Pharmaceutical use of ketoamide-based compound

A pharmaceutical composition comprising (a) the ketoamide compound represented by formula (A), or the pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof;

• and (b) a pharmaceutically acceptable carrier,
• wherein,
• * indicates that the stereochemical isomerism of carbon atoms is independently R and/or S respectively;
• R1 and R2 are each independently selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl C1-C10 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C10 alkylene, substituted or unsubstituted C3-C20 heteroaryl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl C2-C10 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C2-C10 alkenylene, acyl, and sulfonyl;
• R3 is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C10 alkylene, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C10 alkylene, substituted or unsubstituted C3-C20 heteroaryl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C2-C6 alkenylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkynylene, and substituted or unsubstituted C3-C20 heteroaryl C2-C6 alkynylene;
• R4 is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C6 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkynylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene, substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkenylene, and substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkynylene;
• R6 is selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C6 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene, substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkenylene, acyl and sulfonyl;
• when —NR5 and its adjacent —(C═O)—CH2— form a ring, R5 is —(CH2)n—, n is 2 or 3;
• when —NR5 does not form a ring with its adjacent —(C═O)—CH2—, R5 is selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C6 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene, substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkenylene, acyl and sulfonyl;
• wherein, in R1, R2, R3, R4, R5 and R6, the “substituted” each independently refers to being substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxyl, mercapto, nitro, cyano, amino, imino, tertiary amino, azido, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkylthio, C1-C8 alkoxycarbonyl, and trifluoromethyl;
• the heterocycloalkyl and the heteroaryl each independently contain 1, 2, 3 or 4 heteroatoms selected from N, O, and S.

A method for inhibiting the activity of the 3CL protease of the 2019 novel coronavirus (2019-nCov), comprising the step of contacting a ketoamide compound represented by formula (A), or its pharmaceutically acceptable salt, enantiomer, diastereomer or racemate with the 3CL protease of 2019-nCov, thereby inhibiting the activity of the 3CL protease of 2019-nCov:

• wherein,
• * indicates that the stereochemical isomerism of carbon atoms is independently R and/or S respectively;
• R1 is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C10 alkylene, and substituted or unsubstituted C6-C10 aryl C1-C10 alkylene;
• R2 is selected from the group consisting of hydrogen, deuterium, and C1-C6 alkyl;
• R3 is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C5 alkylene, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted C6-C10 aryl C1-C5 alkylene;
• R4 is selected from the group consisting of substituted or unsubstituted quinoxalinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted indolyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted imidazole [1,2-A] pyridyl, substituted or unsubstituted imidazole [1,5-A] pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted benzothienyl, and substituted or unsubstituted benzofuranyl;
• wherein the substituted means that the hydrogen atom on the group is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and C1-C6 alkylthio;
• R6 is hydrogen or C1-C6 alkyl;
• when —NR5 and its adjacent —(C═O)—CH2— form a ring, R5 is —(CH2)n—, n is 2 or 3;
• when —NR5 does not form a ring with its adjacent —(C═O)—CH2—, R5 is selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C6 alkyl, and C3-C8 cycloalkyl;
• wherein, in R1 and R3, each of the term “substituted” independently refers to being substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxyl, mercapto, nitro, cyano, amino, imino, tertiary amino, azido, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkylthio, C1-C8 alkoxycarbonyl, and trifluoromethyl.

A method for inhibiting the activity of human cathepsin L, comprising the step of contacting a ketoamide compound represented by formula (A), or the pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof with human cathepsin L, thereby inhibiting the activity of human cathepsin L:

