MACROCYCLIC PEPTIDOMIMETIC PROTEASE INHIBITOR AND USE THEREOF

Abstract

The present disclosure provides a compound. The compound is a compound shown in formula (1) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the compound shown in formula (1). The compound shown in formula (1) can significantly inhibit M.sup.pro or inhibit coronavirus replication, and has excellent metabolic stability.

##STR00001##

Claims

1. A compound, being a compound shown in formula (I) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the compound shown in formula (I), ##STR00064## L.sub.1 being a linker; L.sub.2 being (CH.sub.2).sub.mCONR.sub.1 or ##STR00065## being C or N; R.sub.1 being H, F, Cl, Br, CN, NO.sub.2, OR.sup.b, NR.sup.cR.sup.d, or C.sub.1-6 alkyl; R.sub.2a and R.sub.2b being each independently H, C(?O)R.sup.a, C(?O)OR.sup.b, S(?O).sub.2R.sup.b, C(?O)NR.sup.cR.sup.d, NC(?O)R.sup.cR.sup.d, OR.sup.b, NR.sup.cR.sup.d, R.sup.bOC.sub.1-4 alkylene, R.sup.dR.sup.cNC.sub.1-4 alkylene, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.1-4 alkylene, heterocyclyl including 3-12 atoms, (heterocyclyl including 3-12 atoms)-C.sub.1-4 alkylene, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-4 alkylene, heteroaryl including 5-10 atoms, or (heteroaryl including 5-10 atoms)-C.sub.1-4 alkylene, C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkyl-C.sub.1-4 alkylene, heterocyclyl including 3-12 atoms, (heterocyclyl including 3-12 atoms)-C.sub.1-4 alkylene, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-4 alkylene, heteroaryl including 5-10 atoms, and (heteroaryl including 5-10 atoms)-C.sub.1-4 alkylene being each independently unsubstituted or substituted with one, two, three, or four substituents, the substituent being independently F, Cl, Br, CN, ?O, OR.sup.b, NR.sup.cR.sup.d, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, R.sup.bOC.sub.1-4 alkylene, or R.sup.dR.sup.cNC.sub.1-4 alkylene, and R.sub.2a and R.sub.2b being not all H; ring A being optionally heterocyclyl including 3-10 atoms or heteroaryl including 5-10 atoms that is substituted with one or more R; Z being cyano, aziridine, epoxypropane, trifluoromethyl ketone, aldehyde, CH(O(C?O)R.sub.3)SO.sub.3Na, CH(O(C?O)OR.sub.3)SO.sub.3Na, CH(O(C?O)NHR.sub.3)SO.sub.3Na, (C?O)(C?O)NHR.sub.3, (C?O)(P?O)(OR.sub.3), (C?O)COOR.sub.3, acetoxymethyl ketone, Michael receptor, or substituted or unsubstituted heterocyclyl including 3-6 atoms or heteroaryl including 5-10 atoms, R.sub.3 being H, F, Cl, Br, CN, NO.sub.2, OR.sup.b, NR.sup.cR.sup.d, S(?O).sub.2R.sup.b, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, C.sub.3-8 cycloalkyl-C.sub.1-4 alkylene, heterocyclyl including 3-12 atoms, (heterocyclyl including 3-12 atoms)-C.sub.1-4 alkylene, C.sub.6-10 aryl, C.sub.6-10 aryl-C.sub.1-4 alkylene, heteroaryl including 5-10 atoms, or (heteroaryl including 5-10 atoms)-C.sub.14 alkylene; m being an integer between 1 and 6; n being 1 or 2; k being 0 or 1; R being independently H, F, Cl, Br, CN, NO.sub.2, ?O, OR.sup.b, NR.sup.cR.sup.d, S(?O).sub.2R.sup.b, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, heterocyclyl including 3-12 atoms, C.sub.6-10 aryl, or heteroaryl including 5-10 atoms, C.sub.3-8 cycloalkyl, heterocyclyl including 3-12 atoms, C.sub.6-10 aryl, or heteroaryl including 5-10 atoms being independently unsubstituted or substituted with one, two, three, or four substituents, and the substituent being independently F, Cl, Br, CN, ?O, OR.sup.b, NR.sup.cR.sup.d, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, R.sup.bOC.sub.1-4 alkylene, or R.sup.dR.sup.cNC.sub.1-4 alkylene; and R.sup.a, R.sup.b, R.sup.c, and R.sup.d being each independently H, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, heterocyclyl including 3-6 atoms, C.sub.6-10 aryl, heteroaryl including 5-10 atoms, or heterocycle including 3-6 atoms that is formed by R.sup.c, R.sup.d, and nitrogen atoms linked to R.sup.c and R.sup.d, C.sub.1-6 alkyl, heterocycle including 3-6 atoms, C.sub.6-10 aryl, and heteroaryl including 5-10 atoms being each independently unsubstituted or substituted with one, two, three, or four substituents, and the substituent being independently F, Cl, CN, OH, NH.sub.2, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.1-6 alkoxy, or C.sub.1-6 alkylamino.

2. The compound according to claim 1, wherein the compound is a compound shown in formula (II) or formula (III) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the compound shown in formula (II) or formula (III), ##STR00066##

3. The compound according to claim 1, wherein the compound is a compound shown in formula (IV) or formula (V) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the compound shown in formula (IV) or formula (V), ##STR00067##

4. The compound according to claim 1, wherein the compound is a compound shown in formula (VI) or formula (VII) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the compound shown in formula (VI) or formula (VII), ##STR00068##

5. The compound according to claim 1, wherein the compound is a compound shown in formula (VIII) or formula (IX) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the compound shown in formula (VIII) or formula (IX) ##STR00069##

6. The compound according to claim 1, wherein the compound is a compound shown in formula (X) or formula (XI) or a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the compound shown in formula (X) or formula (XI), ##STR00070##

7. The compound according to claim 1, wherein L.sub.1 is a chain linker, and an atomic number of a main chain of the chain linker is 5, 6, 7, 8, 9, or 10, preferably, the atomic number of the main chain of the chain linker is 6.

8. The compound according to claim 1, wherein L.sub.1 is optionally substituted R.sub.e, R.sub.eCH(OH)R.sub.f, R.sub.eC(?O)R.sub.f, R.sub.eC(?O)OR.sub.f, R.sub.eOC(?O)R.sub.f, R.sub.eC(?O)SR.sub.f, R.sub.eSC(?O)R.sub.f, R.sub.eC(?O)N(R.sub.g)R.sub.f, R.sub.eN(R.sub.g)C(?O)R.sub.f, R.sub.eS(?O).sub.2N(R.sub.g)R.sub.f, R.sub.eN(R.sub.g)S(?O).sub.2R.sub.f, R.sub.eN(R.sub.g)C(?O)OR.sub.f, R.sub.eOC(?O)N(R.sub.g)R.sub.f, R.sub.eOR.sub.f, R.sub.eNR.sub.f, R.sub.eN?R.sub.f, R.sub.eOOR.sub.f, R.sub.eSR.sub.f, R.sub.eSSR.sub.f, R.sub.eSSSR.sub.f, R.sub.eR.sub.hR.sub.f, or R.sub.eOR.sub.hR.sub.f, R.sub.g being H or substituted or unsubstituted alkyl, R.sub.e being (CH.sub.2).sub.t1, C.sub.3-C.sub.30 branched alkylene, C.sub.2-C.sub.30 straight-chain alkenylene, C.sub.3-C.sub.30 branched alkenylene, C.sub.2-C.sub.30 straight-chain alkynylene, or C.sub.3-C.sub.30 branched alkynylene or bond, R.sub.f being (CH.sub.2).sub.t2, C.sub.3-C.sub.30 branched alkylene, C.sub.2-C.sub.30 straight-chain alkenylene, C.sub.3-C.sub.30 branched alkenylene, C.sub.2-C.sub.30 straight-chain alkynylene, or C.sub.3-C.sub.30 branched alkynylene or bond, R.sub.h being C.sub.3-8 cycloalkyl, heterocyclyl including 3-12 atoms, C.sub.6-10 aryl, or heteroaryl including 5-10 atoms, and t1 and t2 being independently integers not less than 1.

9. The compound according to claim 1, wherein L.sub.1 is optionally substituted R.sub.e, R.sub.eS(?O).sub.2N(R.sub.g)R.sub.f, R.sub.eN(R.sub.g)S(?O).sub.2R.sub.f, R.sub.eOR.sub.f, R.sub.eNR.sub.f, R.sub.eN?R.sub.f, R.sub.eR.sub.hR.sub.f, or R.sub.eOR.sub.hR.sub.f, R.sub.g being H or substituted or unsubstituted alkyl, R.sub.e being (CH.sub.2).sub.t1, C.sub.3-C.sub.30 branched alkylene, C.sub.2-C.sub.30 straight-chain alkenylene, C.sub.3-C.sub.30 branched alkenylene, C.sub.2-C.sub.30 straight-chain alkynylene, or C.sub.3-C.sub.30 branched alkynylene or bond, R.sub.f being (CH.sub.2).sub.t2, C.sub.3-C.sub.30 branched alkylene, C.sub.2-C.sub.30 straight-chain alkenylene, C.sub.3-C.sub.30 branched alkenylene, C.sub.2-C.sub.30 straight-chain alkynylene, or C.sub.3-C.sub.30 branched alkynylene or bond, R.sub.h being C.sub.3-8 cycloalkyl, heterocyclyl including 3-12 atoms, C.sub.6-10 aryl, or heteroaryl including 5-10 atoms, and t1 and t2 being independently integers not less than 1.

