111.68, 104.08, 51.49, 48.04, 47.90, 47.76, 47.62, 47.47, 47.33, 47.19, 40.14, 38.85, 38.34, 33.39, 32.45, 32.22, 27.36, 26.19, 25.96, 25.84, 6.83. ESI-MS m / z 560.25 [M+H] + .

[0090] Synthesis of N-sulfonyl amide compound (2)

[0091]

[0092] Synthesis step same as example 1 step 5. 1H NMR (400 MHz, Methanol-d4) δ 7.62 - 7.56 (m, 1H), 7.44 - 7.37 (m, 1H), 7.23 - 7.13 (m, 2H), 7.04 (ddt, J = 8.4, 7.1, 1.4 Hz, 1H), 4.63 (dt, J = 12.0, 7.8 Hz, 1H), 4.48 (ddd, J = 28.4, 9.3, 4.5 Hz, 1H), 3.26 - 3.19 (m, 2H), 2.98 - 2.81 (m, 2H), 2.61 - 2.45 (m, 1H), 2.32 - 2.13 (m, 2H), 1.85 - 1.57 (m, 9H), 1.44 (td, J = 7.3, 3.6 Hz, 1H), 1.24 - 1.11 (m, 4H), 1.06 - 0.91 (m, 4H).

[0093] 13 C NMR (151 MHz, Methanol-d4) δ 123.90, 121.49, 119.85, 111.68, 104.09, 51.53, 48.04, 47.90, 47.76, 47.62, 47.48, 47.34, 47.19, 40.13, 38.85, 38.29, 34.11, 33.40, 32.54, 32.21, 30.45, 27.33, 26.19, 25.95, 25.84, 4.91, 4.87. ESI-MS m / z 572.25 [M+H] + .

[0094] Example 3 Synthesis of N-sulfonyl amide compound (3)

[0095] Step 1 Synthesis of methyl (S)-2-((S)-2-(((tert-butoxycarbonyl)amino)-3-(3- fluorophenyl)propanoate)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (3-2)

[0096]

[0097] The synthesis step is the same as step 3 of Example 1. 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (d, J = 8.1 Hz, 1H), 7.59 (s, 1H), 7.27 (q, J = 7.4 Hz, 1H), 7.14 - 7.04 (m, 2H), 7.02 - 6.89 (m, 2H), 4.34 (ddd, J = 9.3, 4.5, 1.7 Hz, 1H), 4.22 - 4.09 (m, 1H), 3.97 - 3.82 (m, 1H), 3.79 - 3.64 (m, 1H), 3.62 - 3.48 (m, 1H), 3.46 - 3.34 (m, 1H), 3.33 - 3.20 (m, 1H), 3.19 - 3.06 (m, 1H), 2.99 - 2.86 (m, 1H), 2.85 - 2.72 (m, 1H), 2.71 - 2.58 (m, 1H), 2.57 - 2.44 (m, 1H), 2.44 - 2.31 (m, 1H), 2.30 - 2.17 (m, 1H), 2.17 - 2.04 (m, 1H), 2.04 - 1.91 (m, 1H), 1.90 - 1.77 (m, 1H), 1.77 - 1.64 (m, 1H), 1.64 - 1.51 (m, 1H), 1.51 - 1.38 (m, 1H), 1.38 - 1.25 (m, 1H), 1.25 - 1.12 (m, 1H), 1.12 - 0.99 (m, 1H), 0.99 - 0.86 (m, 1H).

[0098] 12.1,8.3,4.2Hz,1H),4.13(td,J=9.3,8.5,4.2Hz,1H),3.58(s,3H),3.14–3.00(m,2H),2.91(dd,J=13.7,4.3Hz,1H),2.71(dd,J=13.7,10.4Hz,1H),2.26(dd,J=13.9,6.7Hz,1H),2.12–1.99(m,2H),1.57(ddt,J=13.7,10.7,6.6Hz,2H),1.25(s,9H).ESI-MS m / z 452.23[M+H] + .

[0099] Synthesis of (S)-methyl 2-((S)-3-(3-fluorophenyl)-2-(lH-indole-2-carboxamido) propanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (3-3)

[0100]

[0101] Synthesis procedure was same as Example 1, step 4. 1 H NMR (400 MHz, Methanol-d4) δ 7.58 (dt, J = 8.1, 1.0 Hz, 1H), 7.38 (dq, J = 8.3, 1.0 Hz, 1H), 7.28 - 7.23 (m, 1H), 7.18 (ddd, J = 8.3, 7.0, 1.1 Hz, 1H), 7.13 - 7.01 (m, 4H), 6.94 - 6.89 (m, 1H), 4.86 - 4.82 (m, 1H), 4.52 (dd, J = 11.6, 4.0 Hz, 1H), 3.68 (s, 3H), 3.26 - 3.06 (m, 4H), 2.52 (ddt, J = 10.3, 8.5, 5.1 Hz, 1H), 2.30 - 2.23 (m, 1H), 2.15 (ddd, J = 14.0, 11.5, 4.2 Hz, 1H), 1.83 - 1.69 (m, 2H). ESI-MS m / z 495.20 [M+H] + .