• wherein,
• * indicates that the stereochemical isomerism of carbon atoms is independently R and/or S respectively;
• R1 is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C10 alkylene, and substituted or unsubstituted C6-C10 aryl C1-C10 alkylene,
• R2 is selected from the group consisting of hydrogen, deuterium, and C1-C6 alkyl;
• R3 is selected from the group consisting of substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C5 alkylene, substituted or unsubstituted C6-C10 aryl, and substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C10 aryl C1-C5 alkylene;
• R4 is selected from the group consisting of substituted or unsubstituted quinoxalinyl, substituted or unsubstituted quinazolinyl, substituted or unsubstituted cinnolinyl, substituted or unsubstituted indolyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted indazolyl, substituted or unsubstituted imidazole [1,2-A] pyridyl, substituted or unsubstituted imidazole [1,5-A] pyridyl, substituted or unsubstituted quinolinyl, substituted or unsubstituted isoquinolinyl, substituted or unsubstituted benzothienyl, and substituted or unsubstituted benzofuranyl;
• wherein the substituted means that the hydrogen atom on the group is substituted by 1, 2 or 3 substituents selected from the group consisting of F, Cl, Br, I, hydroxyl, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy, and C1-C6 alkylthio;
• R6 is hydrogen or C1-C6 alkyl;
• when —NR5 and its adjacent —(C═O)—CH2— form a ring, R5 is —(CH2)n—, n is 2 or 3;
• when —NR5 does not form a ring with its adjacent —(C═O)—CH2—, R5 is selected from the group consisting of hydrogen C1-C6 alkyl, and C3-C8 cycloalkyl;
• wherein, in R1 and R3, each of the term “substituted” independently refers to being substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxyl, mercapto, nitro, cyano, amino, imino, tertiary amino, azido, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkylthio, C1-C8 alkoxycarbonyl, and trifluoromethyl.

A compound of formula (A), or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof,

• wherein,
• * indicates that the stereochemical isomerism of carbon atoms is independently R and/or S respectively;
• R1 and R2 are each independently selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 cycloalkyl C1-C10 alkylene, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C10 alkylene, substituted or unsubstituted C3-C20 heteroaryl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl C2-C10 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C2-C10 alkenylene, acyl, and sulfonyl;
• R3 is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C3-C8 cycloalkyl C1-C10 alkylene, substituted or unsubstituted C3-C8 heterocycloalkyl, substituted or unsubstituted C3-C8 heterocycloalkyl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C10 alkylene, substituted or unsubstituted C3-C20 heteroaryl C1-C10 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C2-C6 alkenylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkynylene, and substituted or unsubstituted C3-C20 heteroaryl C2-C6 alkynylene;
• R4 is selected from the group consisting of substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C2-C10 alkenyl, substituted or unsubstituted C2-C10 alkynyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C6 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkynylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene, substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkenylene, and substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkynylene;
• R6 is selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C6 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene, substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkenylene, acyl and sulfonyl;
• when —NR5 and its adjacent —(C═O)—CH2— form a ring, R5 is —(CH2)n—, n is 2 or 3;
• when —NR5 does not form a ring with its adjacent —(C═O)—CH2—, R5 is selected from the group consisting of hydrogen, deuterium, tritium, amino, hydroxyl, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C3-C10 cycloalkyl, substituted or unsubstituted C3-C10 heterocycloalkyl, substituted or unsubstituted C6-C20 aryl, substituted or unsubstituted C3-C20 heteroaryl, substituted or unsubstituted C6-C20 aryl C1-C6 alkylene, substituted or unsubstituted C6-C20 aryl C2-C6 alkenylene, substituted or unsubstituted C3-C20 heteroaryl C1-C9 alkylene, substituted or unsubstituted C3-C20 heteroaryl C2-C9 alkenylene, acyl and sulfonyl;
• wherein, in R1, R2, R3, R4, R5 and R6, each of the “substituted” independently refers to being substituted by 1, 2, 3 or 4 substituents selected from the group consisting of halogen, hydroxyl, mercapto, nitro, cyano, amino, imino, tertiary amino, azido, C1-C8 alkyl, halogenated C1-C8 alkyl, C1-C8 alkoxy, halogenated C1-C8 alkoxy, C1-C6 alkylcarbonyl, C1-C6 alkylthio, C1-C8 alkoxycarbonyl, and trifluoromethyl;
• the heterocycloalkyl and the heteroaryl each independently comprise 1, 2, 3 or 4 heteroatoms selected from N, O, and S.