10. The compound according to claim 8, wherein the substituent is F, Cl, Br, CN, NO.sub.2, ?O, OR.sup.b, NR.sup.cR.sup.d, S(?O).sub.2R.sup.b, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, heterocyclyl including 3-12 atoms, C.sub.6-10 aryl, or heteroaryl including 5-10 atoms.

11. The compound according to claim 9, wherein the substituent is F, Cl, Br, CN, NO.sub.2, ?O, OR.sup.b, NRR.sup.d, S(?O).sub.2R.sup.b, C.sub.1-6 alkyl, C.sub.1-6 haloalkyl, C.sub.3-8 cycloalkyl, C.sub.3-8 cycloalkenyl, heterocyclyl including 3-12 atoms, C.sub.6-10 aryl, or heteroaryl including 5-10 atoms.

12. The compound according to claim 1, wherein: R.sub.2a and R.sub.2b are each independently H, OR.sup.b, or NC(?O)R.sup.cR.sup.d, and R.sub.2a and R.sub.2b are not all H; the ring A is optionally heterocyclyl including 5-10 atoms that is substituted with one or more R; Z is cyano; m is 1; and/or R is independently F, Cl, Br, C.sub.1-6 alkyl, or C.sub.1-6 haloalkyl.

13. The compound according to claim 1, wherein the compound is of the following structures or is a stereoisomer, a tautomer, a nitrogen oxide, a solvate, a metabolite, a pharmaceutically acceptable salt, or a prodrug of the following structures, ##STR00071## ##STR00072## ##STR00073## ##STR00074## ##STR00075## ##STR00076## ##STR00077## ##STR00078## ##STR00079## ##STR00080## ##STR00081## ##STR00082## ##STR00083## ##STR00084## ##STR00085## ##STR00086## ##STR00087## ##STR00088##

14. A pharmaceutical composition, comprising an effective amount of the compound according to claim 1.

15. The pharmaceutical composition according to claim 14, further comprising a pharmaceutically acceptable carrier, an adjuvant, a medium, or a combination thereof.

16. The pharmaceutical composition according to claim 14, further comprising one or more therapeutic agents, the therapeutic agent being at least one of other drugs against coronaviruses and drugs suppressing cytokine storms.

17. A method of using the compound according to claim 1 in preparation of drugs, the drugs being used for preventing coronavirus infection or treating or reducing associated diseases of patients caused by coronavirus infection, and/or the drugs being used for inhibiting M.sup.Pro or inhibiting coronavirus replication.

18. The method according to claim 17, wherein the coronavirus comprises at least one of HCOV-229E, HCoV-OC43, HCoV-NL63, HCoV-HKU1, SARS-COV, 2019-nCOV, and MERS-Cov.

19. A method for preventing coronavirus infection or treating or reducing associated diseases of patients caused by coronavirus infection, comprising administering to a subject a pharmaceutically acceptable dose of the compound according to claim 1.

20. A method for inhibiting M.sup.Pro or inhibiting coronavirus replication, comprising contacting M.sup.pro or the coronavirus with the compound according to claim 1.

Description

DESCRIPTION OF EMBODIMENTS

[0254] The following examples are intended to illustrate various embodiments of the present disclosure, but are not intended to limit the scope of the present disclosure.

Preparation Examples

[0255] In the following preparation examples, the preparation processes of the compounds of the present disclosure are described in detail by using some of the compounds of the present disclosure as examples.

Example 1

Synthesis of N-((3S, 15S, 18aS, 19aR, 19bS)-3-cyano-19,19-dimethyl-1,6,16-trioxyeicosanylhydro-2H-cyclopropyl[3,4]pyrrole[1,2-a][1,4, 9]triazocyclooctadecyl-15-yl)-2,2,2-trifluoroacetamide (compound 1)

[0256] ##STR00039## ##STR00040## ##STR00041##

Step 1

[0257] A compound 1-1 (2.0 g, 7.66 mmol) and a compound 1-2 (716 mg, 8.43 mmol) were dissolved in dichloromethane (30 mL), and DIEA (2.96 g, 22.98 mmol), HOBT (1.34 g, 9.96 mmol), and EDCI (1.9 g, 9.96 mmol) were added, to react at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was purified by SGC (PE:EA=2:1) to obtain a colorless oily compound 1-3 (1.3 g, yield: 52%). LCMS (M+Na).sup.+=351.2.

Step 2

[0258] The compound 1-3 (330 mg, 1 mmol) was dissolved in methanol (1 mL), a 4M hydrochloric acid methanol solution (2.5 mL, 10 mmol) was added at zero degrees to react for 2 h, and concentrated to remove the solvent, to obtain a colorless oily compound 1-4 (230 mg, yield: 100%). LCMS (M+H).sup.+=229.3.

Step 3

[0259] A compound 1-5 (3 g, 13.1 mmol), a compound 1-6 (2.43 g, 14.4 mmol), and DIEA (5.07 g, 39.3 mmol) were dissolved in DMF (30 mL), and HATU (6.47 g, 17.03 mmol) was added, to react at room temperature overnight. The reaction was quenched with water at zero degree, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was purified by SGC (PE:EA=2:1) to obtain a colorless oily compound 1-7 (3 g, yield: 60.2%). LCMS (M+Na).sup.+=381.3.

Step 4

[0260] The compound 1-7 (380 mg, 1 mmol) was dissolved in THF (10 mL) and added dropwise at zero degrees in LiOH (72 mg, 3 mmol) dissolved in water to react at room temperature for 2 h, adjusted with 1M hydrochloric acid to pH 4-5, extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a colorless oily compound 1-8 (300 mg, yield: 79%). LCMS (M+Na).sup.+=389.3.

Step 5

[0261] The compound 1-8 (180 mg, 0.49 mmol) and the compound 1-4 (123 mg, 0.54 mmol) were dissolved in a mixed solvent of dichloromethane (5 mL) and DMF (5 mL), and DIEA (190 mg, 0.42 mmol), HOBT (105 mg, 0.64 mmol), and EDCI (122 mg, 0.64 mmol) were added, to react at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was purified by SGC (PE:EA=2:1) to obtain a colorless oily compound 1-9 (160 mg, yield: 57%). LCMS (M+H).sup.+=577.2.

Step 6

[0262] The compound 1-9 (110 mg, 0.19 mmol) was dissolved in dichloromethane (110 mL), and the Grubbs 2.sup.nd catalyst (16 mg, 0.02 mmol) was added, to react at room temperature overnight. 1 mL of ethyl vinyl ether was added at zero degrees and stirred for 1 h for quenching. The reaction solution was filtered and concentrated to remove the solvent, to obtain a colorless oily compound 1-10a&b (90 mg, yield: 86%). LCMS (M+H).sup.+=549.4.

Step 7

[0263] The compound 1-10a&b (90 mg, 0.16 mmol) was dissolved in ethanol (20 mL), PtO.sub.2 (18 mg, 0.08 mmol) was added, and hydrogen substitution was carried out three times, to react at room temperature for 0.5 h. The reaction solution was filtered and concentrated to remove the solvent, to obtain a colorless oily compound 1-11 (75 mg, yield: 85%). LCMS (M+H).sup.+=551.3.

Step 8

[0264] The compound 1-11 (75 mg, 0.14 mmol) was dissolved in 7M ammonia in methanol (20 mL), to react in a sealed tube at room temperature for 24 h. The reaction solution was concentrated to remove the solvent, to obtain a colorless oily compound 1-12 (70 mg, yield: 93%). LCMS (M+H).sup.+=536.4.

Step 9

[0265] The compound 1-12 (15 mg, 0.03 mmol) was dissolved in DCM (5 mL), and added dropwise in TFA (0.5 mL) in an ice-water bath. The reaction solution reacted at zero degrees for 3 h. The reaction solution was concentrated to remove the solvent, to obtain a colorless oily compound 1-13 (10 mg, yield: 77%). LCMS (M+H).sup.+=436.3.

Step 10

[0266] The compound 1-13 (10 mg, 0.02 mmol) was dissolved in THF (10 mL), and added dropwise in pyridine (16 mg, 0.2 mmol) in an ice-water bath. TFAA (13 mg, 0.06 mmol) was added dropwise after stirring in the ice-water bath for 15 min. The reaction solution reacted at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was subjected to Prep-HPLC to obtain a white solid compound 1 (7.2 mg, yield: 70%). LCMS (M+H).sup.+=514.3. 1H NMR (400 MHz, DMSO) ? 9.60 (d, J=6 Hz, 1H), 9.04 (d, J=8.8 Hz, 1H), 7.60 (dd, J=3.6 Hz, 7.6 Hz, 1H), 5.00-4.94 (m, 1H), 4.40-4.35 (m, 1H), 4.14 (s, 1H), 3.87-3.83 (m, 1H), 3.75 (d, J=10 Hz, 1H), 3.40-3.36 (m, 1H), 2.81-2.78 (m, 1H), 2.24-2.04 (m, 4H), 1.83-1.80 (m, 2H), 1.57 (dd, J=5.2 Hz, 7.6 Hz, 1H), 1.46-1.41 (m, 2H), 1.34-1.23 (m, 9H), 1.02 (s, 3H), 0.91 (s, 3H).

Example 2

Synthesis of N-((3S, 15S, 18aS, 19aR, 19bS)-3-cyano-7,19,19-trimethyl-1,6,16-trioxyeicosanylhydro-2H-cyclopropyl[3,4]pyrrole[1,2-a][1,4,9]triazocyclooctadecene-15-yl)-2,2,2-trifluoroacetamide (compound 2)

[0267] ##STR00042## ##STR00043## ##STR00044##

Step 1

[0268] A compound 2-1 (2.0 g, 16.5 mmol) and TEA (3.56 g, 33.0 mmol) were dissolved in dichloromethane (30 mL), and (Boc).sub.2O (3.6 g, 22.98 mmol) was added dropwise at 0? C., to react at room temperature for 8 h. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a colorless oily compound 2-2 (1.6 g, yield: 52%). LCMS (M+Na).sup.+=186.2.

