US 7,169,780 B2 · N-substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase

Abstract

N-substituted 5-hydroxypyrimidin-6-one-4-carboxamides of formula (I): are described as inhibitors of HIV integrase and inhibitors of HIV replication, wherein R1, R2, R3 and R4 are defined herein. These 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. Methods of preventing, treating or delaying the onset of AIDS and methods of preventing or treating infection by HIV are also described

A compound of Formula (I):

wherein
R1 is
(1) —H,
(2) —C1-6 alkyl, which is optionally substituted with one or more substituents each of which is independently halogen, —OH, —CN, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —C(═O)Ra, —CO2Ra, —SRa, —S(═O)Ra, —N(RaRb), —C(═O)—C0-6 alkyl-N(RaRb), N(Ra)—C(═O)—C0-6 alkyl-N(RbRc), —SO2Ra, —N(Ra)SO2Rb, —SO2N(RaRb), —N(Ra)—C(═O)Rb,
or —N(Ra)C(═O)C(═O)N(RaRb),
(3) —Rk,
(4) —C1-6 alkyl-Rk, wherein:
(i) the alkyl is optionally substituted with one or more substituents each of which is independently halogen, —OH, —CN, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —N(RaRb), —N(Ra)CO2Rb, —N(Ra)C(═O)—C0-6 alkyl-N(RbRc), or —N(Ra)—C2-6 alkyl-OH with the proviso that the —OH is not attached to the carbon alpha to N(Ra);
and
(ii) the alkyl is optionally mono-substituted with —Rs, —C1-6 alkyl-Rs, —N(Ra)—C(═O)—C0-6 alkyl-Rs, —N(Ra)—C0-6 alkyl-Rs, —O—C0-6 alkyl-RS, or —N(Ra)—C(═O)—C0-6 alkyl-Rs;
wherein Rs is
(a) aryl which is optionally substituted with one or more substituents each of which is independently halogen, —OH, —C1-6 alkyl, —C1-6 alkyl-ORa, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, methylenedioxy attached to two adjacent carbon atoms, or aryl;
(b) a 4- to 8-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S;
wherein the saturated heterocyclic ring is optionally substituted with one or more substituents each of which is independently halogen, —C1-6 alkyl, —C1-6 alkyl-ORa, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-16 haloalkyl, —C(═O)Ra, —CO2Ra, —C(═O)—C0-6 alkyl-N(RaRb), —SO2Ra, oxo, aryl, or —C1-6 alkyl-aryl;
or
(c) a 5- to 7-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S;
wherein the heteroaromatic ring is optionally substituted with one or more substituents each of which is independently halogen, —C1-6 alkyl, —C1-6 alkyl-ORa, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, oxo, or aryl;
(5) —C0-6 alkyl-O—C0-6 alkyl-Rk,
(6) —C0-6 alkyl-S(O)n—C0-6 alkyl-Rk,
(7) —O—C1-16 alkyl-ORk,
(8) —O—C1-16 alkyl-O—C1-6 alkyl-Rk,
(9) —O—C1-6 alkyl-S(O)nRk,
(10) —C0-6 alkyl-N(Ra)—Rk,
(11) —C0-6 alkyl-N(Ra)—C1-6 alkyl-Rk,
(12) —C0-6 alkyl-N(Ra)—C1-6 alkyl-ORk,
(13) —C0-6 alkyl-C(═O)—Rk,
(14) —C0-6 alkyl-C(═O)N(Ra)—C0-6 alkyl-Rk,
(15) —C0-6 alkyl-N(Ra)C(═O)—C0-6 alkyl-Rk,
(16) —C0-6 alkyl-N(Ra)C(═O)—O—C0-6 alkyl-Rk, or
(17) —C0-6 alkyl-N(Ra)C(═O)C(═O)Rk;
R2 is —C1-6 alkyl which is optionally substituted with one or more substituents each of which is independently
(1) halogen,
(2) —OH,
(3) —CN,
(4) —O—C1-6 alkyl,
(5) —O—C1-6 haloalkyl,
(6) —C(═O)Ra,
(7) —CO2Ra,
(8) —SRa,
(9) —S(═O)Ra,
(10) —N(RaRb),
(11) —C(═O)N(RaRb),
(12) —N(Ra)—C(═O)—C1-6 alkyl-N(RbRc),
(13) —SO2Ra,
(14) —N(Ra)SO2Rb,
(15) —SO2N(RaRb),
(16) —N(Ra)—C(Rb)═O,
(17) —C3-8 cycloalkyl,
(18) aryl, wherein the aryl is optionally substituted with one or more substituents each of which is independently halogen, —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —C0-6 alkyl-N(RaRb), or —C1-6 alkyl substituted with a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S;
wherein the saturated heterocyclic ring is optionally substituted with from 1 to 3 substituents each of which is independently —C1-6 alkyl, oxo, or a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S;
or
(19) a 5- to 8-membered monocyclic heterocycle which is saturated or unsaturated and contains from 1 to 4 heteroatoms independently selected from N, O and S;
wherein the heterocycle is optionally substituted with one or more substituents each of which is independently —C1-6 alkyl, —O—C1-6 alkyl, oxo, phenyl, or naphthyl;