[0102] Synthesis of N-sulfonyl amide compound (3)

[0103]

[0104] Synthesis procedure was same as Example 1, step 5. 1H NMR (400 MHz, Methanol-d4) δ 7.59 (dt, J = 8.0, 1.1 Hz, 1H), 7.40 (dq, J = 8.3, 1.0 Hz, 1H), 7.31 - 6.99 (m, 6H), 6.95 - 6.88 (m, 1H), 4.75 (t, J = 7.7 Hz, 1H), 4.48 (dd, J = 8.1, 4.8 Hz, 1H), 3.63 - 3.45 (m, 1H), 3.34 - 3.31 (m, 1H), 3.25 - 3.10 (m, 4H), 2.25 - 2.07 (m, 3H), 1.75 - 1.62 (m, 2H), 1.24 (q, J = 7.1 Hz, 3H).

[0105] 13 C NMR (151 MHz, Methanol-d4) δ 172.55, 171.81, 129.81, 129.75, 127.50, 124.97, 123.93, 121.50, 119.87, 115.83, 115.69, 111.70, 103.91, 54.57, 52.59, 48.05, 47.91, 47.76, 47.62, 47.49, 47.34, 47.20, 46.99, 40.09, 38.26, 36.78, 32.25, 27.32, 6.80. ESI-MS m / z 572.19

[0106] [M+H] + .

[0107] Synthesis of N-sulfonyl amide compound (4)

[0108]

[0109] Synthesis step is same as example 1 step 5. 1H NMR (400 MHz, Methanol-d4) δ 7.57 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.3 Hz, 1H), 7.21 (dq, J = 18.1, 7.6 Hz, 2H), 7.12 - 6.99 (m, 4H), 6.89 (td, J = 8.5, 2.6 Hz, 1H), 4.87 - 4.84 (m, 1H), 4.42 (dd, J = 11.0, 4.3 Hz, 1H), 3.25 (t, J = 4.5 Hz, 1H), 3.23 - 3.18 (m, 1H), 3.10 (dd, J = 14.0, 9.0 Hz, 1H), 2.90 (dt, J = 8.2, 3.6 Hz, 1H), 2.47 (dt, J = 13.9, 7.0 Hz, 1H), 2.32 - 2.22 (m, 1H), 2.16 (ddd, J = 15.3, 10.9, 4.5 Hz, 1H), 1.84 - 1.71 (m, 2H), 1.32 - 1.12 (m, 3H), 1.03 (d, J = 8.0 Hz, 2H).

[0110] 13 C NMR (151 MHz, Methanol-d4) δ 121.48, 119.85, 111.68, 103.89, 54.63, 48.04, 47.90, 47.76, 47.62, 47.47, 47.33, 47.19, 40.09, 38.29, 36.79, 32.71, 4.83. ESI-MS m / z 583.19

[0111] [M+H] + .

[0112] Synthesis of N-sulfonyl amide compound (5)

[0113]

[0114] Synthesis procedure was same as compound 1. ESI-MS m / z 549.23 [M+H] + .

[0115] Synthesis of N-sulfonyl amide compound (6)

[0116]

[0117] Synthesis procedure was same as compound 1. ESI-MS m / z 561.23 [M+H] + .

[0118] Synthesis of N-N-sulfonyl amide compound (7)

[0119]

[0120] Synthesis procedure was same as compound 1. ESI-MS m / z 519.22 [M+H] + .

[0121] Example 8 Synthesis of N-sulfonyl amide compound (8)

[0122]

[0123] Synthesis procedure was same as compound 1. ESI-MS m / z 510.21 [M+H] + Example 9 Synthesis of N-sulfonyl amide compound (9)

[0124]

[0125] Synthesis procedure was same as compound 1. ESI-MS m / z 520.21 [M+H] + Example 10 Synthesis of N-sulfonyl amide compound (10)

[0126]

[0127] Synthesis procedure was same as compound 1. ESI-MS m / z 494.22 [M+H] + Example 11 Synthesis of N-sulfonyl amide compound (11)

[0128]

[0129] Synthesis procedure was same as compound 1. ESI-MS m / z 506.22 [M+H] + Example 12 Synthesis of N-sulfonyl amide compound (12)

[0130]

[0131] Synthesis procedure was same as compound 1. ESI-MS m / z 485.19 [M+H] + Example 13 Synthesis of N-sulfonyl amide compound (13)

[0132]

[0133] Synthesis procedure was same as compound 1. ESI-MS m / z 484.21 [M+H] + .

[0134] Example 14 Synthesis of N-sulfonyl amide compound (14)

[0135]

[0136] Synthetic procedure was same as compound 1. 1 H NMR (400 MHz, Methanol-d4) δ 7.31 (dd, J = 8.4, 5.4 Hz, 2H), 7.21 (s, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.99 (q, J = 8.4 Hz, 3H), 6.50 (d, J = 7.8 Hz, 1H), 4.36 (s, 1H), 3.92 (s, 3H), 3.65 (q, J = 5.4 Hz, 1H), 3.59 (dd, J = 11.2, 4.9 Hz, 1H), 3.51 (dd, J = 11.2, 5.9 Hz, 1H), 3.29 - 3.19 (m, 6H), 3.08 (dd, J = 14.0, 8.8 Hz, 1H), 2.43 (s, 1H), 2.30 (s, 1H), 2.18 (dd, J = 18.5, 10.8 Hz, 1H), 1.80 (dd, J = 15.2, 6.2 Hz, 2H), 1.28 (d, J = 6.8 Hz, 4H).

