PHARMACEUTICAL COMPOSITION FOR TREATING OR PREVENTING MIDDLE EAST RESPIRATORY SYNDROME

Abstract

The present invention relates to an amide derivative compound or a pharmaceutically acceptable salt thereof, which can be beneficially used in the treatment or prevention of Middle East Respiratory Syndrome (MERS). In addition, the present invention relates to a pharmaceutical composition for treating or preventing MERS, comprising said compound or a pharmaceutically acceptable salt thereof.

Claims

1. A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof: ##STR00033## Wherein, R.sub.1 is —OR.sub.7 or —SR.sub.7, R.sub.7 is C6-C12 aryl, C6-C12 arylalkyl, C3-C12 cycloalkyl, C3-C12 cycloalkylalkyl, C3-10 heteroaryl, C3-10 heteroarylalkyl, C3-10 heterocycloalkyl or C3-10 heterocycloalkylalkyl, substituted or unsubstituted by one or more substituent selected among halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, C6-C12 arylalkyl, C3-C12 cycloalkyl, C3-C12 cycloalkylalkyl, C3-10 heteroaryl, C3-10 heteroarylalkyl, C3-10 heterocycloalkyl and C3-10 heterocycloalkylalkyl; R.sub.2 and R.sub.3 are each independently a hydrogen atom, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, C6-C12 arylalkyl, C3-C12 cycloalkyl, C3-C12 cycloalkylalkyl, C3-10 heteroaryl, C3-10 heteroarylalkyl, C3-10 heterocycloalkyl, or C3-10 heterocycloalkylalkyl; R.sub.5 is ##STR00034## in case that R.sub.4 is a hydrogen atom, R.sub.6 is C6-C12 aryl, C6-C12 arylalkyl, C3-C12 cycloalkyl, C3-C12 cycloalkylalkyl, C3-10 heteroaryl, C3-10 heteroarylalkyl, C3-10 heterocycloalkyl or C3-10 heterocycloalkylalkyl, substituted or unsubstituted by one or more substituent selected among halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, C6-C12 arylalkyl, C3-C12 cycloalkyl, C3-C12 cycloalkylalkyl, C3-10 heteroaryl, C3-10 heteroarylalkyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkylalkyl, —CF.sub.3 and —CN; in case that R.sub.4 is C1-C6 alkyl, R.sub.6 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, C6-C12 arylalkyl, C3-C12 cycloalkyl, C3-C12 cycloalkylalkyl, C3-10 heteroaryl, C3-10 heteroarylalkyl, C3-10 heterocycloalkyl, or C3-10 heterocycloalkylalkyl; R.sub.4 and R.sub.6 can combine with each other to form C6-C12 aryl, C3-C12 cycloalkyl, C3-10 heteroaryl or C3-10 heterocycloalkyl.

2. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.2 and R.sub.3 are each independently a C6-C12 aryl, C6-C12 arylalkyl, C3-10 heteroaryl or C3-10 heteroarylalkyl.

3. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.4 is a hydrogen atom, and R.sub.6 is C6-C12 aryl, C6-C12 arylalkyl, C3-10 heteroaryl or C3-10 heteroarylalkyl, substituted or unsubstituted by one or more substituent selected among halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, C6-C12 arylalkyl, C3-C12 cycloalkyl, C3-C12 cycloalkylalkyl, C3-10 heteroaryl, C3-10 heteroarylalkyl, C3-10 heterocycloalkyl, C3-10 heterocycloalkylalkyl, —CF.sub.3 and —CN.

4. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein R.sub.4 is C1-C6 alkyl, and R.sub.6 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6-C12 aryl, C6-C12 arylalkyl, C3-C12 cycloalkyl, C3-C12 cycloalkylalkyl, C3-10 heteroaryl, C3-10 heteroarylalkyl, C3-10 heterocycloalkyl, or C3-10 heterocycloalkylalkyl.

5. The compound or pharmaceutically acceptable salt thereof according to claim 1, wherein the compound represented by Formula 1 is selected from the group consisting of: ##STR00035##

6. A pharmaceutical composition for treating or preventing Middle East Respiratory Syndrome, comprising the compound or pharmaceutically acceptable salt thereof according to claim 1.

7. The pharmaceutical composition according to claim 6, wherein it is administered simultaneously or sequentially with one or more antiviral agents.

