Broad-spectrum non-covalent coronavirus protease inhibitors
This invention pertains to materials and methods for the treatment of patients with coronavirus infection and the control of zoonotic disease outbreaks using broad-spectrum non-covalent coronavirus protease inhibitors.
1. A compound of formula (I)
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
R 1 is 1H-imidazole-4-yl;
R 3 is an alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl, each of which is optionally substituted;
R 4 is an alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl, each of which is optionally substituted, and R 4 is not t-butyl;
R 5 represents 1˜4 substituents each of which is independently hydrogen, halo, or an alkyl, alkoxy, acyl, alkyl amide, cycloalkyl, cycloalkenyl, cycloalkyl amide, or aryl, each of which is optionally substituted; or R 5 represents 2-4 substituents where 2 adjacent substituents are taken together with the attached carbons to form an optionally substituted cyclic or heterocyclic moiety, and where any remaining substituents are each independently selected from the group as defined above; and
R 6 is halo or an alkyl amide, cycloalkyl amide, alkyl, alkenyl, alkoxy, acyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl, each of which is optionally substituted.
2. The compound of claim 1 , wherein R 3 is an aryl or heterocycle, each of which is optionally substituted.
3. The compound of claim 2 , wherein R 3 is thiophene-3-yl or pyridin-3-yl.
4. The compound of claim 1 , wherein R 4 is an alkyl, cycloalkyl, or aryl, each of which is optionally substituted, but R 4 is not t-butyl.
5. The compound of claim 4 , wherein R 4 is cyclohexyl, cyclopentyl, isobutyl, neopentyl, 3′-pyridylmethyl, or benzyl.
6. The compound of claim 1 , wherein R 5 is hydrogen.
7. The compound of claim 1 , wherein R 6 is an alkyl, alkylamide, cycloalkyl, or cycloalkylamide, each of which is optionally substituted.
8. The compound of claim 7 , wherein R 6 is isobutyramide or t-butyl.
9. The compound of claim 1 , wherein R 5 is hydrogen and R 6 is isobutyramide or t-butyl.
10. The compound of claim 1 , wherein R 3 is pyridin-3-yl; R 5 is hydrogen; and R 6 is isobutyramide or t-butyl.
11. The compound of claim 1 , wherein R 3 is pyridin-3-yl; R 5 is hydrogen; R 6 is t-butyl; and R 4 is selected from the group consisting of cyclohexyl, cyclopentyl, isobutyl, neopentyl, and benzyl.
12. The compound of claim 1 , wherein R 1 is 1H-imidazole-4-yl; R 3 is pyridyl pyridin-3-yl; R 5 is hydrogen; and R 4 is selected from the group consisting of cyclohexyl, cyclopentyl, isobutyl, neopentyl, and benzyl.
13. The compound of claim 1 , wherein R 1 is 1H-imidazole-4-yl; R 3 is pyridin-3-yl; R 5 is hydrogen; R 6 is t-butyl; and R 4 is selected from the group consisting of cyclohexyl, cyclopentyl, isobutyl, neopentyl, and benzyl.
14. The compound of claim 1 , wherein the compound has the following structure of
or a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carriers, diluents, and excipients.
16. A method for treating a patient with a viral infection, the method comprising the step of administering a therapeutically effective amount of a compound of claim 1 , together with one or more pharmaceutically acceptable carriers, diluents, and excipients, to the patient in need of relief from said viral infection.
17. A method for treating a patient with a viral infection, the method comprising the step of administering a therapeutically effective amount of a compound of claim 1 , in combination with one or more therapeutically effective compounds, to the patient in need of relief from said viral infection.
18. A method for treating a patient with a viral infection, the method comprising the step of administering a therapeutically effective amount of a compound of formula (I):
or a pharmaceutically acceptable salt or hydrate thereof, wherein:
R 1 is 1H-imidazole-4-yl;
R 3 is an alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl, each of which is optionally substituted;
R 4 is an alkyl, alkenyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl, each of which is optionally substituted, and R 4 is not t-butyl;
R 5 represents 1˜4 substituents each of which is independently hydrogen, halo, or an alkyl, alkoxy, acyl, alkyl amide, cycloalkyl, cycloalkenyl, cycloalkyl amide, or aryl, each of which is optionally substituted; or R 5 represents 2-4 substituents where 2 adjacent substituents are taken together with the attached carbons to form an optionally substituted cyclic or heterocyclic moiety, and where any remaining substituents are each independently selected from the group as defined above; and
R 6 is halo or an alkyl amide, cycloalkyl amide, alkyl, alkenyl, alkoxy, acyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, or heteroaryl, each of which is optionally substituted.