Step 2

[0269] The compound 2-2 (1.6 g, 8.6 mmol) was dissolved in THF (30 mL), and NaH (516 mg, 12.9 mmol) was added in batches at 0? C. CH.sub.3I (6.1 g, 43 mmol) was added dropwise after stirring for 0.5 h, to react at 50? C. for 2 h. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was purified by SGC (DCM:MeOH=50:1) to obtain a colorless oily compound 2-3 (1.6 g, yield: 93%). LCMS (M+Na).sup.+=200.2.

Step 3

[0270] The compound 2-3 (1.6 g, 8.0 mmol) was dissolved in EA (10 mL), a 4M hydrochloric acid ethyl acetate solution (20 mL) was added at zero degrees to react for 2 h, and concentrated to remove the solvent, to obtain a colorless oily compound 2-4 (800 mg, yield: 100%). LCMS (M+H).sup.+=100.3.

Step 4

[0271] The compound 2-4 (800 mg, 8.0 mmol) and a compound 2-5 (2.1 g, 8.0 mmol) were dissolved in dichloromethane (25 mL), and DIEA (5.2 g, 40 mmol), HOBT (1.3 g, 10.0 mmol), and EDCI (1.9 g, 10.0 mmol) were added, to react at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was purified by SGC (PE:EA=2:1) to obtain a colorless oily compound 2-6 (1.4 g, yield: 52%). LCMS (M+Na).sup.+=343.1.

Step 5

[0272] The compound 2-6 (1.4 g, 4.1 mmol) was dissolved in EA (10 mL), a 4M hydrochloric acid ethyl acetate solution (20 mL) was added at zero degrees to react for 2 h, and concentrated to remove the solvent, to obtain a colorless oily compound 2-7 (990 mg, yield: 100%). LCMS (M+H).sup.+=243.3.

Step 6

[0273] A compound 2-8 (3 g, 13.1 mmol), a compound 2-9 (2.43 g, 14.4 mmol), and DIEA (5.07 g, 39.3 mmol) were dissolved in DMF (30 mL), and HATU (6.47 g, 17.03 mmol) was added, to react at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was purified by SGC (PE:EA=2:1) to obtain a colorless oily compound 2-10 (3 g, yield: 60.2%). LCMS (M+Na)+=381.3.

Step 7

[0274] The compound 2-10 (3.3 g, 7.9 mmol) was dissolved in THF (20 mL) and added dropwise at zero degrees in LiOH (569 mg, 23.7 mmol) dissolved in water to react at room temperature for 2 h, adjusted with 1M hydrochloric acid to pH 4-5, extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a colorless oily compound 2-11 (3.2 g, yield: 100%). LCMS (M+Na).sup.+=367.2.

Step 8

[0275] The compound 2-11 (450 mg, 1.2 mmol) and the compound 2-7 (300 mg, 1.2 mmol) were dissolved in a mixed solvent of dichloromethane (5 mL) and DMF (5 mL), and DIEA (464 mg, 3.6 mmol), HOBT (195 mg, 1.2 mmol), and EDCI (267 mg, 1.4 mmol) were added, to react at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was purified by SGC (PE:EA=2:1) to obtain a colorless oily compound 2-12 (350 mg, yield: 49%). LCMS (M+Na).sup.+=591.2.

Step 9

[0276] The compound 2-12 (300 mg, 0.51 mmol) was dissolved in dichloromethane (100 mL), and the Grubbs 2.sup.nd catalyst (16 mg, 0.05 mmol) was added, to react at room temperature overnight. 2 mL of ethyl vinyl ether was added at zero degrees and stirred for 1 h for quenching. The reaction solution was filtered and concentrated to remove the solvent, to obtain a colorless oily compound 1-13a&b (290 mg, yield: 94%). LCMS (M+H).sup.+=563.4.

Step 10

[0277] The compound 2-13a&b (100 mg, 0.18 mmol) was dissolved in ethanol (20 mL), PtO.sub.2 (18 mg, 0.08 mmol) was added, and hydrogen substitution was carried out three times, to react at room temperature for 0.5 h. The reaction solution was filtered and concentrated to remove the solvent, to obtain a colorless oily compound 2-14 (90 mg, yield: 89%). LCMS (M+H).sup.+=565.3.

Step 11

[0278] The compound 2-14 (90 mg, 0.14 mmol) was dissolved in 7M ammonia in methanol (20 mL), to react in a sealed tube at room temperature for 24 h. The reaction solution was concentrated to remove the solvent, to obtain a colorless oily compound 2-15 (75 mg, yield: 97%). LCMS (M+H).sup.+=550.4.

Step 12

[0279] The compound 2-15 (35 mg, 0.06 mmol) was dissolved in DCM (5 mL), and added dropwise in TFA (0.5 mL) in an ice-water bath. The reaction solution reacted at zero degrees for 3 h. The reaction solution was concentrated to remove the solvent, to obtain a colorless oily compound 2-16 (20 mg, yield: 70%). LCMS (M+H).sup.+=450.3.

Step 13

[0280] The compound 2-16 (20 mg, 0.04 mmol) was dissolved in THF (10 mL), and added dropwise in pyridine (16 mg, 0.2 mmol) in an ice-water bath. TFAA (13 mg, 0.06 mmol) was added dropwise after stirring in the ice-water bath for 15 min. The reaction solution reacted at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was subjected to Prep-HPLC to obtain a white solid compound 2 (7.2 mg, yield: 70%).

[0281] LCMS (M+H).sup.+=528.3. 1H NMR (400 MHz, DMSO) ? 9.71 (d, J=4 Hz, 1H), 8.90 (d, J=4.8 Hz, 1H), 4.97-4.92 (m, 1H), 4.42-4.34 (m, 1H), 4.17-4.15 (m, 1H), 4.13 (s, 1H), 3.86-3.78 (m, 2H), 2.81 (s, 3H), 2.58-2.54 (m, 2H), 2.41-2.33 (m, 2H), 2.17-2.03 (m, 1H), 1.85-1.75 (m, 2H), 1.57-1.54 (m, 1H), 1.48-1.19 (m, 5H), 1.14-1.10 (m, 6H), 1.02 (s, 3H), 0.92 (s, 3H).

Example 3

Synthesis of N-((11S, 14S, 15R, 3S, 13S)-13-cyano-16,16-dimethyl-2,10,15-trioxo-13,9,14-triaza-1(3,4)-bicyclo[3.1.0]hexane-4(1,3)-benzocyclopentane-3-yl)-2,2,2-trifluoroacetamide (compound 3)

[0282] ##STR00045## ##STR00046## ##STR00047##

Step 1

[0283] A compound 3-1 (400 mg, 1.2 mmol) and a compound 3-2 (245 mg, 1.2 mmol) were dissolved in dichloromethane (15 mL), and DIEA (497 mg, 3.6 mmol) and HATU (532 mg, 1.4 mmol) were added, to react at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was purified by SGC (PE:EA=2:1) to obtain a colorless oily compound 3-3 (350 mg, yield: 61%). LCMS (M+H).sup.+=481.2.

Step 2

[0284] The compound 3-3 (300 mg, 0.6 mmol) was dissolved in dioxane (3 mL) and water (1 mL). Potassium carbonate (166 mg, 1.2 mmol) and a compound 3-4 (65 mg, 0.9 mmol) were added. The catalyst Pd(dppf)Cl.sub.2 (44 mg, 0.06 mmol) was added in a nitrogen atmosphere. The system was subjected to nitrogen displacement three times, heated to 100? C. and stirred to react overnight, and concentrated to remove most of the solvent. Ethyl acetate was redissolved. The organic phase was washed with water, washed with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was purified by SGC (PE:EA=2:1) to obtain a white solid compound 3-5 (250 mg, yield: 94%). LCMS (M+H).sup.+=429.1.

Step 3

[0285] The compound 3-5 (250 mg, 0.58 mmol) was dissolved in THF (3 mL) and water (3 mL), and lithium hydroxide (43 mg, 1.8 mmol) was added and stirred at room temperature to react for 1 h, adjusted with 1M dilute hydrochloric acid to weak acidity, and extracted with ethyl acetate. The organic phase was backwashed with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a white solid compound 3-6 (240 mg, yield: 99%). LCMS (M+H).sup.+=415.2.

Step 4

[0286] The compound 3-6 (240 mg, 0.58 mmol) and the compound 1-4 (123 mg, 0.58 mmol) were dissolved in a mixed solvent of dichloromethane (5 mL) and DMF (5 mL), and DIEA (374 mg, 2.9 mmol), HOBT (115 mg, 0.70 mmol), and EDCI (134 mg, 0.70 mmol) were added, to react at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was purified by SGC (PE:EA=2:1) to obtain a colorless oily compound 3-7 (240 mg, yield: 68%). LCMS (M+Na).sup.+=611.2.

Step 5

[0287] The compound 3-7 (240 mg, 0.39 mmol) was dissolved in dichloromethane (110 mL), and the Grubbs 2.sup.nd catalyst (16 mg, 0.02 mmol) was added, to react at room temperature overnight. 3 mL of ethyl vinyl ether was added at zero degrees and stirred for 1 h for quenching. The reaction solution was filtered and concentrated to remove the solvent, to obtain a colorless oily compound 1-8a&b (45 mg, yield: 20%). LCMS (M+H).sup.+=583.4.

