Compounds, compositions, and methods for the treatment of disease
Disclosed are compounds and compositions for the activation or induction of expression of a pattern recognition receptor (e.g., STING, RIG-I, MDA5), and methods of use thereof.
1. A compound of Formula (I):
or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:
Z is either S or O;
B 1 is a purinyl nucleobase and B 2 is a pyrimidinyl nucleobase; or B 2 is a purinyl nucleobase and B 1 is a pyrimidinyl nucleobase;
each of X 1 and X 2 is independently O or S;
each of Y 1 and Y 2 is independently O, S, or NR 5 ;
each of L 1 and L 2 is independently absent, C 1 -C 6 alkyl or C 1 -C 6 heteroalkyl, wherein each alkyl and heteroalkyl is optionally substituted with R 6 ;
each of R 1 and R 2 is independently hydrogen, halo, —CN, C 1 -C 20 alkyl, or OR 7 ;
each of R 3 and R 4 is independently hydrogen, C 1 -C 20 alkyl, C 1 -C 20 heteroalkyl, OC(O)OC 1 -C 20 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, heteroalkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 8 ;
R 5 is hydrogen or C 1 -C 20 alkyl;
R 6 is halo, —CN, C 1 -C 20 alkyl, OR 7 , oxo, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 9 ;
R 7 is hydrogen, C 1 -C 20 alkyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl, wherein each alkyl, cycloalkyl, heterocyclyl, aryl, and heteroaryl is optionally substituted with one or more R 9 ;
each R 8 is independently C 1 -C 20 alkyl, C 1 -C 20 heteroalkyl, C(O)—C 1 -C 20 alkyl, OC(O)—C 1 -C 20 alkyl, C(O)O—C 1 -C 20 alkyl, OC(O)O—C 1 -C 20 alkyl, C(O)N(R 5 )—C 1 -C 20 alkyl, N(R 5 )C(O)—C 1 -C 20 alkyl, OC(O)N(R 5 )—C 1 -C 20 alkyl, O-aryl, O-heteroaryl, C(O)-aryl, C(O)-heteroaryl, OC(O)-aryl, C(O)O-aryl, OC(O)-heteroaryl, C(O)O-heteroaryl, C(O)O-aryl, C(O)O-heteroaryl, C(O)N(R 5 )-aryl, C(O)N(R 5 )-heteroaryl, N(R 5 )C(O)-aryl, N(R 5 ) 2 C(O)-aryl, or N(R 5 )C(O)-heteroaryl, S(O) 2 N(R 5 )-aryl, wherein each alkyl, heteroalkyl, aryl, and heteroaryl is optionally substituted by one or more R 9 ; and
each R 9 is independently C 1 -C 20 alkyl, O—C 1 -C 20 alkyl, C 1 -C 20 heteroalkyl, halo, —CN, OH, oxo, aryl, heteroaryl, O-aryl, or O-heteroaryl.
2. The compound of claim 1 , wherein the compound is a compound of Formula (I-a), (I-b), (I-c), or (I-d):
or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , wherein Z is O.
4. The compound of claim 1 , wherein Z is S.
5. The compound of claim 1 , wherein B 2 is adeninyl and B 1 is uracilyl.
6. The compound of claim 1 , wherein B 1 is adeninyl or guaninyl and B 2 is cytosinyl, thyminyl, or uracilyl; or B 2 is adeninyl or guaninyl and B 1 is cytosinyl, thyminyl, or uracilyl.
7. The compound of claim 1 , wherein B 1 is adeninyl and B 2 is uracilyl.
8. The compound of claim 1 , wherein each of R 1 and R 2 is independently hydrogen, halo, or OR 7 .
9. The compound of claim 1 , wherein each of R 1 and R 2 is independently halo.
10. The compound of claim 1 , wherein each of X 1 and X 2 is independently O.
11. The compound of claim 1 , wherein each of Y 1 and Y 2 is independently O or S.
12. The compound of claim 1 , wherein one of Y 1 or Y 2 is O and the other of Y 1 or Y 2 is S.
13. The compound of claim 1 , wherein each of L 1 and L 2 is independently C 1 -C 6 alkyl.
14. The compound of claim 1 , wherein each of R 3 and R 4 is independently hydrogen, aryl, or heteroaryl, wherein aryl and heteroaryl is optionally substituted with 1-5 R 8 .
15. The compound of claim 1 , wherein R 3 is aryl or heteroaryl, each of which is optionally substituted with 1-5 R 8 , and R 4 is hydrogen.
16. The compound of claim 1 , wherein R 3 is phenyl substituted with 1 R 8 and R 4 is hydrogen.
17. The compound of claim 1 , wherein each of R 3 and R 4 is independently phenyl substituted with 1 R 8 .
18. The compound of claim 1 , wherein each of Y 1 and Y 2 is O and each of R 3 and R 4 is independently hydrogen.
19. The compound of claim 1 , wherein Y 2 is O and R 4 is hydrogen.
20. The compound of claim 1 , wherein Y 1 is S and R 3 is substituted with 1 R 8 .
21. The compound of claim 1 , wherein R 8 is C(O)-aryl optionally substituted by 1-5 R 9 .
22. The compound of claim 21 , wherein R 9 is O—C 1 -C 12 alkyl.
23. The compound of claim 1 , wherein R 8 is OC(O)-aryl optionally substituted by 1-5 R 9 .
24. The compound of claim 1 , wherein the compound is selected from the following table:
Compound
No.
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
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
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
219
220
221
222
223
224
225
226
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
or a pharmaceutically acceptable salt thereof.
25. A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
26. The method of claim 25 , wherein the cancer is a cancer of the breast, bone, brain, cervix, colon, gastrointestinal tract, eye, gall bladder, lymph nodes, blood, lung, liver, skin, mouth, prostate, ovary, penis, pancreas, uterus, testicles, stomach, thymus, thyroid, or other part of the body.
27. The method of claim 26 , wherein the cancer is a cancer of the liver.
28. The method of claim 25 , further comprising administering an effective amount of an additional agent.
29. The method of claim 28 , wherein the additional agent comprises methotrexate, 5-fluorouracil, doxorubicin, vincristine, bleomycin, vinblastine, dacarbazine, toposide, cisplatin, epirubicin, or sorafenib tosylate.
30. A method of inducing the expression of a pattern recognition receptors (PRRs) for immune-modulation in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
31. A method of inducing the expression of a pattern recognition receptors for immunomodulation and inducing a therapeutic response in a subject having cancer, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
32. A method of inducing an immune response in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
33. The method of claim 32 , wherein the immune response comprises antitumoral immunity.
34. The method of claim 32 , wherein the immune response comprises induction of a PRR.
35. A method of treating a microbial infection in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
36. A method of inducing the expression of a pattern recognition receptor in a subject suffering from a microbial infection, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
37. A method of treating a viral infection in a subject, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
38. The method of claim 37 , wherein the viral infection is Hepatitis C virus, Norovirus, Junin virus, Respiratory syncytial virus, or Dengue virus.