Aryldiazepine derivatives as RSV inhibitors
The present invention discloses compounds of Formula (I), and 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 selected from the group consisting of:
1) Optionally substituted heteroaryl; and
2) Optionally substituted aryl;
B is selected from the group consisting of:
1) Optionally substituted heteroaryl; and
2) Optionally substituted aryl;
L is —NH—;
X is —CH 2 —, or —C(O)—;
R 1 is selected from the group consisting of:
1) Optionally substituted heteroaryl; and
2) Optionally substituted aryl;
R 2 is absent or is 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 1 -C 8 alkoxy;
5) Optionally substituted aryloxy;
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 arylalkyl;
11) Optionally substituted heteroaryl;
12) Optionally substituted heteroarylalkyl;
13) —NR 13 R 14 ;
14) —CO—NR 13 R 14 ; and
15) —SO 2 —NR 13 R 14 ;
Each R 3 is 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 12 , —NR 13 R 14 , and —CO—NR 13 R 14 ;
R 12 is 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;
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 3 -C 8 cycloalkenyl; optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl; optionally substituted heteroaryl; optionally substituted —C 1 -C 8 -alkoxy, —C(O)R 12 , —S(O) 2 R 12 , and —S(O) 2 NHR 12 ;
alternatively, R 13 and R 14 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring;
R 4 is selected from hydrogen and —C 1 -C 8 alkyl; and
n is 0 to k, wherein k is the total number of CH and NH groups in A when A is unsubstituted.
2. The compound of claim 1 , represented by Formula (Ib) or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , R 4 , A, B, L, X, and n are as defined in claim 1 .
3. The compound of claim 1 , represented by Formula (III-1) or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , R 4 , A, B, L, and n are as defined in claim 1 .
4. 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 is optionally substituted with one or more substituents which are not R 3 when possible.
5. The compound of claim 1 , wherein B is selected from one of the following by removal of one or two hydrogen atoms:
wherein each of the above shown is optionally substituted when it is possible.
6. The compound of claim 1 , wherein R 2 is selected from one of the following by removal of one ring hydrogen atom:
wherein each of the above shown is optionally substituted.
7. The compound of claim 1 , wherein R 2 is selected from the following:
wherein each group 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
90
91
92
93
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
147
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
178
179
180
181
182
183
184
185
186
9. A compound selected from the compounds set forth below or a pharmaceutically acceptable salt thereof:
Com-
pound
Structure
1
2
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
21
10. A pharmaceutical composition comprising a compound according to claim 1 , in combination with a pharmaceutically acceptable carrier, diluent or excipient.
11. 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 represented by Formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
A is selected from the group consisting of:
1) Optionally substituted heteroaryl; and
2) Optionally substituted aryl;
B is selected from the group consisting of:
1) Optionally substituted heteroaryl; and
2) Optionally substituted aryl;
L is —NH—, —NHC(O)—, or —NHC(O)NH—;
X is —CH 2 —, or —C(O)—;
R 1 is selected from the group consisting of:
1) Optionally substituted heteroaryl; and
2) Optionally substituted aryl;
R 2 is absent or is 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 1 -C 8 alkoxy;
5) Optionally substituted aryloxy;
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 arylalkyl;
11) Optionally substituted heteroaryl;
12) Optionally substituted heteroarylalkyl;
13) —NR 13 R 14 ;
14) —CO—NR 13 R 14 ; and
15) —SO 2 —NR 13 R 14 ;
Each R 3 is 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 12 , —NR 13 R 14 , and —CO—NR 13 R 14 ;
R 12 is 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;
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 3 -C 8 cycloalkenyl; optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl; optionally substituted heteroaryl; optionally substituted —C 1 -C 8 -alkoxy, —C(O)R 12 , —S(O) 2 R 12 , and —S(O) 2 NHR 12 ;
alternatively, R 13 and R 14 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic ring;
R 4 is selected from hydrogen and optionally substituted —C 1 -C 8 alkyl; and
n is 0 to k, wherein k is the total number of CH and NH groups in A when A is unsubstituted.
12. The method of claim 11 , further comprising administering to the subject a steroid anti-inflammatory compound.
13. The method of claim 11 , further comprising the step of administering to the subject an additional anti-RSV agent.
14. The method of claim 11 , further comprising administering to the subject an anti-influenza compound.
15. The method of claim 13 , wherein the compound and the additional anti-RSV agent are co-formulated.
16. The method of claim 13 , wherein the compound and the additional anti-RSV agent are co-administered.
17. The compound of claim 1 , represented by Formula (III-2) or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , R 4 , A, B, L, and n are as defined in claim 1 .
18. The compound of claim 1 , represented by Formula (Ia) or a pharmaceutically acceptable salt thereof:
wherein R 1 , R 2 , R 3 , R 4 , A, B, L, X, and n are as defined in claim 1 .