Heterocyclic compounds as RSV inhibitors
The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof: which inhibit Respiratory Syncytial Virus (RSV). The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from RSV infection. The invention also relates to methods of treating an RSV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.
1. A compound represented by Formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
{circle around (A)} is selected from the group consisting of:
1) optionally substituted aryl;
2) optionally substituted heteroaryl;
3) optionally substituted —C 3 -C 12 cycloalkenyl;
4) optionally substituted 3- to 12-membered heterocycloalkyl;
5) optionally substituted arylalkyl;
6) optionally substituted heteroarylalkyl;
7) optionally substituted-C 3 -C 12 cycloalkyl-C 1 -C 6 alkyl;
8) optionally substituted-C 3 -C 12 cycloalkenyl-C 1 -C 6 alkyl; and
9) optionally substituted 3- to 12-membered heterocycloalkyl-C 1 -C 6 alkyl;
{circle around (B)} is selected from the groups below;
{circle around (C)} is aryl or heteroaryl;
L is absent, —CONH—, or —NHCO—;
One of X and Y is selected from O, S, and NR 4 , and the other is N or CR 5 ;
Each R 1 and R 2 is independently selected from the group consisting of: halogen, cyano, nitro, hydroxyl, protected hydroxyl, amino, protected amino, optionally substituted —C 1 -C 8 alkyl, and optionally substituted —C 1 -C 8 alkoxy;
Each R 3 is independently selected from the group consisting of:
1) halogen;
2) optionally substituted —C 1 -C 8 alkoxy;
3) optionally substituted —C 1 -C 8 alkyl;
4) optionally substituted —C 2 -C 8 alkenyl;
5) optionally substituted —C 2 -C 8 alkynyl;
6) optionally substituted —C 3 -C 12 cycloalkyl;
7) optionally substituted —C 3 -C 12 cycloalkenyl;
8) optionally substituted 3- to 12-membered heterocycloalkyl;
9) optionally substituted aryl;
10) optionally substituted heteroaryl;
11) optionally substituted arylalkyl;
12) optionally substituted aryloxy;
13) —C(O)R 12 ;
14) —C(O)NR 13 R 14 ;
15) —C(O)NR 11 S(O) 2 R 12 ;
16) —S(O) 2 NR 13 R 14 ;
17) —NR 13 R 14 ;
18) —NR 11 S(O) 2 R 12 ;
19) —NR 11 C(O)R 12 ;
20) —NR 11 C(O)NR 13 R 14 ; and
21) —NR 11 C(O)NHS(O) 2 R 12 ,
n is 0, 1, 2, 3 or 4;
m is 0, 1, 2, 3 or 4;
v is 0, 1, 2, or 3;
R 4 is hydrogen or optionally substituted —C 1 -C 8 alkyl;
R 5 is hydrogen, halogen, optionally substituted —C 1 -C 8 alkyl, or optionally substituted —C 1 -C 8 alkoxy;
R 12 at each occurrence is independently selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) Hydroxyl;
4) optionally substituted —C 1 -C 8 alkoxy;
5) optionally substituted —C 1 -C 8 alkyl;
6) optionally substituted —C 2 -C 8 alkenyl;
7) optionally substituted —C 2 -C 8 alkynyl;
8) optionally substituted —C 3 -C 8 cycloalkyl;
9) optionally substituted —C 3 -C 8 cycloalkenyl;
10) optionally substituted 3- to 8-membered heterocycloalkyl;
11) optionally substituted aryl;
12) optionally substituted arylalkyl;
13) optionally substituted heteroaryl; and
14) optionally substituted heteroarylalkyl;
R 11 , R 13 and R 14 are each independently selected from hydrogen, optionally substituted —C 1 -C 8 -alkyl, optionally substituted —C 2 -C 8 -alkenyl, optionally substituted —C 2 -C 8 -alkynyl;
optionally substituted —C 3 -C 8 -cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl, and optionally substituted heteroarylalkyl; alternatively R 13 and R 14 are taken together with the nitrogen atom they attached to form a heterocyclic ring.
2. The compound of claim 1 , wherein L is —CONH— or —NHCO—.
3. The compound of claim 1 , wherein {circle around (A)} is derived from one of the groups below by removal of a ring hydrogen atom:
wherein each group is optionally substituted.
4. The compound of claim 1 , wherein {circle around (A)} is one of the groups below
wherein each group is optionally substituted.
5. The compound of claim 1 , wherein {circle around (C)} is derived from one of the groups below by removal of one hydrogen atom:
6. The compound of claim 1 , wherein R 3 is selected from one of the following groups, wherein each of the groups is optionally substituted:
7. The compound of claim 1 , wherein
is represented by
where R is hydrogen or methyl.