with the proviso that none of the following substituents is attached to the carbon atom in the —C1-6 alkyl group that is attached to the ring nitrogen:
halogen, —OH, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —SRa, —S(═O)Ra, —N(RaRb), or —N(Ra)—C(Rb)═O;
R3 is —H or —C1-6 alkyl;
R4 is
(1) C1-6 alkyl which is substituted with one or more substituents each of which is independently halogen, —OH, O—C1-6 alkyl, —O—C1-6 haloalkyl, —NO2, —N(RaRb), —C(═O)Ra, —CO2Ra, —SRa, —S(═O)Ra, —SO2Ra, or —N(Ra)CO2Rb,
(2) C1-6 alkyl which is optionally substituted with one or more substituents each of which is independently halogen, —OH, or O—C1-4 alkyl, and which is substituted with 1 or 2 substituents each of which is independently:
(i) C3-8 cycloalkyl,
(ii) aryl,
(iii) a fused bicyclic carbocycle consisting of a benzene ring fused to a C5-7 cycloalkyl,
(iv) a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S,
(v) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or
(vi) a 9- or 10-membered fused bicyclic heterocycle containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein at least one of the rings is aromatic,
(3) C2-5 alkynyl optionally substituted with aryl,
(4) C3-8 cycloalkyl optionally substituted with aryl,
(5) aryl,
(6) a fused bicyclic carbocycle consisting of a benzene ring fused to a C5-7 cycloalkyl,
(7) a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S,
(8) a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or
(9) a 9- or 10-membered fused bicyclic heterocycle containing from 1 to 4 heteroatoms independently selected from N, O and S, wherein at least one of the rings is aromatic;
wherein
each aryl in (2)(ii) or the aryl (3), (4) or (5) or each fused carbocycle in (2)(iii) or the fused carbocycle in (6) is optionally substituted with one or more substituents each of which is independently halogen, —OH, —C1-6 alkyl, —C1-6 alkyl-ORa, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —CN, —NO2, —N(RaRb), —C1-6 alkyl-N(RaRb), —C(═O)N(RaRb), —C(═O)Ra, —CO2Ra, —C1-6 alkyl-CO2Ra, —OCO2Ra, —SRa, —S(═O)Ra, —SO2Ra, —N(Ra)SO2Rb, —SO2N(RaRb), —N(Ra)C(═O)Rb, —N(Ra)CO2Rb, —C1-6 alkyl-N(Ra)CO2Rb, aryl, —C1-6 alkyl-aryl, —O-aryl, or —C0-6 alkyl-het wherein het is a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, and het is optionally fused with a benzene ring, and is optionally substituted with one or more substituents each of which is independently —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, oxo, or —CO2Ra;
each saturated heterocyclic ring in (2)(iv) or the saturated heterocyclic ring in (7) is optionally substituted with one or more substituents each of which is independently halogen, —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, oxo, aryl, or a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S;
and
each heteroaromatic ring in (2)(v) or the heteroaromatic ring in (8) or each fused bicyclic heterocycle in (2)(vi) or the fused bicyclic heterocycle in (9) is optionally substituted with one or more substituents each of which is independently halogen, —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, oxo, aryl, or —C1-6 alkyl-aryl;
or alternatively R3 and R4 together with the N to which both are attached form a C3-7 azacycloalkyl which is optionally substituted with one or more substituents each of which is independently —C1-6 alkyl or oxo;
each Ra, Rb, Rc, and Rd is independently —H or —C1-6 alkyl;
Rk is carbocycle or heterocycle, wherein the carbocycle or heterocycle is optionally substituted with one or more substituents each of which is independently
(1) halogen,
(2) —OH,
(3) —CN,
(4) —C1-6 alkyl, which is optionally substituted with one or more substituents each of which is independently halogen, —OH, —CN, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —C(═O)Ra, —CO2Ra, —SRa, —S(═O)Ra, —N(RaRb), —C(═O)—(CH2)0-2N(RaRb), N(Ra)—C(═O)—(CH2)0-2N(RbRc), —SO2Ra, —N(Ra)SO2Rb, —SO2N(RaRb), or —N(Ra)—C(Rb)═O,
(5) —O—C1-6 alkyl, which is optionally substituted with one or more substituents each of which is independently halogen, —OH, —CN, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —C(═O)Ra, —CO2Ra, —SRa, —S(═O)Ra, —N(RaRb), —C(═O)—(CH2)0-2N(RaRb), N(Ra)—C(═O)—(CH2)0-2N(RbRc), —SO2Ra, —N(Ra)SO2Rb, —SO2N(RaRb), or —N(Ra)—C(Rb)═O,
