US 7,598,264 B2 · HIV integrase inhibitors

Abstract

Hydroxy (tetra- or hexa-)hydronaphthyridine dione compounds of Formula I are inhibitors of HIV integrase and inhibitors of HIV replication: (I) wherein a, R1?, R2?, R3?, R4? and R5? are defined herein. The compounds are useful in the prevention and treatment of infection by HIV and in the prevention, delay in the onset, and treatment of AIDS. The compounds are employed against HIV infection and AIDS as compounds per se or in the form of pharmaceutically acceptable salts. The compounds and their salts can be employed as ingredients in pharmaceutical compositions, optionally in combination with other antivirals, immunomodulators, antibiotics or vaccines.

A compound of Formula I, or a pharmaceutically acceptable salt thereof:

wherein:
bond
in the ring is a single bond or a double bond;
R1 is —C1-6 alkyl substituted with RJ, wherein RJ is:
(A) (i) aryl or (ii) aryl fused to a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the aryl or fused aryl is:
(a) optionally substituted with from 1 to 5 substituents each of which is independently:
(1) —C1-6 alkyl optionally substituted with —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —CN, —NO2, —N(Ra)Rb, —C(═O)N(Ra)Rb, —C(═O)Ra, —CO2Ra, —S(O)nRa, —SO2N(Ra)Rb, —N(Ra)C(═O)Rb, —N(Ra)CO2Rb, —N(Ra)SO2Rb, —N(Ra)SO2N(Ra)Rb, —OC(═O)N(Ra)Rb, or —N(Ra)C(═O)N(Ra)Rb,
(2) —O—C1-6 alkyl,
(3) —C1-6 haloalkyl,
(4) —O—C1-6 haloalkyl,
(5) —OH,
(6) halogen,
(7) —CN,
(8) —NO2,
(9) —N(Ra)Rb,
(10) —C(═O)N(Ra)Rb,
(11) —C(═O)Ra,
(12) —CO2Ra,
(13) —SRa,
(14) —S(═O)Ra,
(15) —SO2Ra,
(16) —SO2N(Ra)Rb,
(17) —N(Ra)SO2Rb,
(18) —N(Ra)SO2N(Ra)Rb,
(19) —N(Ra)C(═O)Rb,
(20) —N(Ra)C(═O)—C(═O)N(Ra)Rb, or
(21) —N(Ra)CO2Rb, and
(b) optionally substituted with 1 or 2 substituents each of which is independently:
(1) phenyl,
(2) benzyl,
(3) —HetA,
(4) —C(═O)—HetA, or
(5) —HetB;
wherein each HetA is independently a C4-7 azacycloalkyl or a C3-6 diazacycloalkyl, either of which is optionally substituted with from 1 to 4 substituents each of which is independently oxo or C1-6 alkyl;
and
wherein each HetB is independently a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, C1-6 alkyl, C1-6 haloalkyl, O—C1-6 alkyl, O—C1-6 haloalkyl, or hydroxy;
or
(B) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is:
(i) optionally substituted with from 1 to 4 substituents each of which is independently halogen, —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, or hydroxy;
and
(ii) optionally substituted with 1 or 2 substituents each of which is independently aryl or —C1-6 alkyl substituted with aryl;
R2 and R3 are each independently —H or —C1-6 alkyl;
R4 is:
(1) —H,
(2) —C1-6 alkyl,
(3) —C1-6 haloalkyl,
(4) —C1-6 alkyl substituted with —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —CN, —N(Ra)Rb, —C(═O)N(Ra)Rb, —C(═O)Ra, —CO2Ra, —C(═O)—N(Ra)—C1-6 alkylene-ORb with the proviso that the —N(Ra)— moiety and the —ORb moiety are not both attached to the same carbon of the —C1-6 alkylene-moiety, —S(O)nRa, —SO2N(Ra)Rb, —N(Ra)C(═O)—Rb, —N(Ra)CO2Rb, —N(Ra)SO2Rb, —N(Ra)SO2N(Ra)Rb, —N(Ra)C(═O)N(Ra)Rb, or —OC(═O)N(Ra)Rb,
(5) —C(═O)Ra,
(6) —CO2Ra,
(7) —C(═O)N(Ra)Rb,
(8) —C(═O)—N(Ra)—C1-6 alkylene-ORb with the proviso that the —N(Ra)— moiety and the —ORb moiety are not both attached to the same carbon of the —C1-6 alkylene-moiety,
(9) —N(Ra)—C(═O)—Rb,
(10) —N(Ra)—C(═O)—C(═O)N(Ra)Rb,
(11) —N(Ra)SO2Rb,
(12) —N(Ra)SO2N(Ra)Rb,
(13) —N(Ra)C(═O)N(Ra)Rb,
(14) —OC(═O)N(Ra)Rb,
(15) —RK,
(16) —C(═O)—RK,
(17) —C(═O)N(Ra)—RK,
(18) —C(═O)N(Ra)—C1-6 alkylene-RK,