Description

EXAMPLES

[0058] Hereinafter, preferred examples are presented to help the understanding of the present invention. However, the following examples are provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples. Those of ordinary skill in the art may make various modifications to the present invention within the scope not departing from the inventive concept.

Example 1

Preparation of Compounds of Formula 1

[0059] In the following, examples of preparation of compounds of Formula 1 according to the present disclosure are described below. Preparation steps and Representative examples corresponding thereto are described below. Compounds having different substituents were prepared through similar steps, but not all examples are described here. Referring to the following representative examples, those skilled in the art will be able to easily prepare compounds of Formula 1 or salts thereof having different substituents.

[0060] 1-1. Preparation of Compound C According to Scheme 1

[0061] Compounds of Formula 1 according to the present invention may be prepared according to Scheme 1 as follows:

##STR00003##

[0062] According to Scheme 1 above, Compound C was prepared from Compound A and Compound B via EDCI binding reaction. Compound C is a representative example of the compounds of Formula 1.

[0063] As an example of Compound C, (S)-N-((2S, 4S, 5S)-5-(2-(2,6-dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexane-2-yl)-2-(2-oxotetrahydropyrimidin-1(2H)-yl)propanamide was obtained by using Reaction example 1 and the reaction conditions as follows:

[0064] [Reaction Example 1]

##STR00004##

[0065] (i) Reaction conditions: after dissolving Compound a (100 mg, 0.22 mmol) in 3 mL of dimethylformamide, Compound b (43.0 mg, 0.25 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (52 mg, 0.34 mmol) and 1-hydroxybenzotriazole (52 mg, 0.34 mmol) were added and stirred at room temperature for 16 hours. After confirming the completion of the reaction, extraction was performed using 10 mL of ethyl acetate and 20 mL of distilled water. The extracted organic layer was dried using anhydrous sodium sulfate then filtered, and the filtrate was distilled via vacuum distillation and purified using column chromatography. As a result, Compound c (72 mg, yield 54%) was obtained.

[0066] The relevant characterization data of (S)-N-((2S, 4S, 5S)-5-(2-(2,6-dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexane-2-yl)-2-(2-oxotetrahydropyrimidin-1(2H)-yl)propanamide are as follows:

[0067] .sup.1H-NMR 400 MHz (MeOD): δ 7.337.13 (10H, m), 7.02-7.00 (2H, d, J=7.2 Hz), 6.95-6.91 (1H, dd, J=8.4 Hz, J=6.4 Hz), 4.83-4.76 (1H, q, J=7.2 Hz), 4.50-4.38 (2H, m), 4.16-4.05 (2H, dd, J=27.6 Hz, J=14.8 Hz), 3.77 (1H, t, J=8.0 Hz), 3.19-3.13 (2H, m), 3.06-3.00 (1H, m), 2.98-2.87 (2H, m), 2.84-2.79 (1H, m), 2.73-2.65 (2H, m), 2.18 (6H, s), 1.72-1.70 (4H, q, J=6.8Hz), 1.17-1.15 (3H, d, J=7.2 Hz);

[0068] .sup.13C-NMR 175 MHz (MeOD): 5175.71, 173.37, 160.84, 158.29, 142.27, 142.24, 134.14, 133.01, 132.91, 132.53, 131.83, 129.83, 129.76, 128.23, 73.56, 72.32, 56.96, 55.95, 44.28, 44.13, 43.26, 42.91, 41.67, 25.26, 18.91, 16.65;

[0069] LRMS(ESI) calcd for C.sub.35H.sub.44N.sub.4O.sub.5 [M+H]+: 601.3, Found 601.3.

[0070] 1-2. Preparation of Compound A according to Scheme 2

[0071] Compound A used as a starting material in Formula 1 can be prepared according to Scheme 2 as follows:

##STR00005##

[0072] In Scheme 2, Compound E was synthesized from Compound D through a coupling reaction of (2,6-dimethylphenoxy)acetic acid and EDCI. Compound A was synthesized by deprotecting the Compound E using trifluoroacetic acid. Compound A is a representative example of a starting material used in preparing the compound of Formula 1.