[0137] ESI-MS m / z 602.20 [M+H] + .

[0138] Synthesis of N-sulfonyl amide compound (15)

[0139]

[0140] Synthetic procedure was same as compound 1. 1 H NMR (400 MHz, Methanol-d4) δ 7.31 (dd, J = 8.4, 5.4 Hz, 2H), 7.21 (s, 1H), 7.14 (t, J = 8.0 Hz, 1H), 6.99 (q, J = 8.4 Hz, 3H), 6.50 (d, J = 7.8 Hz, 1H), 4.36 (s, 1H), 3.92 (s, 3H), 3.65 (q, J = 5.4 Hz, 1H), 3.59 (dd, J = 11.2, 4.9 Hz, 1H), 3.51 (dd, J = 11.2, 5.9 Hz, 1H), 3.29 - 3.19 (m, 6H), 3.08 (dd, J = 14.0, 8.8 Hz, 1H), 2.43 (s, 1H), 2.30 (s, 1H), 2.18 (dd, J = 18.5, 10.8 Hz, 1H), 1.80 (dd, J = 15.2, 6.2 Hz, 2H), 1.28 (d, J = 6.8 Hz, 4H).

[0141] ESI-MS m / z 548.21 [M+H] + .

[0142] Synthesis of N-sulfonyl amide compound (15)

[0143] Step 1. Synthesis of methyl (S)-2-((S)-2-(((tert-butoxycarbonyl)amino)-3-(3,4- difluorophenyl)propanoate

[0144]

[0145] The synthetic procedure is same as Example 1, Step 3. 1 H NMR (400 MHz, Methanol-d4) δ 8.55 (d, J = 8.4 Hz, 1H), 7.20 - 7.10 (m, 2H), 7.05 - 6.98 (m, 1H), 4.50 (ddd, J = 11.9, 8.5, 4.0 Hz, 1H), 4.25 (dd, J = 8.9, 5.9 Hz, 1H), 3.68 (s, 3H), 3.33 (d, J = 2.3 Hz, 1H), 3.27 - 3.22 (m, 1H), 3.04 (dd, J = 13.9, 5.9 Hz, 1H), 2.81 (dd, J = 13.9, 8.9 Hz, 1H), 2.49 (qd, J = 10.3, 3.8 Hz, 1H), 2.31 (dtd, J = 13.0, 8.6, 7.7, 4.2 Hz, 1H), 2.12 (ddd, J = 13.9, 11.7, 3.9 Hz, 1H), 1.84 - 1.71 (m, 2H), 1.36 (s, 9H). ESI-MS m / z 470.20 [M+H] + .

[0146] Step 2. Synthesis of methyl (S)-2-((S)-3-(3,4-difluorophenyl)-2-(4-methoxy-1H- indole-2-carboxamido)propanoate

[0147]

[0148] The synthetic procedure is same as Example 1, Step 4. 1H NMR (400 MHz, Methanol-d4) δ 7.26 - 7.15 (m, 2H), 7.15 - 7.04 (m, 3H), 6.96 (dt, J = 8.4, 0.8 Hz, 1H), 6.46 (d, J = 7.7 Hz, 1H), 4.82 (dd, J = 8.7, 6.2 Hz, 1H), 4.51 (dd, J = 11.5, 4.0 Hz, 1H), 3.88 (d, J = 1.4 Hz, 3H), 3.67 (s, 3H), 3.26 - 3.13 (m, 3H), 3.05 (dd, J = 13.9, 8.7 Hz, 1H), 2.52 (tdd, J = 10.2, 8.4, 4.1 Hz, 1H), 2.24 (dddd, J = 12.3, 8.7, 6.8, 2.4 Hz, 1H), 2.14 (ddd, J = 13.9, 11.6, 4.1 Hz, 1H), 1.82 - 1.66 (m, 2H). ESI-MS m / z 543.19 [M+H] + .

[0149] Step 3 Synthesis of N-sulfonyl amide compound (16)

[0150]

[0151] Synthetic procedure same as Example 1, step 5. 1 H NMR (400 MHz, Methanol-d4) δ 7.26 - 6.96 (m, 6H), 6.51 - 6.45 (m, 1H), 4.80 (dd, J = 8.5, 6.0 Hz, 1H), 4.37 (dd, J = 11.3, 4.3 Hz, 1H), 3.90 (s, 3H), 3.46 - 3.32 (m, 2H), 3.28 - 3.17 (m, 3H), 3.06 (dd, J = 13.9, 8.5 Hz, 1H), 2.97 (s, 1H), 2.53 - 2.44 (m, 1H), 2.30 - 2.22 (m, 1H), 2.15 (ddd, J = 14.0, 11.3, 4.8 Hz, 1H), 1.85 - 1.70 (m, 2H), 1.30 (t, J = 7.3 Hz, 3H).

[0152] 13 C NMR (151 MHz, Methanol-d4) δ 125.57, 104.77, 65.50, 54.54, 54.31, 52.55, 48.03, 47.89, 47.75, 47.61, 47.46, 47.32, 47.18, 46.97, 40.08, 36.27, 32.26, 14.04, 6.77. ESI-MS m / z 620.18 [M+H] +.