(19) —C1-6 alkyl substituted with —RK,
(20) —C1-6 alkyl substituted with —C(═O)—RK,
(21) —C1-6 alkyl substituted with —C(═O)N(Ra)—RK, or
(22) —C1-6 alkyl substituted with —C(═O)N(Ra)—C1-6 alkylene-RK,
wherein RK is
(i) C3-8 cycloalkyl which is optionally substituted with from 1 to 4 substituents each of which is independently halogen, —OH, —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, or —O—C1-6 haloalkyl,
(ii) aryl, which is optionally substituted with from 1 to 5 substituents each of which is independently —C1-6 alkyl, —C1-6 alkylene-OH, —C1-6 alkylene-O—C1-6 alkyl, —C1-6 alkylene-O—C1-6 haloalkyl, —C1-6 alkylene-N(Ra)Rb, —C1-6 alkylene-C(═O)N(Ra)Rb, —C1-6 alkylene-C(═O)Ra, —C1-6 alkylene-CO2Ra, —C1-6 alkylene-S(O)nRa, —O—C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 haloalkyl, —OH, halogen, —N(Ra)Rb, —C(═O)N(Ra)Rb, —C(═O)Ra, —CO2Ra, —S(O)nRa, or —SO2N(Ra)Rb,
(iii) HetK, which is a 4- to 7-membered saturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is:
(a) optionally substituted with from 1 to 6 substituents each of which is independently halogen, —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, oxo;
and
(b) optionally substituted with aryl or HetC;
wherein HetC is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally fused with a benzene ring, and the optionally fused heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, or hydroxy;
or
(iv) —HetL, which is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently halogen, —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, or hydroxy;
R5 is:
(1) —H,
(2) —C1-6alkyl,
(3) —C3-8 cycloalkyl optionally substituted with from 1 to 4 substituents each of which is independently halogen,—OH, C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl,
(4) —C1-6 alkyl substituted with C3-8 cycloalkyl, wherein the cycloalkyl is optionally substituted with from 1 to 4 substituents each of which is independently halogen, —OH, —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, or —O—C1-6 haloalkyl,
(5) —C1-6 alkyl substituted with aryl, wherein the aryl is optionally substituted with from 1 to 5 substituents each of which is independently —C1-6 alkyl, —C1-6 alkylene-OH, —C1-6 alkylene- O—C1-6 alkyl, —C1-6 alkylene-O—C1-6 haloalkyl, —C1-6 alkylene-N(Ra)Rb, —C1-6 alkylene-C(═O)N(Ra)Rb, —C1-6 alkylene-C(═O)Ra, —C1-6 alkylene-CO2Ra, —C1-6 alkylene-S(O)nRa, —O—C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 haloalkyl, —OH, halogen, —N(Ra)Rb, —C(═O)N(Ra)Rb, —C(═O)Ra, —CO2Ra, —S(O)nRa, or —SO2N(Ra)Rb, or
(6) —C1-6 alkyl substituted with HetD, wherein HetD is:
(i) a 4- to 7-membered saturated heterocyclic ring containing at least one carbon atom and from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heterocyclic ring is optionally substituted with from 1 to 5 substituents each of which is independently halogen, —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, or oxo;
or
(ii) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein the heteroaromatic ring is optionally substituted with from 1 to 4 substituents each of which is independently —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, or hydroxy;
each aryl is independently phenyl, naphthyl, or indenyl;
each Ra is independently H or C1-6 alkyl;
each Rb is independently H or C1-6 alkyl;
and
each n is independently an integer equal to zero, 1, or 2.

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HIV integrase inhibitors

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HIV integrase inhibitors

Life of this patent

Abstract

Claims11