US 8,283,309 B2 · Bridged carbocyclic oxime hepatitis C virus serine protease inhibitors

Abstract

The present invention discloses compounds of formula I, or 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. More specifically, the invention relates to oxime compounds containing a carbocyclic P2 unit, and the oxime is tethered to one of the carboxylic acid on P2. 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.

A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein:
A is absent or NR1;
R1 is selected from the group consisting of:
H, substituted or unsubstituted C1-C8 alkyl, substituted or unsubstituted C2-C8 alkenyl and substituted or unsubstituted —C3-C8 cycloalkyl;
E is absent or selected from the group consisting of —(C═O)—, —S(O)—, —S(O)2—, —(C═N—OR2)—,—(C═N—CN)—, and —(C═N—R2)—;
R2 is selected from the group consisting of:
(i) aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl;
(ii) heterocycloalkyl or substituted heterocycloalkyl;
and
(iii) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
—C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl;
—C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
J is selected from the group consisting of —C(R3R4)—, —O—, and —NR5—;
R3, R4, and R5 are independently selected from the group consisting of:
(i) hydrogen;
(ii) aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl;
and
(iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
—C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl;
—C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
Q is selected from the group consisting of:
(i) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(ii) substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(iii) —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl;
(iv) —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
and
(v) aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl;
U is absent or selected from O, S, SO, CO, SO2, NR1, NH(CO), NH(CO)NH, NHSO2, NHSO2NH, O(CO), and O(CO)NH;
X and Y are independently selected from the group consisting of:
(i) absent for X or hydrogen for Y;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) heterocyclic or substituted heterocyclic;
(vii) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(viii) substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(ix) —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(x) —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
and
(xi) —W—R6, where W is (CO), (CO)O, (CO)NH, (SO), (SO2), (SO2)NH;
and R6 are independently selected from the group consisting of:
(a) aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl;
(b) heterocyclic;
substituted heterocyclic;
(c) —C1-C8 alkyl;
—C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(d) substituted —C1-C8 alkyl;
substituted —C2-C8 alkenyl;
or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(e) —C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
and
(f) —C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
or X and Y taken together with the carbon atom to which they are attached form a cyclic moiety selected from:
substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocylic;
substituted or unsubstituted cycloalkyl, cycloalkenyl, and heterocylic fused with one or more aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocylic, cycloalkyl, substituted cycloalkyl, and cycloalkenyl or substituted cycloalkenyl;
L is selected from the group consisting of:
(i) hydrogen;
(ii) aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl;
and
(iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
—C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl;
—C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
Z is selected from the group consisting of:
(i) hydrogen;
(ii) aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl;
and
(iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
—C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl;
—C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
G is selected from the group consisting of —NHS(O)2—R7;
—NH(SO2)NR8R9;
OR8, and NR8R9;
where:
R7 is selected from the group consisting of:
(i) aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl
(ii) heterocycloalkyl or substituted heterocycloalkyl;
and
(iii) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N, substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
—C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl;
—C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
R8 and R9 are independently selected from the group consisting of:
(i) hydrogen;
(ii) aryl;
substituted aryl;
heteroaryl;
substituted heteroaryl;
(iii) heterocycloalkyl or substituted heterocycloalkyl;
and
(iv) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
substituted —C1-C8 alkyl, substituted —C2-C8 alkenyl, or substituted —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
—C3-C12 cycloalkyl, or substituted —C3-C12 cycloalkyl;
—C3-C12 cycloalkenyl, or substituted —C3-C12 cycloalkenyl;
T is absent or is selected from the group consisting of NR8, NR1(CO) and NR1(CO)O;
denotes a carbon-carbon single or double bond;
k=0 or 1;
m=0, 1, 2 or 3;
n=0, 1, 2 or 3;
and
p=1, 2 or 3.

125 more elements

Bridged carbocyclic oxime hepatitis C virus serine protease inhibitors

Life of this patent

Bridged carbocyclic oxime hepatitis C virus serine protease inhibitors

Life of this patent

Abstract

Claims14