[0073] As an example of Compound A, N-((2S, 4S, 55)-5-amino-3-hydroxy-1,6-diphenylhexan-2-yl)-2-(2,6-dimethylphenoxy)acetamide was obtained by using Reaction example 2 and the reaction conditions as follows:

[0074] [Reaction Example 2]

##STR00006##

[0075] (i) Reaction conditions: Compound d (1.00 g, 2.60 mmol) was dissolved in 25 mL of dimethylformamide followed by (2,6-dimethylphenoxy)acetic acid (563 mg, 3.12 mmol), 1-ethyl-3-(3-dimethylaminopropyl) Carbodiimide (606 mg, 3.90 mmol) and 1-hydroxybenzotriazole (600 mg, 3.90 mmol) were added and stirred at room temperature for 16 hours. After confirming the completion of the reaction, extraction was performed using 100 mL of ethyl acetate and 150 mL of distilled water. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified using column chromatography. As a result, Compound e (1.17 g, yield 82%) was obtained.

[0076] (ii) Reaction conditions: After dissolving Compound E in dichloromethane (1.17 g, 2.14 mmol), trifluoroacetic acid (4.92 mL, 64.2 mmol) was slowly added over 20 minutes, followed by stirring at room temperature for 3 hours. After confirming the completion of the reaction, the remaining trifluoroacetic acid and the solvent were removed by distillation under reduced pressure. Then, it was extracted using 50 mL of ethyl acetate and 50 mL of sodium bicarbonate aqueous solution. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and purified using column chromatography. As a result, Compound A (940 mg, 98%) was obtained and was confirmed to be N-((2S, 4S, 5S)-5-amino-3-hydroxy-1,6-diphenylhexan-2-yl)-2-(2,6-dimethylphenoxy)acetamide.

[0077] 1-3. Preparation of Compound B according to Scheme 3

[0078] Compound B used as a starting material in Formula 1 can be prepared according to Scheme 3 as follows:

##STR00007##

[0079] In Scheme 3, Compound G was synthesized from Compound F through Schotten-Baumann acylation using phenylchloroformate. A chloropropylurea intermediate was formed from Compound G by using 3-chloropropylamine. Compound B was prepared through a cyclization reaction frame using tert-potassium butoxideg. Compound B is a representative example of the starting material used in the preparation of the compound of Formula 1.

[0080] As an example of Compound B, (S)-2-(2-oxotetrahydropyrimidin-1(2H)-yl)propanoic acid was obtained by using Reaction example 3 and the reaction conditions as follows:

[0081] [Reaction Example 3]

##STR00008##

[0082] (i) Reaction conditions: Compound f (200 mg, 2.25 mmol) and sodium bicarbonate (283 mg, 3.37 mmol) were dissolved in 4 mL of distilled water, and phenylchloroformate (0.3 mL, 2.36 mmol) was added thereto, and the pH was adjusted to 8.15 to 8.6 using 50% aqueous sodium hydroxide solution. The mixture was stirred for 90 minutes, and 50% aqueous sodium hydroxide solution was periodically added to maintain the pH at 8.5 to 8.7 while stirring. After confirming the completion of the reaction, the pH was adjusted to 8.9 and dissolved solids with diethyl ether. Then, the water layer was adjusted to pH 2.0 by adding 30% aqueous sulfuric acid and extracted with diethyl ether to obtain Compound G (398 mg, yield 85%).

[0083] (ii) Reaction conditions: Compound g (300 mg, 1.67 mmol) was dissolved in 3 mL of tetrahydrofuran, and 3-chloropropylamine hydrochloride (245 mg, 1.83 mmol) and solid sodium hydroxide (202 mg, 5.05 mmol) were added, and mixed in 0° then stirred for 2 hours after raising the temperature up to 10 ° C. After confirming that the intermediate propylurea was formed, 4.20 mL of tert-potassium butoxide (1.0 M in THF) was added for 15 minutes then the mixture was stirred at room temperature for 16 hours. After confirming the completion of the reaction, the pH was adjusted to 9 using a 3N aqueous hydrochloric acid solution, and the aqueous layer was extracted. The pH of the extracted aqueous layer was adjusted to 3 then added 20 mL of ethyl acetate for extraction. The extracted organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure. As a result, Compound b (102 mg, yield 41%) was obtained, and Compound b was confirmed to be (S)-2-(2-oxotetrahydropyrimidin-1(2H)-yl)propanoic acid.

[0084] In the following, characterization data including the properties, NMR data, and molecular weights of the representatively prepared compounds belonging to Formula 1 are shown below. Compounds belonging to Formula 1 with different substituents were prepared similar to the method described in Example 1.