Step 6

[0288] The compound 3-8a&b (45 mg, 0.07 mmol) was dissolved in ethanol (20 mL), PtO.sub.2 (18 mg, 0.08 mmol) was added, and hydrogen substitution was carried out three times, to react at room temperature for 0.5 h. The reaction solution was filtered and concentrated to remove the solvent, to obtain a colorless oily compound 3-9 (33 mg, yield: 73%). LCMS (M+H).sup.+=585.3.

Step 7

[0289] The compound 3-9 (33 mg, 0.06 mmol) was dissolved in 7M ammonia in methanol (20 mL), to react in a sealed tube at room temperature for 24 h. The reaction solution was concentrated to remove the solvent, to obtain a colorless oily compound 3-10 (22 mg, yield: 68%). LCMS (M+H).sup.+=570.4.

Step 8

[0290] The compound 3-10 (22 mg, 0.04 mmol) was dissolved in DCM (5 mL), and added dropwise in TFA (0.5 mL) in an ice-water bath. The reaction solution reacted at zero degrees for 3 h. The reaction solution was concentrated to remove the solvent, to obtain a colorless oily compound 3-11 (18 mg, yield: 100%). LCMS (M+H).sup.+=470.3.

Step 9

[0291] The compound 3-11 (18 mg, 0.05 mmol) was dissolved in THF (10 mL), and added dropwise in pyridine (16 mg, 0.2 mmol) in an ice-water bath. TFAA (13 mg, 0.06 mmol) was added dropwise after stirring in the ice-water bath for 15 min. The reaction solution reacted at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was subjected to Prep-HPLC to obtain a white solid compound 3 (10.5 mg, yield: 50%).

[0292] LCMS (M+H).sup.+=548.1. 1H NMR (400 MHz, DMSO) ? 9.89 (d, J=5.9 Hz, 1H), 9.11 (d, J=8.9 Hz, 1H), 7.66 (t, J=5.4 Hz, 1H), 7.31-7.23 (m, 2H), 7.21 (s, 1H), 7.15 (d, J=6.4 Hz, 1H), 5.57 (d, J=5.9 Hz, 1H), 4.94 (dd, J=15.5, 8.2 Hz, 1H), 4.23 (s, 1H), 3.74 (d, J=10.5 Hz, 1H), 3.35-3.23 (m, 2H), 2.88 (d, J=8.2 Hz, 1H), 2.39-2.20 (m, 2H), 2.13 (dd, J=13.7, 7.0 Hz, 2H), 1.85-1.75 (m, 1H), 1.67-1.31 (m, 6H), 1.26 (d, J=7.6 Hz, 1H), 1.02 (s, 3H), 1.00 (s, 3H).

Example 4

Synthesis of N-((3S, 15S, 18aS, 19aR, 19bS, Z)-3-cyano-19,19-dimethyl-1,6,16-trioxo-1,3,4,5,6,7,8,9,10,13,14,15,16,18,18a,19,19a,19b-octadec ahydro-2H-cyclopropane[3,4]pyrrole[1,2-a][1,4,9]triazacyclooctadecene-15-yl)-2,2,2-trifluoroaceta mide (compound 4)

[0293] ##STR00048## ##STR00049##

Step 1

[0294] The compound 1-10a&b (75 mg, 0.14 mmol) was dissolved in 7M ammonia in methanol (20 mL), to react in a sealed tube at room temperature for 24 h. The reaction solution was concentrated to remove the solvent, to obtain colorless oily compounds 4-2a and 4-2b (70 mg, yield: 93%). LCMS (M+H).sup.+=534.3.

Step 2

[0295] The compounds 4-2a and 4-2b (30 mg, 0.06 mmol) were dissolved in DCM (5 mL), and added dropwise in TFA (0.5 mL) in an ice-water bath. The reaction solution reacted at zero degrees for 3 h. The reaction solution was concentrated to remove the solvent, to obtain colorless oily compounds 4-3a and 4-3b (20 mg, yield: 77%). LCMS (M+H).sup.+=434.3.

Step 3

[0296] The compounds 4-3a and 4-3b (20 mg, 0.05 mmol) were dissolved in THF (10 mL), and added dropwise in pyridine (32 mg, 0.4 mmol) in an ice-water bath. TFAA (26 mg, 0.12 mmol) was added dropwise after stirring in the ice-water bath for 15 min. The reaction solution reacted at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was subjected to Prep-HPLC to obtain a white solid compound 4 (13 mg, yield: 51%).

[0297] LCMS (M+H).sup.+=512.3. 1H NMR (400 MHz, DMSO) ? 9.67 (d, J=5.6 Hz, 1H), 9.06 (d, J=8.8 Hz, 1H), 7.08 (dd, J=4.8 Hz, 6.4 Hz, 1H), 5.42-5.22 (m, 2H), 4.91-4.82 (m, 1H), 4.45-4.40 (m, 1H), 4.14 (s, 1H), 3.88-3.84 (m, 1H), 3.79 (d, J=11.2 Hz, 1H), 3.41-3.36 (m, 1H), 3.33-3.31 (m, 1H), 2.36-2.24 (m, 3H), 2.17-2.10 (m, 2H), 1.89-1.59 (m, 7H), 1.36 (d, J=5.4 Hz, 1H), 1.24-1.22 (m, 1H), 1.24 (s, 3H), 0.95 (s, 3H).

Example 5

Synthesis of N-((3S, 15S, 18aS, 19aR, 19bS, E/Z)-3-cyano-7.19,19-trimethyl-1,6,16-trioxo-1,3,4,5,6,7,8,9,10,13,14,15,16,18,18a,19,19a,19b-oct adecahydro-2H-cyclopropane[3,4]pyrrole[1,2-a][1,4,9]triazacyclooctadecene-15-yl)-2,2,2-trifluoroa cetamide (compounds 5a and 5b)

[0298] ##STR00050## ##STR00051##

Step 1

[0299] The compounds 2-13a and 2-13b (100 mg, 0.18 mmol) were dissolved in 7M ammonia in methanol (20 mL), to react in a sealed tube at 35? C. for 24 h. The reaction solution was concentrated to remove the solvent, to obtain colorless oily compounds 5-2a and 5-2b (50 mg, yield: 50%). LCMS (M+H).sup.+=548.4.

Step 2

[0300] The compounds 5-2a and 5-2b (50 mg, 0.09 mmol) were dissolved in DCM (5 mL), and added dropwise in TFA (0.5 mL) in an ice-water bath. The reaction solution reacted at zero degrees for 3 h. The reaction solution was concentrated to remove the solvent, to obtain colorless oily compounds 5-3a and 5-3b (40 mg, yield: 98%). LCMS (M+H).sup.+=448.3.

Step 3

[0301] The compounds 5-3a and 5-3b (40 mg, 0.09 mmol) were dissolved in THF (10 mL), and added dropwise in pyridine (16 mg, 0.2 mmol) in an ice-water bath. TFAA (13 mg, 0.06 mmol) was added dropwise after stirring in the ice-water bath for 15 min. The reaction solution reacted at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was subjected to Prep-HPLC to obtain white solid compounds 5a (15 mg, yield: 32%) and 5b (3.5 mg, yield: 7%). LCMS (M+H).sup.+=526.3.

[0302] 5a or 5b: .sup.1H NMR (400 MHz, DMSO) ? 9.68 (d, J=5.5 Hz, 1H), 8.94 (d, J=9.2 Hz, 1H), 5.37 (d, J=6.5 Hz, 2H), 4.92 (t, J=9.7 Hz, 1H), 4.35 (dd, J=13.1, 6.7 Hz, 1H), 4.22-4.07 (m, 2H), 3.89-3.73 (m, 2H), 3.12 (d, J=60.7 Hz, 1H), 2.85 (s, 2H), 2.75 (s, 1H), 2.38-2.22 (m, 2H), 2.14 (d, J=20.8 Hz, 2H), 1.75 (dd, J=26.7, 21.7 Hz, 2H), 1.62 (d, J=6.5 Hz, 2H), 1.56 (dd, J=13.1, 8.5 Hz, 2H), 1.34 (d, J=9.1 Hz, 2H), 1.24 (s, 2H), 0.95 (s, 3H), 0.89 (s, 3H).

[0303] 5b or 5a: .sup.1H NMR (400 MHz, DMSO) ? 9.80-9.45 (m, 1H), 9.14-8.85 (m, 1H), 5.34 (s, 2H), 4.99-4.80 (m, 1H), 4.41 (dd, J=14.6, 8.4 Hz, 1H), 4.20 (t, J=23.9 Hz, 2H), 3.97-3.83 (m, 1H), 3.79 (d, J=10.1 Hz, 2H), 2.79 (d, J=5.7 Hz, 3H), 2.33 (s, 2H), 2.04 (d, J=42.2 Hz, 4H), 1.77 (dd, J=46.6, 17.2 Hz, 4H), 1.63-1.33 (m, 4H), 1.10-1.02 (s, 3H), 0.89 (s, 3H).

