Benzodiazepine derivatives 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:
A is optionally substituted heteroaryl;
n is 0, 1, 2, 3, or 4;
m is 0, 1, 2, 3, or 4;
R 1 and R 2 are each independently selected from the group consisting of:
1) Halogen;
2) —CN;
3) Optionally substituted —C 1 -C 8 alkyl;
4) Optionally substituted —C 2 -C 8 alkenyl;
5) Optionally substituted —C 2 -C 8 alkynyl; and
6) Optionally substituted —C 1 -C 8 alkoxyl;
R 3 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) —CN;
4) —NR 6 R 7 ;
5) Optionally substituted —C 1 -C 8 alkyl;
6) Optionally substituted —C 1 -C 8 alkoxyl;
7) Optionally substituted —C 2 -C 8 alkenyl;
8) Optionally substituted —C 2 -C 8 alkynyl;
9) Optionally substituted —C 3 -C 8 cycloalkyl;
10) Optionally substituted —C 3 -C 8 cycloalkenyl;
11) Optionally substituted 3- to 8-membered heterocyclyl;
12) Optionally substituted aryl; and
13) Optionally substituted heteroaryl;
wherein R 6 and R 7 are each independently selected from the group consisting of:
1) Hydrogen;
2) Optionally substituted —C 1 -C 8 alkyl;
3) Optionally substituted —C 3 -C 8 cycloalkyl;
4) Optionally substituted —C 3 -C 8 cycloalkenyl;
5) Optionally substituted 3- to 8-membered heterocyclic;
6) Optionally substituted aryl; and
7) Optionally substituted heteroaryl;
alternatively, R 6 and R 7 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring;
and R 4 and R 5 are each independently selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) —CN;
4) Optionally substituted —C 1 -C 8 alkyl;
5) Optionally substituted —C 1 -C 8 alkoxyl;
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; and
10) Optionally substituted 3- to 8-membered heterocyclic.
2. The compound of claim 1 , wherein the compound is represented by Formula (Ib):
or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , n, m, and A are as defined in claim 1 .
3. The compound of claim 1 , wherein A is selected from the group consisting of:
wherein one of the indicated valences is the point of attachment to the 1,3,4-oxadiazole ring, and the other is the point of attachment to the pyrimidine ring; R 11 , R 12 , and R 13 are each independently selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) —NO 2 ;
4) —NR 6 R 7 ;
5) —CN;
6) Optionally substituted —C 1 -C 8 alkyl;
7) Optionally substituted —C 1 -C 8 alkoxyl;
8) Optionally substituted —C 2 -C 8 alkenyl;
9) Optionally substituted —C 2 -C 8 alkynyl;
10) Optionally substituted —C 3 -C 8 cycloalkyl;
11) Optionally substituted —C 3 -C 8 cycloalkenyl;
12) Optionally substituted 3- to 8-membered heterocyclyl;
13) Optionally substituted aryl; and
14) Optionally substituted heteroaryl; and
R 14 is selected from the group consisting of:
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 —C 3 -C 8 cycloalkenyl;
7) Optionally substituted 3- to 8-membered heterocyclyl;
8) Optionally substituted aryl; and
9) Optionally substituted heteroaryl.
4. The compound of claim 1 , represented by one of Formulae (II-1)˜(II-6), or a pharmaceutically acceptable salt thereof,
wherein R 1 , R 2 , R 3 , R 4 , R 5 , n, m, are as defined in claim 1 , and R 11 , R 12 , and R 13 are each independently selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) —NO 2 ;
4) —NR 6 R 7 ;
5) —CN;
6) Optionally substituted —C 1 -C 8 alkyl;
7) Optionally substituted —C 1 -C 8 alkoxyl;
8) Optionally substituted —C 2 -C 8 alkenyl;
9) Optionally substituted —C 2 -C 8 alkynyl;
10) Optionally substituted —C 3 -C 8 cycloalkyl;
11) Optionally substituted —C 3 -C 8 cycloalkenyl;
12) Optionally substituted 3- to 8-membered heterocyclyl;
13) Optionally substituted aryl; and
14) Optionally substituted heteroaryl.