[0153] Example 17 Synthesis of N-sulfonyl amide compound (17)

[0154]

[0155] The synthetic steps were the same as compound 1. ESI-MS m / z 561.23 [M+H] + .

[0156] Example 18 Synthesis of N-sulfonyl amide compound (18)

[0157]

[0158] The synthetic steps were the same as compound 1. ESI-MS m / z 613.20 [M+H] + .

[0159] Example 19 Synthesis of N-sulfonyl amide compound (19)

[0160]

[0161] The synthetic steps were the same as compound 1. ESI-MS m / z 559.21 [M+H] + .

[0162] Example 20 Synthesis of N-sulfonyl amide compound (20)

[0163]

[0164] The synthetic steps were the same as compound 1. ESI-MS m / z 631.19 [M+H] + .

[0165] Example 21 Synthesis of N-sulfonyl amide compound (21)

[0166]

[0167] The synthetic steps were the same as compound 1. ESI-MS m / z 505.20 [M+H] + .

[0168] Example 22 Synthesis of N-sulfonyl amide compound (22)

[0169]

[0170] The synthetic steps were the same as compound 1. 1H NMR (400 MHz, Methanol-d4) δ 7.32 (s, 1H), 7.18 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.2 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 4.66 (dd, J = 9.6, 5.2 Hz, 1H), 4.44 (s, 1H), 3.96 (s, 3H), 3.65 - 3.50 (m, 2H), 3.34 (s, 4H), 3.16 (s, 3H), 2.59 (s, 1H), 2.34 (s, 1H), 2.18 (d, J = 11.7 Hz, 1H), 1.82 (tt, J = 15.8, 9.1 Hz, 6H), 1.05 (d, J = 5.7 Hz, 3H), 1.01 (d, J = 5.7 Hz, 3H).

[0171] ESI-MS m / z 536.21 [M+H] + .

[0172] Synthesis of N-sulfonyl amide compound (23)

[0173]

[0174] Synthesis procedure was same as compound 1. ESI-MS m / z 533.23 [M+H] + .

[0175] Synthesis of N-sulfonyl amide compound (24)

[0176]

[0177] Synthesis procedure was same as compound 1. ESI-MS m / z 563.24 [M+H] + .

[0178] Synthesis of N-sulfonyl amide compound (25)

[0179] Step 1. Synthesis of methyl (S)-2-((S)-2-((tert-butoxycarbonyl)amino)-3-(4- fluorophenyl)propanoate)-3-((S)-2-oxopyridazin-3-yl)propanoate (25-3)

[0180]

[0181] Synthesis procedure was same as example 1, step 3. 1HNMR (400 MHz, CDC13) δ: 7.10 (dd, J = 8.3, 5.5 Hz, 2H), 6.85 (t, J = 8.7 Hz, 2H), 5.46 (d, J = 8.1 Hz, 1H), 4.48 (s, 1H), 3.61 (d, J = 4.1 Hz, 3H), 3.17 (s, 2H), 3.06 (dd, J = 13.9, 5.2 Hz, 1H), 2.86 (dd, J = 13.4, 7.0 Hz, 1H), 2.41 - 2.26 (m, 1H), 2.21 (d, J = 3.4 Hz, 1H), 1.99 (s, 1H), 1.77 (d, J = 9.3 Hz, 2H), 1.68 - 1.53 (m, 1H), 1.45 (dd, J = 25.1, 14.0 Hz, 1H), 1.28 (s, 9H). ESI-MS m / z 466.1 [M+H] + .

[0182] Step 2 Synthesis of methyl (3S,6S,8S)-2-[2-(l,3-dioxo-2-phenylisoindolin-5- ylcarbamido)-l-oxo-3-(4-fluorophenyl)]-propylamino-3-(2-oxo-3-piperidinyl)- propanoate (25-5)

[0183]

[0184] The synthesis step is the same as Example 1, Step 4. 1 H NMR (400 MHz, DMSO-D6) δ 9.09 (d, J = 8.3 Hz, 1H), 8.80 (d, J = 7.7 Hz, 1H), 8.37 - 8.32 (m, 1H), 8.24 (d, J = 1.5 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.54 - 7.48 (m, 2H), 7.41 (d, J = 9.1 Hz, 4H), 7.37 (dd, J = 10.0, 7.0 Hz, 2H), 7.06 (dd, J = 9.9, 7.9 Hz, 2H), 4.72 (dt, J = 15.0, 5.4 Hz, 1H), 4.41 - 4.32 (m, 1H), 3.60 (d, J = 5.8 Hz, 3H), 3.16 - 3.03 (m, 3H), 3.00 - 2.92 (m, 1H), 2.47 (s, 6H), 2.30 - 2.17 (m, 2H), 1.84 (dd, J = 9.2, 5.5 Hz, 1H), 1.67 (td, J = 10.7, 5.6 Hz, 2H), 1.58 - 1.46 (m, 1H), 1.34 (td, J = 13.4, 3.1 Hz, 1H). ESI-MS m / z 615.1

[0185] [M+H]+ .

[0186] Step 3 Synthesis of N-sulfonyl amide compound (25)

[0187]

[0188] Synthetic procedure same as Example 1, step 5. ESI-MS m / z 691.21 [M+H] + .