[0085] Compound 1: (S)-N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexane-2-yl)-2-(2-oxotetrahydropyrimidin-1(2H)-yl)-3-phenylpropanamide

[0086] Chemical structure of Compound 1 is:

##STR00009##

[0087] Compound 1 was obtained as a white solid compound and the relevant characterization data are as follows:

[0088] .sup.1H-NMR 400 MHz (MeOD): δ 7.367.12 (15H, m), 7.03-7.01 (2H, d, J=7.6Hz), 6.96-6.93 (1 H, dd, J=8.4Hz, J=6.4Hz), 5.05-5.01 (1 H, dd, J=7.2 Hz, J=1.2 Hz), 4.52 (1H, t, J=6.8Hz), 4.46-4.40 (1H, m), 4.18-4.02 (2H, dd, J=38.4Hz, J=14.8Hz), 3.64 (1H, t, J=6.4Hz), 3.15-3.01 (4H, m), 2.92-2.78 (4H, m), 2.73-2.64 (2H, m), 2.18 (6H, s), 1.68-1.53 (4H, m);

[0089] .sup.13C-NMR 175MHz (MeOD): 5174.28, 173.39, 160.74, 158.28, 142.36, 142.29, 141.44, 134.14, 130.02, 132.97, 132.61, 132.53, 131.88, 131.81, 130.00, 129.82, 129.68, 128.22, 73.53, 72.64, 61.39, 56.72, 44.76, 44.46, 43.14, 43.09, 41.74, 37.65, 25.06, 18.91;

[0090] LRMS(ESI) calcd for C.sub.41H.sub.48N.sub.4O.sub.5 [M−H]−: 675.3, Found: 675.3.

[0091] Compound 2: (S)-N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexane-2-yl)-2,3-dimethyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanamide

[0092] Chemical structure of Compound 2 is:

##STR00010##

[0093] Compound 2 was obtained as a white solid compound and the relevant characterization data are as follows:

[0094] .sup.1H-NMR 400 MHz (MeOD): δ 7.337.13 (10H, m), 7.03-7.01 (2H, d, J=7.6 Hz), 6.97-6.93 (1H, dd, J=8.4 Hz, J=6.4 Hz), 4.40 (1H, t, J=6.4 Hz), 4.33-4.28 (1H, m), 4.13-4.02 (2H, dd, J=22.8 Hz, J=14.8 Hz), 3.85 (1H, t, J=6.0 Hz), 3.38-3.37 (1H, m), 3.31-3.21 (2H, m), 3.00-2.78 (4H, m), 2.75-2.69 (1H, dd, J=13.6 Hz, J=7.2 Hz), 2.17 (6H, s), 1.95-1.90 (2H, m), 1.74-1.62 (2H, m), 1.19 (3H, s), 0.92-0.85 (6H, dd, J=21.2Hz, J=6.4Hz);

[0095] .sup.13C-NMR 175 MHz (MeOD): δ 179.17, 173.23, 161.43, 158.26, 142.39, 142.36, 134.13, 133.11, 133.05, 131.79, 129.78, 129.71, 128.22, 73.51, 72.78, 70.97, 57.35, 46.29, 44.47, 43.09, 42.08, 41.61, 35.22, 25.94, 22.05, 20.80, 20.58, 18.93;

[0096] LRMS(ESI) calcd for C.sub.38H.sub.50N.sub.4O.sub.5[M−H]−: 641.3, Found : 641.3.

[0097] Compound 3: (R)-N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexane-2-yl)-2,3-dimethyl-2-(2-oxotetrahydropyrimidin-1(2H)-yl)butanamide

[0098] Chemical structure of Compound 3 is:

##STR00011##

[0099] Compound 3 was obtained as a white solid compound and the relevant characterization data are as follows:

[0100] .sup.1H-NMR 400 MHz (MeOD): δ 7.347.10 (10H, m), 7.03-7.01 (2H, d, J=7.6 Hz), 6.96-6.93 (1H, dd, J=8.4 Hz, J=6.4 Hz), 4.44-4.36 (2H, m), 4.13-4.09 (1H, d, J=14.8 Hz), 4.02-3.99 (1H, d, J=14.8 Hz), 3.95 (1H, t, J=6.0Hz), 3.25-3.22 (2H, m), 3.03-2.98 (1H, dd, J=13.6 Hz, J=5.6 Hz), 2.92-2.75 (4H, m), 2.17 (6H, s), 1.94-1.91 (2H, m), 1.73-1.68 (2H, m), 1.14 (3H, s), 0.91-0.84 (6H, dd, J=23.2 Hz, J=6.4 Hz);

