Anti-viral compounds
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure:
wherein:
Ring A 1 is
Ring A 2 is an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl;
R 1 is selected from the group consisting of cyano, an unsubstituted or a substituted C 2-5 alkynyl, an unsubstituted or a substituted ketoamide, —CH(OH)—(S(═O) 2 —O − ), —CH(OH)((P═O)(OR 6 ) 2 ) and —C(═O)CH 2 —O—((P═O)(OR 7 ) 2 ),
R 2 is hydrogen, deuterium or halogen;
R 3 is an unsubstituted or a substituted C-amido(C 1-4 alkyl), an unsubstituted or a substituted monocyclic nitrogen-containing heteroaryl(C 1-4 alkyl), an unsubstituted or a substituted monocyclic nitrogen-containing heterocyclyl(C 1-4 alkyl), an unsubstituted or a substituted bicyclic nitrogen-containing heteroaryl(C 1-4 alkyl) or an unsubstituted or a substituted bicyclic nitrogen-containing heterocyclyl(C 1-4 alkyl);
R 4 is hydrogen, deuterium or halogen;
R 8a is selected from the group consisting of an unsubstituted or a substituted C 2-6 alkyl, an unsubstituted or a substituted C 2-6 alkenyl, an unsubstituted or a substituted C 2-6 alkynyl, an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl, an unsubstituted or a substituted bicyclic C 5-8 cycloalkyl and an unsubstituted or a substituted monocyclic 4- to 6-membered heterocyclyl,
wherein when the C 2-6 alkyl is substituted, the C 2-6 alkyl is substituted 1, 2, 3 or 4 times with a substituent independently selected from the group consisting of halogen, cyano, an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl, an unsubstituted C 1-4 alkoxy and an unsubstituted C 1-4 haloalkoxy, or the C 2-6 alkyl is substituted 1 to 13 times with deuterium;
wherein when the C 2-6 alkenyl, the C 2-6 alkynyl, the monocyclic C 3-6 cycloalkyl, the bicyclic C 5-8 cycloalkyl and the monocyclic 4- to 6-membered heterocyclyl are substituted, the C 2-6 alkenyl, the C 2-6 alkynyl, the monocyclic C 3-6 cycloalkyl, the bicyclic C 5-8 cycloalkyl and the monocyclic 4- to 6-membered heterocyclyl are substituted 1, 2, 3 or 4 times with a substituent independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 2-4 alkenyl, an unsubstituted C 2-4 alkynyl, an unsubstituted C 1-6 haloalkyl, an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl and an unsubstituted C 1-4 alkoxy; and
R 8b is selected from the group consisting of an unsubstituted or a substituted C 1-6 alkyl, an unsubstituted or a substituted C 1-6 haloalkyl, an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl, an unsubstituted or a substituted bicyclic C 5-6 cycloalkyl, an unsubstituted or a substituted monocyclic heteroaryl and an unsubstituted or a substituted monocyclic heterocyclyl, wherein the substituted C 1-6 alkyl is substituted 1 or 2 times with an unsubstituted C 1-4 alkoxy, wherein the substituted monocyclic C 3-6 cycloalkyl is substituted 1, 2, 3 or 4 times with a substituent independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 2-4 alkenyl, an unsubstituted C 1-4 alkoxy, an unsubstituted C 1-4 haloalkyl and an unsubstituted monocyclic C 3-6 cycloalkyl, and wherein the substituted C 1-6 haloalkyl is substituted 1 or 2 times with an unsubstituted C 1-4 alkoxy; and
each R 6 and each R 7 are independently hydrogen, an unsubstituted C 1-6 alkyl, an unsubstituted C 2-6 alkenyl, an unsubstituted C 1-6 haloalkyl, an unsubstituted or a substituted aryl or an unsubstituted or a substituted aryl(C 1-4 alkyl).
2. The compound of claim 1 , wherein Ring A 2 is an unsubstituted monocyclic C 3-6 cycloalkyl.
3. The compound of claim 2 , wherein R 8a is an unsubstituted C 2-6 alkyl; and R 8b is an unsubstituted C 1-6 haloalkyl.
4. The compound of claim 2 , wherein R 5 is selected from the group consisting of:
5. The compound of claim 1 , wherein R 1 is cyano.
6. The compound of claim 1 , wherein R 3 is an unsubstituted or a substituted monocyclic nitrogen-containing heterocyclyl(C 1-4 alkyl).
7. The compound of claim 6 , wherein the monocyclic nitrogen-containing heterocyclyl(C 1-4 alkyl) is azepan-2-one(C 1-4 alkyl), imidazolidin-2-one(C 1-4 alkyl), tetrahydropyrimidin-2-one(C 1-4 alkyl), pyrrolidin-2-one(C 1-4 alkyl), piperidin-2-one(C 1-4 alkyl), pyrazolidin-3-one(C 1-4 alkyl), oxazolidin-4-one(C 1-4 alkyl) 1,4-oxazepan-3-one(C 1-4 alkyl) or morpholin-3-one(C 1-4 alkyl).
8. The compound of claim 1 , wherein R 3 is
9. The compound of claim 1 , wherein R 3 is selected from the group consisting of:
10. The compound of claim 1 , wherein R 2 is hydrogen; and R 4 is hydrogen.
11. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or pharmaceutically acceptable salt of any of the foregoing.
12. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or pharmaceutically acceptable salt of any of the foregoing.
13. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and excipient.
14. A method for treating a coronavirus infection in a subject comprising administering to the subject in need thereof an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
15. The method of claim 14 , further comprising administering an additional agent selected from the group consisting of an ACE inhibitor, an anticoagulant, an anti-inflammatory, an ARB, an ASO, a Covid-19 convalescent plasma, an entry inhibitor, an H 2 pump antagonist, an H-conducting channel, an HIV protease inhibitor, an HMG-CoA reductase inhibitor, an immune globulin, an immunosuppressant, an immunotherapeutic agent, a neuraminidase inhibitor, a nucleoside inhibitor, a nucleoside analog inhibitor, a polymerase inhibitor, a protease inhibitor, an siRNA, a statin, a tissue plasminogen activator, an antibiotic, an antimicrobial and a vaccine.
16. A method for inhibiting a coronavirus protease comprising contacting a cell infected with a coronavirus with an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound selectively inhibits the coronavirus protease of the coronavirus compared to Cathepsin L.
17. The compound of claim 2 , wherein the unsubstituted monocyclic C 3-6 cycloalkyl is an unsubstituted cyclopropyl.
18. The compound of claim 9 , wherein R 3 is selected from the group consisting of:
19. The compound of claim 4 , wherein R 5 is selected from the group consisting of:
20. The compound of claim 19 , wherein R 2 is hydrogen; and R 4 is hydrogen.
21. The compound of claim 20 , wherein R 1 is cyano.
22. The compound of claim 21 , wherein R 3 is an unsubstituted or a substituted monocyclic nitrogen-containing heterocyclyl(C 1-4 alkyl).
23. The compound of claim 22 , wherein R 3 is selected from the group consisting of: