Heterocyclic antiviral agents
The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts, thereof: which inhibit coronavirus replication activity. The invention further relates to pharmaceutical compositions comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof, and methods of treating or preventing a coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.
1. A compound represented by Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
A is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclic;
B is optionally substituted aryl or optionally substituted heteroaryl;
R 1 , R 2 , and R 4 are each independently selected from:
1) Hydrogen;
2) Optionally substituted —C 1 -C 8 alkyl;
3) Optionally substituted —C 2 -C 8 alkenyl;
4) Optionally substituted —C 2 -C 8 alkynyl;
5) Optionally substituted —C 3 -C 8 cycloalkyl;
6) Optionally substituted 3- to 8-membered heterocycloalkyl;
7) Optionally substituted aryl;
8) Optionally substituted arylalkyl;
9) Optionally substituted heteroaryl; and
10) Optionally substituted heteroarylalkyl;
alternatively, R 1 and R 2 are taken together with the carbon atom to which they are attached to form an optionally substituted 3-to 8-membered carbocyclic ring or an optionally substituted 3-to 8-membered heterocyclic ring;
R 3 is selected from:
1) —CN;
2) —C(O)R 15 ;
3) —CH(OH)SO 3 R 16 ;
4) —C(O)NR 13 R 14 ;
5) —C(O)C(O)NR 13 R 14 ; and
6) Optionally substituted —C 2 -C 8 alkynyl;
R 13 and R 14 are each independently selected from:
1) Hydrogen;
2) Optionally substituted —C 1 -C 8 alkyl;
3) Optionally substituted —C 2 -C 8 alkenyl;
4) Optionally substituted —C 2 -C 8 alkynyl;
5) Optionally substituted —C 3 -C 8 cycloalkyl;
6) Optionally substituted 3-to 8-membered heterocycloalkyl;
7) Optionally substituted aryl;
8) Optionally substituted arylalkyl;
9) Optionally substituted heteroaryl; and
10) Optionally substituted heteroarylalkyl;
alternatively, R 13 and R 14 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3-to 8-membered heterocyclic ring;
R 15 is hydrogen, hydroxy, or optionally substituted —C 1 -C 8 alkyl; and
R 16 is hydrogen or Na + .
2. The compound of claim 1 , wherein R 3 is —CN and R 4 is hydrogen.
3. The compound of claim 1 , wherein A is one of the following and is optionally substituted:
4. The compound of claim 1 , represented by Formula (VI), or a pharmaceutically acceptable salt thereof:
wherein each R 9 is independently selected from:
1) Halogen;
2) —CN;
3) —OR 13 ;
4) —SR 13 ;
5) —NR 13 R 14 ;
6) —OC(O)NR 13 R 14 ;
7) Optionally substituted —C 1 -C 6 alkyl;
8) Optionally substituted —C 3 -C 8 cycloalkyl;
9) Optionally substituted 3-to 8-membered heterocycloalkyl;
10) Optionally substituted aryl; and
11) Optionally substituted heteroaryl;
n is 0, 1, 2, 3, or 4; and A, R 1 , R 2 , R 3 , R 4 , R 13 , and R 14 are as defined in claim 1 .
5. The compound of claim 1 , represented by one of Formulae (X-1)˜(X-4), or a pharmaceutically acceptable salt thereof:
wherein each R 10 is independently selected from:
1) Halogen;
2) —CN;
3) —OR 13 ;
4) —SR 13 ;
5) —NR 13 R 14 ;
6) —OC(O)NR 13 R 14 ;
7) Optionally substituted —C 1 -C 6 alkyl;
8) Optionally substituted —C 3 -C 8 cycloalkyl;
9) Optionally substituted 3-to 8-membered heterocycloalkyl;
10) Optionally substituted aryl; and
11) Optionally substituted heteroaryl;
m is 0, 1, 2, 3, or 4; and R 1 , R 13 , and R 14 are as defined in claim 1 .
6. The compound of claim 1 , selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:
Compound
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22-a
22-b
22-c
23
24
25-a
25-b
26-a
26-b
7. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.
8. A method of treating or preventing a virus infection, the method comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
9. A method of treating or preventing a coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds according to claim 1 .
10. The method according to claim 9 , wherein the coronavirus is a 229E, NL63, OC43, HKU1, SARS-COV or a MERS coronavirus.
11. A method of inhibiting viral 3C protease or viral 3CL protease in a subject, comprising administering to said subject an effective amount of a compound according to claim 1 .
12. The method according to claim 11 , wherein the subject is a human.
13. A method of treating a respiratory disorder in a subject in need thereof, comprising administering to the subject an effective amount of a compound of claim 1 .
14. The method according to claim 13 , wherein the compound is administered orally, subcutaneously, intravenously or by inhalation.