[0304] Note: The NMR data above indicates that when the compound 5a is NMR-characterized as .sup.1H NMR (400 MHz, DMSO) ? 9.68 (d, J=5.5 Hz, 1H), 8.94 (d, J=9.2 Hz, 1H), 5.37 (d, J=6.5 Hz, 2H), 4.92 (t, J=9.7 Hz, 1H), 4.35 (dd, J=13.1, 6.7 Hz, 1H), 4.22-4.07 (m, 2H), 3.89-3.73 (m, 2H), 3.12 (d, J=60.7 Hz, 1H), 2.85 (s, 2H), 2.75 (s, 1H), 2.38-2.22 (m, 2H), 2.14 (d, J=20.8 Hz, 2H), 1.75 (dd, J=26.7, 21.7 Hz, 2H), 1.62 (d, J=6.5 Hz, 2H), 1.56 (dd, J=13.1, 8.5 Hz, 2H), 1.34 (d, J=9.1 Hz, 2H), 1.24 (s, 2H), 0.95 (s, 3H), 0.89 (s, 3H), the compound 5b is NMR-characterized as .sup.1H NMR (400 MHz, DMSO) ? 9.80-9.45 (m, 1H), 9.14-8.85 (m, 1H), 5.34 (s, 2H), 4.99-4.80 (m, 1H), 4.41 (dd, J=14.6, 8.4 Hz, 1H), 4.20 (t, J=23.9 Hz, 2H), 3.97-3.83 (m, 1H), 3.79 (d, J=10.1 Hz, 2H), 2.79 (d, J=5.7 Hz, 3H), 2.33 (s, 2H), 2.04 (d, J=42.2 Hz, 4H), 1.77 (dd, J=46.6, 17.2 Hz, 4H), 1.63-1.33 (m, 4H), 1.10-1.02 (s, 3H), 0.89 (s, 3H); or

[0305] when the compound 5a is NMR-characterized as .sup.1H NMR (400 MHz, DMSO) ? 9.80-9.45 (m, 1H), 9.14-8.85 (m, 1H), 5.34 (s, 2H), 4.99-4.80 (m, 1H), 4.41 (dd, J=14.6, 8.4 Hz, 1H), 4.20 (t, J=23.9 Hz, 2H), 3.97-3.83 (m, 1H), 3.79 (d, J=10.1 Hz, 2H), 2.79 (d, J=5.7 Hz, 3H), 2.33 (s, 2H), 2.04 (d, J=42.2 Hz, 4H), 1.77 (dd, J=46.6, 17.2 Hz, 4H), 1.63-1.33 (m, 4H), 1.10-1.02 (s, 3H), 0.89 (s, 3H), the compound 5b is NMR-characterized as .sup.1H NMR (400 MHz, DMSO) ? 9.68 (d, J=5.5 Hz, 1H), 8.94 (d, J=9.2 Hz, 1H), 5.37 (d, J=6.5 Hz, 2H), 4.92 (t, J=9.7 Hz, 1H), 4.35 (dd, J=13.1, 6.7 Hz, 1H), 4.22-4.07 (m, 2H), 3.89-3.73 (m, 2H), 3.12 (d, J=60.7 Hz, 1H), 2.85 (s, 2H), 2.75 (s, 1H), 2.38-2.22 (m, 2H), 2.14 (d, J=20.8 Hz, 2H), 1.75 (dd, J=26.7, 21.7 Hz, 2H), 1.62 (d, J=6.5 Hz, 2H), 1.56 (dd, J=13.1, 8.5 Hz, 2H), 1.34 (d, J=9.1 Hz, 2H), 1.24 (s, 2H), 0.95 (s, 3H), 0.89 (s, 3H).

Example 6

Synthesis of N-((3S, 16S, 19aS, 20aR, 20bS)-3-cyano-20,20-dimethyl-1,6,17-trioxydocosanylhydrocyclopropa[3,4]pyrrole[1,2-a][1,4,9]tri azacyclononanedioic acid-16-yl)-2,2,2-trifluoroacetamide (compound 6)

[0306] ##STR00052## ##STR00053##

Step 1

[0307] A compound 6-1 (650 mg, 2.67 mmol) and a compound 6-2 (460 mg, 2.67 mmol) were dissolved in DMF (10 mL), and HATU (1.52 g, 4.01 mmol) and TEA (540 mg, 5.35 mmol) were added. The reaction system reacted at room temperature under nitrogen protection for 1 h. The reaction system was quenched with water and extracted with ethyl acetate (60 mL). The organic phase was washed with water (50 mL?3), dried with anhydrous sodium sulfate, and spin-dried to obtain a light-yellow colloidal compound 6-3 (1.2 g, crude product). LCMS (M+H).sup.+=395.4.

Step 2

[0308] The compound 6-3 (1.1 g, 2.79 mmol) was dissolved in methanol (12 mL), and a solution of LiOH.Math.H.sub.2O (585 mg, 14.0 mmol) in water (10 mL) was added. The reaction system reacted at room temperature for 2 h. The reaction system was adjusted to pH 5 by adding a 1M hydrochloric acid solution, and spin-dried to remove the methanol. The reaction system was extracted with ethyl acetate (15 mL). The organic phase was washed with water (10 mL?2), dried with anhydrous sodium sulfate, and spin-dried to obtain a light-yellow solid compound 6-4 (980 mg, yield: 92%). LCMS (M+H).sup.+=381.4.

Step 3

[0309] The compound 6-4 (490 mg, 1.29 mmol) and the compound 1-4 (294 mg, 1.29 mmol) were dissolved in DMF (7 mL), and HATU (1735 mg, 1.94 mmol) and TEA (260 mg, 2.58 mmol) were added. The reaction system reacted at room temperature under nitrogen protection for 2 h. The reaction system was quenched with water (30 mL) and extracted with ethyl acetate (60 mL). The organic phase was back-extracted with water (50 mL?3), dried with anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was separated by medium-pressure liquid chromatography to obtain a colorless colloidal compound 6-5 (460 mg, yield: 61%). LCMS (M+H).sup.+=591.4.

Step 4

[0310] The Grubbs 2.sup.nd catalyst (170 mg, 0.20 mmol) was added in a solution of the compound 6-5 (400 mg, 0.68 mmol) in anhydrous dichloromethane (150 mL) under nitrogen protection. The reaction system reacted at room temperature under nitrogen protection for 2 h. The reaction system was spin-dried to obtain a crude product. The crude product was separated by medium-pressure liquid chromatography to obtain a light-yellow colloidal compound 6-6a&b (230 mg, yield: 60%). LCMS (M+H).sup.+=563.3.

Step 5

[0311] The compound 6-6a&b (90 mg, 0.16 mmol) was dissolved in methanol (10 mL), and wet palladium carbon (20 mg) was added. The reaction system reacted at room temperature under hydrogen protection for 2 h. The reaction systwas filtered with diatomaceous earth to obtain a filtrate, and the filtrate was spin-dried to obtain a colorless colloidal compound 6-7 (91 mg, yield: 100%). LCMS (M+H).sup.+=565.4.

Step 6

[0312] The compound 6-7 (130 mg, 0.23 mmol) was dissolved in methanol (5 mL), and a 7M ammonia in methanol solution (10 mL) was added. The reaction system reacted in a tetrafluoro tank at 70 degrees overnight. The reaction system was spin-dried to obtain a colorless colloidal compound 6-8 (120 mg, yield: 95%). LCMS (M+H).sup.+=550.3.

Step 7

[0313] The compound 6-8 (120 mg, 0.22 mmol) was dissolved in methanol (5 mL), and a 4M hydrogen chloride ethyl acetate solution (5 mL) was added. The reaction system reacted at room temperature for 2 h. The reaction system was spin-dried to obtai colorless colloidal compound 6-9 (95 mg, yield: 90%). LCMS (M+H).sup.+=450.3.

Step 8

[0314] The compound 6-9 (95 mg, 0.21 mmol) was dissolved in anhydrous THF (5 mL) under nitrogen protection, and pyridine (0.3 mL) and TFAA (0.3 mL) were added in an ice-water bath. The reaction solution reacted at room temperature for 2 h. The reaction solution was poured in ice water (20 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with water (20 mL), dried with anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was separated by high-performance liquid chromatography to obtain a white solid 6 (28 mg, yield: 25%).

[0315] LCMS: (M+H).sup.+=528.3. .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.69 (br, 1H), 9.07 (d, J=7.6 Hz, 1H), 8.03 (t, J=5.6 Hz, 1H), 4.75 (q, J=7.2 Hz, 1H), 4.15 (s, 1H), 3.86 (dd, J=10.4, 5.6 Hz, 1H), 3.75 (d, J=10.4 Hz, 1H), 3.23-3.33 (m, 1H), 2.81-2.87 (m, 1H), 2.25-2.33 (m, 1H), 2.12-2.19 (m, 1H), 1.97-2.03 (m, 1H), 1.81-1.89 (m, 2H), 1.53-1.56 (m, 2H), 1.22-1.39 (m, 12H), 1.02 (s, 3H), 0.89 (s, 3H).

Example 7

Synthesis of N-((3S, 14S, 17aS, 18aR, 18bS)-3-cyano-18,18-dimethyl-1,6,15-trioxyeicosanylhydrocyclopropyl[3,4]pyrrole[1,2-a][1,4,9]tri azacycloheptanedioic acid-14-yl)-2,2,2-trifluoroacetamide (compound 7)

[0316] ##STR00054## ##STR00055##

Step 1

[0317] A compound 7-1 (500.0 mg, 2.3 mmol) and a compound 7-2 (524 mg, 2.56 mmol) were dissolved in DMF (30 mL), and DIEA (900 mg, 7.0 mmol) and HATU (1.06 g, 2.8 mmol) were added, to react at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was purified by SGC (PE:EA=2:1) to obtain a colorless oily compound 7-3 (650 mg, yield: 76%). LCMS (M+Na).sup.+=367.2.

Step 2

[0318] The compound 7-3 (650 mg, 1.8 mmol) was dissolved in THF (20 mL) and added dropwise at zero degrees in LiOH (128 mg, 5.3 mmol) dissolved in water to react at room temperature for 2 h, adjusted with 1M hydrochloric acid to pH 4-5, extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a colorless oily compound 7-4 (500 mg, yield: 80%). LCMS (M+Na).sup.+=353.2.

Step 3

[0319] The compound 7-4 (500 mg, 1.4 mmol) and the compound 1-4 (320 mg, 1.4 mmol) were dissolved in a mixed solvent of dichloromethane (5 mL) and DMF (5 mL), and DIEA (542 mg, 4.2 mmol), HOBT (277 mg, 1.7 mmol), and EDCI (325 mg, 1.7 mmol) were added, to react at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was purified by SGC (PE:EA=2:1) to obtain a colorless oily compound 7-5 (300 mg, yield: 38%). LCMS (M+Na).sup.+=563.2.

Step 4

[0320] The compound 7-5 (300 mg, 0.53 mmol) was dissolved in dichloromethane (150 mL), and the Grubbs 2.sup.nd catalyst (16 mg, 0.05 mmol) was added, to react at room temperature overnight. 1 mL of ethyl vinyl ether was added at zero degrees and stirred for 1 h for quenching. The reaction solution was filtered and concentrated to remove the solvent, to obtain a brown oily compound 7-6a&b (285 mg, yield: 100%). LCMS (M+H).sup.+=535.4.

Step 5

[0321] The compound 7-6a&b (100 mg, 0.18 mmol) was dissolved in ethanol (20 mL), PtO.sub.2 (18 mg, 0.08 mmol) was added, and hydrogen substitution was carried out three times, to react at room temperature for 0.5 h. The reaction solution was filtered and concentrated to remove the solvent, to obtain a colorless oily compound 7-7 (80 mg, yield: 80%). LCMS (M+H).sup.+=537.3.

Step 6

[0322] The compound 7-7 (80 mg, 0.15 mmol) was dissolved in 7M ammonia in methanol (10 mL), to react in a sealed tube at room temperature for 24 h. The reaction solution was concentrated to remove the solvent, to obtain a colorless oily compound 7-8 (50 mg, yield: 64%). LCMS (M+H).sup.+=522.4.

Step 7

[0323] The compound 7-8 (50 mg, 0.06 mmol) was dissolved in DCM (5 mL), and added dropwise in TFA (0.5 mL) in an ice-water bath. The reaction solution reacted at zero degrees for 3 h. The reaction solution was concentrated to remove the solvent, to obtain a colorless oily compound 7-9 (40 mg, yield: 99%). LCMS (M+H).sup.+=422.3.

Step 8

[0324] The compound 7-9 (40 mg, 0.04 mmol) was dissolved in THF (10 mL), and added dropwise in pyridine (16 mg, 0.2 mmol) in an ice-water bath. TFAA (13 mg, 0.06 mmol) was added dropwise after stirring in the ice-water bath for 15 min. The reaction solution reacted at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was subjected to Prep-HPLC to obtain a white solid compound 7 (15 mg, yield: 31%).

[0325] LCMS (M+H).sup.+=500.2. 1H NMR (400 MHz, DMSO) ? 9.75 (d, J=6.9 Hz, 1H), 9.31 (d, J=7.6 Hz, 1H), 7.87 (dd, J=7.4, 4.0 Hz, 1H), 4.91 (dd, J=12.7, 7.4 Hz, 1H), 4.47 (d, J=7.0 Hz, 1H), 4.13 (s, 1H), 3.93 (dd, J=10.4, 5.4 Hz, 1H), 3.71 (d, J=10.5 Hz, 1H), 3.54-3.43 (m, 1H), 2.74-2.66 (m, 1H), 2.34-2.27 (m, 2H), 2.04-1.86 (m, 2H), 1.77 (dd, J=13.7, 7.0 Hz, 1H), 1.54 (dt, J=15.4, 7.8 Hz, 2H), 1.34 (d, J=7.6 Hz, 4H), 1.27-1.13 (m, 5H), 1.02 (s, 3H), 0.87 (s, 3H).

Example 8

Synthesis of N-((3S, 16S, 19aS, 20aR, 20bS, Z/E)-3-cyano-20,20-dimethyl-1,6,17-trioxo-1,2,3,4,5,6,7,8,9,10,13,14,15,16,17,19,19a,20,20a,20b-e icosanylhydrocyclopropyl[3,4]pyrrole[1,2-a][1,4,9]triazacyclonon-16-yl)-2,2,2-trifluoroacetamide (compounds 8a and 8b)

[0326] ##STR00056## ##STR00057##

Step 1

[0327] The compound 6-6a&b (140 mg, 0.25 mmol) was dissolved in methanol (5 mL), and a 7M ammonia in methanol solution (10 mL) was added. The reaction system reacted in a tetrafluoro tank at 70 degrees overnight. The reaction system was spin-dried to obtain colorless colloidal compounds 8-2a and 8-2b (135 mg, yield: 99%). LCMS (M+H).sup.+=548.4.

Step 2

[0328] The compounds 8-2a and 8-2b (130 mg, 0.24 mmol) were dissolved in methanol (5 mL), and a 4M hydrogen chloride ethyl acetate solution (4 mL) was added. The reaction system reacted at room temperature for 2 h. The reaction system was spin-dried to obtain colorless solid compounds 8-3a and 8-3b (110 mg, yield: 96%). LCMS (M+H).sup.+=448.4.

Step 3

[0329] The compounds 8-3a and 8-3b (110 mg, 0.23 mmol) were dissolved in anhydrous THF (5 mL), and pyridine (0.3 mL) and TFAA (0.3 mL) were added in an ice-water bath. The reaction solution reacted at room temperature for 2 h. The reaction solution was poured in ice water (20 mL) and extracted with ethyl acetate (20 mL). The organic phase was washed with water (20 mL), dried with anhydrous sodium sulfate, and spin-dried to obtain a crude product. The crude product was separated by high-performance liquid chromatography to obtain white solid compounds 8a (13 mg, yield: 11%) and 8b (28 mg, yield: 23%). LCMS: (M+H).sup.+=526.2.

[0330] The compound 8a or 8b is NMR-characterized as: .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.75 (d, J=6.8 Hz, 1H), 9.23 (d, J=6.8 Hz, 1H), 7.83 (t, J=5.6 Hz, 1H), 5.30-5.39 (m, 2H), 4.70 (q, J=7.2 Hz, 1H), 4.38 (q, J=7.2 Hz, 1H), 4.11 (s, 1H), 3.88 (dd, J=10.4, 5.6 Hz, 1H), 3.73 (d, J=10.4 Hz, 1H), 3.15-3.22 (m, 1H), 2.91-2.97 (m, 1H), 2.30-2.36 (m, 1H), 2.18-2.25 (m, 1H), 1.99-2.09 (m, 2H), 1.86-1.98 (m, 5H), 1.43-1.58 (m, 6H), 1.32-1.36 (m, 1H), 1.02 (s, 3H), 0.88 (s, 3H).

[0331] The compound 8b or 8a is NMR-characterized as: .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.75 (d, J=6.4 Hz, 1H), 9.05 (d, J=8.0 Hz, 1H), 7.56 (t, J=5.6 Hz, 1H), 5.34-5.37 (m, 2H), 4.81-4.87 (m, 1H), 4.32-4.37 (m, 1H), 4.13 (s, 1H), 3.81-3.85 (m, 1H), 3.70-3.73 (m, 1H), 3.13-3.18 (m, 1H), 2.94-2.99 (m, 1H), 2.16-2.21 (m, 2H), 1.86-2.06 (m, 7H), 1.66-1.74 (m, 1H), 1.53-1.58 (m, 2H), 1.40-1.49 (m, 3H), 1.30-1.36 (m, 1H), 1.02 (s, 3H), 0.89 (s, 3H).

[0332] Note: The NMR data above indicates that when the compound 8a is NMR-characterized as .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.75 (d, J=6.8 Hz, 1H), 9.23 (d, J=6.8 Hz, 1H), 7.83 (t, J=5.6 Hz, 1H), 5.30-5.39 (m, 2H), 4.70 (q, J=7.2 Hz, 1H), 4.38 (q, J=7.2 Hz, 1H), 4.11 (s, 1H), 3.88 (dd, J=10.4, 5.6 Hz, 1H), 3.73 (d, J=10.4 Hz, 1H), 3.15-3.22 (m, 1H), 2.91-2.97 (m, 1H), 2.30-2.36 (m, 1H), 2.18-2.25 (m, 1H), 1.99-2.09 (m, 2H), 1.86-1.98 (m, 5H), 1.43-1.58 (m, 6H), 1.32-1.36 (m, 1H), 1.02 (s, 3H), 0.88 (s, 3H), the compound 8b is NMR-characterized as .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.75 (d, J=6.4 Hz, 1H), 9.05 (d, J=8.0 Hz, 1H), 7.56 (t, J=5.6 Hz, 1H), 5.34-5.37 (m, 2H), 4.81-4.87 (m, 1H), 4.32-4.37 (m, 1H), 4.13 (s, 1H), 3.81-3.85 (m, 1H), 3.70-3.73 (m, 1H), 3.13-3.18 (m, 1H), 2.94-2.99 (m, 1H), 2.16-2.21 (m, 2H), 1.86-2.06 (m, 7H), 1.66-1.74 (m, 1H), 1.53-1.58 (m, 2H), 1.40-1.49 (m, 3H), 1.30-1.36 (m, 1H), 1.02 (s, 3H), 0.89 (s, 3H); or

[0333] when the compound 8a is NMR-characterized as .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.75 (d, J=6.4 Hz, 1H), 9.05 (d, J=8.0 Hz, 1H), 7.56 (t, J=5.6 Hz, 1H), 5.34-5.37 (m, 2H), 4.81-4.87 (m, 1H), 4.32-4.37 (m, 1H), 4.13 (s, 1H), 3.81-3.85 (m, 1H), 3.70-3.73 (m, 1H), 3.13-3.18 (m, 1H), 2.94-2.99 (m, 1H), 2.16-2.21 (m, 2H), 1.86-2.06 (m, 7H), 1.66-1.74 (m, 1H), 1.53-1.58 (m, 2H), 1.40-1.49 (m, 3H), 1.30-1.36 (m, 1H), 1.02 (s, 3H), 0.89 (s, 3H), the compound 8b is NMR-characterized as .sup.1H NMR (400 MHz, DMSO-d.sub.6) ? 9.75 (d, J=6.8 Hz, 1H), 9.23 (d, J=6.8 Hz, 1H), 7.83 (t, J=5.6 Hz, 1H), 5.30-5.39 (m, 2H), 4.70 (q, J=7.2 Hz, 1H), 4.38 (q, J=7.2 Hz, 1H), 4.11 (s, 1H), 3.88 (dd, J=10.4, 5.6 Hz, 1H), 3.73 (d, J=10.4 Hz, 1H), 3.15-3.22 (m, 1H), 2.91-2.97 (m, 1H), 2.30-2.36 (m, 1H), 2.18-2.25 (m, 1H), 1.99-2.09 (m, 2H), 1.86-1.98 (m, 5H), 1.43-1.58 (m, 6H), 1.32-1.36 (m, 1H), 1.02 (s, 3H), 0.88 (s, 3H).