[0101] .sup.13C-NMR 175 MHz (MeOD): 5179.24, 173.26, 161.63, 158.21, 142.52, 142.51, 134.14, 133.06, 132.51, 131.74, 129.73, 129.69, 128.22, 73.47, 73.26, 70.88, 57.66, 46.20, 44.61, 43.05, 42.96, 41.63, 33.53, 25.86, 21.97, 20.77, 20.54, 18.91;

[0102] LRMS(ESI) calcd for C.sub.38H.sub.50N.sub.4O.sub.5[M−H]−: 641.3, Found: 641.3.

[0103] Compound 4: N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexan-2-yl)-1-(2-oxotetrahydropyrimidine-1 (2H)-yl) cyclopentanecarboxamide

[0104] Chemical structure of Compound 4 is:

##STR00012##

[0105] Compound 4 was obtained as a white solid compound and the relevant characterization data are as follows:

[0106] .sup.1H-NMR 400 MHz (MeOD): δ 7.357.14 (10H, m), 7.03-7.01 (2H, d, J=7.6 Hz), 6.97-6.93 (1H, dd, J=8.4 Hz, J=6.4 Hz), 4.51-4.47 (1H, ddd, J=9.2 Hz, J=6.0 Hz, J=1.6 Hz), 4.16-4.12 (1H, d, J=14.8 Hz), 4.06-4.02 (1H, d, J=14.8 Hz), 3.89 (1H, t, J=6.0 Hz), 3.30-3.27 (2H, m), 3.21 (2H, t, J=6.0 Hz), 3.01-2.97 (1H, dd, J=14.0 Hz, J=6.0 Hz), 2.93-2.87 (1H, dd, J=13.2 Hz, J=9.2 Hz), 2.80-2.79 (2H, d, J=7.2 Hz), 2.19 (6H, s), 2.15-2.05 (2H, m), 1.91-1.88 (2H, t, J=6.0 Hz), 1.83-1.78 (2H, m), 1.71 (2H, t, J=7.2 Hz), 1.61-1.57 (4H, m);

[0107] .sup.13C-NMR 175 MHz (MeOD): δ 179.45, 173.32, 161.66, 158.25, 142.44, 134.15, 133.04, 132.53, 131.75, 129.74, 128.23, 75.95, 73.50, 73.04, 57.41, 46.73, 44.58, 43.08, 43.03, 41.72, 39.43, 39.29, 27.46, 27.40, 18.90;

[0108] LRMS(ESI) calcd for C.sub.35H.sub.48N.sub.4O.sub.5[M−H]−: 639.3, Found: 639.3.

[0109] Compound 5: (S)-N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexane-2-yl)-2-(2-oxotetrahydropyrimidin-1(2H)-yl)-3-(m-tolyl)propanamide

[0110] Chemical structure of Compound 5 is:

##STR00013##

[0111] Compound 5 was obtained as a white solid compound and the relevant characterization data are as follows:

[0112] .sup.1H-NMR 400 MHz (MeOD): δ 7.35-7.12 (11H, m), 7.07-6.93(6H, m), 5.02 (1H, t, J=8.0 Hz), 4.55-4.51 (1H, m), 4.46-4.41 (1H, m), 4.18-4.04 (2H, dd, J=39.6 Hz, J=14.8 Hz), 3.63 (1H, t, J=6.4 Hz), 3.16-3.02 (4H, m), 2.90-2.63 (6H, m), 2.27 (3H, s), 2.18 (6H, s), 1.71-1.54 (4H, m);

[0113] LRMS(ESI) calcd for C.sub.42H.sub.50N.sub.4O.sub.5 [M−H]−: 689.3, Found: 689.3.