5. The compound of claim 1 , represented by one of Formulae (Vb-1)˜(Vb-6), or a pharmaceutically acceptable salt thereof,
wherein R 1 , R 2 , R 3 , R 4 , R 5 , n, and m are as defined in claim 1 , and R 11 and R 12 are each independently selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) —NO 2 ;
4) —NR 6 R 7 ;
5) —CN;
6) Optionally substituted —C 1 -C 8 alkyl;
7) Optionally substituted —C 1 -C 8 alkoxyl;
8) Optionally substituted —C 2 -C 8 alkenyl;
9) Optionally substituted —C 2 -C 8 alkynyl;
10) Optionally substituted —C 3 -C 8 cycloalkyl;
11) Optionally substituted —C 3 -C 8 cycloalkenyl;
12) Optionally substituted 3- to 8-membered heterocyclyl;
13) Optionally substituted aryl; and
14) Optionally substituted heteroaryl;
and R 14 is selected from the group consisting of:
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 —C 3 -C 8 cycloalkenyl;
7) Optionally substituted 3- to 8-membered heterocyclyl;
8) Optionally substituted aryl; and
9) Optionally substituted heteroaryl.
6. The compound of claim 1 , represented by one of Formulae (VI-1)˜(VI-6), or a pharmaceutically acceptable salt thereof,
wherein R 1 and R 3 , are as defined in claim 1 , and R 11 , R 12 , and R 13 are each independently selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) —NO 2 ;
4) —NR 6 R 7 ;
5) —CN;
6) Optionally substituted —C 1 -C 8 alkyl;
7) Optionally substituted —C 1 -C 8 alkoxyl;
8) Optionally substituted —C 2 -C 8 alkenyl;
9) Optionally substituted —C 2 -C 8 alkynyl;
10) Optionally substituted —C 3 -C 8 cycloalkyl;
11) Optionally substituted —C 3 -C 8 cycloalkenyl;
12) Optionally substituted 3- to 8-membered heterocyclyl;
13) Optionally substituted aryl; and
14) Optionally substituted heteroaryl.
7. The compound of claim 1 , represented by one of Formulae (VIII-1)˜(VIII-4), or a pharmaceutically acceptable salt thereof,
wherein X is H or R 1 ; R 1 is as defined in claim 1 ; and R 11 and R 12 are each independently selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) —NO 2 ;
4) —NR 6 R 7 ;
5) —CN;
6) Optionally substituted —C 1 -C 8 alkyl;
7) Optionally substituted —C 1 -C 8 alkoxyl;
8) Optionally substituted —C 2 -C 8 alkenyl;
9) Optionally substituted —C 2 -C 8 alkynyl;
10) Optionally substituted —C 3 -C 8 cycloalkyl;
11) Optionally substituted —C 3 -C 8 cycloalkenyl;
12) Optionally substituted 3- to 8-membered heterocyclyl;
13) Optionally substituted aryl; and
14) Optionally substituted heteroaryl.
8. The compound of claim 1 , represented by one of Formulae (VIIIb-1)˜(VIIIb-4), or a pharmaceutically acceptable salt thereof,
wherein X is H or R 1 ; R 1 is as defined in claim 1 ; R 11 and R 12 are each independently selected from the group consisting of:
1) Hydrogen;
2) Halogen;
3) —NO 2 ;
4) —NR 6 R 7 ;
5) —CN;
6) Optionally substituted —C 1 -C 8 alkyl;
7) Optionally substituted —C 1 -C 8 alkoxyl;
8) Optionally substituted —C 2 -C 8 alkenyl;
9) Optionally substituted —C 2 -C 8 alkynyl;
10) Optionally substituted —C 3 -C 8 cycloalkyl;
11) Optionally substituted —C 3 -C 8 cycloalkenyl;
12) Optionally substituted 3- to 8-membered heterocyclyl;
13) Optionally substituted aryl; and
14) Optionally substituted heteroaryl.
