US 2004/0167116 A1 · Novel sulfonamide inhibitors of aspartyl protease

Abstract

The present invention relates to a novel class of sulfonamides which are aspartyl protease inhibitors. In one embodiment, this invention relates to a novel class of HIV aspartyl protease inhibitors characterized by specific structural and physicochemical features. This invention also relates to pharmaceutical compositions comprising these compounds. The compounds and pharmaceutical compositions of this invention are particularly well suited for inhibiting HIV-1 and HIV-2 protease activity and consequently, may be advantageously used as anti-viral agents against the HIV-1 and HIV-2 viruses. This invention also relates to methods for inhibiting the activity of HIV aspartyl protease using the compounds of this invention and methods for screening compounds for anti-HIV activity.

A compound of formula I:

654
wherein:
A is selected from the group consisting of H;
Het;
—R1-Het;
—R1—C1-C6 alkyl, which may be optionally substituted with one or more groups selected from the group consisting of hydroxy, C1-C4 alkoxy, Het, —O-Het, —NR2—CO—N(R2)(R2) and —CO—N(R2)(R2);
and —R1—C2-C6 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of hydroxy, C1-C4 alkoxy, Het, —O-Het, —NR2—CO—N(R2)(R2) and —CO—N(R2)(R2);
each R1 is independently selected from the group consisting of —C(O)—, —S(O)2—, —C(O)—C(O)—, —O—C(O)—, —O—S(O)2, —NR2—S(O)2—, —NR2—C(O)— and —NR2—C(O)—C(O)—;
each Het is independently selected from the group consisting of C3-C7 cycloalkyl;
C5-C7 cycloalkenyl;
C6-C10 aryl;
and 5-7 membered saturated or unsaturated heterocycle, containing one or more heteroatoms selected from N, N(R2), O, S and S(O)n, wherein said heterocycle may optionally be benzofused;
and wherein any member of said Het may be optionally substituted with one or more substituents selected from the group consisting of oxo, —OR2, —R2, —N(R2)(R2), —R2—OH, —CN, —CO2R2, —C(O)—N(R2)(R2), —S(O)2—N(R2)(R2), —N(R2)—C(O)—R2, —C(O)—R2, —S(O)n—R2, —OCF3, —S(O)n—Ar methylenedioxy, —N(R2)—S(O)2(R2), halo, —CF3, —NO2, Ar and —O—Ar;
each R2 is independently selected from the group consisting of H and C1-C3 alkyl optionally substituted with Ar;
B, when present, is —N(R2)—C(R3)(R3)—C(O)—;
x is 0 or 1;
each R3 is independently selected from the group consisting of H, Het, C1-C6 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl and C5-C6 cycloalkenyl, wherein any member of said R3, except H, may be optionally substituted with one or more substituents selected from the group consisting of —OR2, —C(O)—NH—R2, —S(O)n—N(R2)(R2), Het, —CN, —SR2, —CO2R2, NR2—C(O)—R2;
each n is independently 1 or 2;
D and D′ are independently selected from the group consisting of Ar;
C1-C4 alkyl, which may be optionally substituted with one or more groups selected from C3-C6 cycloalkyl, —OR2, —R3, —O—Ar and Ar;
C2-C4 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of C3-C6 cycloalkyl, —OR2, —R3, —O—Ar and Ar;
C3-C6 cycloalkyl, which may be optionally substituted with or fused with Ar;
and C5-C6 cycloalkenyl, which may be optionally substituted with or fused with Ar;
each Ar is independently selected from the group consisting of phenyl;
3-6 membered carbocyclic ring and 5-6 membered heterocyclic ring containing one or more heteroatoms selected from O, N, S, S(O)n and N(R2), wherein said carbocyclic or heterocyclic ring may be saturated or unsaturated and optionally substituted with one or more groups selected from the group consisting of oxo, —OR2, —R2, —N(R2)(R2), —N(R2)—C(O)—R2, —R2—OH, —CN, —CO2R2, —C(O)—N(R2)(R2), halo and —CF3;
E is selected from the group consisting of Het;
O-Het;
Het-Het;
—O—R3;
—NR2R3;
C1-C6 alkyl, which may be optionally substituted with one or more groups selected from the group consisting of R4 and Het;
C2-C6 alkenyl, which may be optionally substituted with one or more groups selected from the group consisting of R4 and Het;
C3-C6 saturated carbocycle, which may optionally be substituted with one or more groups selected from the group consisting of R4 and Het;
and C5-C6 unsaturated carbocycle, which may optionally be substituted with one or more groups selected from the group consisting of R4 and Het;
and
each R4 is independently selected from the group consisting of —OR2, —C(O)—NHR2, —S(O)2—NHR2, halo, —NR2—C(O)—R2 and —CN.

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Novel sulfonamide inhibitors of aspartyl protease

Life of this patent

Novel sulfonamide inhibitors of aspartyl protease

Life of this patent

Abstract

Claims27