[0114] Compound 6: (S)-N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexane-2-yl)-2-(2-oxotetrahydropyrimidin-1(2H)-yl)-3-(p-tolyl)propenamide

[0115] Chemical structure of Compound 6 is:

##STR00014##

[0116] Compound 6 was obtained as a white solid compound and the relevant characterization data are as follows:

[0117] .sup.1H-NMR 400 MHz (MeOD): δ 7.35-7.10 (12H, m), 7.07-7.01 (4H, m), 6.97-6.93 (1H, m), 5.01 (1H, t, J=8.8 Hz), 4.53-4.49 (1H, m), 4.46-4.41 (1H, m), 4.18-4.04 (2H, dd, J=36.4 Hz, J =14.8 Hz), 3.64 (1H, t, J=7.6 Hz), 3.16-3.02 (4H, m), 2.91-2.63 (6H, m), 2.26 (3H, s), 2.18 (6H, s), 1.72-1.54 (4H, m);

[0118] LRMS(ESI) calcd for C.sub.42H.sub.50N.sub.4O.sub.5 [M−H]−: 689.3, Found: 689.3.

[0119] Compound 7: (S)-N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexane-2-yl)-3-(4-fluorophenyl)-2-(2-oxotetrahydropyrimidin-1(2H)-yl)propanamide

[0120] Chemical structure of Compound 7 is:

##STR00015##

[0121] Compound 7 was obtained as a white solid compound and the relevant characterization data are as follows:

[0122] .sup.1H-NMR 400 MHz (MeOD): δ 7.36-7.15 (12H, m), 7.03-6.93 (5H, m), 5.01 (1H, t, J=8.0 Hz), 4.56-4.52 (1H, m), 4.46-4.40 (1H, m), 4.18-4.05 (2H, dd, J=38.0 Hz, J=14.8 Hz), 3.67 (1H, t, J=7.6 Hz), 3.16-3.02 (4H, m), 2.94-2.77 (4H, m), 2.71-2.64 (2H, m), 2.18 (6H, s), 1.72-1.54 (4H, m);

[0123] LRMS(ESI) calcd for C.sub.41H.sub.47FN.sub.4O.sub.5 [M−H]−: 693.3, Found: 693.3.

[0124] Compound 8: (S)-N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexane-2-yl)-2-(2-oxotetrahydropyrimidin-1(2H)-yl)-3-(4-(trifluoromethyl)phenyl)propanamide

[0125] Chemical structure of Compound 8 is:

##STR00016##

[0126] Compound 8 was obtained as a white solid compound and the relevant characterization data are as follows:

[0127] .sup.1H-NMR 400 MHz (MeOD): δ 7.56-7.54 (2H, d, J=8.0 Hz), 7.45-7.43 (2H, d, J=8.0 Hz), 7.37-7.14 (10H, m), 7.03-7.01 (2H, m), 6.97-6.93 (1H, dd, J=8.4 Hz, J=6.4 Hz), 5.12-5.08 (1H, dd, J=8.8 Hz, J=6.8 Hz), 4.61-4.52 (1H, m), 4.49-4.44 (1H, m), 4.18-4.04 (2H, dd, J=36.8 Hz, J=14.8 Hz), 3.68 (1H, t, J=6.8 Hz), 3.18-3.01 (4H, m), 2.94-2.79 (4H, m), 2.68-2.62 (2H, m), 2.18 (6H, s), 1.73-1.54 (4H, m);

[0128] LRMS(ESI) calcd for C.sub.42H.sub.47F.sub.3N.sub.4O.sub.5 [M−H]−: 743.3, Found: 743.3.

[0129] Compound 9: (S)-3-(4-cyanophenyl)-N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexan-2-yl)-2-(2-oxotetrahydropyrimidin-1(2H)-yl)propanamide

[0130] Chemical structure of Compound 9 is:

##STR00017##

[0131] Compound 9 was obtained as a white solid compound and the relevant characterization data are as follows:

[0132] .sup.1H-NMR 400 MHz (MeOD): δ 7.62-7.60 (2H, d, J=8.0 Hz), 7.44-7.42 (2H, d, J=8.0 Hz), 7.36-7.16 (10H, m), 7.03-7.01 (2H, d, J=7.2 Hz), 6.98-6.93 (1H, dd, J=8.4 Hz, J=6.4 Hz), 5.11-5.07 (1 H, dd, J=8.8 Hz, J=7.2 Hz), 4.56-4.53 (1 H, m), 4.48-4.44 (1H, m), 4.21-4.06 (2H, dd, J=38.0 Hz, J=14.8 Hz), 3.66 (1H, t, J=7.6 Hz), 3.18-3.01 (4H, m), 2.93-2.80 (4H, m), 2.68-2.60 (2H, m), 2.18 (6H, s), 1.74-1.54 (4H, m);

[0133] LRMS(ESI) calcd for C.sub.42H.sub.47N.sub.5O.sub.5 [M−H]−: 700.3, Found: 700.3.

