Quinoxalinyl dipeptide 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:
or a pharmaceutically acceptable, salt, ester or prodrug thereof, wherein
R is selected from —(C═O)—R 1 , —(C═O)—O—R 2 , —C(═O)—NHR 2 , or —S(O) 2 —R 2 , —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; and
(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; the representative substitutents include, but are not limited to: hydroxyl, halo, —O—C 1 -C 6 alkyl, —S—C 1 -C 6 alkyl, —SO—C 1 -C 6 alkyl, —SO 2 —C 1 -C 6 alkyl, —O-aryl or substituted —O-aryl, —S-aryl, or substituted —S-aryl, —SO-aryl or substituted —SO-aryl, —SO 2 -aryl or substituted —SO 2 -aryl;
R 2 is selected from the group consisting of:
(i) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(ii) heterocycloalkyl or substituted heterocycloalkyl; and
(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′ is 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; and
(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; and
(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 are independently selected from:
(i) hydrogen;
(ii) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl; or
(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;
alternatively, R 4 and R 5 taken together with the carbon atom to which they are attached form cyclic moiety consisting of: substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocylic; substituted or unsubstituted cycloalkenyl, or heterocylic;
X and Y taken together with the carbon atoms to which they are attached form a cyclic moiety which is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
W is absent, or selected from —O—, —S—, —NH—, —N(Me)—, —C(O)NH—, and —C(O)N(Me)—;
Z is selected from the group consisting of:
(i) hydrogen;
(ii) aryl, substituted aryl;
(iii) heteroaryl, substituted heteroaryl;
(iv) —C 3 -C 12 cycloalkyl, substituted —C 3 -C 12 cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl;
(v) —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;
(vi) —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; and
(vii) —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
or a pharmaceutically acceptable, salt, ester or prodrug thereof, wherein R 101 is selected from the group consisting of:
(i) aryl; substituted aryl; heteroaryl; substituted heteroaryl;
(ii) heterocycloalkyl or substituted heterocycloalkyl; and
(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;
(iv) Hydrogen;
where X, Y, G, W, Z are as previously defined.
3. The compound of claim 1 , wherein the compound is of Formula III:
or a pharmaceutically acceptable, salt, ester, or prodrug thereof,
where X 1 -X 4 are independently selected from —CR 6 and N, wherein R 6 is 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; or
(vi) heterocycloalkyl or substituted heterocycloalkyl;
where R 101 , G, W, Z are as previously defined.
4. The compound of claim 1 , wherein the compound is of Formula IV:
or a pharmaceutically acceptable, salt, ester or prodrug thereof,
where Y 1 -Y 3 are independently selected from CR 6 , N, NR 6 , S and O; where R 6 , R 101 , G, W, Z are as previously defined.
5. A compound according to any one of claims 1 - 4 , wherein W is absent and Z is thiophenyl.
6. A compound according to any one of claims 1 - 4 , wherein W is —CH═CH— and Z is thiophenyl.
7. A compound according to claim 1 which is selected from compounds 1-93 of Formula V:
or a pharmaceutically acceptable, salt, ester or prodrug thereof,
wherein R 201 , Q and G are delineated for each example in Table 1:
TABLE 1
Example #
R 201
Q
G
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.
—OH
76.
—OH
77.
—OH
78.
—OH
79.
—OH
80.
—OH
81.
—OH
82.
—OH
83.
—OH
84.
—OH
85.
—OH
86.
—OH
87.
—OH
88.
—OH
89.
—OH
90.
—OH
91.
—OH
92.
—OH
93.
—OH.
8. A pharmaceutical composition comprising an inhibitory amount of a compound according to claim 1 and a pharmaceutically acceptable carrier or excipient.
9. A method of treating a hepatitis C viral infection in a subject, comprising administering to the subject an inhibitory amount of a pharmaceutical composition according to claim 8 .
10. The method of claim 9 further comprising administering concurrently an additional anti-hepatitis C virus agent.
11. The method of claim 10 , wherein said additional anti-hepatitis C virus agent is selected from the group consisting of: α-interferon, β-interferon, ribavarin, and adamantine.
12. The method of claim 10 , wherein said additional anti-hepatitis C virus agent is an inhibitor of hepatitis C virus helicase, polymerase, metalloprotease, or IRES.
13. A pharmaceutical composition of claim 8 further comprising an additional anti-hepatitis C virus agent.
14. A pharmaceutical composition of claim 13 wherein said additional anti-hepatitis C virus agent is selected from the group consisting of: α-interferon, β-interferon, ribavarin, and adamantine.
15. A compound of claim 1 wherein said compound is in a substantially pure form.