Example 9

Synthesis of N-((3S, 14S, 17aS, 18aR, 18bS, E/Z)-3-cyano-18,18-dimethyl-1,6,15-trioxo-1,2,3,4,5,6,7,8,9,10,13,14,15,17,17a,18,18a,18b-octade cyclopropyl[3,4]pyrrole[1,2-a][1,4,9]triazacycloheptene-14-yl)-2,2-trifluoroacetamide (compounds 9a and 9b)

[0334] ##STR00058## ##STR00059## ##STR00060##

Step 1

[0335] The compounds 7-6a and 7-6b (100 mg, 0.19 mmol) were dissolved in 7M ammonia in methanol (10 mL), to react in a sealed tube at room temperature for 24 h. The reaction solution was concentrated to remove the solvent, to obtain a crude product. The crude product was subjected to Prep-HPLC to obtain white solid compounds 9-1a (25 mg, yield: 26%) and 9-1b (10 mg, yield: 10%). LCMS (M+H).sup.+=520.2.

Step 2

[0336] The compounds 9-1a (25 mg, 0.05 mmol) and 9-2b (10 mg, yield: 0.02) were respectively dissolved in DCM (5 mL), and added dropwise in TFA (0.5 mL) in an ice-water bath. The reaction solution reacted at zero degrees for 3 h. The reaction solution was concentrated to remove the solvent, to obtain colorless oily compounds 9-2a (20 mg, yield: 99%) and 9-2b (8 mg, yield: 99%). LCMS (M+H).sup.+=420.3.

Step 10

[0337] The compounds 9-2a (20 mg, 0.05 mmol) and 9-2b (8 mg, 0.02 mmol) were respectively dissolved in THF (10 mL), and added dropwise in pyridine (16 mg, 0.2 mmol) in an ice-water bath. TFAA (13 mg, 0.06 mmol) was added dropwise after stirring in the ice-water bath for 15 min. The reaction solution reacted at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was subjected to Prep-HPLC to obtain white solid compounds 9a (15 mg, yield: 63%) and 9b (5 mg, yield: 53%). LCMS (M+H).sup.+=498.1.

[0338] 9a or 9b: .sup.1H NMR (400 MHz, DMSO) ? 9.92 (d, J=7.7 Hz, 1H), 9.61 (d, J=6.9 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H), 5.37 (dd, J=13.1, 7.3 Hz, 1H), 5.10 (dd, J=12.9, 7.2 Hz, 1H), 4.82 (dd, J=11.3, 6.0 Hz, 1H), 4.49 (d, J=9.1 Hz, 1H), 4.09 (s, 1H), 3.97 (dd, J=10.6, 5.4 Hz, 1H), 3.52 (d, J=10.5 Hz, 2H), 2.76-2.66 (m, 2H), 2.43 (d, J=5.8 Hz, 2H), 2.13-2.07 (m, 1H), 1.98 (d, J=5.8 Hz, 3H), 1.83 (d, J=9.7 Hz, 1H), 1.53 (dd, J=13.7, 8.3 Hz, 3H), 1.37 (d, J=7.6 Hz, 1H), 1.01 (s, 3H), 0.83 (s, 3H).

[0339] 9b or 9a: .sup.1H NMR (400 MHz, DMSO) ? 9.96 (s, 1H), 9.48 (d, J=6.2 Hz, 1H), 7.96 (s, 1H), 5.40-5.25 (m, 2H), 4.71 (d, J=3.8 Hz, 1H), 4.55 (dd, J=9.3, 5.2 Hz, 1H), 4.08 (s, 1H), 3.95 (dd, J=10.7, 5.4 Hz, 1H), 3.64 (d, J=10.7 Hz, 1H), 2.82 (d, J=13.2 Hz, 1H), 2.67 (s, 1H), 2.40-2.28 (m, 2H), 2.24-1.91 (m, 5H), 1.84 (s, 1H), 1.58-1.49 (m, 2H), 1.39 (t, J=12.7 Hz, 2H), 1.01 (s, 3H), 0.83 (s, 3H).

[0340] Note: The NMR data above indicates that when the compound 9a is NMR-characterized as .sup.1H NMR (400 MHz, DMSO) ? 9.92 (d, J=7.7 Hz, 1H), 9.61 (d, J=6.9 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H), 5.37 (dd, J=13.1, 7.3 Hz, 1H), 5.10 (dd, J=12.9, 7.2 Hz, 1H), 4.82 (dd, J=11.3, 6.0 Hz, 1H), 4.49 (d, J=9.1 Hz, 1H), 4.09 (s, 1H), 3.97 (dd, J=10.6, 5.4 Hz, 1H), 3.52 (d, J=10.5 Hz, 2H), 2.76-2.66 (m, 2H), 2.43 (d, J=5.8 Hz, 2H), 2.13-2.07 (m, 1H), 1.98 (d, J=5.8 Hz, 3H), 1.83 (d, J=9.7 Hz, 1H), 1.53 (dd, J=13.7, 8.3 Hz, 3H), 1.37 (d, J=7.6 Hz, 1H), 1.01 (s, 3H), 0.83 (s, 3H), the compound 9b is NMR-characterized as .sup.1H NMR (400 MHz, DMSO) ? 9.96 (s, 1H), 9.48 (d, J=6.2 Hz, 1H), 7.96 (s, 1H), 5.40-5.25 (m, 2H), 4.71 (d, J=3.8 Hz, 1H), 4.55 (dd, J=9.3, 5.2 Hz, 1H), 4.08 (s, 1H), 3.95 (dd, J=10.7, 5.4 Hz, 1H), 3.64 (d, J=10.7 Hz, 1H), 2.82 (d, J=13.2 Hz, 1H), 2.67 (s, 1H), 2.40-2.28 (m, 2H), 2.24-1.91 (m, 5H), 1.84 (s, 1H), 1.58-1.49 (m, 2H), 1.39 (t, J=12.7 Hz, 2H), 1.01 (s, 3H), 0.83 (s, 3H); or

[0341] when the compound 9b is NMR-characterized as .sup.1H NMR (400 MHz, DMSO) ? 9.92 (d, J=7.7 Hz, 1H), 9.61 (d, J=6.9 Hz, 1H), 7.71 (d, J=7.3 Hz, 1H), 5.37 (dd, J=13.1, 7.3 Hz, 1H), 5.10 (dd, J=12.9, 7.2 Hz, 1H), 4.82 (dd, J=11.3, 6.0 Hz, 1H), 4.49 (d, J=9.1 Hz, 1H), 4.09 (s, 1H), 3.97 (dd, J=10.6, 5.4 Hz, 1H), 3.52 (d, J=10.5 Hz, 2H), 2.76-2.66 (m, 2H), 2.43 (d, J=5.8 Hz, 2H), 2.13-2.07 (m, 1H), 1.98 (d, J=5.8 Hz, 3H), 1.83 (d, J=9.7 Hz, 1H), 1.53 (dd, J=13.7, 8.3 Hz, 3H), 1.37 (d, J=7.6 Hz, 1H), 1.01 (s, 3H), 0.83 (s, 3H), the compound 9a is NMR-characterized as .sup.1H NMR (400 MHz, DMSO) ? 9.96 (s, 1H), 9.48 (d, J=6.2 Hz, 1H), 7.96 (s, 1H), 5.40-5.25 (m, 2H), 4.71 (d, J=3.8 Hz, 1H), 4.55 (dd, J=9.3, 5.2 Hz, 1H), 4.08 (s, 1H), 3.95 (dd, J=10.7, 5.4 Hz, 1H), 3.64 (d, J=10.7 Hz, 1H), 2.82 (d, J=13.2 Hz, 1H), 2.67 (s, 1H), 2.40-2.28 (m, 2H), 2.24-1.91 (m, 5H), 1.84 (s, 1H), 1.58-1.49 (m, 2H), 1.39 (t, J=12.7 Hz, 2H), 1.01 (s, 3H), 0.83 (s, 3H).

Example 10

Synthesis of N-((3S, 14S, 17aR, 20aS, 20bS)-3-cyano-1,6,15-trioxodococarbodihydrocyclopentane[3,4]pyrrole[1,2-a][1,4,9]triazacyclic heptapeptide-14-yl)-2,2,2-trifluoroacetamide (compound 10)

[0342] ##STR00061## ##STR00062## ##STR00063##

Step 1

[0343] A compound 10-1 (220 mg, 1.42 mmol) was dissolved in a mixed solution of dichloromethane (10 mL) and methanol (1 mL), and a compound 10-2 (0.75 mL, 1.49 mmol) was added dropwise at zero degrees, to react at room temperature for 2 h. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a light-yellow oily compound 10-3 (150 mg, yield: 63%). LCMS (M+Na).sup.+=170.2.

