US 6,306,891 B1 · HIV integrase inhibitors

Abstract

Nitrogen-containing heteroaryl dioxo-butyric acid derivatives are described as inhibitors of HIV integrase and inhibitors of HIV replication. These compounds are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by HIV are also described.

A compound of structural formula (I):

and tautomers and pharmaceutically acceptable salts thereof, wherein:
A is a five-membered heteroaromatic ring containing 1 or 2 nitrogen atoms and substituted on carbon or nitrogen by R1, R2 and R8;
the heteroaromatic ring may optionally be fused with a phenyl ring to form a fused ring system, provided that when A is a fused ring system, the nitrogen-containing heteroaromatic ring is substituted by the dioxobutyric acid/ester moiety;
R1 is selected from:
(1) —H,
(2) —C1-5 alkyl,
(3) —CF3,
(4) -halo,
(5) —NO2,
(6) —N(R4)(R5),
(7) —R6,
(8) —C2-5 alkenyl-R3,
(9) —C2-5 alkynyl-R3,
(10) —O—R6,
(11) —O—C1-6 alkyl, and
(12) —C(O)CH2C(O)C(O)OR7;
R2 is selected from:
(1) —H,
(2) —R3,
(3) —C1-6 alkyl,
(4) —C1-6 alkyl substituted with R3,
(5) —O—R6,
(6) —O—C1-6 alkyl-OR6,
(7) —S(O)n-R6,
(8) —C1-6 alkyl (OR6)(R4),
(9) —C1-6 alkyl-N(R4)(R6),
(10) —C1-6 alkyl S(O)n-R6,
(11) —C1-6 alkyl C(O)—R6,
(12) —C1-6 alkyl C(S)—R6,
(13) —C1-6 alkyl NR4C(O)—R6, and
(14) —C1-6 alkyl-C(O)N(R4)(R5);
each R3 is independently selected from:
(1) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, 2, 3, or 4 heteroatoms selected from oxygen, nitrogen and sulfur, unsubstituted or substituted on a nitrogen or carbon atom by 1 to 5 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) phenyl,
(e) —CF3,
(f) —OCF3,
(g) —CN,
(h) hydroxy,
(i) phenyloxy, and
(j) substituted phenyloxy with 1, 2, or 3 substituents selected from:
(i) halogen,
(ii) C1-6 alkyl,
(iii) —CF3, and
(iv) hydroxy;
(2) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, unsubstituted or substituted with 1 to 5 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN,
(g) ═O, and
(h) hydroxy;
(3) unsubstituted or substituted hexahydrothieno[3,4-d]imidazolyl with one or two substituents selected from:
(a) oxo,
(b) halogen,
(c) C1-6 alkyl,
(d) C1-6 alkyloxy-,
(e) —CF3,
(f) —OCF3,
(g) —CN, and
(h) hydroxy;
(4) a 5 or 6 membered aromatic or heteroaromatic ring, containing 0, 1, or 2 heteroatoms selected from oxygen, nitrogen and sulfur, fused with a phenyl ring;
wherein the ring system is unsubstituted or substituted on a nitrogen or carbon atom by 1 to 3 substituents selected from:
(a) -halogen,
(b) —C1-6 alkyl,
(c) —C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN, and
(g) -hydroxy;
(5) a 3 to 6 membered saturated ring containing 0 or 1 heteroatoms selected from oxygen, nitrogen or sulfur, fused with a phenyl ring, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN,
(g) ═O, and
(h) hydroxy;
and
(6) a 5 to 6 membered ring containing 0, 1 or 2 heteroatoms selected from oxygen, nitrogen or sulfur, containing 2 or 3 double bonds, unsubstituted or substituted with 1 or 2 substituents selected from:
(a) halogen,
(b) C1-6 alkyl,
(c) C1-6 alkyloxy-,
(d) —CF3,
(e) —OCF3,
(f) —CN,
(g) ═O, and
(h) hydroxy;
each R4 is independently selected from:
(1) —H,
(2) —C1-3 alkyl,
(3) —CF3,
(4) —R3,
(5) —C2-3 alkenyl,
(6) —C1-3 alkyl-R3,
(7) —C2-3 alkenyl-R3,
(8) —S(O)n—R3, and
(9) —C(O)—R3;
each R5 is independently selected from:
(1) —H,
(2) —C1-3 alkyl,
(3) —CF3,
(4) —R3,
(5) —C2-3 alkenyl,
(6) —C1-3 alkyl-R3,
(7) —C2-3 alkenyl-R3,
(8) —S(O)n—R3, and
(9) —C(O)—R3;
each R6 is independently selected from:
(1) —C1-3 alkyl-R3, and
(2) —R3;
R7 is selected from:
(1) —H, and
(2) C1-6 alkyl;
R8 is selected from:
(1) —H,
(2) C1-6 alkyl-oxy, and
(3) C1-6 alkyl;
and
each n is independently selected from 0, 1 and 2;
and
further provided that when R7 is C1-6 alkyl, then R2 is not —H or —C1-6 alkyl.

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HIV integrase inhibitors

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HIV integrase inhibitors

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Abstract

Claims31