[0189] Example 26 Synthesis of N-sulfonyl amide compound (26)

[0190] Step 1 Synthesis of methyl (3S,6S,8S)-2-[2-(1-(3-fluorobenzyl)-1H-indole-5- carboxamido)-1-oxo-3-(4-fluorophenyl)]-propylamino-3-(2-oxo-3-pyridinyl)- propanoate (26-2)

[0191]

[0192] Synthetic procedure same as Example 1, step 4. 1 H NMR (400 MHz, DMSO-D6) δ 8.65 (dd, J = 16.7, 8.2 Hz, 1H), 8.44 - 8.37 (m, 1H), 8.11 (dd, J = 5.3, 1.3 Hz, 1H), 7.64 - 7.56 (m, 2H), 7.51 - 7.31 (m, 5H), 7.13 - 7.04 (m, 3H), 7.03 - 6.96 (m, 2H), 6.61 (d, J = 3.1 Hz, 1H), 5.48 (s, 2H), 4.81 - 4.66 (m, 1H), 4.40 (ddd, J = 16.1, 11.7, 4.9 Hz, 1H), 3.62 (d, J = 3.3 Hz, 3H), 3.11 - 2.93 (m, 4H), 2.24 (dd, J = 15.7, 8.1 Hz, 1H), 1.89 - 1.77 (m, 1H), 1.74 - 1.63 (m, 2H), 1.52 (dd, J = 9.4, 4.1 Hz, 1H), 1.37 - 1.20 (m, 2H). ESI-MS m / z 617.25 [M+H] + .

[0193] Step 2 Synthesis of N-sulfonyl amide compound (26)

[0194]

[0195] Synthetic procedure same as Example 1, step 5. ESI-MS m / z 693.24 [M+H] + .

[0196] Synthesis of N-sulfonyl amide compound (27)

[0197] Step 1 Synthesis of methyl (3S,6S,8S)-2-[2-(1-(2-fluoro-5-methylphenyl)-5- methyl-1H-1,2,3-triazole-4-carboxamido)-1-oxo-3-(4-fluorophenyl)]- propylamino-3-(2-oxo-3-pyridinyl) propanoate (27-2)

[0198]

[0199] The synthetic procedure was same as Example 1, step 4. 1 H NMR (400 MHz, DMSO-D6) δ 8.92 (d, J = 8.2 Hz, 1H), 7.55-7.43 (m, 3H), 7.37-7.31 (m, 2H), 7.10 (dd, J = 9.0, 6.7 Hz, 2H), 4.75 (q, J = 7.5 Hz, 1H), 3.66 (s, 3H), 3.18 (dd, J = 13.3, 6.4 Hz, 3H), 2.41-2.32 (m, 6H). ESI-MS m / z 583.24 [M+H] + .

[0200] Step 2 Synthesis of N-sulfonyl amide compound (27)

[0201]

[0202] The synthetic procedure was same as Example 1, step 5. ESI-MS m / z 659.23 [M+H] + .

[0203] Example 28 Synthesis of N-sulfonyl amide compound (28)

[0204] Step 1 Synthesis of methyl (3S,6S,8S)-2-[2-(4-fluoro-3-(morpholinosulfonyl) benzamide)-1-oxo-3-(4-fluorophenyl)]-propylamino-3-(2-oxo-3-pyridinyl) propanoate (28-2)

[0205]

[0206] The synthetic procedure was same as Example 1, step 4. 1H NMR (400 MHz, DMSO-D6) δ 9.02 (dd, J = 8.3, 5.1 Hz, 1H), 8.80 (dd, J = 24.6, 7.9 Hz, 1H), 8.18 (t, J = 10.3 Hz, 2H), 7.61 (s, 1H), 7.45 (d, J = 8.9 Hz, 1H), 7.38 (s, 2H), 7.06 (s, 2H), 4.74 (dtd, J = 14.6, 10.4, 5.6 Hz, 1H), 4.44 - 4.33 (m, 1H), 3.63 (t, J = 6.4 Hz, 7H), 3.14 - 2.91 (m, 8H), 2.30 - 2.16 (m, 1H), 2.03 (s, 1H), 1.88 - 1.60 (m, 3H), 1.50 (dd, J = 18.9, 7.6 Hz, 1H), 1.35 (dd, J = 19.6, 13.7 Hz, 1H). ESI-MS m / z 637.21 [M+H] + .

[0207] Synthesis of N-sulfonyl amide compound (28)

[0208]

[0209] Synthesis procedure was same as Example 1, step 5. ESI-MS m / z 713.20 [M+H] + .