Step 2

[0344] A compound 10-3 (150 mg, 0.89 mmol), a compound 10-4 (203 mg, 0.89 mmol), and DIEA (344 mg, 2.67 mmol) were dissolved in DMF (5 mL), and HATU (6.47 g, 0.89 mmol) was added, to react at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was purified by SGC (PE:EA=2:1) to obtain a colorless oily compound 10-5 (150 mg, yield: 46.2%). LCMS (M+Na).sup.+=366.3.

Step 3

[0345] The compound 10-5 (150 mg, 0.41 mmol) was dissolved in THF (10 mL) and added dropwise at zero degrees in LiOH (28.8 mg, 1.2 mmol) dissolved in water to react at room temperature for 2 h, adjusted with 1M hydrochloric acid to pH 4-5, extracted with ethyl acetate, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a colorless oily compound 10-6 (120 mg, yield: 83%). LCMS (M+Na).sup.+=353.2.

Step 4

[0346] The compound 10-6 (120 mg, 0.34 mmol) and the compound 1-4 (77 mg, 0.34 mmol) were dissolved in a mixed solvent of dichloromethane (5 mL) and DMF (5 mL), and DIEA (87 mg, 0.68 mmol), HOBT (66 mg, 0.41 mmol), and EDCI (78 mg, 0.41 mmol) were added, to react at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was purified by SGC (PE:EA=2:1) to obtain a colorless oily compound 10-7 (170 mg, yield: 89%). LCMS (M+Na).sup.+=563.2.

Step 5

[0347] The compound 10-7 (170 mg, 0.30 mmol) was dissolved in dichloromethane (80 mL), and the Grubbs 2.sup.nd catalyst (24 mg, 0.03 mmol) was added, to react at room temperature overnight. 1 mL of ethyl vinyl ether was added at zero degrees and stirred for 1 h for quenching. The reaction solution was filtered and concentrated to remove the solvent, to obtain a colorless oily olefin cis-trans mixture 10-8a&b (150 mg, yield: 94%). LCMS (M+H).sup.+=535.4.

Step 6

[0348] The compound 10-8a&b (150 mg, 0.28 mmol) was dissolved in ethanol (20 mL), PtO.sub.2 (18 mg, 0.08 mmol) was added, and hydrogen substitution was carried out three times, to react at room temperature for 0.5 h. The reaction solution was filtered and concentrated to remove the solvent, to obtain a colorless oily compound 10-9 (120 mg, yield: 80%). LCMS (M+H).sup.+=537.3.

Step 7

[0349] The compound 10-9 (120 mg, 0.22 mmol) was dissolved in 7M ammonia in methanol (20 mL), to react in a sealed tube at room temperature for 24 h. The reaction solution was concentrated to remove the solvent, to obtain a colorless oily compound 10-10 (80 mg, yield: 70%). LCMS (M+H).sup.+=522.4.

Step 8

[0350] The compound 10-10 (40 mg, 0.08 mmol) was dissolved in DCM (5 mL), and added dropwise in TFA (0.5 mL) in an ice-water bath. The reaction solution reacted at zero degrees for 3 h. The reaction solution was concentrated to remove the solvent, to obtain a colorless oily compound 10-11 (25 mg, yield: 77%). LCMS (M+H).sup.+=422.3.

Step 9

[0351] The compound 10-11 (25 mg, 0.06 mmol) was dissolved in THF (10 mL), and added dropwise in pyridine (16 mg, 0.2 mmol) in an ice-water bath. TFAA (13 mg, 0.06 mmol) was added dropwise after stirring in the ice-water bath for 15 min. The reaction solution reacted at room temperature overnight. The reaction was quenched with water at zero degrees, extracted with ethyl acetate, dried with saturated brine, dried with anhydrous sodium sulfate, and concentrated to remove the solvent, to obtain a crude product. The crude product was subjected to Prep-HPLC to obtain a white solid compound 10 (8.0 mg, yield: 27%).

[0352] LCMS (M+H).sup.+=500.1. 1H NMR (400 MHz, DMSO) ? 9.69 (d, J=6.6 Hz, 1H), 9.12 (d, J=7.9 Hz, 1H), 7.75 (s, 1H), 4.91 (d, J=5.5 Hz, 1H), 4.52 (d, J=6.7 Hz, 1H), 4.13 (d, J=3.6 Hz, 1H), 3.82 (dd, J=10.3, 7.9 Hz, 1H), 3.62 (dd, J=10.5, 3.7 Hz, 1H), 2.73 (d, J=7.6 Hz, 2H), 2.53 (s, 2H), 2.36-2.20 (m, 2H), 2.08-1.98 (m, 1H), 1.91-1.70 (m, 4H), 1.68-1.47 (m, 4H), 1.29 (ddd, J=27.6, 12.5, 6.2 Hz, 9H).

Examples of Activity Tests

[0353] In the following examples, the inhibitory activity against M.sup.pro and pharmacokinetic properties of the compounds of the present disclosure are detected by using some of the compounds of the present disclosure as examples.

Example A: Inhibitory Activity Against M.SUP.pro

[0354] An objective of this experiment is to detect the in vitro inhibitory activity against M.sup.pro of the compound of the present disclosure.

Experimental materials: [0355] GST-AVLQ-3Clpro-GP-6His (CP, Lot. No. CP20200526001); [0356] MCA-AVLQSGFR-Lys(Dnp)-Lys-NH.sub.2 (GL, Customized); and [0357] 384-well plate (Perkin Elmer, Cat. No. 6007279).
Experimental steps and methods: [0358] 1. Prepare a 1? buffer solution (modified Tris buffer solution). [0359] 2. Transfer a to-be-tested compound to the assay plate with Echo's 100% DMSO solution to a final DMSO content of 0.5%. [0360] 3. Prepare a mixed protein solution: Add GST-AVLQ-3Clpro-GP-6His in a 1? assay buffer solution to support the mixed protein solution. [0361] 4. Prepare a mixed substrate solution: Add the polypeptide (MCA-AVLQSGFR-Lys(Dnp)-Lys-NH.sub.2) in a 1? assay buffer solution to obtain the substrate solution. [0362] 5. Add 10 ?L of 2? mixed protein solution in the assay plate, centrifuge for 30s, shake for 30s, and incubate the solution at room temperature for 15 min. [0363] 6. Add 10 ?L of 2? mixed substrate solution in the assay plate, centrifuge for 30, and shake for 30s. [0364] 7. Read the data dynamically on Synergy (Ex320/Em405).

[0365] Table 1 shows experimental data of the inhibitory activity against M.sup.pro of some of the compounds of the present disclosure.

TABLE-US-00001 TABLE 1 Compound No. M.sup.pro IC.sub.50 (nM) 1 254 4 411 6 379 7 16 8b 138

[0366] The experimental results indicate that the compound of the present disclosure has good inhibitory activity against M.sup.pro.

Example B: Pharmacokinetic Evaluation of the Disclosed Compound in Mice by Intravenous Injection or Oral Administration

[0367] An objective of this experiment is to detect the pharmacokinetic properties of the compound of the present disclosure in mice.

[0368] Experimental steps and methods are shown in the following table:

TABLE-US-00002 Category Item Description Animal CD-1 mice Male, N = 12 for each compound, fasted overnight prior species to oral administration, fed 4 hours after administration. Administered IV, PO IV&PO: provided by the client formulation Animal Group 1: IV, XX mg/kg, The dose for administration is provided by Party A. A XX ml/kg, N = 3/time whole blood sample (whole blood is centrifuged within point 30 minutes to separate plasma) is collected by the experiment Group 2: PO, XX mg/kg, semi-continuous method in a tube containing the XX mL/kg, N = 3/time anticoagulant EDTA-K2. Design of sampling time point points: A total of six time points (no overtime sampling). A total of 36 plasma samples are collected for the two groups. Bioanalysis Analytical method Develop an LC-MS/MS method for the determination of development the concentration of a to-be-determined substance in the plasma samples. Sample testing The 36 plasma samples are tested for one to-be-determined substance. For sample quantity ?12, one standard curve is used for quantification; and for sample quantity >12, two standard curves are used for quantification and accompanied by a proper quantity of QC samples. The accuracy of at least five concentrations of each standard curve is 80%-120% of the true concentration (the accuracy of LLOQ has to be 75%-125%). Data processing and reporting Calculate the PK parameters by using WinNonlin, and provide an English data report in Excel

[0369] The experimental results indicate that the compound of the present disclosure has good metabolic stability in the animals to be tested and has significant advantages.

[0370] In the description of this specification, the term an embodiment, some embodiments, example, specific example, or some examples is intended to indicate that specific features, structures, materials, or characteristics described in conjunction with the embodiment or example are included in at least one embodiment or example of the present disclosure. In this specification, schematic expressions of the foregoing terms do not necessarily refer to the same embodiment or example. In addition, the specific features, structures, materials, or characteristics described may be combined in any one or more embodiments or examples in a suitable manner. Moreover, without contradicting each other, a person skilled in the art may combine different embodiments or examples and features of different embodiments or examples described in this specification.

[0371] Although the embodiments of the present disclosure have been shown and described above, it may be understood that the foregoing embodiments are exemplary and are not to be construed as a limitation on the present disclosure. A person of ordinary skill in the art may make changes, modifications, substitutions, and variations of the foregoing embodiments within the scope of the present disclosure.