(6) —NO2,
(7) oxo,
(8) —C(═O)Ra,
(9) —CO2Ra,
(10) —SRa,
(11) —S(═O)Ra,
(12) —N(RaRb),
(13) —C(═O)N(RaRb),
(14) —C(═O)—C1-6 alkyl-N(RaRb),
(15) —N(Ra)C(═O)Rb,
(16) —SO2Ra,
(17) —SO2N(RaRb),
(18) —N(Ra)SO2Rb,
(19) —Rm,
(20) —C1-6 alkyl-Rm, wherein the alkyl is optionally substituted with one or more substituents each of which is independently halogen, —OH, —CN, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —C(═O)Ra, —CO2Ra, —SRa, —S(═O)Ra, —N(RaRb), —N(Ra)CO2Rb, —SO2Ra, —N(Ra)SO2Rb, —SO2N(RaRb), or —N(Ra)—C(Rb)═O,
(21) —C0-6 alkyl-N(Ra)—C0-6 alkyl-Rm,
(22) —C0-6 alkyl-O—C0-6 alkyl-Rm,
(23) —C0-6 alkyl-S—C0-6 alkyl-Rm,
(24) —C0-6 alkyl-C(═O)—C0-6 alkyl-Rm,
(25) —C(═O)—O—C0-6 alkyl-Rm,
(26) —C(═O)N(Ra)—C0-6 alkyl-Rm,
(27) —N(Ra)C(═O)—Rm,
(28) —N(Ra)C(═O)—C1-6 alkyl-Rm, wherein the alkyl is optionally substituted with one or more substituents each of which is independently halogen, —OH, —CN, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —C(═O)Ra, —CO2Ra, —SRa, —S(═O)Ra, —N(RaRb), —N(Ra)CO2Rb, —SO2Ra, —N(Ra)SO2Rb, —SO2N(RaRb), or —N(Ra)—C(Rb)═O,
(29) —N(Ra)—C(═O)—N(Rb)—C0-6 alkyl-Rm,
(30) —N(Ra)—C(═O)—O—C0-6 alkyl-Rm,
(31) —N(Ra)—C(═O)—N(Rb)—SO2—C0-6 alkyl-Rm,
(32) —C(═O)—C(═O)—N(RaRb),
(33) —C(═O)—C1-6 alkyl-SO2Ra, or
(34) —C(═O)—C(═O)Rm;
carbocycle in Rk is (i) a C3 to C8 monocyclic, saturated or unsaturated ring, (ii) a C7 to C12 bicyclic ring system, or (iii) a C11 to C16 tricyclic ring system, wherein each ring in (ii) or (iii) is independent of or fused to the other ring or rings and each ring is saturated or unsaturated;
heterocycle in Rk is (i) a 4- to 8-membered, saturated or unsaturated monocyclic ring, (ii) a 7- to 12-membered bicyclic ring system, or (iii) an 11 to 16-membered tricyclic ring system;
wherein each ring in (ii) or (iii) is independent of or fused to the other ring or rings and each ring is saturated or unsaturated;
the monocyclic ring, bicyclic ring system, or tricyclic ring system contains from 1 to 6 heteroatoms selected from N, O and S and a balance of carbon atoms;
and wherein any one or more of the nitrogen and sulfur heteroatoms is optionally be oxidized, and any one or more of the nitrogen heteroatoms is optionally quaternized;
each Rm is independently C3-8 cycloalkyl;
aryl;
a 5- to 8-membered monocyclic heterocycle which is saturated or unsaturated and contains from 1 to 4 heteroatoms independently selected from N, O and S;
or a 9- to 10-membered bicyclic heterocycle which is saturated or unsaturated and contains from 1 to 4 heteroatoms independently selected from N, O and S;
wherein any one or more of the nitrogen and sulfur heteroatoms in the heterocycle or bicyclic heterocycle is optionally oxidized and any one or more of the nitrogen heteroatoms is optionally quaternized;
and wherein
the cycloalkyl or the aryl defined in Rm is optionally substituted with one or more substituents each of which is independently halogen, —C1-6 alkyl optionally substituted with —O—C1-4 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, —N(RaRb), aryl, or —C1-6 alkyl-aryl;
and
the monocyclic or bicyclic heterocycle defined in Rm is optionally substituted with one or more substituents each of which is independently halogen, —C1-6 alkyl, —C1-6 haloalkyl, —O—C1-6 alkyl, —O—C1-6 haloalkyl, oxo, aryl, —C1-6 alkyl-aryl, —C(═O)-aryl, —CO2-aryl, —CO2—C1-6 alkyl-aryl, a 5- or 6-membered saturated heterocyclic ring containing from 1 to 4 heteroatoms independently selected from N, O and S, or a 5- or 6-membered heteroaromatic ring containing from 1 to 4 heteroatoms independently selected from N, O and S;
and
each n is independently an integer equal to zero, 1 or 2;
or a pharmaceutically acceptable salt thereof.

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N-substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase

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N-substituted hydroxypyrimidinone carboxamide inhibitors of HIV integrase

Life of this patent

Abstract

Claims44