Heterocyclic compounds as anti-viral agents
The present invention discloses compounds of Formula (I), or pharmaceutically acceptable salts, esters, or prodrugs thereof: which inhibit Respiratory Syncytial Virus (RSV) or HMPV. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from RSV or HMPV infection. The invention also relates to methods of treating an RSV or HMPV 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:
A is an optionally substituted aryl or optionally substituted heteroaryl;
B is O or S;
R 1 and R 2 are each independently hydrogen or an optionally substituted C 1 -C 4 alkyl;
alternatively, R 1 and R 2 are taken together with carbon atom to which they attached to form an optionally substituted 3-6-membered cyclic ring;
R 3 is selected from the group consisting of hydrogen, hydroxy, and optionally substituted C 1 -C 6 alkoxy;
R 4 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkenyl, optionally substituted C 1 -C 6 alkynyl, optionally substituted C 3 -C 6 cycloalkyl, and optionally substituted 3-6 membered heterocyclic;
Z is selected from the group consisting of hydrogen, halogen, cyano, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, and optionally substituted C 1 -C 6 alkoxy;
E is an optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclic;
G is NR 5 R 6 ;
R 5 and R 6 are each independently selected from:
1) hydrogen,
2) optionally substituted C 1 -C 6 alkyl,
3) optionally substituted C 3 -C 6 cycloalkyl,
4) optionally substituted 3-6 membered heterocyclic,
5) optionally substituted aryl,
6) optionally substituted heteroaryl,
7) —C(═O)R 7 ,
8) —C(═O)OR 7 ,
9) —C(═O)NHR 7 ,
10) —C(═NH)R 7 ,
11) —C(═NH)NHR 7 ,
12) —C(═NH)NHCN,
13) —C(═NH)NHC(═O)R 7 ,
14) —SO 2 R 7 , and
15) —SO 2 NHR 7 ,
alternatively, R 5 and R 6 are taken together with the nitrogen they are attached to form an optionally substituted 3-8-membered heterocyclic ring;
wherein, R 7 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3-6 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; and
n is 1, 2 or 3.
2. The compound of claim 1 , wherein E is selected from the groups set forth below,
3. The compound of claim 1 , wherein G is selected from the groups below:
4. The compound of claim 1 , represented by Formula (IIIa) or a pharmaceutically acceptable salt thereof:
wherein A, G, n, E, R 3 , and R 4 are as defined in claim 1 .
5. The compound of claim 1 , represented by one of Formulas (Va′) to (Vd′), or a pharmaceutically acceptable salt thereof:
wherein A, R 4 , E and G are as defined in claim 1 .
6. The compound of claim 1 , represented by one of Formulas (VIIa) and (VIIb), or a pharmaceutically acceptable salt thereof:
wherein each R 11 is independently optionally substituted —C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted —C 3 -C 6 cycloalkyl, halo, —CN, or —NR 7 R 8 ; m is 0, 1, 2, 3, 4 or 5; R 8 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3-6 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; and A, G, R 3 , R 4 , and R 7 are as defined in claim 1 .
7. The compound of claim 1 , represented by one of Formulas (VIIIa) to (VIIIf), or a pharmaceutically acceptable salt thereof:
wherein each R 11 is independently optionally substituted —C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted —C 3 -C 6 cycloalkyl, halo, —CN, or —NR 7 R 8 ; R 8 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3-6 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; each p is independently 0, 1, 2 or 3; each p′ is 0, 1 or 2; each m′ is independently 1, 2 or 3; and G, R 3 , R 4 , and R 7 are as defined in claim 1 .
8. The compound of claim 1 , represented by one of Formulas (Xa), (Xb), (Xc-1), (Xd)˜(Xh), (Xi-1), (Xj), (Xk-1), and (Xm-1), or a pharmaceutically acceptable salt thereof:
wherein each R 11 is independently optionally substituted —C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted —C 3 -C 6 cycloalkyl, halo, —CN, or —NR 7 R 8 ; R 8 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3-6 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; each R 12 is independently hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted —C 3 -C 6 cycloalkyl, halo, —CN, or —NR 7 R 8 ; each R 13 is hydrogen, halo, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 3 -C 6 cycloalkyl, or optionally substituted 3-6-membered heterocyclic; each p is independently 0, 1, 2 or 3; each m′ is independently 1, 2 or 3; and G, R 3 , R 4 , and R 7 are as defined in claim 1 .
9. The compound of claim 1 , represented by one of Formulas (XIVa) to (XIVb), or a pharmaceutically acceptable salt thereof:
wherein each R 11 is independently optionally substituted —C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted —C 3 -C 6 cycloalkyl, halo, —CN, or —NR 7 R 8 ; each R 12 is independently hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted C 1 -C 6 alkoxyl, optionally substituted —C 3 -C 6 cycloalkyl, halo, —CN, or —NR 7 R 8 ; each R 13 is hydrogen, halo, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 3 -C 6 cycloalkyl, or optionally substituted 3-6-membered heterocyclic; R 8 is selected from the group consisting of hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted C 3 -C 6 cycloalkyl, optionally substituted 3-6 membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl; R 7 , G and R 4 are as defined in claim 1 .
10. 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
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
55c
55d
59b
59c
59d
59e
78
79
80
81
82
83
84
11. A pharmaceutical composition comprising the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient.
12. A method of treating or preventing an RSV infection in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound or a combination of compounds of claim 1 .
13. The method of claim 12 , further comprising the step of administering to the subject an additional anti-RSV agent.
14. The method of claim 12 , further comprising administering to the subject a steroid anti-inflammatory compound.
15. 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.
16. The method of claim 14 , wherein the compound and the additional anti-RSV agent are co-formulated.
17. The method of claim 14 , wherein the compound and the additional anti-RSV agent are co-administered.
18. The method of claim 14 , wherein the additional anti-RSV agent is administered at a lower dose or frequency as compared to the dose or frequency of the additional anti-RSV agent which is therapeutically effective when administered alone.
19. A method of treating or preventing an HMPV 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 .
20. The method of claim 19 , further comprising the step of administering to the subject an additional anti-HMPV agent.
21. The method of claim 19 , further comprising administering to the subject a steroid anti-inflammatory compound.
22. The method of claim 20 , wherein the compound and the additional anti-HMPV agent are co-formulated.
23. The method of claim 20 , wherein the compound and the additional anti-HMPV agent are co-administered.