Spiropyrrolidine derived antiviral agents
The present invention discloses compounds of Formula (Ia), and pharmaceutically acceptable salts, thereof: which inhibit coronavirus replication activity. The invention further relates to pharmaceutical compositions comprising a compound of Formula (Ia) 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 (Ia) or a pharmaceutically acceptable salt thereof.
1 . A compound represented by Formula (Ia):
or a pharmaceutically acceptable salt thereof, wherein:
A is selected from:
1) —R 11 ;
2) —OR 12 ; and
3) —NR 13 R 14 ;
B is an optionally substituted aryl or optionally substituted heteroaryl;
X is selected from:
1) —CN;
2) —C(O)R 15 ;
3) —CH(OH)SO 3 R 16 ;
4) —C(O)NR 13 R 14 ; and
5) —C(O)C(O)NR 13 R 14 ;
R 1 and R 2 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 hydrogen or optionally substituted —C 1 -C 6 alkyl;
R 4 is hydrogen, optionally substituted —C 1 -C 4 alkyl, optionally substituted —C 2 -C 4 alkenyl, or optionally substituted —C 3 -C 6 cycloalkyl;
R 11 and R 12 are each independently selected from:
1) Optionally substituted —C 1 -C 8 alkyl;
2) Optionally substituted —C 2 -C 8 alkenyl;
3) Optionally substituted —C 2 -C 8 alkynyl;
4) Optionally substituted —C 3 -C 8 cycloalkyl;
5) Optionally substituted 3- to 8-membered heterocycloalkyl;
6) Optionally substituted aryl;
7) Optionally substituted arylalkyl;
8) Optionally substituted heteroaryl; and
9) Optionally substituted heteroarylalkyl;
R 13 and R 14 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 A is selected from the groups set forth below, and A is optionally substituted:
3 . The compound of claim 1 , wherein X is —CN, —C(O)R 5 , or —C(O)C(O)NR 13 R 14 , and R 13 , R 14 , and R 5 are as defined in claim 1 .
4 . The compound of claim 1 , represented by Formula (Ia-2), or a pharmaceutically acceptable salt thereof:
wherein A, B, R 1 , R 3 , R 4 , and X are as defined in claim 1 .
5 . The compound of claim 1 , represented by Formula (IIa), or a pharmaceutically acceptable salt thereof:
wherein n is 0, 1, 2, 3, or 4; each R 9 is independently selected from: halogen; —CN; —OR 11 ; —SR 11 ; —NR 13 R 14 ; —OC(O)NR 13 R 14 ; optionally substituted —C 1 -C 6 alkyl; optionally substituted —C 3 -C 8 cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; and optionally substituted heteroaryl; and A, R 1 , R 2 , R 3 , R 4 , R 11 , R 13 , R 14 , and X are as defined in claim 1 .
6 . The compound of claim 1 , represented by one of Formulas (VIII-1a) to (VIII-5a), or a pharmaceutically acceptable salt thereof;
wherein R 9 is independently selected from: halogen; —CN; —OR 11 ; —SR 11 ; —NR 13 R 14 ; —OC(O)NR 13 R 14 ; optionally substituted —C 1 -C 6 alkyl; optionally substituted —C 3 -C 8 cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; and optionally substituted heteroaryl; R 11 , R 13 , R 14 , A, R 1 , and R 3 are as defined in claim 1 .
7 . The compound of claim 1 , represented by one of Formulas (XIII-1) to (XIII-6), or a pharmaceutically acceptable salt thereof:
wherein each n is 0, 1, 2, 3, or 4; m is 0, 1, 2, 3, 4 or 5; v is 0, 1 or 2; each R 9 is independently selected from: halogen; —CN; —OR 11 ; —SR 11 ; —NR 13 R 14 ; —OC(O)NR 13 R 14 ; optionally substituted —C 1 -C 6 alkyl; optionally substituted —C 3 -C 8 cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; and optionally substituted heteroaryl; each R 10 is optionally substituted —C 1 -C 4 alkyl or optionally substituted —C 3 -C 6 cycloalkyl; and R 4 , R 11 , R 13 , and R 14 are as defined in claim 1 .
8 . The compound of claim 1 represented by Formula (XVIII-1) or Formula (XVIII-2):
wherein n is 0, 1, 2, 3, or 4; R 9 is independently selected from: halogen; —CN; —OR 11 ; —SR 11 ; —NR 13 R 14 ; —OC(O)NR 13 R 14 ; optionally substituted —C 1 -C 6 alkyl; optionally substituted —C 3 -C 8 cycloalkyl; optionally substituted 3- to 8-membered heterocycloalkyl; optionally substituted aryl; and optionally substituted heteroaryl; one U is N or NR 13 , another U is N, NR 13 , or CR 13 , another U is N, NR 13 , or CR 13 , and the fourth U is O, S, N, NR 13 , or CR 13 ; each Vis independently CR 13 or N; and R 1 , R 3 , R 4 , R 9 , R 13 , R 14 , and X are as defined in claim 1 .
9 . A compound selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:
Compound
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10 . A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
11 . A method of treating a coronavirus infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
12 . The method according to claim 11 , wherein the coronavirus is selected from a 229E, NL63, OC43, HKU1, SARS-COV or MERS coronavirus.
13 . The method of claim 12 , wherein the coronavirus is SARS-COV-2.