8. The compound of claim 1 , represented by one of Formulas (IIa-1)˜(IIa-4), or (IIb-1)˜(IIb-4), or (IIc-1)˜(IIc-4), or a pharmaceutically acceptable salt thereof:
wherein {circle around (A)}, {circle around (B)}, {circle around (C)}, R 1 , R 2 , R 3 , R 5 , n, m, and v are as defined in claim 1 .
9. The compound of claim 1 , represented by one of Formulas (IIIa)˜(IIId), or a pharmaceutically acceptable salt thereof:
wherein {circle around (B)}, {circle around (C)}, L, R 1 , R 2 , R 3 , n, m, and v are as defined in claim 1 ; m1 is 0, 1, 2, 3 or 4; m2 is 0, 1 or 2; each R 22 is independently selected from hydrogen and —CH 3 ; and each R 21 is independently selected from halogen, —NH 2 , optionally substituted —C 1 -C 3 alkyl, and optionally substituted —C 1 -C 3 alkoxy.
10. The compound of claim 1 , represented by one of Formulas (IIIa-1)˜(IIId-1), or (IIIa-2)˜(IIId-2), or (IIIa-3)˜(IIId-3), or (IIIa-4)˜(IIId-4), or a pharmaceutically acceptable salt thereof:
wherein {circle around (B)}, X, Y, L, R 1 , R 2 , R 3 , n and m are as defined in claim 1 , m1 is 0, 1, 2, 3 or 4; m2 is 0, 1 or 2; v′ is 0, 1, 2, or 3; v″ is 0, 1, or 2; each R 22 is independently selected from hydrogen and —CH 3 ; and each R 21 is independently selected from halogen, —NH 2 , optionally substituted —C 1 -C 3 alkyl, and optionally substituted —C 1 -C 3 alkoxy.
11. The compound of claim 1 , represented by one of Formulas (IVa-1)˜(IVd-1), or (IVa-2)˜(IVd-2), or (IVa-3)˜(IVd-3), or (IVa-4)˜(IVd-4), or a pharmaceutically acceptable salt thereof:
wherein {circle around (B)}, X, Y, L, R 1 , R 2 , R 3 , n and m are as defined in claim 1 , m1 is 0, 1, 2, 3 or 4; m2 is 0, 1 or 2; v′ is 0, 1, 2, or 3; v″ is 0, 1, or 2; each R 22 is independently selected from hydrogen and —CH 3 ; and each R 21 is independently selected from halogen, —NH 2 , optionally substituted —C 1 -C 3 alkyl, and optionally substituted —C 1 -C 3 alkoxy.
12. The compound of claim 1 , represented by one of Formulas (V-1) to (V-4), or a pharmaceutically acceptable salt thereof:
wherein {circle around (A)}, {circle around (C)}, X, Y, L, R 1 , R 2 , R 3 , n, m, and v are as defined in claim 1 .
13. The compound of claim 1 , represented by one of Formulas (VI-1) to (VI-4), or a pharmaceutically acceptable salt thereof:
wherein {circle around (C)}, X, Y, L, R 1 , R 2 , R 3 , n, m, and v are as defined in claim 1 ; w is 1, 2 or 3; and {circle around (a)} is derived from one of the following groups by removal of a ring hydrogen atom:
wherein each group is optionally substituted.
14. The compound of claim 1 , represented by one of Formulas (VII-1)˜(VII-4), or a pharmaceutically acceptable salt thereof:
wherein {circle around (B)}, {circle around (C)}, L, R 1 , R 2 , R 3 , R 5 , n, m, and v are as defined in claim 1 ; w is 1, 2 or 3; and {circle around (a)} is derived from one of the following groups by removal of a ring hydrogen atom:
wherein each group is optionally substituted.
15. The compound of claim 1 , represented by one of Formulas (VIII-1)˜(VIII-4), or a pharmaceutically acceptable salt thereof:
wherein {circle around (B)}, L, X, Y, R 1 , R 2 , R 3 , n, m, and v are as defined in claim 1 ; v′ is 0, 1, 2, or 3; v″ is 0, 1, or 2; w is 1, 2 or 3; and {circle around (a)} is derived from one of the following groups by removal of a ring hydrogen atom:
wherein each group is optionally substituted.
16. A compound selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:
Com-
pound
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17. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier, diluent or excipient.
18. A method of treating an RSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound or a combination of compounds of claim 1 .
19. The method of claim 18 further comprising the step of administering to the subject an additional anti-RSV agent.
20. The method of claim 18 , further comprising administering to the subject a steroid anti-inflammatory compound.
21. A method of treating RSV and influenza in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 and a therapeutically effective amount of an anti-influenza agent.
22. The method of claim 19 , wherein the compound and the additional anti-RSV agent are co-formulated.
23. The method of claim 19 , wherein the compound and the additional anti-RSV agent are co-administered.