US 7,582,605 B2 · Phosphorus-containing hepatitis C serine protease inhibitors

Abstract

The present invention relates to phosphorus-derived compounds of Formula I or Formula II, 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.

A compound represented by Formula III or Formula IV:

or a pharmaceutically acceptable salt, ester, or prodrug thereof;
wherein
A is selected from —(C═O)—O—R1, —(C═O)—R2, —C(═O)—NH—R2, —S(O)2—R1, and —S(O)2NHR2;
R1 is selected from the group consisting of:
(i) aryl;
(ii) substituted aryl;
(iii) heteroaryl;
(iv) substituted heteroaryl;
(v) heterocycloalkyl;
(vi) substituted heterocycloalkyl;
(vii) —C1-C8 alkyl;
(viii) —C2-C8 alkenyl;
(ix) —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(x) substituted —C1-C8 alkyl;
(xi) substituted —C2-C8 alkenyl;
(xii) substituted —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(xiii) —C3-C12 cycloalkyl;
(xiv) substituted —C3-C12 cycloalkyl;
(xv) —C3-C12 cycloalkenyl;
and
(xvi) substituted —C3-C12 cycloalkenyl;
R2 is selected from the group consisting of:
(i) hydrogen;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) heterocycloalkyl;
(vii) substituted heterocycloalkyl;
(viii) —C1-C8 alkyl;
(ix) —C2-C8 alkenyl;
(x) —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(xi) substituted —C1-C8 alkyl;
(xii) substituted —C2-C8 alkenyl;
(xiii) substituted —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(xiv) —C3-C12 cycloalkyl;
(xv) substituted —C3-C12 cycloalkyl;
(xvi) —C3-C12 cycloalkenyl;
and
(xvii) substituted -C3-C12 cycloalkenyl;
L is selected from the group consisting of:
(i) —C1-C8 alkyl;
(ii) —C2-C8 alkenyl;
(iii) —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(iv) substituted —C1-C8 alkyl;
(v) substituted —C2-C8 alkenyl;
(vi) substituted —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(vii) —C3-C12 cycloalkyl;
(viii) substituted —C3-C12 cycloalkyl;
(ix) —C3-C12 cycloalkenyl;
(x) substituted —C3-C12 cycloalkenyl;
(xi) heterocyclic;
(xii) substituted heterocyclic;
(xiii) aryl;
and
(xiv) substituted aryl;
W is selected from —CH2—, —O—, —S—, —S(O)2, —CO—, —C(O)O—, —C(O)NH—, —CHF—, —CF2—, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
U and V are independently chosen from the following groups:
(i) R5;
and
(ii) XR6;
or, in the alternative, U and V taken together with the phosphorus atom to which they are attached form a phosphorus-derived heterocyclic moiety;
R5 is selected from the group consisting of:
(i) aryl;
(ii) substituted aryl;
(iii) heteroaryl;
(iv) substituted heteroaryl;
(v) heterocycloalkyl;
(vi) substituted heterocycloalkyl;
(vii) —C1-C8 alkyl;
(viii) —C2-C8 alkenyl;
(ix) —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(x) substituted —C1-C8 alkyl;
(xi) substituted —C2-C8 alkenyl;
(xii) substituted —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(xiii) —C3-C12 cycloalkyl;
(xiv) substituted —C3-C12 cycloalkyl;
(xv) —C3-C12 cycloalkenyl;
and
(xvi) substituted —C3-C12 cycloalkenyl;
R6 is selected from the group consisting of:
(i) hydrogen;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) heterocycloalkyl;
(vii) substituted heterocycloalkyl;
(viii) —C1-C8 alkyl;
(ix) —C2-C8 alkenyl;
(x) —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(xi) substituted —C1-C8 alkyl;
(xii) substituted —C2-C8 alkenyl;
(xiii) substituted —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(xiv) —C3-C12 cycloalkyl;
(xv) substituted —C3-C12 cycloalkyl;
(xvi) —C3-C12 cycloalkenyl;
and
(xvii) substituted —C3-C12 cycloalkenyl;
X is absent or is selected from the group consisting of:
(i) O;
(ii) S;
and
(iii) NR3;
J is absent, O, S, NR5, CO, (CO)NR5, (CO)O, NR5(CO), NH(CO)NH or NR5SO2;
R7 is selected from aryl, substituted aryl, heteroaryl, and substituted heteroaryl;
R81, R82, R83, and R84 are independently selected from:
(i) hydrogen;
(ii) halogen;
(iii) —NO2;
(iv) —CN;
(v) MR9, wherein M is absent O, S or NR3R6;
(vi) aryl;
(vii) substituted aryl;
(viii) heteroaryl;
(ix) substituted heteroaryl;
(x) heterocycloalkyl;
and
(xi) substituted heterocycloalkyl;
R9 is selected from the group consisting of:
(i) hydrogen;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) heterocycloalkyl;
(vii) substituted heterocycloalkyl;
(viii) —C1-C8 alkyl;
(ix) —C2-C8 alkenyl;
(x) —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(xi) substituted —C1-C8 alkyl;
(xii) substituted —C2-C8 alkenyl;
and
(xiii) substituted —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
R3 is selected from the group consisting of:
(i) hydrogen;
(ii) aryl;
(iii) substituted aryl;
(iv) heteroaryl;
(v) substituted heteroaryl;
(vi) heterocycloalkyl;
(vii) substituted heterocycloalkyl;
(viii) —C1-C8 alkyl;
(ix) —C2-C8 alkenyl;
(x) —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S, or N;
(xi) substituted —C1-C8 alkyl;
(xii) substituted —C2-C8 alkenyl;
(xiii) substituted —C2-C8 alkynyl containing 0, 1, 2, or 3 heteroatoms selected from O, S or N;
(xiv) —C3-C12 cycloalkyl;
(xv) substituted —C3-C12 cycloalkyl;
(xvi) —C3-C12 cycloalkenyl;
and
(xvii) substituted —C3-C12 cycloalkenyl;
j is 0, 1, 2, 3, or 4;
k is 1, 2, or 3;
m is 0, 1, or 2;
and
n is 1, 2, or 3.

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Phosphorus-containing hepatitis C serine protease inhibitors

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Phosphorus-containing hepatitis C serine protease inhibitors

Life of this patent

Abstract

Claims9