Quinoxalinyl tripeptide hepatitis C virus inhibitors
The present invention relates to compounds of Formula I, or a pharmaceutically acceptable salt, ester, or prodrug, 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 I:
Wherein
A is selected from —(C═O)—O—R 1 , —(C═O)—R 2 , —C(═O)—NH—R 2 , or —S(O) 2 —R 1 , —S(O) 2 NHR 2 ;
R 1 is selected from the group consisting of:
(i) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(ii) heterocycloalkyl or substituted heterocycloalkyl;
(iii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
R 2 is independently selected from the group consisting of:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl;
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
R and R′ are independently selected from the group consisting of:
(i) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 4 -C 12 alkylcycloalkyl, or substituted —C 4 -C 12 alkylcycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl; —C 4 -C 12 alkylcycloalkenyl, or substituted —C 4 -C 12 alkylcycloalkenyl;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl;
(iv) hydrogen; deuterium;
G is selected from —OH, —NHS(O) 2 —R 3 , —NH(SO 2 )NR 4 R 5 ;
R 3 is selected from:
(i) aryl; substituted aryl; heteroaryl; substituted heteroaryl
(ii) heterocycloalkyl or substituted heterocycloalkyl;
(iii) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
R 4 and R 5 is independently selected from:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl;
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
X and Y taken together with the carbon atoms to which they are attached form a cyclic moiety which selected from aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
W is absent, or selected from —O—, —S—, —NH—, —N(Me)—, —C(O)NH—, or —C(O)N(Me)—;
Z is selected from the groups consisting of:
Z is selected from the groups consisting of:
(i) aryl, substituted aryl;
(ii) heteroaryl, substituted heteroaryl;
(iii) —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl;
(iv) —C 1 -C 6 alkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
(v) —C 2 -C 6 alkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
(vi) —C 2 -C 6 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N, optionally substituted with one or more substituent selected from halogen, aryl, substituted aryl, heteroaryl, or substituted heteroaryl;
W-Z taken together, is —CN, —N 3 , halogen, —NH—N═CH(R 2 ), where R 2 is as previously defined
m=0, 1, or 2;
m′=1 or 2.
2. The compound of claim 1 , wherein the compound is of Formula II:
where X 1 -X 4 are independently selected from —CR 6 and N, wherein R 6 is independently selected from:
(i) hydrogen; halogen; —NO 2 ; —CN;
(ii) -M-R 4 , M is O, S, NH, where R 4 is as previously defined;
(iii) NR 4 R 5 , where R 4 and R 5 are as previously defined;
(iv) —C 1 -C 8 alkyl, —C 2 -C 8 alkenyl, or —C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N; substituted —C 1 -C 8 alkyl, substituted —C 2 -C 8 alkenyl, or substituted —C 2 -C 8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N; —C 3 -C 12 cycloalkyl, or substituted —C 3 -C 12 cycloalkyl; —C 3 -C 12 cycloalkenyl, or substituted —C 3 -C 12 cycloalkenyl;
(v) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(vi) heterocycloalkyl or substituted heterocycloalkyl;
where A, G, W, Z are as previously defined.
3. A compound according to claim 1 which is selected from compounds of Formula IV, table 1
TABLE 1
(IV)
Example#
A
Q
G
1
—OH
2
3
H
4
5
6
7
8
9
10
11
12
13
—OH
14
—OH
15
—OH
16
—OH
17
—OH
18
—OH
19
—OH
20
—OH
21
—OH
22
—OH
23
—OH
24
—OH
25
—OH
26
—OH
27
—OH
28
—OH
29
—OH
30
—OH
31
—OH
32
—OH
33
—OH
34
—OH
35
—OH
36
—OH
37
—OH
38
—OH
39
—OH
40
—OH
41
—OH
42
—OH
43
—OH
44
—OH
45
—OH
46
—OH
47
—OH
48
—OH
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
4. A compound of Formula IV:
wherein A is selected from the groups set forth in Table 2, Q is selected from the groups set forth in Table 3 and G is selected from the groups set forth in Table 4:
TABLE 2
A-Matrix
TABLE 3
Q-Matrix
TABLE 4
G-Matrix
—OH
G01
5. A pharmaceutical composition comprising an inhibitory amount of a compound according to claim 1 or 4 alone or in combination with a pharmaceutically acceptable carrier or excipient.