[0134] Compound 10: (S)-N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexane-2-yl)-2-(2-oxotetrahydropyrimidin-1(2H)-yl)-3-(thiophen-2-yl)propenamide

[0135] Chemical structure of Compound 10 is:

##STR00018##

[0136] Compound 10 was obtained as a white solid compound and the relevant characterization data are as follows:

[0137] .sup.1H-NMR 400 MHz (MeOD): δ 7.36-7.15 (10H, m) 7.03-7.01 (2H, d, J=7.6 Hz), 6.97-6.89 (3H, m), 4.99-4.94 (1 H, dd, J=8.8 Hz, J=7.2 Hz), 4.55-4.52 (1 H, m), 4.47-4.43 (1 H, m), 4.19-4.15 (1H, d, J=14.8 Hz), 4.10-4.06 (1H, J=14.8 Hz), 3.70 (1H, t, J=7.6 Hz), 3.30-3.24 (2H, m), 3.16-3.00 (4H, m), 2.91-2.89 (2H, d, J=7.6 Hz), 2.85-2.80 (2H, dd, J=14.0 Hz, J=5.6 Hz), 2.72-2.64 (2H, m), 2.19 (6H, s), 1.71-1.57 (4H, m);

[0138] LRMS(ESI) calcd for C.sub.39H.sub.46N.sub.4O.sub.5S [M−H]−: 681.3, Found: 681.3.

[0139] Compound 11: (S)-N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexane-2-yl)-2-(2-oxotetrahydropyrimidin-1(2H)-yl)-3-(thiazol-5-yl)propanamide

[0140] Chemical structure of Compound 11 is:

##STR00019##

[0141] Compound 11 was obtained as a white solid compound and the relevant characterization data are as follows:

[0142] .sup.1H-NMR 400 MHz (MeOD): δ 8.91 (1H, s), 7.37-7.16 (10H, m) 7.03-7.02 (2H, d, J=7.2 Hz), 6.97-6.93 (1H, dd, J=8.4 Hz, J=6.8 Hz), 5.22-5.18 (1H, dd, J=9.6 Hz, J=6.4 Hz), 4.54-4.51 (1H, m), 4.47-4.43 (1H, m), 4.19-4.15 (1H, d, J=14.8 Hz), 4.08-4.04 (1H, J=14.8 Hz), 3.75 (1 H, t, J=8.0 Hz), 3.25-3.22 (1 H, m), 3.15-3.04 (4H, m), 2.95-2.83 (3H, m), 2.73-2.66 (2H, m), 2.19 (6H, s), 1.74-1.55 (5H, m);

[0143] LRMS(ESI) calcd for C.sub.38H.sub.45N.sub.5O.sub.5S [M−H]−: 682.3, Found: 682.3.

[0144] Compound 12: (S)-3-cyclopentyl-N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexan-2-yl)-2-(2-oxotetrahydropyrimidin-1(2-yl)propenamide

[0145] Chemical structure of Compound 12 is:

##STR00020##

[0146] Compound 12 was obtained as a white solid compound and the relevant characterization data are as follows:

[0147] .sup.1H-NMR 400 MHz (MeOD): δ 7.35-7.15 (10H, m), 7.03-7.01 (2H, d, J=7.2 Hz), 6.97-6.93 (1H, dd, J=8.4 Hz, J=6.4 Hz), 5.11-5.07 (1H, dd, J=8.8 Hz, J=7.2 Hz), 4.79-4.76 (1H, m), 4.55-4.51 (1H, m), 4.46-4.41 (1H, m), 4.18-4.07 (2H, dd, J=31.6 Hz, J=14.8 Hz), 3.80 (1H, t, J=7.2 Hz), 3.21-3.17 (2H, m), 3.07-3.01 (1H, m), 2.95-2.93 (2H, d, J=7.6 Hz), 2.86-2.81 (1H, dd, J=13.6 Hz, J=5.6 Hz), 2.78-2.65 (2H, m), 2.19 (6H, s), 1.82-1.79 (2H, m), 1.75-1.47 (12H, m), 1.20-1.12 (2H, m);

[0148] LRMS(ESI) calcd for C.sub.40H.sub.52N.sub.4O.sub.5 [M−H]−: 667.3, Found: 667.3.

