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:
Z 1 is —C(═O)— or —CH(CF 3 )—;
Z 2 is O, S or NR 8 , wherein R 8 is H or an unsubstituted C 1-4 alkyl;
Z 3 is N or C, and when Z 3 is N, then R 5 is absent;
Ring A 1 is selected from the group consisting of an unsubstituted or a substituted azetidine, an unsubstituted or a substituted pyrrolidine and an unsubstituted or a substituted piperidine, wherein the azetidine, the pyrrolidine and the piperidine can be optionally substituted with one or more R x groups independently selected from the group consisting of deuterium, halogen, an unsubstituted or a substituted C 1-4 alkyl, an unsubstituted or a substituted C 2-4 alkenyl, an unsubstituted or a substituted C 1-8 alkoxy, an unsubstituted or a substituted C 3-6 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted heterocyclyl and an unsubstituted C 1-4 haloalkyl, and wherein the azetidine, the pyrrolidine and the piperidine can be connected to a cyclic moiety selected from the group consisting of a monocyclic C 3-7 cycloalkyl, a bicyclic C 5-9 cycloalkyl, a monocyclic C 3-7 cycloalkenyl, a bicyclic C 5-9 cycloalkenyl and phenyl, wherein the cyclic moiety is connected to the azetidine, the pyrrolidine and the piperidine in a fused-fashion or a spiro-fashion that can be optionally substituted with one or more moieties independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl, an unsubstituted C 2-4 alkenyl and an unsubstituted or a substituted C 3-6 monocyclic 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, an unsubstituted or a substituted —C(═O)—N-sulfonamido, CH(OH)((P═O)(OR 9 ) 2 ), —C(═O)CH 2 'O—(P═O)(OR 10 ) 2 ), —C(═O)CH 2 —O—C(R 11A ) 2 —O—((P═O)(OR 11B ) 2 ), —C(═O)CH 2 —O—C(R 12A ) 2 —O—C(═O)—OR 12B and —C(═O)CH 2 —O—C(R 13A ) 2 —O—C(═O)—R 13B , wherein each R 9 , each R 10 , each R 11B and R 12B and R 13B 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);
each R 11A , each R 12A and each R 13A are independently hydrogen or an unsubstituted C 1-4 alkyl;
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(C1-4 alkyl);
R 4 is hydrogen, deuterium or halogen;
R 5 is selected from the group consisting of hydrogen, deuterium, halogen, an unsubstituted C 1-6 alkyl and an unsubstituted C14 haloalkyl; and
R 6 and R 7 are independently selected from the group consisting of hydrogen, deuterium, halogen, an unsubstituted or a substituted C 1-6 alkyl, an unsubstituted or a substituted phenyl, an unsubstituted or a substituted acyl, an unsubstituted or a substituted C-carboxy and an unsubstituted or a substituted sulfonyl; or
R 6 and R 7 are taken together with the carbon to which R 6 and R 7 are each attached to form an optionally substituted 4-9 membered saturated or unsaturated ring or ring system that can optionally contain 1 or 2 ring heteroatoms selected from the group consisting of O, N and S.
2. The compound of claim 1 , wherein R 1 is an unsubstituted or a substituted ketoamide.
3. The compound of claim 1 , wherein R 1 is CH(OH)((P═O)(OR 9 ) 2 ), wherein each R 9 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), or —C(═O)CH 2 —O—((P═O)(OR 10 ) 2 ), wherein each R 10 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).
4. The compound of claim 1 , wherein Z 1 is —C(═O)—.
5. The compound of claim 1 , wherein Ring A 1 is an unsubstituted or a substituted pyrrolidine.
6. The compound of claim 1 , wherein Ring A 1 is an unsubstituted or a substituted azetidine, wherein the azetidine is connected to a cyclic moiety selected from the group consisting of a monocyclic C 3-7 cycloalkyl, a bicyclic C 5-9 cycloalkyl, a monocyclic C 3-7 cycloalkenyl, a bicyclic C 5-9 cycloalkenyl and phenyl, wherein the cyclic moiety is connected to the azetidine in a fused-fashion or a spiro-fashion that can be optionally substituted with one or more moieties independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl and an unsubstituted C 2-4 alkenyl, or an unsubstituted or a substituted pyrrolidine, wherein the pyrrolidine is connected to a cyclic moiety selected from the group consisting of a monocyclic C 3-7 cycloalkyl, a bicyclic C 5-9 cycloalkyl, a monocyclic C 3-7 cycloalkenyl, a bicyclic C 5-9 cycloalkenyl and phenyl, wherein the cyclic moiety is connected to the pyrrolidine in a fused-fashion or a spiro-fashion that can be optionally substituted with one or more moieties independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl and an unsubstituted C 2-4 alkenyl, or an unsubstituted or a substituted piperidine, wherein the piperidine is connected to a cyclic moiety selected from the group consisting of a monocyclic C 3-7 cycloalkyl, a bicyclic C 5-9 cycloalkyl, a monocyclic C 3-7 cycloalkenyl, a bicyclic C 5-9 cycloalkenyl and phenyl, wherein the cyclic moiety is connected to the piperidine in a fused-fashion or a spiro-fashion that can be optionally substituted with one or more moieties independently selected from the group consisting of halogen, an unsubstituted C 1-4 alkyl and an unsubstituted C 2-4 alkenyl.
7. The compound of claim 1 , wherein Z 2 is NR 8 ; and Z 3 is CR 5 .
8. The compound of claim 1 , wherein R 6 and R 7 are taken together with the carbon to which R 6 and R 7 are each attached to form an optionally substituted 4-7 membered unsaturated ring that can optionally contain 1 or 2 ring heteroatoms selected from the group consisting of O, N and S.
9. The compound of claim 8 , wherein R 6 and R 7 are taken together with the carbon to which R 6 and R 7 are each attached to form an optionally substituted phenyl ring.
10. The compound of claim 1 , wherein R 3 is an unsubstituted or a substituted monocyclic nitrogen-containing heterocyclyl(C 1-4 alkyl) or an unsubstituted or a substituted bicyclic nitrogen-containing heterocyclyl(C 1-4 alkyl).
11. The compound of claim 1 , wherein R 2 is hydrogen; and R 4 is hydrogen.
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. The compound of claim 1 , wherein the compound is selected from the group consisting of:
or pharmaceutically acceptable salt of any of the foregoing.
14. A pharmaceutical composition comprising an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and excipient.
15. 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.
16. The method of claim 15 , 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.
17. A method for treating a 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, wherein the infection is selected from the group consisting of a picornavirus infection and a norovirus infection.
18. 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, or a pharmaceutically acceptable salt thereof, selectively inhibits the coronavirus protease compared to a host protease.