[0210] Synthesis of N-sulfonyl amide compound (29)

[0211] Step 1 Synthesis of (4S,7S,9S)-2-[2-((2,3-dihydro-benzo[l,4]dioxin-6)- acetylamido)-l-carbonyl-3-(4-fluorophenyl)]-propylamino-3-(2-carbonyl-3- pyridyl)-propionic acid methyl ester (29-2)

[0212]

[0213] Synthesis procedure was same as Example 1, step 4. 1H NMR (400 MHz, DMSO-D6) δ 8.64 (d, J = 7.8 Hz, 1H), 8.27-8.18 (m, 1H), 7.49 (d, J = 10.7 Hz, 1H), 7.28-7.18 (m, 2H), 7.02 (d, J = 20.2 Hz, 2H), 6.71-6.48 (m, 3H), 4.55-4.46 (m, 1H), 4.36 (ddd, J = 12.0, 7.8, 4.5 Hz, 1H), 4.18 (s, 4H), 3.61 (d, J = 4.7 Hz, 3H), 3.24 (q, J = 14.0 Hz, 2H), 3.08 (d, J = 3.1 Hz, 2H), 2.98 (dd, J = 13.7, 4.4 Hz, 1H), 2.73 (dd, J = 13.7, 10.0 Hz, 1H), 2.21 (ddd, J = 36.9, 14.3, 7.9 Hz, 2H), 1.81 (s, 1H), 1.75-1.61 (m, 2H), 1.57-1.43 (m, 1H), 1.39-1.26 (m, 1H). ESI-MS m / z 542.22 [M+H] + .

[0214] Synthesis of N-sulfonyl amide compound (29)

[0215]

[0216] Synthetic procedure same as Example 1, step 5. ESI-MS m / z 618.22 [M+H] + .

[0217] Synthesis of N-sulfonyl amide compound (30)

[0218] Step 1 Synthesis of (5S,8S,10S)-2-[2-(1H-benzimidazol-2-ylthio)propanamido)-1- carbonyl-3-(4-fluorophenyl)]-propanamido-3-(2-carbonyl-3-pyridyl)-propanoic acid methyl ester (30-2)

[0219]

[0220] Synthetic procedure same as Example 1, step 4. ESI-MS m / z 592.22 [M+H]+.

[0221] Synthesis of N-sulfonyl amide compound (30)

[0222]

[0223] Synthetic procedure same as Example 1, step 5. ESI-MS m / z 669.21 [M+H]+ .

[0224] Synthesis of N-sulfonyl amide compound (31)

[0225]

[0226] The synthesis procedure was same as Example 1, step 5. 1 H NMR (600 MHz, Methanol-d4) δ 7.27 - 7.19 (m, 2H), 7.15 - 7.05 (m, 3H), 7.00 (d, J = 8.3 Hz, 1H), 6.50 (d, J = 7.7 Hz, 1H), 4.82 (d, J = 5.9 Hz, 1H), 4.43 (dd, J = 11.1, 4.5 Hz, 1H), 3.91 (s, 3H), 3.28 - 3.19 (m, 6H), 3.08 (dd, J = 14.0, 8.7 Hz, 1H), 2.51 (tdd, J = 9.8, 8.5, 4.9 Hz, 1H), 2.27 (dddd, J = 12.5, 8.6, 7.0, 2.6 Hz, 1H), 2.20 - 2.11 (m, 1H), 1.86 - 1.73 (m, 2H).

[0227] 13 C NMR (151 MHz, Methanol-d4) δ 180.21, 125.05, 104.78, 101.55, 98.96, 54.61, 54.31, 52.36, 48.04, 47.90, 47.76, 47.62, 47.48, 47.34, 47.19, 40.08, 39.97, 38.22, 36.28, 32.28, 27.31. ESI-MS m / z 606.18 [M+H] + .

[0228] Synthesis of N-sulfonyl amide compound (32)

[0229]

[0230] The synthesis procedure was same as Example 1, step 5. 1H NMR (600 MHz, Methanol-d4) δ 7.25 - 7.19 (m, 2H), 7.16 - 7.04 (m, 3H), 7.01 (d, J = 8.3 Hz, 1H), 6.49 (d, J = 7.7 Hz, 1H), 4.83 (s, 1H), 4.39 (dd, J = 11.1, 4.5 Hz, 1H), 3.91 (s, 3H), 3.69 (dt, J = 13.8, 6.9 Hz, 1H), 3.24 (dddd, J = 21.3, 19.6, 10.7, 3.5 Hz, 3H), 3.07 (dt, J = 14.1, 9.1 Hz, 1H), 2.49 (qd, J = 9.6, 5.0 Hz, 1H), 2.27 (dddd, J = 15.9, 14.0, 8.1, 4.6 Hz, 1H), 2.17 (ddd, J = 13.9, 11.1, 4.9 Hz, 1H), 1.85 - 1.73 (m, 2H), 1.38 - 1.33 (m, 6H).

[0231] 13 C NMR (151 MHz, Methanol-d4) δ 125.06, 104.79, 101.55, 98.96, 54.50, 54.31, 53.36, 52.70, 48.04, 47.90, 47.75, 47.61, 47.47, 47.33, 47.19, 40.09, 38.31, 36.29, 32.29, 27.32, 14.33. ESI-MS m / z 634.21 [M+H] + .

[0232] Synthesis of N-sulfonyl amide compound (33)

[0233] Step 1. Synthesis of (S)-methyl 2-((S)-3-(3-fluorophenyl)-2-(4-methoxy-lH- indole-2-carboxamido)propanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (33-1)

[0234]

[0235] The synthesis step is the same as step 4 of Example 1. 1H NMR (400 MHz, Methanol-d4) δ 7.25 (td, J = 8.0, 6.0 Hz, 1H), 7.17 (d, J = 0.9 Hz, 1H), 7.13 - 7.04 (m, 3H), 6.97 (dt, J = 8.3, 0.8 Hz, 1H), 6.93 - 6.87 (m, 1H), 6.50 - 6.44 (m, 1H), 4.84 (dd, J = 8.8, 5.9 Hz, 1H), 4.52 (dd, J = 11.5, 4.0 Hz, 1H), 3.89 (s, 3H), 3.67 (s, 3H), 3.27 - 3.05 (m, 4H), 2.51 (tdd, J = 10.3, 8.5, 4.2 Hz, 1H), 2.25 (dddd, J = 12.4, 8.7, 6.8, 2.5 Hz, 1H), 2.15 (ddd, J = 14.0, 11.6, 4.2 Hz, 1H), 1.82 - 1.67 (m, 2H). ESI-MS m / z 525.21 [M+H] + .

[0236] Synthesis of N-sulfonyl amide compound (33)

[0237]

[0238] Synthetic procedure same as Example 1, Step 5. 1 H NMR (600 MHz, Methanol-d4) δ 7.27 - 7.19 (m, 2H), 7.15 - 7.05 (m, 3H), 7.00 (d, J = 8.3 Hz, 1H), 6.89 (td, J = 8.5, 2.6 Hz, 1H), 6.49 (d, J = 7.8 Hz, 1H), 4.88 - 4.86 (m, 1H), 4.43 (dd, J = 11.1, 4.4 Hz, 1H), 3.90 (s, 3H), 3.27 (dd, J = 14.0, 5.7 Hz, 1H), 3.22 (s, 4H), 3.11 (dd, J = 14.0, 8.9 Hz, 1H), 2.49 (qd, J = 9.4, 4.7 Hz, 1H), 2.31 - 2.23 (m, 1H), 2.20 - 2.12 (m, 1H), 1.87 - 1.68 (m, 2H).

[0239] 13C NMR (151 MHz, Methanol-d4) δ 172.62, 129.82, 125.06, 124.97, 115.80, 113.24, 104.81, 101.58, 98.98, 54.66, 54.32, 52.45, 48.05, 47.91, 47.77, 47.63, 47.48, 47.34, 47.20, 40.09, 39.96, 38.21, 36.77, 32.36, 27.32. ESI-MS m / z 588.19 [M+H] + .

[0240] Example 34 Synthesis of N-sulfonyl amide compound (34)

[0241]

[0242] Synthetic procedure same as Example 1, step 5. 1 H NMR (400 MHz, Methanol-d4) δ 7.24 (td, J = 7.9, 6.0 Hz, 1H), 7.18 (d, J = 0.9 Hz, 1H), 7.14 - 7.03 (m, 3H), 6.98 (dt, J = 8.3, 0.8 Hz, 1H), 6.93 - 6.87 (m, 1H), 6.48 (d, J = 7.7 Hz, 1H), 4.82 (dd, J = 8.8, 5.8 Hz, 1H), 4.37 (dd, J = 11.2, 4.3 Hz, 1H), 3.90 (s, 3H), 3.38 (dq, J = 27.8, 7.3 Hz, 2H), 3.27 - 3.17 (m, 3H), 3.09 (dd, J = 13.9, 8.7 Hz, 1H), 2.46 (qd, J = 9.7, 4.6 Hz, 1H), 2.30 - 2.21 (m, 1H), 2.15 (ddd, J = 13.9, 11.2, 4.7 Hz, 1H), 1.84 - 1.70 (m, 2H), 1.30 (t, J = 7.4 Hz, 3H).

[0243] 13 C NMR (151 MHz, Methanol-d4) δ 172.62, 129.82, 125.06, 124.97, 115.80, 113.24, 104.81, 101.58, 98.98, 54.66, 54.32, 52.45, 48.05, 47.91, 47.77, 47.63, 47.48, 47.34, 47.20, 40.09, 39.96, 38.21, 36.77, 32.36, 27.32. ESI-MS m / z 588.19 [M+H] + .

[0244] Example 35 Synthesis of N-sulfonyl amide compound (35)

[0245]

[0246] The synthetic procedure is same as Example 1, step 5. 1 H NMR (400 MHz, Methanol-d4) δ 7.25 (td, J = 8.1, 6.1 Hz, 1H), 7.19 - 7.04 (m, 4H), 6.98 (dt, J = 8.4, 0.8 Hz, 1H), 6.94 - 6.88 (m, 1H), 6.48 (dd, J = 7.7, 0.7 Hz, 1H), 4.82 (dd, J = 8.7, 5.8 Hz, 1H), 4.35 (dd, J = 11.2, 4.3 Hz, 1H), 3.91 (s, 3H), 3.68 (p, J = 6.9 Hz, 1H), 3.28 - 3.20 (m, 3H), 3.09 (dd, J = 13.9, 8.6 Hz, 1H), 2.46 (qd, J = 9.6, 4.7 Hz, 1H), 2.31 - 2.23 (m, 1H), 2.20 - 2.11 (m, 1H), 1.86 - 1.71 (m, 2H), 1.35 (dd, J = 9.0, 6.9 Hz, 6H).

[0247] 13 C NMR (151 MHz, Methanol-d4) δ 125.06, 104.80, 101.58, 98.98, 54.55, 54.32, 53.43, 52.68, 48.06, 47.91, 47.77, 47.63, 47.49, 47.35, 47.20, 40.09, 36.77, 32.20, 27.32, 15.16, 14.29. ESI-MS m / z 616.22 [M+H] + .