[0149] Compound 13: (S)-2-cyclopentyl-N-((2S,4S,5S)-5-(2-(2,6-dimethylphenoxy)acetamido)-4-hydroxy-1,6-diphenylhexan-2-yl)-2-(2-oxotetrahydropyrimidin-1(2-yl)acetamide

[0150] Chemical structure of Compound 13 is:

##STR00021##

[0151] Compound 13 was obtained as a white solid compound and the relevant characterization data are as follows:

[0152] .sup.1H-NMR 400 MHz (MeOD): δ 7.36-7.15 (10H, m), 7.03-7.01 (2H, d, J=7.6 Hz), 6.97-6.93 (1H, dd, J=8.4 Hz, J=6.4 Hz), 4.62-4.56 (1H, m), 4.45-4.39(2H, m), 4.20-4.17 (1H, d, J=14.8 Hz), 4.09-4.05 (1H, J=14.8 Hz), 3.82 (1H, t, J=7.6 Hz), 3.20-3.08 (3H, m), 2.97-2.92 (2H, m), 2.88-2.82 (2H, m), 2.65-2.59 (2H, dd, J=13.6 Hz, J=9.2 Hz), 2.49-2.35 (1H, m), 2.20 (6H, s), 1.80-1.47 (11H, m);

[0153] LRMS(ESI) calcd for C.sub.39H.sub.50N.sub.4O.sub.5 [M−H]−: 653.3, Found: 653.3.

Example 2

Antiviral Activity Evaluation Test

[0154] For the host cells, 1.2×10.sup.4 vero cells (ATCC CCL-81) were seeded into each well of 384-well plates (black, pClear plates). Vero cells were cultured in Opti-PRO™ SFM supplemented with 4 mM L-glutamine and 1× Antibiotic-Antimycotic (Gibco/Thermo Fisher Scientific). Test compounds were added to each well immediately prior to MERS-CoV infection. The final concentration of the test compound was 10 μM, and the DMSO concentration was kept below 0.5%. The compounds prepared in Example 1 were used as test compounds, and Lopinavir, a drug for MERS-CoV, as a positive control.

[0155] Plates containing vero cells and test compounds were transferred into BL-3 medium, and infected with MERS-CoV at an MOI of 0.0625. After 24 hours, Vero cells were fixed with 4% PFA, and immunofluorescence staining was performed to detect virus-infected cells. MERS-CoV infection was observed using a Rabbit anti-MERS-CoV spike antibody, and cell viability was evaluated through Hoechst 33342 staining.

[0156] The EC50 values and CC50 values analyzed and calculated and with GraphPad Prism software are shown in Table 1 below respectively. Here, EC50 (50% efficient concentration) refers to the concentration of a compound that inhibits viral replication by 50%, and the lower the value, the better the compound can inhibit the proliferation of viruses. In addition, CC50 (50% cytotoxicity concentration) refers to the concentration of a compound that kills 50% of the host cells, and higher the value, the lower the toxicity of the compound to the host cells.

[0157] The SI value was calculated by dividing the calculated CC50 value by the EC50 value. SI (selectivity index) indicates the relative effectiveness of a specific compound, and a higher value means that it exhibits maximum antiviral activity with minimum cytotoxicity.

TABLE-US-00001 TABLE 1 Compounds EC50 CC50 SI Positive control [00022] 10.47 >50 4.78 1 [00023] 2.03 >50 21.74 2 [00024] N/D >50 N/D 3 [00025] N/D >50 N/D 4 [00026] 7.66 >50 6.53 5 [00027] 2.79 >50 17.91 6 [00028] 2.06 >50 24.26 7 [00029] 2.09 >50 23.96 8 [00030] 1.22 >50 40.88 9 [00031] 2.59 >50 19.33 10 [00032] 3.32 >50 15.06

[0158] As shown in Table 1 above, Compounds 1 to 10 exhibit effective inhibitory activity against viral proliferation and replication of MERS-CoV while exhibiting minimal toxicity to host cells. In particular, it has been demonstrated that the compounds according to the present invention have higher safety and efficacy compared to the positive control, Lopinavir. This shows that the pharmaceutical composition comprising the compound according to the present invention or a pharmaceutically acceptable salt thereof can be used as a standard treatment for Middle East Respiratory Syndrome, particularly as a single treatment.