Covalent inhibitors of coronavirus papain-like protease
A compound having the following structure: wherein: R 1 is a linker having the formula —(CH 2 ) n -L 1 -, wherein L 1 contains 1-6 carbon atoms and at least one —NH— linkage and at least one oxygen-containing or sulfur-containing linkage, and n is an integer of 0-3; R 2 is a group having the formula —C(Y)-E, wherein Y is O or S, and E is a hydrocarbon group and either: (i) at least one carbon-carbon or carbon-nitrogen unsaturated bond or (ii) at least one alkyl halide group; R 3 is selected from H, NR′ 2 , NHC(O)R′, and —(CH 2 ) p -T, wherein T contains at least one —NH— linkage; R a , R b , R c , R d , R e , and R f are independently selected from of H, hydrocarbon groups containing 1-3 carbon atoms, fluorine atom, and chlorine atom; X is N or CR 9 , wherein R 9 is selected from H, hydrocarbon groups containing 1-3 carbon atoms, fluorine atom, and chlorine atom; and pharmaceutically acceptable salts thereof.
1. A compound having the following structure:
wherein:
R 1 is a linker having the formula —(CH 2 ) n -L 1 -, wherein L 1 contains 1-6 carbon atoms and at least one —NH— linkage and at least one oxygen-containing or sulfur-containing linkage, and n is an integer of 0-3;
R 2 is a group having the formula —C(Y)-E, wherein Y is O or S, and E is a hydrocarbon group containing 1-12 carbon atoms and either: (i) at least one carbon-carbon or carbon-nitrogen unsaturated bond or (ii) at least one alkyl halide group;
R 3 is selected from the group consisting of H, NR′ 2 , NHC(O)R′, and —(CH 2 ) p -T, wherein T contains at least one —NH— linkage; R′ is independently selected from H and hydrocarbon groups containing 1-6 carbon atoms; and p is an integer of 0-3;
R a , R b , R c , R d , R e , and R f are independently selected from the group consisting of H, hydrocarbon groups containing 1-3 carbon atoms, fluorine atom, and chlorine atom;
X is N or CR 9 , wherein R 9 is selected from the group consisting of H, hydrocarbon groups containing 1-3 carbon atoms, fluorine atom, and chlorine atom;
and pharmaceutically acceptable salts thereof.
2. The compound of claim 1 , wherein R 1 is a linker having the formula —(CH 2 ) n -L 1 -, wherein L 1 contains 1-6 carbon atoms and at least one —NH— linkage and at least one oxygen-containing linkage selected from the group consisting of C(O), SO 2 , PO 2 , and hydroxy-containing linkages, and n is an integer of 1-3.
3. The compound of claim 1 , wherein R 1 contains a hydrazide linkage.
4. The compound of claim 1 , wherein R 2 is a group having the formula —C(Y)-E, wherein Y is O or S, and E is a hydrocarbon group containing 1-12 carbon atoms and at least one carbon-carbon or carbon-nitrogen unsaturated bond.
5. The compound of claim 4 , wherein R 2 has the formula —C(Y)—(C═C)—C(O)O—V, where Y is O or S, and V is a hydrocarbon group containing 1-12 carbon atoms, optionally substituted with one or more F atoms.
6. The compound of claim 5 , wherein V is a bulky hydrocarbon group selected from the group consisting of branched alkyl, alkenyl, and alkynyl groups containing 3-6 carbon atoms; and groups of the formula —(CH 2 ) r —U, wherein U is a carbocyclic or heterocyclic group and r is an integer of 0-3.
7. The compound of claim 1 , wherein R 2 is a group having the formula —C(Y)-E, wherein Y is O or S, and E is a hydrocarbon group containing 1-12 carbon atoms and at least one alkyl halide group.
8. The compound of claim 7 , wherein R 2 has the formula —C(Y)—(CH 2 ) s —W, wherein W is halogen.
9. The compound of claim 1 , wherein R 3 is H.
10. The compound of claim 1 , wherein R 3 is NH 2 .
11. The compound of claim 1 , wherein R 3 is NHC(O)R′, wherein R′ is independently selected from H and hydrocarbon groups containing 1-6 carbon atoms.
12. The compound of claim 1 , wherein the compound has the following structure:
13. The compound of claim 1 , wherein the compound has the following structure:
14. The compound of claim 1 , wherein the compound has the following structure:
15. The compound of claim 1 , wherein the compound has the following structure:
16. The compound of claim 1 , wherein the compound has the following structure:
17. The compound of claim 16 , wherein R 1 contains a hydrazide linkage.
18. The compound of claim 16 , wherein R 2 is a group having the formula —C(Y)-E, wherein Y is O or S, and E is a hydrocarbon group containing 1-12 carbon atoms and at least one carbon-carbon or carbon-nitrogen unsaturated bond.
19. The compound of claim 18 , wherein R 2 has the formula —C(Y)—(C═C)—C(O)O—V, where Y is O or S, and V is a hydrocarbon group containing 1-12 carbon atoms, optionally substituted with one or more F atoms.
20. The compound of claim 19 , wherein V is a bulky hydrocarbon group selected from the group consisting of branched alkyl, alkenyl, and alkynyl groups containing 3-6 carbon atoms; and groups of the formula —(CH 2 ) r —U, wherein U is a carbocyclic or heterocyclic group and r is an integer of 0-3.
21. The compound of claim 16 , wherein R 2 is a group having the formula —C(Y)-E, wherein Y is O or S, and E is a hydrocarbon group containing 1-12 carbon atoms and at least one alkyl halide group.
22. The compound of claim 21 , wherein R 2 has the formula —C(Y)—(CH 2 ) s —W, wherein W is halogen.
23. A pharmaceutical composition comprising a compound of Formula (1) and a pharmaceutically acceptable carrier.
24. A method of inhibiting papain-like protease (PLpro) activity in a subject, the method comprising administering a therapeutically effective dosage of a compound of Formula (1) to the subject to result in inhibition of PLpro activity in the subject.
25. The method of claim 24 , wherein the PLpro activity is mediated by a coronavirus PLpro.
26. A method of treating coronavirus infection in a subject, the method comprising administering a therapeutically effective dosage of a compound of Formula (1) to the subject to result in inhibition or prevention of one or more coronavirus symptoms in the subject.