Heteroaryldiazepine derivatives as RSV inhibitors
The present invention discloses compounds of Formula (I), and pharmaceutically acceptable salts, esters, or prodrugs thereof: These compounds are useful for treating Respiratory Syncytial Virus (RSV) infection. The present invention further relates to pharmaceutical compositions comprising these 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 to the subject a pharmaceutical composition comprising a compound of the invention.
1. A compound represented by Formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
A is heteroaryl;
B is selected from the group consisting of:
R 1 is optionally substituted aryl or optionally substituted heteroaryl;
R 2 is selected from the group consisting of:
1) optionally substituted —C 3 -C 12 cycloalkyl;
2) optionally substituted —C 3 -C 12 cycloalkenyl;
3) optionally substituted 3- to 12-membered heterocyclyl;
4) optionally substituted aryl;
5) optionally substituted heteroaryl;
6) —NR 13 R 14 ;
7) —CO—NR 13 R 14 ; and
8) —SO 2 —NR 13 R 14 ;
each R 3 is the same or different and independently selected from halogen, hydroxyl, protected hydroxyl, cyano, amino, protected amino, nitro, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 1 -C 8 alkoxy, optionally substituted —NHC 1 -C 8 alkyl, optionally substituted —S—(—C 1 -C 8 alkyl), optionally substituted —SO 2 —(—C 1 -C 8 alkyl), —optionally substituted —SO 2 —NH—(—C 1 -C 8 alkyl), optionally substituted —NH—SO 2 —(—C 1 -C 8 alkyl), —CO 2 R 11 , —NR 13 R 14 , and —CO—NR 13 R 14 ;
each R 11 is independently selected from the group consisting of:
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 —C 3 -C 8 cycloalkenyl;
6) optionally substituted 3- to 8-membered heterocycloalkyl;
7) optionally substituted aryl; and
8) optionally substituted heteroaryl; and
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 —C 1 -C 8 -alkoxy, —C(O)R 11 , —S(O) 2 R 11 , and —S(O) 2 NHR 11 ; alternatively, R 13 and R 14 are taken together with the nitrogen atom to which they attached to form a heterocyclic ring; and n is 0 k, where k is the total number of CH and NH groups in group A when A is unsubstituted.
2. The compound of claim 1 , represented by Formula (Ia) or (Ib), or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , A, B and n are as defined in claim 1 .
3. The compound of claim 1 , represented by Formula (IIa) or (IIb), or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , A, and n are as defined in claim 1 .
4. The compound of claim 1 , represented by one of Formulas (III-1)˜(III-3), (IIIa-1)˜(IIIa-3), and (IIIb-1)˜(IIIb-3), or a pharmaceutically acceptable salt thereof:
wherein R 2 , R 3 , A, and n are as defined in claim 1 .
5. The compound of claim 1 , represented by Formula (IVa-1), (IVa-2), (IVb-1) or (IVb-2), or a pharmaceutically acceptable salt thereof:
wherein one V is S, O, or NR 15 , the other two Vs are independently CR 15 or N; one U is N, another U is CR 15 , and the other two Us are independently CR 15 or N; R 15 is H or R 3 ; and R 1 , R 2 , R 3 , and B are as defined in claim 1 .
6. The compound of claim 1 , wherein A is selected from one of the following by removal of hydrogen atoms from two adjacent ring carbon atoms:
wherein each of the above shown groups is optionally substituted.
7. The compound of claim 1 , wherein R 2 is selected from one of the following by removal of one hydrogen atom:
wherein each of the above shown is optionally substituted.
8. The compound of claim 1 , wherein R 2 is selected from the groups set forth in Table 1:
TABLE 1
Entry
R 2
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
94
95
96
97
98
99
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
179
180
181
182
183
184
185
186
9. The compound of claim 1 , 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
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 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 according to claim 1 , or a pharmaceutically acceptable salt thereof.