Hydrazide-containing hepatitis C serine protease inhibitors
The present invention relates to novel hydrazide-containing compounds of Formula I or Formula II, including pharmaceutically acceptable salts, esters, or prodrugs thereof which inhibit serine protease activity, particularly the activity of hepatitis C virus (HCV) NS3-NS4A protease. Consequently, the compounds of the present invention interfere with the life cycle of the hepatitis C virus and are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from HCV infection. The invention also relates to methods of treating an HCV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.
1. A compound of Formula III or Formula IV:
wherein
A is selected from the following groups:
(i) —(C═O)—O—R 1 ;
(ii) —(C═O)—R 1 ;
(iii) —C(═O)—NH—R 2 ;
(iv) —S(O) 2 —R 1 ; and
(v) —S(O) 2 NHR 2 ;
wherein R l is selected from the following groups:
(i) aryl;
(ii) substituted aryl;
(iii) heteroaryl;
(iv) substituted heteroaryl;
(v) heterocycloalkyl;
(vi) substituted heterocycloalkyl;
(vii) —C 1 -C 8 alkyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(viii) —C 2 -C 8 alkenyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(ix) —C 2 -C 8 alkynyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(x) substituted —C 1 -C 8 alkyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(xi) substituted —C 2 -C 8 alkenyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(xii) substituted —C 2 -C 8 alkenyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(xiii) —C 3 -C 12 cycloalkyl;
(xiv) substituted —C 3 -C 12 cycloalkyl;
(xv) —C 3 -C 12 cycloalkenyl; and
(xvi) substituted —C 3 -C 12 cycloalkenyl;
wherein R 2 is selected from the following groups:
(i) hydrogen;
(ii) —C 1 -C 8 alkyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(iii) —C 2 -C 8 alkenyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(iv) —C 2 -C 8 alknyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(v) substituted —C 1 -C 8 alkyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(vi) substituted —C 2 -C 8 alkenyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; and
(vii) substituted —C 2 -C 8 alkynyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
L is selected from the following groups:
(i) —C 1 -C 8 alkyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(ii) —C 2 -C 8 alkenyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(iii) —C 2 -C 8 alkynyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(iv) substituted —C 1 -C 8 alkyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(v) substituted —C 2 -C 8 alkenyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; and
(vi) substituted —C 2 -C 8 alkynyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
=a bond connected to an undefined stereogenic center;
V is selected from the following groups:
(i) hydrogen;
(ii) —(C═O)—O—R 8 ;
(iii) —(C═O)—R 9 ; and
(iv) —C(═O)—NR 10 R 11 ;
wherein R 8 and R 9 are selected from the following groups:
(i) aryl;
(ii) substituted aryl;
(iii) heteroaryl;
(iv) substituted heteroaryl;
(v) heterocycloalkyl;
(vi) substituted heterocycloalkyl;
(vii) —C 1 -C 8 alkyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(viii) —C 2 -C 8 alkenyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(ix) —C 2 -C 8 alkynyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(x) substituted —C 1 -C 8 alkyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(xi) substituted —C 2 -C 8 alkenyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(xii) substituted —C 2 -C 8 alkynyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(xiii) —C 3 -C 12 cycloalkyl;
(xiv) substituted —C 3 -C 12 cycloalkyl;
(xv) —C 3 -C 12 cycloalkenyl; and
(xvi) substituted —C 3 -C 12 cycloalkenyl;
wherein R 10 and R 11 are selected from the following groups:
(i) hydrogen;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) heterocycloalkyl;
(vii) substituted heterocycloalkyl;
(viii) —C 1 -C 8 alkyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(ix) —C 2 -C 8 alkenyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(x) —C 2 -C 8 alkynyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(xi) substituted —C 1 -C 8 alkyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(xii) substituted —C 2 -C g alkenyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(xiii) substituted —C 2 -C 8 alkynyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(xiv) —C 3 -C 12 cycloalkyl;
(xv) substituted —C 3 -C 12 cycloalkyl;
(xvi) —C 3 -C 12 cycloalkenyl;
(xvii) substituted —C 3 -C 12 cycloalkenyl; and
(xviii) taken together with the nitrogen that they are attached to, R 10 and R 11 may also form a ring;
= either a carbon-carbon single bond or a carbon-carbon double bond
j=0, 1, 2, 3, or 4;
k=1, 2, or 3;
J is either absent or selected from O, S, NR 12 , CO, (CO)NR 12 , (CO)O,NR 12 (CO), NH(CO)NH, and NR 12 SO 2 ;
wherein R 12 is selected from the following groups:
(i) hydrogen;
(ii) —C 1 -C 8 alkyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(iii) —C 3 -C 12 cycloalkyl; and
(iv) substituted —C 3 -C 12 cycloalkyl;
R 13 is selected from the groups consisting of aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R 81 , R 82 , R 83 , and R 84 are independently chosen from the following groups:
(i) hydrogen;
(ii) halogen;
(iii) —NO 2 ;
(iv) —CN;
(v) MR 14 , wherein M is absent, or is selected from O, S, and NR 10 R 11 , wherein R 10 and R 11 are as previously defined;
(vi) aryl;
(vii) substituted aryl;
(viii) heteroaryl;
(ix) substituted heteroaryl;
(x) heterocycloalkyl; and
(xi) substituted heterocycloalkyl;
wherein R 14 is selected from the following groups:
(i) hydrogen;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) heterocycloalkyl;
(vii) substituted heterocycloalkyl;
(viii) —C 1 -C 8 alkyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(ix) —C 2 -C 8 alkenyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(x) —C 2 -C 8 alkynyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(xi) substituted —C 1 -C 8 alkyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(xii) substituted —C 2 -C 8 alkenyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; and
(xiii) substituted —C 2 -C 8 alkynyl, optionally containing 0, 1, 2, or 3 heteroatoms selected from O, S or N.
2. A compound of Formula V or Formula VI:
wherein A, L, j, k, V, R 81 , R 82 , R 83 , and R 84 are all as previously defined.
3. A compound of Formula VII or Formula VIII:
wherein A, L, j, k, V, J, R 13 , R 81 , R 82 R 83 , and R 84 are all as previously defined.
4. A compound selected from compounds 1-113 of Formula IX; wherein A, P*, and V are delineated for each example as set forth in Table 1:
TABLE 1
IX
EXAMPLE #
A
P*
V
1
2
3
H
4
H
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
5. A compound selected from compounds 114-226 of Formula X; wherein A, P*, V, and L are delineated in Table 2:
TABLE 2
X
EXAMPLE
#
A
P*
V
L
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
6. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to claim 1 .
7. The pharmaceutical composition of claim 6 , further comprising a combination with a pharmaceutically acceptable carrier or excipient.
8. The pharmaceutical composition of claim 6 , further comprising an additional anti-hepatitis C virus agent.
9. The pharmaceutical composition of claim 8 wherein said additional anti-hepatitis C virus agent is selected from the group consisting of: α-interferon, β-interferon, ribavarin, and adamantine.
10. A method of treating a hepatitis C viral infection in a subject, comprising administering to the subject a pharmaceutical composition according to claim 6 .