US 8,263,549 B2 · C5-substituted, proline-derived, macrocyclic hepatitis C serine protease inhibitors

Abstract

The present invention relates to 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. 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 a compound of the present invention.

A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein
A is selected from the group consisting of R1, —(C═O)—O—R1, —(C═O)—R2, —C(═O)—NR1R2, —S(O)—R2, —S(O)2—R1, and —S(O)2NR1R2;
B is selected from the group consisting of:
(i) aryl;
(ii) substituted aryl;
(iii) heteroaryl;
(iv) substituted heteroaryl;
(v) heterocyclic or substituted heterocyclic;
(vi) —C1-C8 alkyl, —C2-C8 alkenyl, or —C2-C8 alkynyl each containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(vii) 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;
(viii) —C3-C12 cycloalkyl;
(ix) substituted —C3-C12 cycloalkyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(x) —C3-C12 cycloalkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
and
(xi) substituted —C3-C12 cycloalkenyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
alternatively, B and the carbon atom to which it is attached form a carbonyl group;
R1 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;
R2 is 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;
G is selected from the group consisting of —OH, —NR4R5;
—NHS(O)2—R3 and —NH(SO2)NR4R5;
R3 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;
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;
alternatively, R4 and R5 can be taken together with the nitrogen they are attached to form a heterocylic or substituted heterocylic;
L is selected from the group consisting of —CH2—, —O—, —S—, —NR4— and —S(O)2—;
X is absent or is selected from the group consisting of:
(i) O;
(ii) S;
(iii) NR4;
where R4 is as previously defined above;
and
(iv) O—NH;
Y is absent or is selected from the group consisting of:
(i) —C(═O)—, —C(═O)—NH—, —S(O)2—, —S(O)2NH—;
(ii) —C1-C6 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;
(iii) —C2-C6 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;
(iv) —C2-C6 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;
and
(v) —C3-C12 cycloalkyl-, substituted —C3-C12 cycloalkyl-, heterocycloalkyl, substituted heterocycloalkyl;
Z is selected from the group consisting of hydrogen, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycloalkyl, substituted heterocycloalkyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenyl;
Or X, Y and Z are taken together to form
wherein Z1 and Z2 are independently selected from the group consisting of:
(i) hydrogen;
(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 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;
(x) substituted —C3-C12 cycloalkyl;
(xi) —C3-C12 cycloalkenyl;
(xii) substituted —C3-C12 cycloalkenyl;
and
(xiii) —V—R6, where V is (CO), (CO)O, (CO)NR4, (SO), (SO2), (SO2)NR4;
and R4 is as previously defined,
R6 is selected from the group consisting of:
(i) hydrogen;
(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 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;
(x) substituted —C3-C12 cycloalkyl;
(xi) —C3-C12 cycloalkenyl;
and
(xii) substituted —C3-C12 cycloalkenyl;
or Z1 and Z2 taken together with the carbon atom to which they are attached form a cyclic moiety selected from the group consisting of:
substituted or unsubstituted cycloalkyl, cycloalkenyl, or heterocyclic;
substituted or unsubstituted cycloalkyl, cycloalkenyl, and heterocyclic fused with one or more aryl, substituted aryl, heteroaryl;
substituted heteroaryl, heterocyclic, substituted heterocyclic, cycloalkyl, substituted cycloalkyl, cycloalkenyl, and substituted cycloalkenlyl;
denotes a carbon-carbon single or double bond;
denotes a bond attached to an undefined stereogenic atom;
j=0, 1, 2, 3, or 4;
k=1, 2, or 3;
and
m=0, 1, or 2.

118 more elements

C5-substituted, proline-derived, macrocyclic hepatitis C serine protease inhibitors

Life of this patent

C5-substituted, proline-derived, macrocyclic hepatitis C serine protease inhibitors

Life of this patent

Abstract

Claims18