9. The compound of claim 1 , which is selected from compounds of Formulas (VII-1) and (VII-2), or a pharmaceutically acceptable salt thereof:
wherein X, R 3 , and R 12 for each compound are delineated in the table below,
Entry
X
R 3
R 12
1-1
H
Methyl
Methyl
1-2
H
Methyl
Ethyl
1-3
H
Methyl
Isopropyl
1-4
H
Methyl
Propyl
1-5
H
Methyl
Vinyl
1-6
H
Methyl
Allyl
1-7
H
Methyl
CF 3
1-8
H
Methyl
CHF 2
1-9
H
Methyl
CN
1-10
H
Methyl
1-11
H
Methyl
1-12
H
Methyl
1-13
H
Methyl
1-14
H
Methyl
1-15
H
Methyl
1-16
H
Methyl
1-17
H
Ethyl
Methyl
1-18
H
Ethyl
Ethyl
1-19
H
Ethyl
Isopropyl
1-20
H
Ethyl
Propyl
1-21
H
Ethyl
Vinyl
1-22
H
Ethyl
Allyl
1-23
H
Ethyl
CF 3
1-24
H
Ethyl
CHF 2
1-25
H
Ethyl
CN
1-26
H
Ethyl
1-27
H
Ethyl
1-28
H
Ethyl
1-29
H
Ethyl
1-30
H
Ethyl
1-31
H
Ethyl
1-32
H
Ethyl
1-33
H
Methyl
1-34
H
Ethyl
1-35
H
Isopropyl
1-36
H
Propyl
1-37
H
Vinyl
1-38
H
Allyl
1-39
H
CF 3
1-40
H
CHF 2
1-41
H
CN
1-42
H
1-43
H
1-44
H
1-45
H
1-46
H
1-47
H
1-48
H
1-49
F
Methyl
Methyl
1-50
F
Methyl
Ethyl
1-51
F
Methyl
Isopropyl
1-52
F
Methyl
Propyl
1-53
F
Methyl
Vinyl
1-54
F
Methyl
Allyl
1-55
F
Methyl
CF 3
1-56
F
Methyl
CHF 2
1-57
F
Methyl
CN
1-58
F
Methyl
1-59
F
Methyl
1-60
F
Methyl
1-61
F
Methyl
1-62
F
Methyl
1-63
F
Methyl
1-64
F
Methyl
1-65
F
Ethyl
Methyl
1-66
F
Ethyl
Ethyl
1-67
F
Ethyl
Isopropyl
1-68
F
Ethyl
Propyl
1-69
F
Ethyl
Vinyl
1-70
F
Ethyl
Allyl
1-71
F
Ethyl
CF 3
1-72
F
Ethyl
CHF 2
1-73
F
Ethyl
CN
1-74
F
Ethyl
1-75
F
Ethyl
1-76
F
Ethyl
1-77
F
Ethyl
1-78
F
Ethyl
1-79
F
Ethyl
1-80
F
Ethyl
1-81
F
Methyl
1-82
F
Ethyl
1-83
F
Isopropyl
1-84
F
Propyl
1-85
F
Vinyl
1-86
F
Allyl
1-87
F
CF 3
1-88
F
CHF 2
1-89
F
CN
1-90
F
1-91
F
1-92
F
1-93
F
1-94
F
1-95
F
1-96
F
10. The compound of claim 1 , which is selected from compounds of Formula (VII-3) and (VII-4), or a pharmaceutically acceptable salt thereof:
wherein X, R 3 , and R 11 for each compound are delineated in the table below,
Entry
X
R 3
R 11
2-1
H
Methyl
Methyl
2-2
H
Methyl
Ethyl
2-3
H
Methyl
Isopropyl
2-4
H
Methyl
Butyl
2-5
H
Methyl
t-Butyl
2-6
H
Methyl
Propyl
2-7
H
Methyl
Benzyl
2-8
H
Methyl
Vinyl
2-9
H
Methyl
Allyl
2-10
H
Methyl
CF 3
2-11
H
Methyl
2-12
H
Methyl
2-13
H
Methyl
2-14
H
Methyl
2-15
H
Methyl
2-16
H
Methyl
2-17
H
Ethyl
Methyl
2-18
H
Ethyl
Ethyl
2-19
H
Ethyl
Isopropyl
2-20
H
Ethyl
Butyl
2-21
H
Ethyl
t-Butyl
2-22
H
Ethyl
Propyl
2-23
H
Ethyl
Benzyl
2-24
H
Ethyl
Vinyl
2-25
H
Ethyl
Allyl
2-26
H
Ethyl
CF 3
2-27
H
Ethyl