[0248] Synthesis of N-sulfonyl amide compound (36)

[0249] Step 1. Synthesis of (S)-methyl 2-((S)-3-cyclohexyl-2-(4-methoxy-lH-indole-2- carboxamido)propanamido)-3-((S)-2-oxopyrrolidin-3-yl)propanoate (36-1)

[0250]

[0251] The synthetic procedure is same as Example 1, step 4. 1H NMR (600 MHz, Methanol-d4) δ 7.26 (d, J = 0.9 Hz, 1H), 7.16 - 7.12 (m, 1H), 7.02 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 7.7 Hz, 1H), 4.65 (dd, J = 9.3, 6.1 Hz, 1H), 4.55 (dd, J = 11.7, 4.0 Hz, 1H), 3.92 (s, 3H), 3.72 (s, 3H), 3.29 - 3.22 (m, 2H), 2.59 (tdd, J = 10.4, 8.5, 4.2 Hz, 1H), 2.33 - 2.25 (m, 1H), 2.19 (ddd, J = 13.9, 11.6, 4.2 Hz, 1H), 1.84 (ddt, J = 11.2, 7.5, 4.8 Hz, 3H), 1.76 - 1.70 (m, 4H), 1.66 (dd, J = 11.8, 4.3 Hz, 1H), 1.52 - 1.44 (m, 1H), 1.35 - 1.16 (m, 4H), 1.05 - 0.96 (m, 2H). ESI-MS m / z 513.27 [M+H] + .

[0252] Synthesis of N-sulfonyl amide compound (36)

[0253]

[0254] The synthesis procedure was the same as Example 1, Step 5. 1 H NMR (600 MHz, Methanol-d4) δ 7.28 (s, 1H), 7.14 (t, J = 8.0 Hz, 1H), 7.03 (d, J = 8.3 Hz, 1H), 6.51 (d, J = 7.7 Hz, 1H), 4.68 - 4.61 (m, 1H), 4.47 - 4.32 (m, 1H), 3.92 (s, 3H), 3.67 - 3.49 (m, 1H), 3.28 - 3.20 (m, 3H), 2.55 (s, 1H), 2.37 - 2.25 (m, 1H), 2.18 (d, J = 13.0 Hz, 1H), 1.82 (t, J = 11.0 Hz, 4H), 1.77 - 1.68 (m, 4H), 1.65 (d, J = 11.7 Hz, 1H), 1.46 (ddt, J = 14.7, 11.1, 5.6 Hz, 1H), 1.30 - 1.15 (m, 6H), 1.06 - 0.94 (m, 2H).

[0255] 13C NMR (151 MHz, Methanol-d4) δ 125.01, 104.79, 101.77, 98.96, 54.32, 51.56, 48.04, 47.89, 47.75, 47.61, 47.47, 47.33, 47.18, 40.16, 38.81, 34.15, 33.43, 32.15, 27.46, 26.20, 25.97, 25.84. ESI-MS m / z 590.26 [M+H] + .

[0256] Example 37 Anti-SARS-CoV-2 Activity Assay

[0257] MRC-5 cells were plated at 10,000 cells per well using MEM (Gibco) without phenol red. Various concentrations of compounds (320, 100, 33, 10, 3.3, 1.0, 0.3, or 0.1 mM) were added and cells were infected with SARS_CoV-2 or mock infected with media. After 4 days, cell viability was determined using the XTT dye reduction method. Data is expressed as the percent of the neutral red or luminescent signal in the compound treated cell wells compared to the signal in the uninfected, no compound cell wells. From this, the EC50 of the compound was calculated. 50 and CC 50 .

[0258]

Claims

1. The compound represented by Formula I or a pharmaceutically acceptable salt thereof, in R1 is a C1-C3 alkyl or cyclopropyl group; R2 is a C1-C6 alkyl or cyclohexyl group, or a fluorinated substituted phenyl group; R3 is selected from n is 1 or 2.

2. The compound represented by Formula I or its pharmaceutically acceptable salt, R1 is selected from methyl, ethyl, propyl, and cyclopropyl; R2 is selected from isopropyl, cyclohexyl, 4-fluorophenyl, 3-fluorophenyl, and 3,4-difluorophenyl; R3 is selected from n is 1 or 2.

3. A compound or a pharmaceutically acceptable salt thereof, said compound being selected from:

4. A pharmaceutical composition comprising at least one compound as defined in any one of claims 1-3 or a pharmaceutically acceptable salt thereof.

5. The pharmaceutical composition according to claim 4, further comprising an EV71 antiviral agent.

6. The pharmaceutical composition according to claim 5, wherein the EV71 antiviral agent is an antiviral agent selected from 3D protease inhibitors and VP1 protein inhibitors.

7. The pharmaceutical composition according to any one of claims 4-6, for the prevention / treatment of a subject with a disease related to a virus infection, said virus being coronavirus SARS-CoV-2.

8. Use of the compound or its pharmaceutically acceptable salt according to any one of claims 1-3 in the preparation of a medicament, wherein the medicament is an antiviral drug, and the antiviral drug targets the coronavirus SARS-CoV-2.

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