2-28
H
Ethyl
2-29
H
Ethyl
2-30
H
Ethyl
2-31
H
Ethyl
2-32
H
Ethyl
2-33
H
Methyl
2-34
H
Ethyl
2-35
H
Isopropyl
2-36
H
Butyl
2-37
H
t-Butyl
2-38
H
Propyl
2-39
H
Benzyl
2-40
H
Vinyl
2-41
H
Allyl
2-42
H
CF 3
2-43
H
2-44
H
2-45
H
2-46
H
2-47
H
2-48
H
2-49
F
Methyl
Methyl
2-50
F
Methyl
Ethyl
2-51
F
Methyl
Isopropyl
2-52
F
Methyl
Butyl
2-53
F
Methyl
t-Butyl
2-54
F
Methyl
Propyl
2-55
F
Methyl
Benzyl
2-56
F
Methyl
Vinyl
2-57
F
Methyl
Allyl
2-58
F
Methyl
CF 3
2-59
F
Methyl
2-60
F
Methyl
2-61
F
Methyl
2-62
F
Methyl
2-63
F
Methyl
2-64
F
Methyl
2-65
F
Ethyl
Methyl
2-66
F
Ethyl
Ethyl
2-67
F
Ethyl
Isopropyl
2-68
F
Ethyl
Butyl
2-69
F
Ethyl
t-Butyl
2-70
F
Ethyl
Propyl
2-71
F
Ethyl
Benzyl
2-77
F
Ethyl
Vinyl
2-73
F
Ethyl
Allyl
2-74
F
Ethyl
CF 3
2-75
F
Ethyl
2-76
F
Ethyl
2-77
F
Ethyl
2-78
F
Ethyl
2-79
F
Ethyl
2-80
F
Ethyl
2-81
F
Methyl
2-82
F
Ethyl
2-83
F
Isopropyl
2-84
F
Butyl
2-85
F
t-Butyl
2-86
F
Propyl
2-87
F
Benzyl
2-88
F
Vinyl
2-89
F
Allyl
2-90
F
CF 3
2-91
F
2-92
F
2-93
F
2-94
F
2-95
F
2-96
F
11. A compound selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:
Com-
pound
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
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
12. A pharmaceutical composition, comprising a compound according to claim 6 and a pharmaceutically acceptable carrier, diluent or excipient.
13. 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 a compound or a combination of compounds of claim 6 .
14. The method of claim 13 , further comprising administering to the subject at least one additional therapeutic agent.
15. The method of claim 14 , wherein the at least one additional therapeutic agent is a steroid anti-inflammatory compound.
16. The method of claim 13 , wherein the subject is further in need of treatment for influenza, further comprising administering to the subject a therapeutically effective amount of an anti-influenza compound.
17. The method of claim 14 , wherein the compound and the at least one additional therapeutic agent are co-formulated.
18. The method of claim 14 , wherein the compound and the at least one additional therapeutic agent are co-administered.
19. The method of claim 14 , wherein the at least one additional therapeutic agent is administered at a lower dose or frequency than that required when administered alone to prophylactically treat an RSV infection in an individual in need thereof.